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FDA declines approval of ticagrelor without additional information

The FDA has issued a complete response letter to AstraZeneca that requests additional analyses of the PLATO data in response to the company’s New Drug Application for its P2Y12 inhibitor, ticagrelor. This comes after the Cardiovascular and Renal Drugs Advisory Committee voted 7-1 in July to recommend approval of the drug for the reduction of thrombotic events in patients with acute coronary syndromes.

According to a press release issued by AstraZeneca, the FDA requested only additional analyses of the data presented in the PLATO trial and did not request that additional studies be conducted as a prerequisite for approval. AstraZeneca will be evaluating the contents of the letter and will respond to the agency’s request for additional analyses of the PLATO data as soon as possible, the release stated.

“Our highest priority is to provide the requested PLATO analyses to the FDA and progress to completion of the Brilinta [ticagrelor] New Drug Approval review,” Martin Mackay, president of research and development at AstraZeneca, said in the release.

Click the links to read Cardiology Today’s coverage of the Cardiovascular and Renal Drugs Advisory Committee vote and of the PLATO trial.

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Cryoballoon catheter approved for treatment of paroxysmal AF

Medtronic’s Arctic Front Cardiac CryoAblation Catheter System has been approved by the FDA for use in the setting of paroxysmal atrial fibrillation, making it the first and only cryoballoon indicated for use in this setting, according to a press release.

The FDA’s approval for the catheter came as a result of the Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP AF) trial, which demonstrated efficacy of the device in the treatment of paroxysmal AF. The cryoballoon has currently been used in more than 10,000 patients in more than 200 centers outside of the United States and will now be available for physicians and patients in this country, the release said.

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Biomarkers predicted mortality, hospital readmission in decompensated HF
Xue Y. Eur J Heart Fail. 2010;doi:10.1093/eurjhf/hfq210. S

Small elevations of troponin I and B-type natriuretic peptide in patients with decompensated HF were associated with increased 90-day mortality and hospital readmission, according to researchers at the University of California at San Diego.

Although troponin levels were typically less than detectable levels of contemporary assays and, thus, not used routinely to evaluate patients with HF, new high-sensitive troponin assays make it possible to detect troponin in serum of patients with decompensated HF, according to the report.

The researchers studied 144 patients with acute HF who were followed from the time of their admission to the VA San Diego Medical Center to 90 days after discharge. Blood samples were collected on admission, on discharge and on up to 4 consecutive days during hospitalization. The primary endpoints were all-cause mortality and HF-related readmissions within 90 days after discharge. Troponin levels were able to be quantified in more than 99% of the serum samples.

Of the 144 patients, 38 reached mortality or HF-related readmission. Troponin levels of 23.25 mg/L were associated with an increased risk for mortality and readmission. Mortality and HF-related admission were increased in patients with low troponin and high B-type natriuretic peptide levels; patients with high troponin and low B-type natriuretic peptide levels; and in patients with high troponin and high B-type natriuretic peptide levels. Patients whose levels of troponin increased during treatment also had increased mortality. On multivariate analysis, troponin reached statistical significance but B-type natriuretic peptides did not.

“Troponin trend during hospitalization is an important prognostic factor that needs to be taken into consideration during the treatment course of HF exacerbations,” the researchers wrote.
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High mortality, rehospitalization rates found for Medicare recipients after ischemic stroke
Fonarow G. Stroke. 2010;doi:10.1161/STROKEAHA.110.601831.

Close to two-thirds of Medicare beneficiaries died or were rehospitalized within 1 year of being discharged for ischemic stroke, according to newly published data.

Researchers from the United States and Canada collected and analyzed data from 91,134 Medicare fee-for-service beneficiaries. The patients (mean age, 79.3 years; 58% women) were treated between April 2003 and December 2006 at 625 Get With The Guidelines-Stroke hospitals, a program supported by the American Heart Association and the American Stroke Association.

According to study data, 5,662 patients (6.1%) died during hospitalization for ischemic stroke. The unadjusted mortality rate for 30 days after admission was 14.1%, and at 1 year, it was 31.1%. Overall mortality or readmission rate at 1 year of discharge was 61.9%, with no improvements in either reported during the timeframe of the study.

“This study demonstrates that outcomes early after hospitalization for ischemic stroke for Medicare beneficiaries at the hospital level are often poor,” the researchers wrote, adding that the findings underscore the need for quality improvement interventions and systems of care that will improve early, intermediate and long-term outcomes of patients with acute ischemic stroke

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2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Updating the 2006 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
Wann LS, Curtis AB, January CT, et al.
J Am Coll Cardiol 2011;57:223-242.
Perspective: The following are 10 points to remember about these updated guidelines on the management of patients with atrial fibrillation (AF).

Metoprolol Versus Amiodarone in the Prevention of Atrial Fibrillation After Cardiac Surgery: A Randomized Trial
Halonen J, Loponen P, Jarvinen O, et al.
Ann Intern Med 2010;153:703-709.
Study Question: Is metoprolol as effective as amiodarone for preventing post-cardiac surgery atrial fibrillation (AF)?

Chest-Compression-Only Versus Standard Cardiopulmonary Resuscitation: A Meta-Analysis
Hupfl M, Selig HF, Nagele P.
Lancet 2010;376:1552-1557.
Study Question: Does chest-compression-only resuscitation (CCOR) improve outcomes compared to conventional cardiopulmonary resuscitation (CCPR)?

Mortality Resulting From Congenital Heart Disease Among Children and Adults in the United States, 1999 to 2006
Gilboa SM, Salemi JL, Nembhard WN, Fixler DE, Correa A.
Circulation 2010;122:2254-2263.
Study Question: What are the temporal trends of mortality resulting from congenital heart disease from 1999 to 2006?

Prediction of Cardiovascular Events in Statin-Treated Stable Coronary Patients by Lipid and Nonlipid Biomarkers
Arsenault BJ, Barter P, DeMicco DA, et al.
J Am Coll Cardiol 2011;57:63-69.
Study Question: What is the predictive value of lipid and nonlipid coronary heart disease (CHD) risk biomarker levels achieved during statin therapy, and the incidence of major cardiovascular events (MCVEs) in patients with stable CHD?

Multiple Biomarkers at Admission Significantly Improve the Prediction of Mortality in Patients Undergoing Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction
Damman P, Beijk MA, Kuijt WJ, et al.
J Am Coll Cardiol 2011;57:29-36.
Study Question: What is the predictive ability of multiple biomarkers in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI)?

Association of Troponin T Detected With a Highly Sensitive Assay and Cardiac Structure and Mortality Risk in the General Population
de Lemos JA, Drazner MH, Omland T, et al.
JAMA 2010;304:2503-2512.
Study Question: What are the prevalence and determinants of detectable cardiac troponin T (cTnT) in the population, and are cTnT levels associated with pathological cardiac phenotypes and subsequent mortality

Troponin-Positive, MB-Negative Patients With Non–ST-Elevation Myocardial Infarction: An Undertreated but High-Risk Patient Group: Results From the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network–Get With The Guidelines (NCDR ACTION-GWTG) Registry
Kontos MC, de Lemos JA, Ou FS, et al.
Am Heart J 2010;160:819-825.
Study Question: What is the effect of troponin (Tn) positive ([+]) status without concomitant elevations in creatine kinase-myocardial band (CK-MB) levels on treatment patterns and in-hospital clinical outcomes among non–ST-elevation myocardial infarction (NSTEMI) patients?

Telemonitoring in Patients With Heart Failure
Chaudhry SI, Mattera JA, Curtis JP, et al.
N Engl J Med 2010;363:2301-2309.
Study Question: Does telephone-based computerized monitoring improve outcomes in subjects with heart failure (HF)?

Depression as a Potential Modulator of Beta-Adrenergic–Associated Leukocyte Mobilization in Heart Failure Patients
Redwine LS, Wirtz PH, Hong S, et al.
J Am Coll Cardiol 2010;56:1720-1727.
Study Question: Clinical outcomes are worse for patients with heart failure (HF) presenting with symptoms of depression. Is sympathetically modulated immune dysregulation associated with depression one of the mechanisms leading to worse prognosis?

Meta-Analysis: Effect of B-Type Natriuretic Peptide Testing on Clinical Outcomes in Patients With Acute Dyspnea in the Emergency Setting
Lam LL, Cameron PA, Schneider HG, Abramson MJ, Muller C, Krum H.
Ann Intern Med 2010;153:728-735.
Study Question: Does B-type natriuretic peptide (BNP) or N-terminal BNP (NT-BNP) testing in patients presenting to the emergency room (ER) with acute dyspnea impact outcomes?

Fractional Flow Reserve for the Assessment of Nonculprit Coronary Artery Stenoses in Patients With Acute Myocardial Infarction
Ntalianis A, Sels JW, Davidavicius G, et al.
JACC Cardiovasc Intv 2010;3:1274-1281.
Study Question: What is the reliability of fractional flow reserve (FFR) of nonculprit coronary stenoses during percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI)?

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Sex bias in cardiovascular testing, intervention due to patient preference
Mumma B. Ann Emerg Med. 2010; doi:10.1016/j.annemergmed.2010.09.026

Despite presenting in ED’s with similar symptoms of acute coronary syndrome, women are less likely than men to receive the appropriate diagnostic tests and interventions because they are less apt to follow their physician’s recommendations, according to a cohort study published in Annals of Emergency Medicine.

Researchers enrolled 1,080 patients, 54% of them women, who presented in the ED with symptoms of acute coronary syndrome; 60% were admitted to the hospital. After receiving an explanation of the potential risks and benefits of each test and intervention, patients were surveyed on their preference for noninvasive procedures versus PCI or coronary artery bypass grafting. Patients were also asked about their predilection for compliance with physician recommendations. After 30 days, 96% of study participants were contacted for follow-up on outcomes.

After their initial hospital admission, women were less likely to receive diagnostic testing of any type (38% vs. 45%; 95% CI for the difference –13% to –1.5%). Cardiac catheterization for women was 7% less than for men (10% vs. 17%; 95% CI –11% to –2%). Revascularization was less frequent in either group (4% vs. 6%; 95% CI –5% to 0.6%).

Women and men both preferred stress tests to catheterization (58% vs. 52%; 95% CI –0.06% to 12%), and the proportion of both groups stating they would accept medical advisement for stress testing was similar (85% for both). However, women were less likely than men to state their acceptance for cardiac catheterization (65% vs. 75%; 95 CI –15% to –4%). Women also were less inclined to choose PCI over medical therapy (67% vs. 73%; 95% CI for difference 12% to 0.5%) and less likely to choose coronary artery bypass grafting over medical therapy (61% vs. 68%; 95% CI for difference –13% to 1%).

The researchers posited the disparity in testing and treatment was due in part to women being more risk-averse than men, and to women’s perception that their disease was not severe. “Future studies should focus on delineating why women appear less likely than men to accept physician-recommended evaluation of potential acute coronary syndromes,” the researchers wrote.
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Whey protein beverages lowered BP in young adults
Fluegel S. Int Dairy J. 2010;doi:10.1016/j.idairyj.2010.06.005.

Beverages supplemented with whey protein were associated with lower BP in young adults who had slightly elevated BP or prehypertension, according to researchers from Washington State University.

“Due to the side effects of pharmacological treatment, many people are interested in using diet to control hypertension,” the researchers wrote. “Dairy products contain compounds and minerals that may lower blood pressure, and consumption of dairy and fermented milk products has been associated with lower blood pressure.”

The researchers created whey beverages using whey protein concentrate 80 (WPC80 TemPro, Leprino Foods). Half of the beverages also contained supplemental whey protein, whereas the other half of the beverages served as the control group. Volunteers were recruited using advertisements. The study population was students aged 18 to 26 years, whose BP measurements were taken at the initial screening.

The students were randomly assigned to consume either 28 g per day of the control whey beverage or 28 g per day of the beverage with supplemental protein (along with consuming a normal diet). Among the 71 students enrolled, 25 had normal systolic and diastolic BP at baseline, 42 had prehypertension and four had stage I hypertension.

After 6 weeks of consuming the whey beverages, there was no difference in systolic BP, diastolic BP or mean arterial pressure between the two groups. In the young adults who began the study with elevated diastolic BP and/or systolic BP, the consumption of the whey beverages decreased the systolic BP by 8 mm Hg, decreased the diastolic BP by 8.6 mm Hg and decreased the mean arterial pressure by 6.4 mm Hg.

“The average BP decreases seen in this study are significant from a public health point of view,” the researchers wrote. “Similar decreases in systolic BP and diastolic BP have been associated with large reductions in the risk of stroke, heart disease and overall mortality.”

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Pre-cath abciximab before primary PCI linked to higher infarct-related artery patency rates
Prati F. J Am Coll Cardiol Intv. 2010;3:1284-1291.

Pre-cath lab administration of abciximab, both alone and with half-dose reteplase, when preceding primary percutaneous coronary intervention led to higher rates of infarct-related artery patency at baseline coronary angiography vs. standard primary percutaneous coronary intervention, according to data from the FINESSE-ANGIO trial.

Researchers for the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events-Angiographic (FINESSE-ANGIO) study tested the effects of three different treatments — pre-cath lab administration of half-dose reteplase (Retavase, EKR Therapeutics) plus abciximab (ReoPro, Centocor), abciximab alone or abciximab administered directly before primary PCI — on patency of infarct-related artery during basal coronary angiography. The trial included 637 patients from the FINESSE study.

According to results, patients taking reteplase plus abciximab experienced higher rates of baseline infarct-related artery patency when compared with abciximab alone (76.1% vs. 43.7%; P<.0001) and abciximab taken immediately before PCI procedure (76.1% vs. 32.7%; P<.0001). No significant differences were reported in the post-PCI thrombolysis in MI or the rates of post-PCI TIMI flow grade 3, myocardial blush grade 2/3.

“Primary PCI preceded by pre-catheterization treatment with abciximab alone, and especially with abciximab plus half-dose reteplase, resulted in higher [infarct-related artery] patency rates at baseline coronary angiography compared with standard primary PCI,” the researchers wrote. “Whether clinical benefit correlated with pharmacologically induced or improved pre-PCI myocardial reperfusion may be restricted to higher risk subsets remains to be determined by future prospective studies.”

In an accompanying editorial, Bernard J. Gersh, MB, ChB, DPhil, of the Mayo Clinic, Rochester, Minn.,and Gregg W. Stone, MD,of Columbia University Medical Center, New York, commented on the importance of early treatment.

“For decades, we have appreciated that acute MI is a time-critical phenomenon and that early therapy is crucial for myocardial recovery, especially in the hyperacute phase, when ‘time is myocardium.’ Educating the public to seek treatment at an early stage after symptom onset is likely to reduce mortality to a greater degree than pharmacological facilitation before PCI, although translation of this goal to reality in a community setting is and will continue to be extremely difficult,” Gersh and Stone said.

Disclosure: This study was coordinated in part with research funding from Centocor. Dr. Stone and Dr. Gersh report no relevant financial disclosures.
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Fetal antiretroviral therapy exposure may impair myocardial growth, improve depressed LV function
Lipshultz S. J Am Coll Cardiol. 2011;57:76–85.

Fetal exposure to antiretroviral therapy led to reductions in left ventricular mass and dimension and septal wall thickness, as well as increased left ventricular fractional shortening and contractility. Researchers concluded that exposure to this therapy may cause impairments to myocardial growth while also causing improvements to depressed left ventricular function.

“Abnormalities of LV structure and function are associated with HIV infections, possibly with antiretroviral therapy (ART), and even mild abnormalities independently predict mortality in HIV-infected children,” Steven E. Lipshultz, MD, study investigator, and colleagues wrote. “Nearly 10,000 ART-exposed and HIV-exposed but negative infants are born annually in the US, but are not routinely followed for suspicion of heart disease.”

The US-based researchers analyzed two cohorts of HIV-negative children born to HIV-positive mothers to study the cardiac effects of perinatal exposure to ART. The final study population included 136 ART-exposed, HIV-negative infants from the CHAART-1 trial and 216 non-ART-exposed, HIV-negative infants from the P2C2 HIV study.

According to researchers, unadjusted LV mass z score for CHAART-1 infants at 2 years of age was 0.53 standard deviation (SD) less than in the P2C2 HIV cohort (P=.006), an association that remained, even after adjusting for factors such as sex and ethnicity. Conversely, at 2 years of age, unadjusted LV fractional shortening z score for the ART-exposed infants was 0.45 SD more than that of the non-exposed infants (P=.01). Researchers also reported that septal wall thickness and LV dimension were smaller than expected in ART-exposed
infants, but LV contractility was roughly 1 SD higher at all ages (P<.001).

Based on this data, “We speculate that in utero exposure to ART may impair myocardial growth while initially improving LV function, although LV function was less than normal. These effects are more pronounced in girls,” the researchers wrote. “These findings clearly indicate a need for long-term monitoring of these infants to better define the mechanism of these effects and to evaluate their long-term clinical importance.”
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Complication rates low among patients assigned anticoagulation, antiplatelet therapies undergoing CEA
Rosenbaum A. Ann Vasc Surg. 2010;doi:10.1016/j.avsg.2010.06.007.

Patients assigned anticoagulation and antiplatelet therapies who underwent carotid endarterectomy had a low rate of complications, including MI and stroke, according to data from a retrospective review.

“The number of cases involving patients undergoing vascular procedures who are prescribed clopidogrel or warfarin as treatment options continues to rise,” the researchers wrote. “Our aim was to examine outcomes related to antiplatelet or anticoagulation therapy in patients undergoing carotid endarterectomy. … Similar to previously published data, we reported a low incidence of perioperative stroke, MI and death in patients who underwent carotid endarterectomy and who were either on aspirin, clopidogrel or warfarin.”

Researchers from the Minneapolis Heart Institute Foundation performed the review, which included 260 consecutive patients (mean age, 69.3 years) who were undergoing carotid endarterectomy (CEA) between June 2006 and April 2009. Overall, 171 patients were assigned aspirin, 50 were assigned clopidogrel with or without aspirin, and 10 were assigned warfarin, with the remaining 29 patients not assigned any therapy.

During a mean follow-up of 406 days, researchers reported a complication rate of 7.3% and rates of 30-day stroke of 0.7% and stroke death of 1.1%. Overall, patients who were assigned aspirin, warfarin or clopidogrel had a low incidence of perioperative stroke, MI and death. Additionally, patients assigned clopidogrel were at the highest risk of complication, which the researchers attributed to the higher rates of neck hematomas among patients assigned the drug (16%) when compared with the other three arms (aspirin, 1.7%; warfarin, 0%; no therapy, 0%).

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The most popular news stories that appeared on TCTMD in 2010 provide a snapshot of the year in interventional cardiology with a strong focus on stenting and adjunct pharmacology. Below are the 10 most read stories from the past year in descending order. Interestingly, the most popular story was dissimilar from the rest, describing a novel vascular access technology.

1. From TCT 2010: Vascular Access Device Achieves Low Complication Rates

WASHINGTON, DC—A novel vascular access device produces acceptable compression times and low complication rates, according to a first-in-man study of over 1,000 patients. The product is intended to facilitate access to the common femoral artery and to achieve hemostasis without the use of a closure device. (Read more…)

2. From JACC: Cardiovascular Interventions: FFR Guidance for Questionable Lesions Dramatically Cuts Stenting vs. IVUS

Physiological assessment of intermediate lesions with fractional flow reserve (FFR) reduces percutaneous coronary interventions by two thirds compared with intravascular ultrasound (IVUS) evaluation, according to a retrospective study published in the August 2010 issue of JACC: Cardiovascular Interventions. (Read more…)

3. From AHA 2010: Final Results Provide CLOSURE on Device Therapy for PFOs, Cryptogenic Stroke

CHICAGO, IL—While the announcement that CLOSURE I failed to achieve its primary endpoint came months ago on June 17, 2010, the full results of the randomized study were not formally released until Monday, November 15 at the American Heart Association Scientific Sessions 2010. The findings provide even stronger evidence that percutaneous device closure lacks superiority over medical therapy alone in preventing recurrent stroke and mortality in patients with patent foramen ovale (PFO). (Read more…)

4. From ACC/i2 2010: Studies Compare Multiple Drug-Eluting Stents

ATLANTA, GA—Two late-breaking clinical trials presented Monday, March 15, 2010, at the ACC/i2 Summit show mixed results for Endeavor when tested against a first-generation and a next-generation drug-eluting stent (DES). In SORT OUT III, Endeavor continued to lag behind Cypher at 18 months, with the exception of cardiac death and Academic Research Consortium-defined definite stent thrombosis. The ISAR-TEST-2 trial, meanwhile, showed durable results at 2 years for both Endeavor and a polymer-free sirolimus- and probucol-eluting stent referred to as Dual DES. (Read more…)

5. From JACC: IVUS Offers Insights into Very Late Stent Thrombosis with DES, BMS

IVUS findings suggest that very late stent thrombosis may arise by different mechanisms. Disease progression culminating in neointimal or plaque rupture is associated with the event in both DES and bare metal stents (BMS), while stent malapposition is typically found only in DES thrombosis. The findings appear in a study published in the May 4, 2010, issue of the Journal of the American College of Cardiology. (Read more…)

6. From TCT 2010: SPIRIT III: Everolimus-Eluting Stent Safety, Efficacy Maintained at Four-Year Follow-Up

WASHINGTON, DC—The use of everolimus-eluting stents compared with paclitaxel-eluting stents resulted in significantly reduced rates of the composite safety and efficacy measures of target lesion failure (TLF) and major adverse cardiac events (MACE), according to four-year data from the SPIRIT III trial presented at TCT 2010. In addition, there was no evidence of late catch-up in target lesion revascularization (TLR). (Read more…)

7. From ACC/i2 2010: Extending Clopidogrel Beyond 12 Months Not Supported

ATLANTA, GA—Use of dual antiplatelet therapy after implantation of a DES for longer than 12 months does not reduce rates of myocardial infarction (MI) or cardiac death more than aspirin monotherapy, according to late-breaking trial results presented Monday, March 15, 2010, at the annual American College of Cardiology Scientific Session/i2 Summit. (Read more…)

8. From TCT 2010: SYNTAX at 3 Years: PCI Matches CABG in Left Main Disease

WASHINGTON, DC—New results from the SYNTAX trial showed that patients with three-vessel disease derive less benefit from PCI than from CABG at 3 years. But in left main disease patients, both treatments remain equally safe and effective over the same period, according to 2 clinical trial presentations at TCT 2010. (Read more…)

9. From TCT 2010: HORIZONS-AMI at 3 Years: Taxus, Bivalirudin Hold Their Lead

WASHINGTON, DC—At 3 years, STEMI patients who underwent PCI with bivalirudin and paclitaxel-eluting stents continue to fare best over the long-term compared with those receiving heparin plus a glycoprotein IIb/IIIa inhibitor and a BMS, according to late-breaking results from HORIZONS-AMI. (Read more…)

10. From JACC: Selective In-Lab Clopidogrel a Safe Alternative to Pretreatment

Giving patients a 600-mg loading dose of clopidogrel in the cath lab after diagnostic angiography to establish the need for PCI yields outcomes comparable to routine preloading, according to a study published in the August 10, 2010, issue of the Journal of the American College of Cardiology. The wait-and-see approach to clopidogrel administration avoids unnecessary bleeding risk in patients for whom bypass surgery or medical therapy is deemed more appropriate than PCI. (Read more…)

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Type 1 diabetes mortality rates decreasing
Secrest AM. Diabetes Care. 2010;33:2573-2579.

Mortality rates for people with type 1 diabetes are decreasing, however, overall rates remain seven times higher than those for the general population, a new study reported.

While researchers at the University of Pittsburgh found no significant differences in mortality rates between sexes, women with type 1 diabetes were 13 times more likely to die compared with women who did not have diabetes. The researchers also discovered differences between races: a much higher proportion of blacks with type 1 diabetes (50.6%) died compared with whites (24%).


“This study was an attempt to document mortality rates of childhood-onset type 1 diabetes over the years, including how rates have improved and how they vary by race,” Trevor Orchard, MD, of the department of epidemiology, Graduate School of Public Health, University of Pittsburgh, told Cardiology Today. “The remarkable finding is the dramatic decline in mortality seen throughout the study for those in later diagnosed cohorts.”

Declines over time

Orchard and colleagues used the childhood-onset type 1 diabetes registry in Allegheny County, Pennsylvania, to identify 1,075 people diagnosed with type 1 diabetes from 1965 to 1979. The cohort was divided into three groups: those diagnosed from 1965 to 1969; 1970 to 1974; and 1975 to 1979. As of Jan. 1, 2008, the researchers ascertained the vital status for 1,043 of the 1,075 people identified. There were 34,363 total person-years of follow-up.

During a median follow-up of 33 years, 279 patients with type 1 diabetes died.

According to other results, men with type 1 diabetes were five times more likely to die compared with men in the general population. There was no difference in mortality between black people with type 1 diabetes compared with black men in the general population.

Mortality rates were lowest for those diagnosed in the late 1970s and highest for those diagnosed in the late 1960s. The standard mortality ratios were 9.3 in those diagnosed from 1965 to 1969, 7.5 in those diagnosed from 1970 to 1974, and 5.6 in those diagnosed from 1975 to 1979. The mortality rate was lower in participants who were diagnosed when younger than 10 years vs. those diagnosed when aged 10 years or older.

The mean age of the participants was 42.8 years, and the mean duration of diabetes was 32 years.

Advances in past decades

The researchers postulated that the main improvement in patients who were most recently diagnosed with type 1 diabetes may be related to dramatic reductions in mortality in the first 5 years of diagnosis. Additionally, they attributed improved rates to better management and awareness of diabetes control and acute complications during the 1980s and 1990s, particularly blood glucose self-monitoring, HbA1c testing and use of blood pressure medications such as angiotensin-converting enzyme inhibitors.

“Women appeared to do poorly, but that is improving. Black people have a particularly poor prognosis, but we think this is partly related to socioeconomic status,” Orchard said. “Things are improving considerably, and I am sure mortality is even better with the advances in treatment since those diagnosed in the 1960s and 1970s.” – by Emily Shafer

The latest that this group was diagnosed was 1979, which was before we had any of the current methods of treatment. Blood glucose monitoring was initiated in the late 1970s, replacing urine glucose testing. The development of the rapid-acting and basal insulin analogues in the 1980s allowed for the more physiologic basal bolus method of administering insulin. We also weren’t attuned to use of ACE inhibitors and lipid-lowering drugs in children, like we are today, for abnormal cardiovascular risk factors. So while the findings of this study may certainly be true for people diagnosed in this timeframe, it is anticipated that those people diagnosed in the 1990s and later will have even better long-term outcomes. It is important to note that these people were all diagnosed in childhood, making us even more aware that the complications of diabetes, especially the CV complications, begin early, and we need to be careful about monitoring for CV disease in our teens and young adults, especially.
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Rivaroxaban may offer safe, effective treatment of venous thrombosis
Bauersachs R. N Engl J Med. 2010;363:2499-2510.

Researchers have reported that rivaroxaban may provide a single-drug approach to the short-term and continued treatment of venous thrombosis and may improve the benefit-to-risk profile of anticoagulation.

The Acute DVT trial, one of three randomized trials of the EINSTEIN program, was an open-label, event-driven, noninferiority study comparing oral rivaroxaban (Xarelto, Bayer; n=1,731) with enoxaparin plus a vitamin K antagonist (n=1,718) for 3, 6 or 12 months in patients with acute, symptomatic deep vein thrombosis. Researchers also carried out a continued treatment trial, which was a randomized, double blind, event-driven superiority study comparing rivaroxaban alone (n=602) with placebo (n=594) for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism.

Results from the Acute DVT trial indicated noninferiority efficacy for rivaroxaban regarding the primary efficacy outcome of recurrent venous thromboembolism (2.1% vs. 3%; HR=0.68; 95% CI, 0.44-1.04). The principal safety outcome of major bleeding or clinically relevant nonmajor bleeding occurred in 8.1% of the patients in both groups.

According to data from the continued-treatment trial, rivaroxaban had a superior event rate of recurrent venous thromboembolism compared with placebo (1.3% vs. 7.1%; HR=0.18; 95% CI, 0.09-0.39).

This led researchers to conclude that “oral rivaroxaban, at a dose of 15 mg twice daily for the first 3 weeks, followed by 20 mg once daily thereafter, without the need for laboratory monitoring, may provide an effective, safe, single-drug approach to the initial and continued treatment of venous thrombosis.”

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Biomarkers improved prediction of mortality in patients with STEMI undergoing primary PCI
Damman P. J Am Coll Cardiol. 2011;57:29-36.

The addition of a multimarker to a model that included established risk factors benefited the prediction of mortality in patients with STEMI who were undergoing primary percutaneous coronary intervention.

“This is one of the first studies to evaluate a multimarker approach for the prediction of baseline risk of long-term death in patients undergoing primary PCI for STEMI,” the researchers wrote. “Incorporation of … three predictive biomarkers in the multimarker risk score yields important information regarding baseline risk and mortality.”

The study included 1,034 patients with STEMI undergoing primary PCI from an intervention center in the Netherlands between Jan. 1, 2005, and Jan. 1, 2007. Researchers tested whether combining N-terminal pro-brain natriuretic peptide, CRP, glucose, cardiac troponin T and estimated glomerular filtration rate improved mortality prediction.

During a mean follow-up of 901 days, 120 patients died. Statistically significant predictors of mortality included glucose, N-terminal pro-brain natriuretic peptide and estimated glomerular filtration rate.

According to researchers, a risk score that incorporated these three biomarkers identified a high-risk STEMI subgroup with a higher mortality vs. an intermediate- or low-risk subgroup (P<.001). Additionally, the three biomarkers, when added to established prognostic factors, improved mortality prediction, which was indicated by the net reclassification improvement (P<.001) and integrated discrimination improvement (P<.01).

“The study provides important pathophysiological information confirming the common roots of ACS, either ST segment elevation or non-ST elevation, and promising clinical improvements in STEMI treatment,” Luigi M. Biasucci, MD, and Roberta Della Bona, MD,both with the department of cardiology, Catholic University of the Sacred Heart, Rome, wrote in an accompanying editorial. “Although their efforts fell short of the objectives, we hope that they will contribute to a more accurate and individualized prognostication and therapy, with consequent reduction in events and the flourishing of novel pathophysiological information.”

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Paclitaxel-eluting stent benefits comparable between men, women
Mehran R. J Am Coll Cardiol Intv. 2010;3:1260-1261.
Mikhail GW. J Am Coll Cardiol Intv. 2010;3:1250-1259.

Women undergoing percutaneous coronary intervention treated with a paclitaxel-eluting stent had similar benefits to men who underwent the same procedure, study data indicated.

“To our knowledge, the ‘TAXUS Woman’ analysis, which included more than 3,000 women, is the largest evaluation to date that examines the influence of sex on long-term performance of a single drug-eluting stent across low- to high-risk patient/lesion characteristics,” the researchers wrote. “This analysis demonstrated that women had significantly more adverse baseline risk factors, yet had comparable safety and efficacy outcomes to men.”

The study included 3,114 women and 6,649 men from five randomized trials and two “real-world” registries who were undergoing PCI with a paclitaxel-eluting stent (Taxus, Boston Scientific). Researchers used outcomes of women (n=395) from the trials treated with bare metal stents as a comparison.

Data specific to the randomized trials revealed that women treated with a paclitaxel-eluting stent had a lower rate of target lesion revascularization than women treated with a bare metal stent (11.5% vs. 22.6%; P<.001). Between both stent groups, there were no significant sex-based differences in death, target lesion revascularization, stent thrombosis and MI at 5 years.

When data from both the trials and registries were analyzed, researchers found that women had similar outcomes as men despite having more adverse baseline characteristics, including advanced age, hypertension and diabetes. Conversely, in the expanded-use cohort — those considered to have patient and/or lesion characteristics considered outside the simple-use population, such as lesion length >28 mm and reference vessel diameter <2.5 mm — women had significantly higher rates of death and target lesion revascularization, although only target lesion revascularization remained higher after multivariate analysis.

In an accompanying editorial, Roxana Mehran, MD, and Annapoorna S. Kini, MD, of the Mount Sinai School of Medicine, New York, said they questioned whether this study was powered enough to provide a definitive conclusion regarding the effectiveness of paclitaxel-eluting stents in women compared with men.

“Although close to 10,000 patients were studied in these well-controlled trials, women represented only a small minority of the population. Therefore, the true comparative effectiveness study of paclitaxel-eluting stent vs. bare metal stent in women was based on only 1,050 female subjects (655 paclitaxel-eluting stent vs. 395 bare metal stent) and was hardly powered to answer the question of safety and efficacy of paclitaxel-eluting stent in women,” they wrote.
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NanoCross catheters recalled

The company ev3 has initiated a voluntary recall of the NanoCross .014” OTW PTA Dilation Catheter because of the potential of cracking or breaking during use. The FDA has classified this as a class I recall.

A cracked or broken catheter shaft could result in the inability to inflate or deflate the balloon, resulting in material separation and possible embolization. This could cause unplanned intravascular or open surgery, vasospasm, prolonged tissue ischemia, bleeding and/or death.

The NanoCross .014” OTW PTA Dilation Catheter is used to dilate stenosis in the iliac, femoral, iliofemoral, popliteal, infra-popliteal and renal arteries, and to treat obstructive lesions of native or synthetic arteriovenous dialysis fistulae.

The recall affects certain lots of the NanoCross .014” OTW PTA Dilation Catheters manufactured between May 27, 2010 and October 18, 2010. Only the catheters from the lots specified on this site are affected by the recall.

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Catheter Ablation for Atrial Fibrillation: Are Results Maintained at 5 Years of Follow-Up? Weerasooriya R, Khairy P, Litalien J, et al.
J Am Coll Cardiol 2011;57:160-166.
Study Question: What is the long-term efficacy of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF)?

Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery: Results From the PLATO (Platelet Inhibition and Patient Outcomes) Trial
Held C, Åsenblad N, Bassand JP, et al.
J Am Coll Cardiol 2011;Dec 29:[Epub ahead of print].
Study Question: What is the efficacy and safety of ticagrelor and clopidogrel in patients with acute coronary syndrome (ACS) undergoing coronary artery bypass graft surgery (CABG)?

Cardiac Outcomes After Pregnancy in Women With Congenital Heart Disease
Balint OH, Siu S, Mason J, et al.
Heart 2010; 96:1656-1661.
Study Question: What are the frequency and determinants of late cardiac events (LCEs) after pregnancy in women with congenital heart disease?

“Do GRACE (Global Registry of Acute Coronary events) risk scores still maintain their performance for predicting mortality in the era of contemporary management of acute coronary syndromes?”
Abu-Assi E, Ferreira-González I, Ribera A, et al.
Am Heart J 2010;160:826-834.
Study Question: What is the performance of the GRACE risk scores (RS) for risk stratification in acute coronary syndromes (ACS) in the era of contemporary management of ACS?

Influence of Age on Associations Between Childhood Risk Factors and Carotid Intima-Media Thickness in Adulthood: The Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium
Juonala M, Magnussen CG, Venn A, et al.
Circulation 2010;122:2514-2520.
Study Question: Does age influence the association between childhood risk factors and carotid intima-media thickness (IMT) in adulthood?

Apixaban Versus Enoxaparin for Thromboprophylaxis After Hip Replacement
Lassen MR, Gallus A, Raskob GE, et al.
N Engl J Med 2010;363:2487-2498.
Study Question: What is the relative efficacy and safety of apixaban compared to enoxaparin for thromboprophylaxis following hip replacement?

Variability in the Measurement of Hospital-Wide Mortality Rates
Shahian DM, Wolf RE, Iezzoniet LI, et al.
N Engl J Med 2010;363:2530-2539.
Study Question: What is the clinical rationale, usefulness for informing consumers and practitioners, and statistical method for calculating hospital-wide mortality rates as performance metrics?

Relation Between Renal Function and Response to Cardiac Resynchronization Therapy in Multicenter Automatic Defibrillator Implantation Trial—Cardiac Resynchronization Therapy (MADIT-CRT)
Goldenberg I, Moss AJ, McNitt S, et al.
Heart Rhythm 2010;7:1777-1782.
Study Question: Are markers of prerenal azotemia associated with the response to cardiac resynchronization therapy (CRT)?

Symmetrical and Asymmetrical Dimethylarginine as Predictors for Mortality in Patients Referred for Coronary Angiography: The Ludwigshafen Risk and Cardiovascular Health Study
Meinitzer A, Kielstein JT, Pilz S, et al.
Clin Chem 2011;57:112-121.
Study Question: Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, has been linked to cardiovascular risk. What is the clinical role of its structural isomer, symmetrical dimethylarginine (SDMA)?

Secondary Prevention After Coronary Artery Bypass Graft Surgery: Findings of a National Randomized Controlled Trial and Sustained Society-Led Incorporation Into Practice
Williams JB, DeLong ER, Peterson ED, Dokholyan RS, Ou FS, Ferguson TB Jr, on behalf of the Society of Thoracic Surgeons and the National Cardiac Database.
Circulation 2011;123:39-45.
Study Question: What are the effects of low-intensity continuous quality improvement (CQI) interventions on secondary prevention adherence after coronary artery bypass grafting (CABG)?

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Promising stroke, bleeding rates after cardioversion reported with dabigatran use
Nagarakanti R. Circulation. 2011;123:131-136.

Stroke and major bleeding rates after cardioversion among patients from the RE-LY trial who were taking two doses of dabigatran were low and comparable with those who were treated with warfarin.

In the sub-analysis, investigators analyzed 1,983 cardioversions that were performed on 1,270 patients with nonvalvular atrial fibrillation from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Overall, 647 procedures were performed on patients assigned 110 mg dabigatran (Pradaxa, Boehringer Ingelheim) twice-daily, 672 procedures on those assigned 150 mg dabigatran twice-daily and 664 procedures in patients assigned warfarin (Coumadin, Bristol-Myers Squibb).

At 30 days, stroke and systemic embolism rates were 0.8% in the 110-mg dabigatran arm, 0.3% in 150-mg dabigatran arm and 0.6% in the warfarin group, with differences between both doses of dabigatran not reaching statistical significance when compared with warfarin. Similarly, major bleeding rates between 110 mg dabigatran (1.7%) and 150 mg dabigatran (0.6%) were comparable with warfarin (0.6%).

“The RE-LY trial confirmed the efficacy and safety of warfarin in cardioversion in a large cohort of warfarin-treated patients. It also allowed comparison with the new oral anticoagulant dabigatran. The results show that the two drugs are comparable in this setting,” the researchers concluded.
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Quality measurement of anticoagulation care delivery may lead to better outcomes
Rose A. Circ Cardiovasc Qual Outcomes.2011;doi:10.1161/circoutcomes.110.957738.

New study results have indicated that use of risk-adjusted percent time in therapeutic range data may help oral anticoagulant care delivery sites, especially in large integrated health systems, prevent adverse events from inadequate or excessive anticoagulation. The findings were published online by researchers from Boston University School of Medicine and Bedford Veterans Affairs Medical Center

The researchers profiled the performance of 100 VA outpatient anticoagulation sites based on their respective risk-adjusted percent time in therapeutic range (TTR). Two years of data were collected on 124,551 patients who had received warfarin (Coumadin, Bristol-Myers Squibb) for at least 30 days and had at least two valid intervals of 56 days or less without hospitalization between two INR values. Patients with valvular CVD or with INR values of no more than 1.2 were excluded.

The expected TTR for each patient and each site was calculated based on a risk-adjusted model that included demographics, comorbidities, medications and hospitalizations. The expected TTR site range was 54% to 62%; the observed TTR site range was 38% to 69%. The mean TTR for the entire sample was 58%. Site risk-adjusted performance was 18% less than to 12% more than expected. One site with a challenging patient population (expected TTR, 53.5%; 4.4% less than average) was ranked 27th before risk adjustment (observed TTR, 60.6%; 2.7% more than average) but seventh after risk adjustment, the researchers said. Conversely, another site was ranked 79th before risk adjustment (observed TTR, 53.8%; 4.1% less than average), but “because of its relatively easy case mix” (expected TTR, 58.9%), the site dropped to 92nd.

“Risk adjustment is important for enhancing the credibility of site profiling; without [it], sites could claim that their poor performance was solely because of their case mix,” the researchers wrote. They said risk-adjusted site rankings were consistent from year to year, suggesting their study measured a “quality of care that is stable over time.”

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Lower education level linked with higher rates of STEMI-related mortality
Mehta R. J Am Coll Cardiol. 2011;57:138-146.

Researchers have reported an inverse relationship between years of education and 1-year mortality in patients treated for STEMI.

In the study, data from 11,326 patients with STEMI who received fibrinolysis from the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-III) trial, which was conducted from Oct. 1995 to Jan. 1997, were analyzed. Researchers examined unadjusted in-hospital clinical outcomes and in-hospital, 30-day and 1-year mortality, as well as adjusted 1-year mortality.

They found an inverse association between 1-year mortality and years of education, culminating with a fivefold increase in the mortality rate seen in patients with less than 8 years vs. those with more than 16 years of education (17.5% vs. 3.5%; P<.0001). Although the strength of this relationship varied among different countries, years of education still remained an independent factor of mortality between day 8 and 1 year, with an HR of 0.96 per year of increase in education (95% CI, 0.94-0.98).

In addition, aside from in-hospital bleeding, most in-hospital adverse outcomes, including mortality and reinfarction, were also inversely related to education level.

“This study demonstrates that lower socioeconomic status, as ascertained by years of completed education, was associated with significantly poorer outcomes in subjects who received fibrinolysis after hospitalization for acute STEMI,” the researchers wrote. “Although fewer years of education were associated with adverse demographic, clinical and presenting features that have been shown to portend a poor prognosis in STEMI patients, years of education remained independently correlated with mortality, even after accounting for these high-risk characteristics.”

They said future studies should investigate the behavioral, social, biological and physiological mechanisms that underlie the link between socioeconomic status and CVD outcomes.
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High rate of CHD-related deaths in Sweden occurred out-of-hospital
Dudas K. Circulation. 2011;123:46-52. S

Three in four coronary heart disease-related deaths in Swedish patients who experienced a first major coronary event happened outside the hospital setting, according to study data.

“Case fatality associated with a first coronary event is often underestimated when only those who survive to reach a hospital are considered,” the researchers wrote. “Few studies have examined long-term trends in case fatality associated with a major coronary event that occurs out of the hospital.”

This lack of data led Kerstin Dudas, PhD, and colleagues to conduct a study of all case participants (n=384,597; age 35-84 years) with a first major coronary event in Sweden between 1991 and 2006.

According to researchers, 111,319 patients (28.9%) without previous hospitalization for acute MI died out-of-hospital with CHD as the primary cause of death, whereas 36,552 patients (9.5%) died within 28 days of first hospitalization for acute MI.

During the study period, out-of-hospital deaths as a proportion of all major coronary events declined (adjusted mean annual decrease, 2.2%), although the greatest reduction was reported in the hospitalized group (adjusted mean annual decrease, 5.8%). Conversely, in the out-of-hospital group, male sex and younger age (35-54 years) were associated with a 4% increased event risk each successive calendar year.

“The great majority of all fatal coronary events occur outside the hospital, and this proportion is increasing, particularly among younger individuals,” the researchers said, adding that primary prevention and persuading individuals to seek hospital treatment at the onset of a major coronary event symptom are increasingly important measures in reducing CHD-related fatality.

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Pioglitazone delayed atheroma progression in patients with diabetes
Nicholls S. J Am Coll Cardiol. 2011;57:153-159.

Patients with type 2 diabetes who were treated with pioglitazone had improvements in triglyceride/HDL ratio that were associated with delayed progression of atheroma, new findings suggested.

The study included 360 patients with type 2 diabetes and CAD who were treated with either 15 mg to 45 mg of pioglitazone (Actos, Takeda) with dose titration or 1 mg to 4 mg of glimepiride for 18 months. Researchers used serial IVUS to determine the relationship between changes in percent atheroma volume, total atheroma and biochemical parameters.
According to results, patients treated with pioglitazone had greater increases in HDL, as well as reductions in triglycerides, CRP and hemoglobin, when compared with glimepiride. For patients assigned pioglitazone, changes in percent atheroma correlated with triglycerides (P=.04), glycated hemoglobin (P=.03) and triglyceride/HDL-C ratio (P=.03), whereas for glimepiride use, changes in percent atheroma were associated with changes in LDL (P=.05), apolipoprotein B (P=.04) and apolipoprotein A-I (P=.01).

On multivariable analysis, pioglitazone’s effect on triglyceride/HDL was associated with changes in percent atheroma (P=.03) and total atheroma (P=.02) volume.

The study’s findings, the researchers wrote, “[support] the hypothesis that pioglitazone halted disease progression predominantly because of its properties beyond glycemic control. These findings are also consistent with clinical outcome data indicating the importance of atherogenic dyslipidemia as a target for therapeutic manipulation in patients with diabetes mellitus to achieve more effective prevention of CVD.”

Nicholls et al provides us with some important new information about the effects of pioglitatzone, a drug that is likely to be increasingly prescribed in patients with diabetes. That pioglitazone has the potential to confer CV benefits through secondary mechanisms on triglyceride, HDL and atheroma burden is a win: win for high risk patients who take the drug as part of their diabetes regimen. It may delay or prevent the need for additional triglyceride lowering or HDL raising therapies in some patients, which can minimize cost and pill burden.

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Relation of Obesity to Recurrence Rate and Burden of Atrial Fibrillation
Weerasooriya R, Guglin M, Maradia K, Chen R, Curtis AB.
Am J Cardiol 2011;Jan 3:[Epub ahead of print].
Study Question: Does obesity increase the risk for recurrent atrial fibrillation (AF)?

A Randomized Active-Controlled Study Comparing the Efficacy and Safety of Vernakalant to Amiodarone in Recent-Onset Atrial Fibrillation
Camm AJ, Capucci A, Hohnloser SH, et al., on behalf of the AVRO Investigators.
J Am Coll Cardiol 2011;57:313-321.
Study Question: Is vernakalant more effective than amiodarone for acute conversion of atrial fibrillation (AF)?

Comparative Validation of a Novel Risk Score for Predicting Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: The HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) Score
Lip GY, Frison L, Halperin JL, Lane DA.
J Am Coll Cardiol 2011;57:173-180.
Study Question: What are the predictors of bleeding events among patients with atrial fibrillation (AF)?

Long-Term Comparison of Drug-Eluting Stents and Coronary Artery Bypass Grafting for Multivessel Coronary Revascularization: 5-Year Outcomes From the Asan Medical Center-Multivessel Revascularization Registry
Park DW, Kim YH, Song HG, et al.
J Am Coll Cardiol 2011;57:128-137.
Study Question: What are the long-term (5-year) outcomes of a large cohort of patients who underwent drug-eluting stent (DES) or coronary artery bypass graft (CABG) surgery for multivessel revascularization?

Randomized, Controlled Trial of Individualized Heparin and Protamine Management in Infants Undergoing Cardiac Surgery With Cardiopulmonary Bypass
Gruenwald CE, Manlhiot C, Chan AK, et al.
J Am Coll Cardiol 2010;56:1794-1802.
Study Question: Are postoperative clinical outcomes improved in children less than 1 year of age undergoing cardiopulmonary bypass (CPB) with the use of individualized heparin management with Hemostasis Management System (HMS) Plus rather than traditional weight-based anticoagulation management using activated clotting time (ACT)?

Aortic Valve Reinterventions After Balloon Aortic Valvuloplasty for Congenital Aortic Stenosis: Intermediate and Late Follow-Up
Brown DW, Dipilato AE, Chong EC, Lock JE, McElhinney DB.
J Am Coll Cardiol 2010;56:1740-1749.
Study Question: What is the freedom from aortic valve reintervention, and what are the patient-related and procedural risk factors for reintervention following transcatheter balloon aortic valvuloplasty for congenital aortic stenosis (AS)?

A Randomized Trial of Internet and Telephone Treatment for Smoking Cessation
Graham AL, Cobb NK, Papandonatos GD, et al.
Arch Intern Med 2011;171:46-53.
Study Question: Does Internet and telephone treatment for smoking cessation increase quit rates?

An Online Community Improves Adherence in an Internet-Mediated Walking Program. Part 1: Results of a Randomized Controlled Trial
Richardson CR, Buis LR, Janney AW, et al.
J Med Internet Res 2010;12:e71.
Study Question: Does an online community improve adherence to an Internet-based walking program?

3-Year Follow-Up of Patients With Coronary Artery Spasm as Cause of Acute Coronary Syndrome: The CASPAR (Coronary Artery Spasm in Patients With Acute Coronary Syndrome) Study Follow-Up
Ong P, Athanasiadis A, Borgulya G, Voehringer M, Sechtem U.
J Am Coll Cardiol 2011;57:147-152.
Study Question: What is the long-term outcome of patients with acute coronary syndrome (ACS) who have no identifiable coronary artery disease on angiography, but have evidence of spasm in response to intracoronary acetylcholine?

Evaluation of the Efficacy and Safety of RLY5016, a Polymeric Potassium Binder, in a Double-Blind, Placebo-Controlled Study in Patients With Chronic Heart Failure (the PEARL-HF) Trial
Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Hung IZ, on behalf of the PEARL-HF Investigators.
Eur Heart J 2011;Jan 5:[Epub ahead of print].
Study Question: What is the efficacy and safety of RLY5016 (a non-absorbed, orally administered, potassium [K+]-binding polymer) on serum K+ levels in patients with chronic heart failure (HF) receiving standard therapy and spironolactone?

Generalizability and Longitudinal Outcomes of a National Heart Failure Clinical Registry: Comparison of Acute Decompensated Heart Failure National Registry (ADHERE) and Non-ADHERE Medicare Beneficiaries
Kociol RD, Hammill BG, Fonarow GC, et al.
Am Heart J 2010;160:885-892.
Study Question: Can clinical registry data be generalized to the general population of interest?

Meta-Analysis of Randomized Trials of Glycoprotein IIb/IIIa Inhibitors in High-Risk Acute Coronary Syndromes Patients Undergoing Invasive Strategy
De Luca G, Navarese EP, Cassetti E, Verdoia M, Suryapranata H.
Am J Cardiol 2011;107:198-203.
Study Question: What is the comparative effectiveness of a strategy of upstream administration of glycoprotein (GP) IIb/IIIa inhibitors, aimed at cooling the culprit coronary plaque before angioplasty, to a strategy of downstream selective administration of such drugs?

Lowering the Triglyceride/High-Density Lipoprotein Cholesterol Ratio Is Associated With the Beneficial Impact of Pioglitazone on Progression of Coronary Atherosclerosis in Diabetic Patients: Insights From the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) Study
Nicholls SJ, Tuzcu EM, Wolski K, et al.
J Am Coll Cardiol 2011;57:153-159.
Study Question: What factors are associated with the favorable effect of pioglitazone on atheroma

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SPIRIT IV: Everolimus-eluting stent outperforms paclitaxel-eluting stent in patients without diabetes
Kereiakes D. J Am Coll Cardiol. 2010;56:2084-2089.

The latest results from the SPIRIT-IV trial have shown everolimus-eluting stents to produce superior clinical outcomes in patients without diabetes, despite both stents performing similarly in patients with diabetes.

“The SPIRIT IV trial confirms and extends the observation made in the SPIRIT III trial of a significant interaction between randomized stent type everolimus-eluting stent (Xience V, Abbott Vascular) vs. paclitaxel-eluting stent (Taxus Express, Boston Scientific) and the presence of diabetes on the primary composite safety-plus-efficacy clinical endpoint,” the researchers wrote.

The randomized, prospective, single blind study included 3,687 patients with up to three de novo native coronary artery lesions who received either an everolimus-eluting stent (n=2,458) or a paclitaxel-eluting stent (n=1,229). Clinical outcomes were analyzed in randomly assigned patients with (n=1,185) and without (n=2,498) diabetes.

One-year results indicated that among patients without diabetes, everolimus-eluting stent vs. paclitaxel-eluting stent reduced the primary endpoint of target lesion failure by 54% (3.1% vs. 6.7%; P<.0001) and major adverse CV events by 52% (3.2% vs. 6.7%; P<.0001). Use of everolimus-eluting stent also resulted in lower rates of the major secondary endpoints of ischemia-driven target vessel revascularization, as well as the composite occurrence of cardiac death or target vessel MI (P=.05).

However, among patients with diabetes, there were no statistically significant differences in outcomes at 1 year between randomly assigned stent types for both target lesion failure and major adverse CV events.

“These findings suggest the need for further studies to elucidate the mechanistic pathways underlying the poor prognosis of patients with diabetes mellitus, with a focus toward development of novel drugs and stents to improve outcomes in this high-risk patient cohort,” the researchers wrote.
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P-OM3: Prescription omega-3 no more effective than placebo for paroxysmal AF treatment
American Heart Association Scientific Sessions 2010

CHICAGO — Researchers of the P-OM3 trial have reported that prescription omega-3 was no more beneficial for patients with paroxysmal atrial fibrillation than placebo for the recurrence of symptomatic AF.

“The rationale for this study was that many of our patients do use fish oil products in various doses and preparations in the hope of preventing several CV endpoints,” researcher Peter Kowey, MD, with the Jefferson Medical College, Philadelphia, and a Cardiology Today Editorial Board member, said in a press conference. “There clearly has been equipoise in the area of AF with as many studies producing positive as those producing negative results.”

In the prospective, randomized, double-blind, placebo-controlled study, 663 patients (paroxysmal AF, (n=542; persistent AF, n=121) were assigned to either P-OM3 (Lovaza, GlaxoSmithKline) 4 g daily or placebo and treated for 24 weeks. Patients had no substantial structural heart disease and normal sinus rhythm at baseline and were recruited from 96 sites in the United States between November 2006 and July 2009. The primary outcome was the time to first recurrence of symptomatic AF (including flutter) in subjects with paroxysmal AF.

At the final follow-up in January of this year, there were no significant differences between treatment groups for recurrence of symptomatic AF in the following strata: paroxysmal (HR=1.15; 95% CI, 0.90-1.46), persistent (HR=1.64; 95% CI, 0.92-2.92), and paroxysmal and persistent combined (HR=1.22; 95% CI, 0.98-1.52). The secondary endpoints, including time to first onset of symptomatic AF (excluding flutter; P=.21) and first recurrence of symptomatic or asymptomatic AF or flutter (P=.33), also supported the primary outcome.

“I don’t think there is any ambiguity about the results in this trial [when] looking at patients with paroxysmal AF that the use of high doses of omega-3 fatty acids did not appear to have a significant effect on recurrence of AF,” Kowey told Cardiology Today. “This doesn’t apply to other populations or other CV disease, but I think we’ve put this issue to rest in this particular population.”

Kowey reports having consulted on an ad hoc basis for GlaxoSmithKline.

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Angina common among women, not associated with atherosclerosis
Banks K. J Am Coll Cardiol Img. 20114:65-73.
Bairey Merz CN. J Am Coll Cardiol Img. 20114:74-77.

Data from a new study suggest that angina detected by CT is common among women, but is not associated with subclinical atherosclerosis.

“Angina in women is a morbid condition for which the determinants are poorly characterized,” Kamakki Banks, MD, and fellow investigators wrote. “More than 50% of women with angina may have normal or near-normal coronary arteries visualized at coronary angiography, a rate much higher than is observed among men. Coronary angiography, however, is an insensitive measure of atherosclerosis burden, and some have hypothesized that subclinical atherosclerosis may promote microvascular dysfunction and ischemia in women with angina in the absence of obstructive epicardial coronary disease.”

This hypothesis led the researchers to evaluate the relationship between angina and coronary artery calcium (CAC) in women via data compiled from the multi-ethnic Dallas Heart Study. The final study population included 1,480 women (49% African American) with a mean age of 45 years.

Overall, 6.9% of the population had angina, which was not associated with CAC (P=.20). For women without CAC, variables that included obesity and insulin resistance were associated with angina, whereas independent factors for angina included African-American ethnicity, waist circumference and premature family history of MI (P<.05 for all). Women with angina vs. without had higher levels of reduced aortic compliance (P=.007), soluble vascular cell adhesion molecule-1 (P=.01) and soluble intercellular adhesion molecule-1 (P=.02).

“Typical exertional angina affects one of every 14 women between the ages of 30 and 65 years in Dallas County. Interestingly, angina was not associated with subclinical atherosclerosis among women,” the investigators wrote. “Angina that occurs in the absence of subclinical atherosclerosis was not related to many traditional atherosclerotic risk factors; however, it was associated with measures of vascular stiffness and endothelial dysfunction, suggesting a distinct vascular etiology and alternate potential therapeutic targets for this entity compared with atherosclerosis.”

C. Noel Bairey Merz, MD,with the Women’s Heart Center, Cedars-Sinai Medical Center, Los Angeles, wrote in an accompanying editorial that current alternative strategies utilizing tools to detect vulnerable patients should be useful in diagnosis and may even be preferential in women.

“Novel imaging strategies aimed at pathophysiological pathways, including measures of nonendothelial, endothelial function, vascular and myocardial compliance, as well as myocardial perfusion and flow reserve are actively being investigated as useful risk markers and diagnostic strategies,” she said. “Noninvasive, nonionizing radiation strategies are needed for this purpose, as invasive study has documented the feasibility of identifying future risk by pathophysiological evaluation in women with no obstructive CAD.”

Disclosure: Dr. Bairey Merz has received grants, contract support and lecture honoraria and has acted as a consultant for many companies and institutions. She also reported owning stock in Medtronic and Johnson and Johnson.
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Sedentary time negatively associated with cardiometabolic, inflammatory biomarkers
Healy G. Eur Heart J. 2011;doi:10.1093/eurheartj/ehq451.

Taking many breaks from sedentary time, even just 1-minute breaks, appeared to result in lower levels of C-reactive protein and smaller waist circumferences, according to researchers from The University of Queensland in Australia.

They also found that prolonged periods of sedentary time, even in those who exercised regularly, were associated with larger waist circumferences, lower levels of HDL cholesterol, higher levels of CRP and higher triglycerides.

The cross-sectional study was conducted in participants of the National Health and Nutrition Examination Survey between 2003 and 2006. The sample included 4,757 adults who wore accelerometers and had sufficient data. Researchers measured waist circumference, BP, cholesterol levels and CRP levels. A sub-sample of 2,118 participants was available for fasting analyses for triglycerides, plasma glucose and insulin.

The participants wore the accelerometer for 14.6 hours per day, and the average time spent sedentary was 8.44 hours. Women were more sedentary, but they took more breaks and had a more favorable cardiometabolic profile than men.

“These population-based findings provide further evidence on the deleterious associations of sedentary time with cardiometabolic health in adults, and provide novel evidence on the relationship of sedentary time with the inflammatory biomarker C-reactive protein,” the researchers wrote. “In general, these associations were consistent across sex, age and race/ethnicity.”

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Drug-eluting stents comparable with CABG in patients with multivessel disease
Park D. J Am Coll Cardiol. 2011;57:128-137.

Five-year results from a large cohort of patients with multivessel disease indicated that those who were treated with a drug-eluting stent had similar rates of mortality and composite adverse outcomes with those who underwent CABG, but had a higher rate of revascularization.

Researchers from Seoul, Korea, included 3,042 patients with multivessel disease in the study, 1,547 of whom received a drug-eluting stent and 1,495 underwent CABG. They compared the adverse outcomes of both procedures, which included death, a composite outcome of death, MI or stroke, and repeat revascularization.

After a median follow-up of 5.6 years and adjustments for differences in baseline risk factors, researchers reported that 5-year risk for death (HR=1.00; 95% CI, 0.76-1.32) and the composite outcome risk (HR=0.97; 95% CI, 0.76-1.24) were similar between the drug-eluting stent group and the CABG group. However, revascularization rates were significantly higher in the drug-eluting stent group (HR=2.93; 95% CI, 2.20-3.90). These results were consistent in most high-risk clinical subgroups, including patients with diabetes, age older than 65 years and abnormal ventricular function.

As an area for future research, the investigators suggested a large randomized comparison with longer-term follow-up of 5 or 10 years, which they said will provide more confidence in the long-term safety, durability and efficacy of percutaneous coronary intervention with drug-eluting stents in reference to CABG.

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Alcohol Consumption and Risk of Atrial Fibrillation: A Meta-Analysis
Kodama S, Saito K, Tanaka S, et al.
J Am Coll Cardiol 2011;57:427-436.
Study Question: Does alcohol consumption increase the probability of developing atrial fibrillation (AF)?

Cost-Effectiveness of Dabigatran Compared With Warfarin for Stroke Prevention in Atrial Fibrillation
Freeman JV, Zhu RP, Owens DK, et al.
Ann Intern Med 2011;154:1-11.
Study Question: What is the quality-adjusted survival, costs, and cost-effectiveness of dabigatran compared with adjusted-dose warfarin for preventing ischemic stroke in patients 65 years or older with nonvalvular atrial fibrillation (AF)?

Dabigatran Versus Warfarin in Patients With Atrial Fibrillation: An Analysis of Patients Undergoing Cardioversion
Nagarakanti R, Ezekowitz MD, Oldgren J, et al.
Circulation 2011;123:131-136.
Study Question: Is anticoagulation with dabigatran adequate for stroke prevention in the setting of cardioversion of atrial fibrillation (AF)?


Long-Term Cardiovascular Mortality After Radiotherapy for Breast Cancer
Bouillon K, Haddy N, Delaloge S, et al.
J Am Coll Cardiol 2011;57:445-452.
Study Question: What is the effect of radiotherapy for breast cancer on long-term cardiovascular mortality?

Survival of Patients Undergoing Rescue Percutaneous Coronary Intervention: Development and Validation of a Predictive Tool
Burjonroppa SC, Varosy PD, Rao SV, et al.
JACC Cardiovasc Interv 2011;4:42-50.
Study Question: What are the incidence and predictors of mortality in ST-segment elevation myocardial infarction (STEMI) patients undergoing rescue percutaneous coronary intervention (PCI) after failed fibrinolytic therapy?
Calcium-Channel Blockers Do Not Alter the Clinical Efficacy of Clopidogrel After Myocardial Infarction: A Nationwide Cohort Study
Olesen JB, Gislason GH, Charlot MG, et al.
J Am Coll Cardiol 2011;57:409-417.
Study Question: Do calcium channel blockers (CCBs) reduce the clinical efficacy of clopidogrel?

Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis
Khera AV, Cuchel M, de la Llera-Moya M, et al.
N Engl J Med 2011;364:127-135.
Study Question: Does cholesterol efflux capacity from macrophages predict atherosclerosis burden independently of high-density lipoprotein (HDL) levels?
Reperfusion by Primary Percutaneous Coronary Intervention in Patients With ST-Segment Elevation Myocardial Infarction Within 12 to 24 Hours of the Onset of Symptoms (from a Prospective National Observational Study [PL-ACS])
Gierlotka M, Gasior M, Wilczek K, et al.
Am J Cardiol 2011;Dec 30:[Epub ahead of print].
Study Question: Is there benefit of reperfusion by percutaneous coronary intervention (PCI) performed between 12-24 hours of symptom onset in patients presenting with ST-elevation myocardial infarction (STEMI)?

Effects of n-3 Polyunsaturated Fatty Acids on Left Ventricular Function and Functional Capacity in Patients With Dilated Cardiomyopathy
Nodari S, Triggiani M, Campia U, et al.
J Am Coll Cardiol 2011; Jan 5:[Epub ahead of print].
Study Question: Does n-3 polyunsaturated fatty acid (PUFA) therapy impact left ventricular (LV) function or functional capacity in mild chronic nonischemic heart failure (HF)?
Exercise Training in Heart Failure: Practical Guidance
Conraads VM, Beckers PJ.
Heart 2010;96:2025-2031.
Perspective: This review discusses the clinical application and research supporting the use of exercise training in heart failure (HF). The following are 10 points to remember.

Meta-Analysis: Statin Therapy Does Not Alter the Association Between Low Levels of High-Density Lipoprotein Cholesterol and Increased Cardiovascular Risk
Increased Cardiovascular Risk
Jafri H, Alsheikh-Ali AA, Karas RH.
Ann Intern Med 2010;153:800-808.
Study Question: Does treatment with statins alter the association of low levels of high-density lipoprotein cholesterol (HDL-C) and increased risk for cardiovascular events (CVEs)?

High-Sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart Failure
Ky B, French F, McCloskey K, et al.
Circ Heart Fail 2010;Dec 22:[Epub ahead of print].
Study Question: The ST2 receptor is a member of the toll-like/interleukin-1 receptor family and may be involved in cardioprotective stress-response signaling. Soluble ST2 is predictive of adverse outcomes in acute heart failure (HF), but does ST2 predict chronic HF outcomes?

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Meta-analysis: Hydrochlorothiazide as first-line BP therapy less effective than other drug classes
Messerli F. J Am Coll Cardiol. 2011;57:590-600.

Hydrochlorothiazide as a first-line therapy was inferior to all other drug classes for the reduction of BP, results from a meta-analysis suggested.

Researchers selected 19 randomized studies enrolling 1,463 patients with hypertension for inclusion in the analysis. All studies assessed BP by 24-hour ambulatory monitoring, compared hydrochlorothiazide in a head-to-head fashion with other drug classes and had duration of at least 4 weeks. The primary outcome of interest was a reduction in systolic and diastolic BP from baseline to follow-up.

According to the results, hydrochlorothiazide in the typical dose of 12.5 mg to 25 mg was less effective at lowering systolic BP when compared with ACE inhibitors (by 4.5 mm Hg, P=.001), angiotensin receptor blockers (by 5.1 mm Hg, P=.003), beta-blockers (by 6.2 mm Hg, P<.00001) and calcium antagonists (by 4.5 mm Hg, P=.02). For diastolic BP, hydrochlorothiazide was also inferior when compared with ACE inhibitors (by 4 mm Hg, P<.0001), angiotensin receptor blockers (by 2.9 mm Hg, P=.002), beta-blockers (by 6.7 mm Hg, P<.00001) and calcium antagonists (by 4.2 mm Hg, P=.0001).

There was also no difference in systolic (P=.30) or diastolic (P=.15) 24-hour BP reduction between the 12.5-mg dose of hydrochlorothiazide and the 25-mg dose, but the difference in systolic BP became significant at 50 mg (P=.04) when compared with the 25-mg dose.

“Hydrochlorothiazide in its commonly used dose of 12.5 mg to 25 mg daily lowers BP significantly less well than do all other drug classes as measure in head-to-head studies by ambulatory BP monitoring,” the researchers concluded. “Because of such paltry antihypertensive efficacy and the lack of outcome data at these doses, physicians should refrain from prescribing hydrochlorothiazide as initial antihypertensive therapy.”

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Intervention program improved care practice implementation in Canadian ICUs
Curtis J. JAMA. 2011;doi:10.1001/jama.2011.8.
Scales D. JAMA. 2011;doi:10.1001/jama.2010.2000.

A multicenter quality-improvement program improved the adoption of care practices in a network of community ICUs in Canada, according to new data published online by the Journal of the American Medical Association.

“Community ICUs admit the majority of critically ill patients and have fewer resources for implementing quality improvement initiatives,” the researchers wrote. “Our videoconferencing network is one model for helping health care workers in geographically dispersed community hospitals to improve quality by accessing resources usually restricted to academic hospitals.”

The video conference-based intervention involved expert-led educational sessions, an audit and feedback, as well as the dissemination of algorithms to sequentially improve delivery of six practices. Admissions from 15 community hospital ICUs in Ontario, Canada, were analyzed, 9,269 during the trial period (November 2005-October 2006) and 7,141 during a decay monitoring period (December 2006-August 2007).

According to researchers, compared with controls, the adoption of care practices in the intervention ICUs was noticeably higher (OR=2.79; 95% CI, 1.00-7.74). Adherence to semi-recumbent positioning in the intervention ICUs significantly improved in the first month compared with the last month (49.8%-89.6% of eligible patient-days; OR=6.35; 95% CI, 1.85-21.79), whereas only nonsignificant improvements were reported in the control arm (80.1%-90.2% of eligible patient-days; OR=2.04; 95% CI, 0.82-5.07).

Further, the greatest improvements in delivery from first to last month in intervention ICUs occurred for semi-recumbent positioning to prevent ventilator-associated pneumonia (50% of patient-days in the first month vs. 90% in the last month) and precautions to prevent catheter-related bloodstream infection (10.6% vs. 70% of patients receiving central lines).

In an accompanying editorial, J. Randall Curtis, MD, MPH,of the University of Washington, Seattle, and Mitchell M. Levy, MD,with the Rhode Island Hospital, Providence, said the most interesting aspect of this study is that it was funded by an organization that funds delivery of health care, rather than by a research funding agency.

“To make significant steps toward improving the quality of health care and controlling the rate of increase in health care costs, this is an important model for the future,” they said. “The use of health care reimbursement to encourage and enforce quality is a reality of the US health care system today and in the future, but these quality measures must be selected and implemented based on rigorous science, and the implementation must be demonstrated to be effective without unintended consequences that lower quality in other ways or other areas of health care.”
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Statin therapy questionable for low-risk CVD patients
Taylor F. Cochrane Database Syst Rev. 2011;doi:10.1002/14651858.CD004816.pub4.

The administration of statins for the primary prevention of CVD in patients with no previous history of the disease has come under question by researchers.

Using data from 14 trials that included 34,272 patients, researchers compared outcomes in patients given statins with those given placebos or routine care; eight of the 14 trials involving 28,161 patients provided data on all-cause mortality deaths, and 11 of the 14 provided data on specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). Duration of treatment was a 1-year minimum with a minimum 6-month follow up.

Researchers reported that all-cause mortality was reduced by statins (RR=0.83; 95% CI, 0.723-0.95), and that fatal and nonfatal CVD endpoints were also lower (RR=0.70; 95% CI, 0.61-0.79). Statins were also associated with reduced revascularization rates (RR=0.66, 95% CI, 0.53-0.83) and a reduction in both LDL and total cholesterol. Researchers wrote that they did not find a direct correlation between statin use and adverse events in low-risk CVD patients.

Most of the trials included in the study reported composite outcomes, and one-third reported selected outcomes. Two of the largest studies included in the report were halted, according to researchers, because “significant reductions in primary composite outcomes had been observed.” No adverse events were reported in eight of the studies.

The findings indicate shortcomings in published trials of statins for primary prevention, the researchers wrote.

“Selective reporting and inclusion of people with CVD in many of the trials included in previous reviews of [the role of statins] in primary prevention make the evidence impossible to disentangle without individual patient data,” they wrote.

In an accompanying editorial, Carl Heneghan, BM, BCH, director of the Centre for Evidence-Based Medicine, University of Oxford, wrote that, “To date, only one trial has been publicly funded, while the authors of nine trials reported having been sponsored either fully or partially by pharmaceutical companies. … Although various multiple prevention strategies exist, the most effective for primary prevention in adults at low risk currently remains unclear.”

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Iodine-123 mIBG imaging found beneficial in predicting AF, HF
Akutsu Y. J Am Coll Cardiol Img. 2011;4:78-86.
Crawford M. J Am Coll Cardiol Img. 2011;4:87-88.

Cardiac sympathetic nervous system abnormality measured by iodine-123 meta-iodobenzylguanidine imaging in patients with paroxysmal atrial fibrillation was associated with the occurrence of HF and permanent atrial fibrillation in a new study.

Researchers from Tokyo performed iodine-123 meta-iodobenzylguanidine (123I-mIBG) scintigraphy on 98 consecutive patients with idiopathic paroxysmal AF and preserved left ventricular ejection fraction of at least 50%. They determined sympathetic nervous system activity as the heart-to-mediastinum ratio.

During a median follow-up of 4 ± 3.6 years, 35 patients with paroxysmal AF transited to permanent AF. Overall, HF occurred in 16 patients, with 12 of the cases diagnosed in patients with permanent AF (34.3%) and four cases in patients without permanent AF (6.3%; trend P<.0001).

Independent predictors of transit to permanent AF included lower heart-to-mediastinum ratio (adjusted HR=3.44; 95% CI, 1.9-6.2) and lower LVEF (adjusted HR=1.04; 95% CI, 1.01-1.08). Furthermore, these factors, as well as a higher brain natriuretic peptide, were independent predictors of occurrence of HF with permanent AF (P≤.014 for all three).

“Our major finding is that [sympathetic nervous system] abnormality was an independently powerful factor for predicting not only the transit to permanent AF but also the occurrence of HF with permanent AF in patients with paroxysmal AF and preserved cardiac function,” the researchers concluded. “Our findings may have important implications for the management of patients with paroxysmal AF before the occurrence of remarkable structural remodeling of atria and subsequent cardiac dysfunction of the left ventricle caused by AF.”

Michael H. Crawford, MD, of the University of California San Francisco, commented in an accompanying editorial on the implications of these findings.

“The results … suggest that a low heart/mediastinum ratio in a paroxysmal AF patient should encourage prophylactic therapy, perhaps with at least beta-blockers to try to prevent the development of permanent AF,” Crawford said, adding, however, that a randomized trial is needed to establish such a strategy.
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FDA to streamline, clarify medical device review process

The FDA will enact a 25-point action plan this year to streamline the de novo review process for certain lower-risk medical devices, as well as clarify the premarket notification submission process, which critics had called “unpredictable” and not “robust enough,” according to an FDA press release.

These actions will produce “a smarter medical device program that supports innovation, keeps jobs here at home, and brings important, safe and effective technologies to patients quickly,” Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health (CDRH), said in the release.

According to the action plan, the FDA plans to clarify which device changes require a new premarket notification submission — called a 510(k) — and which changes are eligible for a Special 510(k). Other plans include clarifying when clinical data should be submitted in support of a 510(k), establishing a Center Science Council to ensure timely and consistent science-based decision-making and formalizing the Center’s process for assessing staffing shortages. The entire 25-point action plan is available here.

The plan is the product of two internal working groups created by the CDRH in response to complaints about the 510(k) review process by industry, consumers and health care professionals. The CDRH has also requested a review by the independent, nonprofit Institute of Medicine, the results of which are expected in April.

“We look forward to implementing these changes in support of our overall mission: improving the health of the American public,” Shuren said in an open letter to the public.

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The CONNECT (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision) Trial: The Value of Wireless Remote Monitoring With Automatic Clinician Alerts
Crossley GH, Boyle A, Vitense H, Chang Y, Mead RH, on behalf of the CONNECT Investigators.
J Am Coll Cardiol 2011;Jan 19:[Epub ahead of print].
Study Question: What is the effect of wireless remote monitoring with automatic clinician alerts on time from a clinical event to a clinical decision in response to arrhythmias, cardiovascular (CV) disease progression, and device issues compared to patients receiving standard in-office care?

Outcomes for Endocarditis Surgery in North America: A Simplified Risk Scoring System
Gaca JG, Sheng S, Daneshmand MA, et al.
J Thorac Cardiovasc Surg 2011;141:98-106.
Study Question: Using the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database, can a simple risk scoring system be developed for patients who undergo surgery for infective endocarditis to identify areas for quality improvement?

Outcomes of Coronary Artery Bypass Grafting and Reduction Annuloplasty for Functional Ischemic Mitral Regurgitation: A Prospective Multicenter Study (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve)
Grossi EA, Woo YJ, Patel N, et al.
J Thorac Cardiovasc Surg 2011;141:91-97.
Study Question: What are the outcomes of reduction annuloplasty for ischemic mitral regurgitation (MR)?

The Impact of Adjusting for Reliability on Hospital Quality Rankings in Vascular Surgery
Osborne NH, Ko CY, Upchurch GR Jr, Dimick JB.
J Vasc Surg 2011;53:1-5.
Study Question: What effect would adjusting hospital mortality for statistical reliability have on hospital quality rankings in vascular surgery?

Secondary Prevention After Coronary Artery Bypass Graft Surgery: Findings of a National Randomized Controlled Trial and Sustained Society-Led Incorporation Into Practice
Williams JB, Delong ER, Peterson ED, et al., on Behalf of the Society of Thoracic Surgeons and the National Cardiac Database.
Circulation 2011;123:39-45.
Study Question: Can a low-intensity continuous quality improvement intervention be used to enhance secondary prevention adherence after coronary artery bypass graft surgery (CABG)?

A Multifaceted Intervention for Quality Improvement in a Network of Intensive Care Units: A Cluster Randomized Trial
Scales DC, Dainty K, Hales B, et al.
JAMA 2011;Jan 19:[Epub ahead of print].
Study Question: Can a multicenter quality improvement program increase delivery of evidence-based intensive care unit (ICU) practices?

Vitamin D, Parathyroid Hormone, and Cardiovascular Mortality in Older Adults: The Rancho Bernardo Study
Jassal SK, Chonchol M, von M?hlen D, Smits G, Barrett-Connor E.
Am J Med 2010;123:1114-1120.
Study Question: Is vitamin D and parathyroid hormone (PTH) associated with cardiovascular disease (CVD) mortality among older adults?
The Importance of Population-Wide Sodium Reduction as a Means to Prevent Cardiovascular Disease and Stroke: A Call to Action from the American Heart Association
Appel LJ, Frohlich ED, Hall JE, et al.
Circulation 2011;Jan 13:[Epub ahead of print].
Perspective: The following are 10 points to remember about sodium reduction.

Door-to-Balloon Times for Patients With ST-Segment Elevation Myocardial Infarction Requiring Interhospital Transfer for Primary Percutaneous Coronary Intervention: A Report From the National Cardiovascular Data Registry
Wang TY, Peterson ED, Ou FS, Nallamothu BK, Rumsfeld JS, Roe MT.
Am Heart J 2011;161:76-83.e1.
Study Question: What are the trends in door-to-balloon time in patients with ST-segment elevation myocardial infarction (STEMI) who require transfer to another hospital for primary percutaneous coronary intervention (PCI)?

Transradial Approach (Left vs Right) and Procedural Times During Percutaneous Coronary Procedures: TALENT Study
Sciahbasi A, Romagnoli E, Burzotta F, et al.
Am Heart J 2011;161:172-179.
Study Question: What is the safety and efficacy of the left radial approach (LRA) compared with right radial approach (RRA) for coronary procedures?

Randomized Comparison of Final Kissing Balloon Dilatation Versus No Final Kissing Balloon Dilatation in Patients With Coronary Bifurcation Lesions Treated With Main Vessel Stenting: The Nordic-Baltic Bifurcation Study III
Niemel? M, Kervinen K, Erglis A, et al., on behalf of the Nordic-Baltic PCI Study Group.
Circulation 2011;123:79-86.
Study Question: Should final kissing balloon angioplasty be performed in all patients who undergo bifurcation stenting using a strategy of only main vessel stenting?

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Aggrastat® high dose
bolus EU approval for (NSTE-ACS) PCI patients
re-informs the debate on
triple anti-platelet therapy

Aggrastat® high dose bolus EU approval
Triple anti-platelet therapy—which patients and why? Euro PCR, Paris, 17-20 May 2011
Iroko Cardio

Aggrastat® high dose bolus EU approval
High dose bolus (HDB) Aggrastat® for the treatment of acute coronary syndrome (NSTE-ACS) patients undergoing percutaneous coronary intervention (PCI) received EU regulatory approval in September 2010. National approvals have since followed in The Netherlands, UK, Germany, Finland, and Belgium and the process will be concluded in the Mutual Recognition Process (MRP) member states in 2011. Regulatory variations are in process for other global markets where Aggrastat® is available.

The PCI HDB dosing for Aggrastat® is 25?g/kg over 3 minutes followed by an infusion of 0.15?g/kg/min for 18-24 and up to 48 hoursi.

Triple anti-platelet therapy—which patients and why?
Triple anti-platelet therapy (aspirin, thienopyridine plus GPIIbIIIa receptor antagonist) may not be for everyone but, despite the availability of compelling clinical data and treatment guidelines, high risk patients often remain under-treated. The recent label change was the stimulus for a debate between Dr. A. van't Hof (Netherlands) and Dr. T. Cuisset (France), chaired by Dr. Valgimigli (Italy) hosted near Geneva by Iroko Cardio and joined online by cardiologists from Europe, Middle East, Asia, and Latin America.

Summarising the debate, Dr. Valgimigli concluded that "high risk patients undergoing PCI should be considered for aggressive anti-platelet therapy." Dr. Valgimigli went on to say that "despite the availability of newer agents and more potent oral options, l believe there is still room for GPIs in high risk ACS patients. In this respect, tirofiban offers doctors a potent, safe and cost-effective therapeutic option for their high risk ACS patients."

Euro PCR, Paris, 17-20 May 2011
Iroko Cardio will support a medical information lounge at Euro PCR and welcomes customers to a 'How should I treat' session chaired by Prof. Christian Hamm.

"While there's clear clinical trial evidence that triple anti-platelet therapy is beneficial for high risk PCI's, the underuse of this treatment regimen is unsatisfactory. Therefore, it is important to discuss the appropriate anti-thrombotic regime patient by patient in the context of combining new anti-thrombotic and anti-platelet drugs. At Euro PCR we will use a "how should I treat" session to translate study results to individual patient cases", said Prof. Hamm.

Iroko Cardio
Iroko Cardio is a privately held pharmaceutical company located in Geneva, Switzerland and Philadelphia, USA. It manufactures and markets Aggrastat® worldwide (with the exception of the USA) in collaboration with regional distribution partners. Iroko Cardio aims to contribute to the reduction of MACE.

Aggrastat® is a registered trade mark of Iroko Cardio LLC, Philadelphia USA. For Aggrastat® prescribing information and further information on Iroko Cardio, visit: [Ссылки могут видеть только зарегистрированные и активированные пользователи]

Iroko Cardio does not recommend the use of Aggrastat® in any manner other than as described in local prescribing information. Further information is available from the Iroko Cardio Medical Information Center: [Ссылки могут видеть только зарегистрированные и активированные пользователи], +41 22 907 7970

About Aggrastat®
Aggrastat® is indicated for the prevention of early myocardial infarction in patients presenting with unstable angina or non-Q-wave myocardial infarction with the last episode of chest pain occurring within 12 hours and with ECG changes and/or elevated cardiac enzymes. Patients most likely to benefit from Aggrastat® treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early PTCA.

Patients managed with early invasive strategy (4-48 hrs. after diagnosis)

Initial intravenous infusion rate: 0.4 ?g /kg/min for 30 minutes. Maintenance infusion rate: 0.1 ?g /kg/min

Dosage information for patients undergoing PCI

Patients undergoing PCI demonstrated clinical efficacy with treatment with Aggrastat® utilizing an initial bolus of 25 ?g/kg given over a 3 minute period, followed by a continuous infusion at a rate of 0.15 ?g/kg/min for 18-24, and up to 48 hours.

In patients with severe kidney failure (creatinine clearance <30mL/min), the dosage of Aggrastat® should be reduced by 50%.

Aggrastat® should be administered with unfractionated heparin and oral antiplatelet therapy unless contra-indicated.

Contraindications

Hypersensitivity to active substance or excipient; previous thrombocytopenia with GPIIb/IIIa receptor antagonist; stroke within previous 30 days; history of haemorrhagic stroke; history of intracranial disease; clinically relevant bleeding (within the previous 30 days); malignant hypertension; trauma or major surgical intervention within the past six weeks; thrombocytopenia (platelet count <100,000/mm3), disorders of platelet function; clotting disturbances; severe liver failure.

Warnings and Precautions

Monitor patients for bleeding during treatment. In cases of haemorrhage, consider discontinuing Aggrastat®. In cases of severe uncontrollable bleeding discontinue Aggrastat® immediately.

For all other SPCs please refer to local prescribing information.

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Newly published guidelines suggest expanded use for carotid artery stenting
Brott T. J Am Coll Cardiol. 2011;doi:10.1016/j.jacc.2010.11.005.

The 2011 Guideline on the Management of Patients with Extracranial Carotid and Vertebral Artery Disease was recently published, highlighting the safety and efficacy of carotid artery stenting for patients requiring revascularization.

The guidelines, a joint collaboration between 14 organizations, including the American College of Cardiology Foundation, the American Heart Association and the Society for Cardiac Angiography and Interventions, were based upon a comprehensive review of literature relevant to carotid and vertebral artery interventions up until May 2010. They detail several indications for revascularization and make recommendations on the appropriate treatment regarding carotid artery stenting (CAS), carotid endarterectomy (CEA) and drug therapy, as well as appropriate diagnostic modalities.

Specifically, for selecting patients for carotid revascularization, the guidelines state that CAS may be considered in patients with asymptomatic carotid stenosis with a minimum of 60% detected by angiography or 70% detected by validated Doppler ultrasound. This recommendation follows less than a week after the FDA advisory panel vote that recommended expansion of the availability of CAS in patients at standard risk for surgical complications due to findings of the CREST trial.

The guidelines state that it is reasonable to perform CAS over CEA in patients with neck anatomy unfavorable for surgery and those with transient ischemic attack or stroke without contraindications to early revascularization, whereas CEA is advisable in older patients, as well as asymptomatic patients with more than 70% stenosis if the risk of stroke, MI and death is low.

However, members of the writing committee and task force said there are still many opportunities for future research because the CREST trial, although answering important questions, raised others.

“The most pressing question is how either technique of revascularization compares with intensive contemporary medical therapy, particularly among asymptomatic patients,” they said. “A direct comparative trial should include a sufficiently broad range of patients to permit meaningful analysis of subgroups based on age, sex, ethnicity and risk status.”
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Super Bowl loss linked with increased mortality rates in local men and women
Kloner R. Clin Cardiol. 2011;doi:10.1002/clc.20876.

Residents of Los Angeles County had significantly increased total and cardiac-related death rates after the Super Bowl loss of the Los Angeles Rams in 1980. However, when the Los Angeles Raiders won the Super Bowl in 1984, women and residents aged 65 years or older had reduced rates of mortality.

“It is known that stressors such as intense sporting events may increase cardiac event rates in fans, but there has been little data available on the demographics of these fans,” the researchers wrote. “Based on our linear regression analysis, our study suggested that Los Angeles’ 1980 Super Bowl loss increased total and cardiac deaths in both men and women and triggered more deaths in older patients compared with younger patients. Conversely, the 1984 Super Bowl win showed a trend for reduction of death rates, slightly better in older than younger patients and in women more than men.”

To generate this conclusion, investigators obtained death-certificate data for Los Angeles County from 1980 to 1988 that covered Jan. 15 to the end of February for each year and then used non-Super Bowl days as the control. Mortality data included in the analysis were deaths from all-cause, as well as deaths related to circulatory system diseases, ischemic heart disease, acute MI, HF and congestive HF.

According to study results, after the 1980 Super Bowl loss, researchers reported significant spikes in all-cause mortality (P<.0001), all cardiac deaths (P=.0001) and ischemic heart disease (P=.007) in residents, whereas changes in acute MI and HF/chronic HF did not reach statistical significance.

Four years later, after a Super Bowl victory, reductions were found in deaths due to all-causes (P=.003) and circulatory system diseases (P=.03) in women. Although no reductions were reported in men with the exception of a minimal and nonsignificant reduction in all-cause mortality, residents at least 65 years of age had lower rates of all-cause mortality (P=.03), as well as nonsignificant reductions in death due to circulatory system diseases and ischemic heart disease. – by Brian Ellis
This is an interesting article that focuses on the effect of emotional excitement, stress, despair and frustration on the risk of fatal cardiac events. The absolute changes in death following exciting/disappointing Super Bowls are relatively modest but statistically significant. Previously, emotional stress has been linked to acute stress cardiomyopathy. The lessons should be that football is a game and all fans need to remember that; large wagers/bets should not be levied, it appears.

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Disparity in outcomes reported for women, black stroke survivors
Roth D. Stroke. 2011; doi:10.1161/STROKEAHA.110.595322.

Among incident stroke survivors with family caregivers, women and blacks were at heightened risk for poor outcomes at 1 year after a first-time stroke event vs. men and white survivors, according to new data published in Stroke.

The study participants included 112 survivors of incident stroke from the national Reasons for Geographic and Racial Differences in Stroke (REGARDS) project. The survivors were community-dwelling residents from 28 states who had family caregivers and incident stroke events between Nov. 15, 2004, and Sept. 10, 2009.

Study data revealed a significantly higher percentage of white stroke survivors living with their family caregiver than black survivors (76% vs. 43%; P=.0003). After controlling for age, education and whether the stroke survivors lived with their primary family caregivers, researchers reported that blacks had worse outcomes than whites, and women had worse outcomes than men (P<.05 for both race and gender effects).

“Our results show that previously found race and gender differences in long-term stroke outcome are apparent, even when studied in a prospective population-based sample, and even when a family caregiver is available to all participants,” the researchers wrote. “Future research should more closely examine the mechanisms behind these differences, including more detailed assessments of the involvement of family caregivers and other cultural and demographic factors that may affect service utilization and recovery from stroke.”
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Two-year data promising for drug-eluting stent
Dake M. Presented at: 2011 International Symposium on Endovascular Therapy; Jan. 16-20; Miami Beach.

Patients treated with a drug-eluting stent had improved patency rate at 2 years, as well as patient safety, when compared with percutaneous transluminal angioplasty, according to data from a prospective, randomized trial.

The study, which was recently presented at the International Symposium on Endovascular Therapy, included 479 patients who were treated with either a paclitaxel-coated drug-eluting stent (Zilver PTX, Cook Medical; n=241) or percutaneous transluminal angioplasty (n=238). Among the risk factors patients presented with included hypertension (drug-eluting stent, 89% vs. percutaneous transluminal angioplasty, 82%), high cholesterol (drug-eluting stent, 76% vs. percutaneous transluminal angioplasty, 70%) and diabetes (drug-eluting stent, 49% vs. percutaneous transluminal angioplasty, 42%).

At 2 years, event-free survival was 86.6% in the drug-eluting stent group vs. 77.6% in the percutaneous transluminal angioplasty arm (P<.01). Primary patency was significantly improved in the drug-eluting stent arm (74.8% vs. 51.8%; P<.01), as was provisional patency (81.2% vs. 62.7%; P<.01). Researchers also reported that the drug-eluting stent reduced 24-month restenosis rates by 50% (37.3% vs. 18.8%).

“This 24-month data is important because it shows not only sustained effect of the drug-eluting platform, but an actual widening of the reductions between the drug-eluting stent and the bare metal stent,” Michael D. Dake, MD, with the department of cardiothoracic surgery at Stanford University School of Medicine and researcher on the study, told Cardiology Today.

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Regional Variation in the Use of Implantable Cardioverter-Defibrillators for Primary Prevention: Results From the National Cardiovascular Data Registry
Matlock DD, Peterson PN, Heidenreich PA, et al.
Circ Cardiovasc Qual Outcomes 2011;4:114-121.
Study Question: Is there geographic variability in the use of implantable cardioverter-defibrillators (ICDs)?

Ventricular Tachyarrhythmias After Cardiac Arrest in Public Versus at Home
Weisfeldt ML, Everson-Stewart S, Sitlani C, et al.
N Engl J Med 2011;364:313-321.
Study Question: Is the initial rhythm recorded during resuscitation influenced by the site at which out-of-hospital cardiac arrest (OHCA) occurs?

Safety of Percutaneous Left Atrial Appendage Closure: Results From the Watchman Left Atrial Appendage System for Embolic Protection in Patients With AF (PROTECT AF) Clinical Trial and the Continued Access Registry
Reddy VY, Holmes D, Doshi SK, Neuzil P, Kar S.
Circulation 2011;123:417-424.
Study Question: What is the influence of experience on the safety of percutaneous left atrial appendage closure?

Survival Comparison of the Ross Procedure and Mechanical Valve Replacement With Optimal Self-Management Anticoagulation Therapy: Propensity-Matched Cohort Study
Mokhles MM, K?rtke H, Stierle U, et al.
Circulation 2011;123:31-38.
Study Question: Is there a survival difference among young patients after a Ross procedure (auto-graft aortic valve replacement [AVR]) compared to mechanical AVR with optimal self-management of anticoagulation therapy?

Clinical Referral Patterns for Carotid Artery Stenting Versus Carotid Endarterectomy: Results From the Carotid Artery Revascularization and Endarterectomy Registry
Carotid Artery Revascularization and Endarterectomy Registry
Longmore RB, Yeh RW, Kennedy KF, et al.
Circ Cardiovasc Interv 2011;Jan 11:[Epub ahead of print].
Study Question: What are the clinical profiles of patients referred for carotid artery stenting (CAS) versus carotid endarterectomy (CEA) in a large national database?

Favorable Changes in Cardiac Geometry and Function Following Gastric Bypass Surgery: 2-Year Follow-Up in the Utah Obesity Study
Owan T, Avelar E, Morley K, et al.
J Am Coll Cardiol 2011;57:732-739.
Study Question: Does gastric bypass surgery (GBS) impact cardiac remodeling and function?

2011 ASA/ACCF/AHA/AANN/AANS/ACR/CNS/SAIP/SCAI/SIR/ SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease
Brott TG, Halperin JL, Abbara S, et al.
J Am Coll Cardiol 2011;Jan 31:[Epub ahead of print].
Perspective: The following are 10 points to remember about the guideline on management of patients with extracranial carotid and vertebral artery disease.
Aliskiren and the Calcium Channel Blocker Amlodipine Combination as an Initial Treatment Strategy for Hypertension Control (ACCELERATE): A Randomised, Parallel-Group Trial
Brown MJ, McInnes GT, Papst CC, Zhang J, Macdonald TM.
Lancet 2011;377:312-320.
Study Question: What is the comparative efficacy of a combination of aliskiren and amlodipine to each monotherapy in early control of blood pressure and risk of adverse events?

C-Reactive Protein Concentration and the Vascular Benefits of Statin Therapy: An Analysis of 20 536 Patients in the Heart Protection Study
Heart Protection Study Collaborative Group.
Lancet 2011;Jan 28:[Epub ahead of print].
Study Question: What are the effects of statin therapy in relation to baseline concentrations of C-reactive protein (CRP) and low-density lipoprotein (LDL) cholesterol?

Clinical Guidelines and Performance Measures: Responsible Guidance and Accountability
Masoudi FA, Peterson ED, Anderson JL, Bonow RO, Jacobs AK.
J Am Coll Cardiol 2010;56:2081-2083.
Perspective: The following are 10 points to remember about clinical guidelines and performance measures.

Clinical Follow-Up 3 Years After Everolimus- and Paclitaxel-Eluting Stents: A Pooled Analysis From the SPIRIT II (A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) and SPIRIT III (A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) Randomized Trials
Caixeta A, Lansky AJ, Serruys PW, et al.
JACC Cardiovasc Interv 2010;3:1220-1228.
Study Question: What are the long-term 3-year clinical outcomes of everolimus-eluting stents (EES) versus paclitaxel-eluting stents (PES)?

With the "Universal Definition," Measurement of Creatine Kinase-Myocardial Band Rather Than Troponin Allows More Accurate Diagnosis of Periprocedural Necrosis and Infarction After Coronary Intervention
Lim CC, van Gaal WJ, Testa L, et al.
J Am Coll Cardiol 2011;57:653-661.
Study Question: What is the best biomarker for defining post-percutaneous coronary intervention (PCI) myocardial infarction (MI)?

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Moving the Tipping Point
The Decision to Anticoagulate Patients With Atrial Fibrillation
Mark H. Eckman, MD, MS, Daniel E. Singer, MD, Jonathan Rosand, MD, MSc and Steven M. Greenberg, MD, PhD

+ Author Affiliations
From the Division of General Internal Medicine and the Center for Clinical Effectiveness, University of Cincinnati (M.H.E.), Cincinnati, Ohio; and the Research Group, Departments of Neurology (S.M.G., J.R.) and Clinical Epidemiology Unit (D.E.S.), Massachusetts General Hospital, Boston, Mass.
Correspondence to Mark H. Eckman, MD, University of Cincinnati Medical Center, PO Box 670535, Cincinnati, OH 45267-0535. E-mail [Ссылки могут видеть только зарегистрированные и активированные пользователи]

Next Section
Abstract

Background— The rate of ischemic stroke associated with traditional risk factors for patients with atrial fibrillation has declined over the past 2 decades. Furthermore, new and potentially safer anticoagulants are on the horizon. Thus, the balance between risk factors for stroke and benefit of anticoagulation may be shifting.

Methods and Results— The Markov state transition decision model was used to analyze the CHADS2 score, above which anticoagulation is preferred, first using the stroke rate predicted for the CHADS2 derivation cohort, and then using the stroke rate from the more contemporary AnTicoagulation and Risk Factors In Atrial Fibrillation cohort for any CHADS2 score. The base case was a 69-year-old man with atrial fibrillation. Interventions included oral anticoagulant therapy with warfarin or a hypothetical “new and safer” anticoagulant (based on dabigatran), no antithrombotic therapy, or aspirin. Warfarin is preferred above a stroke rate of 1.7% per year, whereas aspirin is preferred at lower rates of stroke. Anticoagulation with warfarin is preferred even for a score of 0 using the higher rates of the older CHADS2 derivation cohort. Using more contemporary and lower estimates of stroke risk raises the threshold for use of warfarin to a CHADS2 score ≥2. However, anticoagulation with a “new, safer” agent, modeled on the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy trial of dabigatran, leads to a lowering of the threshold for anticoagulation to a stroke rate of 0.9% per year.

Conclusions— Use of a more contemporary estimate of stroke risk shifts the “tipping point,” such that anticoagulation is preferred at a higher CHADS2 score, reducing the number of patients for whom anticoagulation is recommended. The introduction of “new, safer” agents, however, would shift the tipping point in the opposite direction.
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Long-term efficacy of high-dose tirofiban versus double-bolus eptifibatide in patients undergoing percutaneous coronary intervention

Schiariti, Michelea,b; Saladini, Angelaa; Cuturello, Domenicob; Missiroli, Bindoa; Puddu, Paolo Emiliob
Free Access
Article Outline
Author Information

aS. Anna Hospital, Catanzaro, Italy

bDepartment of the Heart and Great Vessels ‘A. Reale’, University ‘La Sapienza’, Rome, Italy

Received 28 January, 2010

Revised 22 April, 2010

Accepted 1 June, 2010

Correspondence to P.E. Puddu, MD, FESC, FACC, Dipartimento del Cuore e Grossi Vasi ‘Attilio Reale’, UOC Biotecnologie Applicate alle Malattie Cardiovascolari, Università degli Studi di Roma ‘La Sapienza’, Viale del Policlinico, 155, Rome 00161, Italy Tel: +39 06 4455291; fax: +39 06 4441600; e-mail: [Ссылки могут видеть только зарегистрированные и активированные пользователи]
Abstract

Background: There is no head-to-head comparison between tirofiban versus eptifibatide in patients undergoing percutaneous coronary intervention (PCI) when added to standard antiaggregating drugs (AAD) to prevent ischemic events within 1 year.

Methods: We compared real-world patients undergoing PCI who were on oral single AAD and were block randomized to receive, immediately preintervention, high-dose tirofiban (n = 519) or double-bolus eptifibatide (n = 147) and a second oral antiplatelet agent. The incidence of composite ischemic events within 1 year, including death, acute myocardial infarction, angina, stent thrombosis or repeat PCI or coronary bypass surgery (primary end-point) was modelled by forced Cox's regression.

Results: There were overall 65 composite ischemic events: 47 (9.1%) in the tirofiban group and 18 (12.2%) in the eptifibatide group (univariate log-rank test: P = 0.22). On the basis of 21 potential covariates fitted simultaneously, multivariable adjusted hazard ratios showed that age [hazard ratio 1.03, 95% confidence interval (CI) 1.01–1.07, P = 0.01], chronic renal failure (hazard ratio 3.21, 95% CI 1.02–10.10, P = 0.05), pre-PCI values of creatine kinase-myocardial band (CK-MB) (hazard ratio 1.002, 95% CI 1.0002–1.0054, P = 0.04), intra-aortic balloon pump (hazard ratio 5.88, 95% CI 12.33–14.85, P = 0.0002) and the presence of eptifibatide (hazard ratio 1.85, 95% CI 1.04–3.29, P = 0.04) were significant risk factors whereas thrombolysis by tenecteplase (hazard ratio 0.19, 95% CI 0.05–0.69, P = 0.01) was a significant protector. Interestingly, eptifibatide versus tirofiban efficacy was explained based on pre-PCI values of CK-MB.

Conclusion: Head-to-head comparison between eptifibatide and tirofiban in patients undergoing PCI while on double AAD showed that eptifibatide had a lower efficacy on the incidence of composite ischemic events within 1 year, which might be explained by a reduced action on CK-MB pre-PCI.
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Quarky Calcium Release in the Heart
Didier X.P. Brochet, Wenjun Xie, Dongmei Yang, Heping Cheng, W. Jonathan Lederer

From the Center for Biomedical Engineering and Technology (BioMET) (D.X.P.B., W.J.L.), University of Maryland, Baltimore; Institute of Molecular Medicine (W.X., H.C.), National Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China; and Laboratory of Cardiovascular Sciences (D.Y.), National Institute on Aging, Baltimore, MD.


Correspondence to Heping (Peace) Cheng, PhD, Institute of Molecular Medicine, Peking University, Beijing 100871, China; (E-mail [Ссылки могут видеть только зарегистрированные и активированные пользователи]); or to Didier X. P. Brochet, PhD, Center for Biomedical Engineering and Technology (BioMET), University of Maryland, 725 W Lombard St, Baltimore, MD 21201 (E-mail [Ссылки могут видеть только зарегистрированные и активированные пользователи]).



Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
Sources of Funding
Disclosures
References
What Is Known
What New Information Does...


Rationale:In cardiac myocytes, "Ca2+ sparks" represent the stereotyped elemental unit of Ca2+ release arising from activation of large arrays of ryanodine receptors (RyRs), whereas "Ca2+ blinks" represent the reciprocal Ca2+ depletion signal produced in the terminal cisterns of the junctional sarcoplasmic reticulum. Emerging evidence, however, suggests possible substructures in local Ca2+ release events.

Objective:With improved detection ability and sensitivity provided by simultaneous spark–blink pair measurements, we investigated possible release events that are smaller than sparks and their interplay with regular sparks.

Methods and Results:We directly visualized small solitary release events amid noise: spontaneous Ca2+ quark-like or "quarky" Ca2+ release (QCR) events in rabbit ventricular myocytes. Because the frequency of QCR events in paced myocytes is much higher than the frequency of Ca2+ sparks, the total Ca2+ leak attributable to the small QCR events is approximately equal to that of the spontaneous Ca2+ sparks. Furthermore, the Ca2+ release underlying a spark consists of an initial high-flux stereotypical release component and a low-flux highly variable QCR component. The QCR part of the spark, but not the initial release, is sensitive to cytosolic Ca2+ buffering by EGTA, suggesting that the QCR component is attributable to a Ca2+-induced Ca2+ release mechanism. Experimental evidence, together with modeling, suggests that QCR events may depend on the opening of rogue RyR2s (or small cluster of RyR2s).

Conclusions:QCR events play an important role in shaping elemental Ca2+ release characteristics and the nonspark QCR events contribute to "invisible" Ca2+ leak in health and disease.
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Inflammation, Immunity, and Hypertension
David G. Harrison; Tomasz J. Guzik; Heinrich E. Lob; Meena S. Madhur; Paul J. Marvar; Salim R. Thabet; Antony Vinh; Cornelia M. Weyand

From the Divison of Cardiology (H.L., M.M., S.T., A.V.), Department of Medicine Emory University School of Medicine and the Atlanta Veteran Administration Hospital, Atlanta, GA; Department of Medicine (T.J.G), Jagiellonian University School of Medicine, Krakow, Poland; Department of Medicine (C.W.), Stanford University School of Medicine, Palo Alto, CA; Divisions of Clinical Pharmacology and Cardiology (D.G.H.), Department of Medicine, Vanderbilt University, Nashville, TN.

Correspondence to David G. Harrison, Division of Clinical Pharmacology, Vanderbilt University, 526 Robinson Research Building, Nashville, TN 37232-6602. E-mail [Ссылки могут видеть только зарегистрированные и активированные пользователи]
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Cardiac Inflammation Contributes to Changes in the Extracellular Matrix in Patients With Heart Failure and Normal Ejection Fraction
Dirk Westermann, MD*, Diana Lindner, PhD*, Mario Kasner, MD, Christine Zietsch, PhD, K. Savvatis, MD, F. Escher, MD, J. von Schlippenbach, MD, C. Skurk, MD, Paul Steendijk, PhD, Alexander Riad, MD, Wolfgang Poller, MD, Heinz-Peter Schultheiss, MD and Carsten Tschöpe, MD

+
Author Affiliations
From the Department of Cardiology and Pneumology (D.W., D.L., M.K., C.Z., K.S., F.E., J.v.S., C.S., A.R., W.P., H.-P.S., C.T.), Charité, Universititäts-Medizin Berlin, Campus Benjamin Franklin, Berlin, Germany, and Department of Cardiology (P.S.), Leiden University Medical Center, Leiden, The Netherlands.
Correspondence to Dirk Westermann, MD, Department of Cardiology, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail [Ссылки могут видеть только зарегистрированные и активированные пользователи]

↵* Drs Westermann and Lindner contributed equally to this work.

Next Section
Abstract

Background— The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF.

Methods and Results— We investigated left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter methods and echocardiography. Endomyocardial biopsy samples were also obtained, and ECM proteins as well as cardiac inflammatory cells were investigated. Primary human cardiac fibroblasts were outgrown from the endomyocardial biopsy samples to investigate the gene expression of ECM proteins after stimulation with transforming growth factor-β. Diastolic dysfunction was present in the HFNEF patients compared with the control patients. In endomyocardial biopsy samples from HFNEF patients, we found an accumulation of cardiac collagen, which was accompanied by a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Moreover, a subset of inflammatory cells, which expressed the profibrotic growth factor transforming growth factor-β, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with transforming growth factor-β resulted in transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of matrix metalloproteinase-1, the major collagenase in the human heart. A positive correlation between cardiac collagen, as well as the amount of inflammatory cells, and diastolic dysfunction was evident and suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction.

Conclusions— Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of ECM.

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Stroke in CABG-treated patients declined during 27-year period
Tarakji K. JAMA. 2011;305:381-390.

Results from a prospective, single-center study conducted between 1982 and 2009 suggest that patients undergoing CABG surgery had a decreased rate of stroke despite an increased patient risk profile.

In the study, 45,432 consecutive patients (mean age, 63 years) from the Cleveland Clinic underwent CABG surgery. Researchers recorded strokes that occurred after CABG and classified them as occurring intraoperatively or postoperatively.

During the 27 years, 705 patients (1.6%) had a stroke, with 279 occurring intraoperatively and 409 occurring postoperatively. The prevalence of stroke peaked at 2.6% in 1988 but decreased by 4.69% per year (P=.04) afterward, even with increasing patient comorbidity.

Older age and variables of arteriosclerotic burden were also reported as risk factors for intraoperative and postoperative stroke. Lowest intraoperative stroke rates were reported with on-pump beating-heart CABG (0%) and off-pump CABG (0.14%), whereas the highest was found with on-pump CABG with hypothermic circulatory arrest (5.3%).

Khaldoun G. Tarakji, MD, and colleagues said the decrease in occurrence of stroke but increase in patient risk profile is likely the result of improving preoperative assessment, intraoperative anesthetic and surgical techniques, and postoperative care.

“Further studies are needed to develop better strategies to minimize the occurrence of stroke among patients undergoing CABG,” they said.
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CDC findings highlight continued need for better control of hypertension, LDL
CDC. MMWR. 2011;60:1-6.
CDC. MMWR. 2011;60:7-12.

Two analyses have found that more than half of those with hypertension in the United States need to have it controlled, and despite improvements, LDL control still remains low. The findings were published in a February release of the CDC’s Morbidity and Mortality Weekly Report.

Hypertension controlled in nearly half of adults

The CDC’s look into hypertension prevalence began with data from the National Health and Nutrition Examination Survey that included 68 million US adults (age >18 years) with hypertension during the 2005-2008 survey period. Hypertension was defined as systolic/diastolic BP of at least 140 mm Hg/90 mm Hg, with less than 140 mm Hg/90 mm Hg defined as controlled hypertension.

Of the study population, 48 million (70%) were receiving pharmacological treatment, with hypertension controlled in 31 million (46%). Populations with hypertension noted for having a low percentage of BP control included those without a usual source of medical care (12%) and those without insurance (29%). Control prevalence was also low in young adults (aged 18-39 years; 31%) and Mexican Americans (37%). Although no changes in the prevalence of hypertension from the 1999-2002 survey period were reported, the CDC said there were significant increases in treatment and control.

Room for more improvement in LDL control

For its analysis of LDL control, the CDC also examined data from the 1999-2002 and 2005-2008 survey cycles of NHANES. The final population from the 2005-2008 cycle included an estimated 71 million US adults aged at least 20 years who had high LDL, as stated in the National Cholesterol Education Program – Adult Treatment Panel III primary prevention guidelines.

According to CDC’s data, 34 million adults (48.1%) had their LDL treated while 23 million (33.2%) had it controlled. Although at a treatment rate roughly 22% lower compared with hypertension, LDL treatment increased nearly 20% compared with 6 years earlier, suggesting a “striking” improvement in the prevalence of treatment and control. Despite this, the CDC said more must be done about the estimated one-third of Americans with high LDL, of which only one-third are controlled.

Other data of note from the analysis were the low prevalence of LDL control among those who reported receiving medical care less than twice in the previous year (11.7%), having income below the poverty level (21.9%), as well as those who were uninsured (13.5%) or Mexican American (20.3%).
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Stroke center admission linked with improved mortality, thrombolytic-therapy use
Xian Y. JAMA. 2011;305:373-380.

Patients admitted to stroke centers for acute ischemic stroke had lower 30-day all-cause mortality and more frequently used thrombolytic therapy when compared with nondesignated hospitals, new data have shown.

“Previous evaluations of stroke center quality performance have primarily focused on process measures with limited information on patient outcomes,” the researchers wrote. “Even though the differences in outcomes between stroke centers and nondesignated hospitals were modest, our study suggests that the implementation and establishment of a [Brain Attack Coalition]-recommended stroke system of care was associated with improvement in some outcomes for patients with acute ischemic stroke.”

Researchers of the observational study collected data from the New York Statewide Planning and Research Cooperative System and compared mortality for patients admitted with acute ischemic stroke (n=30,947) between 2005 and 2006 at designated stroke centers (n=15,297) and nondesignated hospitals (n=15,650).

At 30 days, researchers found that patients admitted to stroke centers had lower all-cause mortality (10.1% vs. 12.5%; P<.001) and were more likely to use thrombolytic therapy (4.8% vs. 1.7%; P<.001) compared with those admitted to nondesignated hospitals. Statistically significant differences were also observed with mortality at 1-day, 7-day and 1-year follow-up.

To determine whether the findings were specific to stroke, researchers also tested 30-day all-cause mortality rates of patients with gastrointestinal hemorrhage and acute MI at designated and nondesignated centers and found that the outcomes were similar.

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Worldwide adult obesity prevalence has doubled since 1980
Finucane M. Lancet. 2011; doi:10.1016/S0140-6736(10)62037-5.
Danaei G. Lancet. 2011; doi:10.1016/S0140-6736(10)62036-3.
Farzadfar F. Lancet. 2011; doi:10.1016/S0140-6736(10)62038-7.

Three studies of global health trends recently published in The Lancet suggested the worldwide prevalence of obesity has doubled since 1980, but that average BP and cholesterol levels have decreased in wealthy Western countries.

The three studies were conducted by the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group. To calculate their totals, the authors culled health data of adults 25 years and older from published and unpublished health examination surveys and epidemiological studies across 199 countries and territories. To define their trends, they compared data from 2008 to data from 1980.
Results from the BMI study indicated that more than one in 10 of the world’s adults was obese in 2008, with women more likely to be obese than men. Obesity was defined as having a BMI above 30 kg/m². Overall, the study estimated that more than half a billion adults worldwide are obese.

The study of systolic blood pressure (SBP) observed a slight decrease in the percentage of the world’s population with uncontrolled hypertension, defined as SBP higher than 140 mm Hg or diastolic blood pressure higher than 90 mm Hg. High-income countries achieved larger reductions in uncontrolled hypertension, with men in North America faring the best by losing 2.8 mm Hg in SBP per decade on average. Increases in SPB in both sexes were observed in Oceania, east Africa, and south and southeast Asia.

The final study reported that the 2008 age-standardized mean cholesterol level worldwide was 4.6 mmol/L for men and 4.76 mmol/L for women. The researchers also found average cholesterol levels decreasing by 0.2 mmol/L per decade in North America, Australia and Europe. Cholesterol increases were observed in east and southeast Asia and the Pacific region (0.8 mmol/L per decade for men and 0.9 mmol/L per decade for women).

"Our results show that overweight and obesity, high BP and high cholesterol are no longer Western problems or problems of wealthy nations. Their presence has shifted towards low- and middle-income countries, making them global problems,” author Majid Ezzati, PhD, Imperial College London, United Kingdom, said in a press release.

"The findings are an opportunity to implement policies that lead to healthier diets, especially lower salt intake, at all levels of economic development, as well as looking at how we improve detection and control through the primary healthcare system.,” Ezzati continued. “Policies and targets for cardiovascular risk factors should get special attention at the High-level Meeting of the United Nations General Assembly on Non-Communicable Diseases in September 2011."
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Women with PAD lost mobility faster than men with PAD
McDermott M. J Am Coll Cardiol. 2011;57:707-714.

Women with lower-extremity peripheral arterial disease experienced faster functional declines than men with the condition. These functional declines included decreased endurance, lowered walking velocity and the development of mobility disabilities, according to a study.

For up to 4 years, researchers had 380 men and women with PAD undergo annual walking tests. A 6-minute walk screened for endurance mobility disability, whereas a 4-minute walk test measured declines in walking velocity. Patients who passed the tests at baseline were tracked annually. A loss of mobility was defined as losing the ability to walk for one-quarter mile or to walk up and down one flight of stairs without assistance.

At 4 years, women were more likely than men to lose the ability to walk for 6 uninterrupted minutes (HR=2.30; 95% CI, 1.30-4.06). The distance women achieved in the 6-minute walk declined faster than men (P=.041). Women were also more likely to develop a mobility disability (HR=1.79; 95% CI, 1.30-3.03), and they had quicker declines in walking velocity (P=.022). These results were adjusted for age, race, BMI, the ankle brachial index, level of physical activities and comorbidities, according to the study.

The researchers also measured the participants’ calf muscles with CT at baseline and 2- and 4-year visits. At baseline, woman had smaller calves, lower muscle density and poorer knee extension strength. When the sex differences in function decline were adjusted for calf differences, the differences in functional decline lost statistical significance.

“These findings suggest that lower calf muscle area and reduced knee extension strength in women at baseline may explain in part the faster rates of functional decline in women with PAD as compared with men with PAD,” the researchers wrote in the study. “Identifying sex differences in lower extremity outcomes among patients with PAD will help clinicians to provide prognostic information and to make optimal therapeutic decisions for patients with PAD.”

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PROSPECT: Major adverse CV events after PCI in patients with ACS attributed to culprit, nonculprit lesions
Stone G. N Engl J Med. 2011;364:226-235.

Data from the PROSPECT trial have indicated that major adverse CV events occurring in patients with acute coronary syndrome who underwent percutaneous coronary intervention were the result of culprit and nonculprit lesions equally.

“The primary purpose of this natural-history study was to provide prospective in vivo confirmation of the hypothesis that ACS arise from atheromas with certain histopathological characteristics, and that these characteristics are not necessarily dependent on the degree of angiographic stenosis at that site,” the researchers wrote. “Although most of the lesions responsible for major adverse CV events during follow-up were angiographically mild, intravascular ultrasonography showed that most had either a small luminal area, a large plaque burden, or both — findings that are consistent with the results of pathological studies.”

The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) trial featured 697 patients with ACS. After PCI, all patients underwent three-vessel coronary angiography and gray-scale and radiofrequency IVUS (Eagle Eye, In-Vision Gold; Volcano) imaging.

After a median follow-up of 3.4 years, researchers reported a 3-year rate of major adverse CV events of 20.4%, which researchers reported was related to culprit lesions in 12.9% of patients and nonculprit lesions in 11.6%.

Furthermore, nonculprit lesions were predominately mild at baseline. After multivariate analysis, nonculprit lesions that were associated with recurrent events were more likely than those not associated to be characterized by plaque burden of at least 70% (HR=5.03; 95% CI, 2.51-10.11), a minimal luminal area of 4 mm2 or less (HR=3.21; 95% CI, 1.61-6.42), or to be classified by radiofrequency intravascular ultrasonography as thin-cap fibroatheromas (HR=3.35; 95% CI, 1.77-6.36).

Initial Cardiology Today coverage of the PROSPECT trial from Cardiovascular Research Technologies 2010 can be viewed here.

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FINESSE-ANGIO: Pre-cath abciximab before primary PCI linked to higher infarct-related artery patency rates
Prati F. J Am Coll Cardiol Intv. 2010;3:1284-1291.

Pre-cath lab administration of abciximab, both alone and with half-dose reteplase, when preceding primary percutaneous coronary intervention led to higher rates of infarct-related artery patency at baseline coronary angiography vs. standard primary percutaneous coronary intervention, according to data from the FINESSE-ANGIO trial.

Researchers for the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events-Angiographic (FINESSE-ANGIO) study tested the effects of three different treatments — pre-cath lab administration of half-dose reteplase (Retavase, EKR Therapeutics) plus abciximab (ReoPro, Centocor), abciximab alone or abciximab administered directly before primary PCI — on patency of infarct-related artery during basal coronary angiography. The trial included 637 patients from the FINESSE study.

According to results, patients taking reteplase plus abciximab experienced higher rates of baseline infarct-related artery patency when compared with abciximab alone (76.1% vs. 43.7%; P<.0001) and abciximab taken immediately before PCI procedure (76.1% vs. 32.7%; P<.0001). No significant differences were reported in the post-PCI thrombolysis in MI or the rates of post-PCI TIMI flow grade 3, myocardial blush grade 2/3.

“Primary PCI preceded by pre-catheterization treatment with abciximab alone, and especially with abciximab plus half-dose reteplase, resulted in higher [infarct-related artery] patency rates at baseline coronary angiography compared with standard primary PCI,” the researchers wrote. “Whether clinical benefit correlated with pharmacologically induced or improved pre-PCI myocardial reperfusion may be restricted to higher risk subsets remains to be determined by future prospective studies.”

In an accompanying editorial, Bernard J. Gersh, MB, ChB, DPhil, of the Mayo Clinic, Rochester, Minn.,and Gregg W. Stone, MD,of Columbia University Medical Center, New York, commented on the importance of early treatment.

“For decades, we have appreciated that acute MI is a time-critical phenomenon and that early therapy is crucial for myocardial recovery, especially in the hyperacute phase, when ‘time is myocardium.’ Educating the public to seek treatment at an early stage after symptom onset is likely to reduce mortality to a greater degree than pharmacological facilitation before PCI, although translation of this goal to reality in a community setting is and will continue to be extremely difficult,” Gersh and Stone said.

Disclosure: This study was coordinated in part with research funding from Centocor. Dr. Stone and Dr. Gersh report no relevant financial disclosures.

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Medicine & Science in Sports & Exercise
Official Journal of the American College of Sports Medicine
Overweight and obesity affects more than 66% of the adult population and is associated with a variety of chronic diseases. Weight reduction reduces health risks associated with chronic diseases and is therefore encouraged by major health agencies. Guidelines of the National Heart, Lung, and Blood Institute (NHLBI) encourage a 10% reduction in weight, although considerable literature indicates reduction in health risk with 3% to 5% reduction in weight. Physical activity is recommended as a component of weight management for prevention of weight gain, for weight loss, and for prevention of weight regain after weight loss. In 2001, the American College of Sports Medicine published a Position Stand that recommended a minimum of 150 minutes per week of moderate–intensity physical activity for overweight and obese adults to improve health; however, 200–300 minutes per week was recommended for long–term weight loss. More recent evidence has supported this recommendation and has indicated more physical activity may be necessary to prevent weight regain after weight loss. To this end, the article reexamines the evidence from 1999 to determine whether there is a level at which physical activity is effective for prevention of weight gain, for weight loss, and prevention of weight regain.
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Dabigatran added to guidelines for management of patients with AF
Wann LS. J Am Coll Cardiol. 2011;doi:10.1016/j.jacc.2011.01.010.

The 2011 Focused Update on the Management of Patients with Atrial Fibrillation has incorporated dabigatran into its recommendations for the treatment of atrial fibrillation.

The focused update was a collaborative effort of the American College of Cardiology Foundation, American Heart Association and the Heart Rhythm Society. The recommendations come after dabigatran (Pradaxa, Boehringer-Ingelheim), an oral direct thrombin inhibitor, was recently approved by the FDA for stroke prevention in patients with nonvalvular AF.

According to the new recommendation, “Dabigatran is useful as an alternative to warfarin (Coumadin, Bristol-Myers Squibb) for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance <15 mL/minute) or advanced liver disease (impaired baseline clotting function).” The level of evidence for the recommendation was categorized as B, which indicates in this instance that the data were derived from a single randomized trial (RE-LY).
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Carotid stenting comparable to carotid endarterectomy for long-term stroke prevention
De Rango P. J Am Coll Cardiol. 2011;57:664-671.

For stroke prevention, carotid artery stenting can have similar 5-year outcomes to carotid endarterectomy, provided the physician uses sound judgment in choosing which technique to perform, according to a recent study.

Researchers prospectively tracked 1,118 patients who were treated by carotid endarterectomy (CEA) and 1,084 patients who underwent carotid artery stenting (CAS). Overall, 71% were men, and the mean age was 71.3 years. All of the patients were either more than 60% symptomatic or more than 70% asymptomatic for carotid stenosis. The choice of revascularization method was left to the treating physician. Typically, patients with known allergies to aspirin, clopidogrel, or contrast media and renal insufficiency were excluded from CAS, as were those patients with aortic arch anatomy, severe peripheral vascular disease precluding femoral access or extremely tortuous carotid anatomy. Patients with high-neck carotid bifurcation and long carotid lesions, as well as obese patients or those taking ongoing dual antiplatelet therapy, were generally excluded from CEA, according to the study.

Overall, 30-day stroke/death rates were 2.8% in the CAS group and 2% in the CEA group — a statistical similarity (P=.27). The risk of 30-day stroke or death was higher in symptomatic (3.5%) vs. asymptomatic (2%) patients (P=.04) but was statistically similar. At 5 years, survival rates were statistically similar between the two groups: 82% in CAS and 87.7% in CEA (P=.05). There were no sex- or age-related significant outcome differences, according to the study.

Per Kaplan-Meier estimates, the composite of any periprocedural stroke or death and ipsilateral stroke at 5 years after the procedure were similar in all patients (4.7% vs. 3.7%; P=.4). Kaplan-Meier estimates were similar for the subgroups of symptomatic (8.7% vs. 4.9%; P=.7) in CEA and asymptomatic (2.5% vs. 3.3%; P=.2) in CAS.

“When physicians use their clinical judgment to select the appropriate technique for carotid revascularization, CAS can offer efficacy and durability comparable to CEA with benefits persisting at 5 years,” the researchers concluded.

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MADIT-CRT: CRT-D more effective in women than men
Arshad A. J Am Coll Cardiol. 2011;57:813-820.

Women in the randomized MADIT-CRT trial had significantly greater reductions in death or HF, HF alone and all-cause mortality with cardiac resynchronization therapy using defibrillator than men.

Researchers of the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) enrolled 1,820 patients (24.9% women) and analyzed sex-specific outcomes comparing the effect of cardiac resynchronization therapy with defibrillator (CRT-D) against implantable cardioverter defibrillator therapy.

They found better results with CRT-D for female patients, culminating with a 70% reduction in HF (P<.001) and a 69% reduction in death or HF (P<.001), which were significantly lower when compared with men (P<.01 for each).

Also reported was a 72% reduction of all-cause mortality in women (P<.02), as well as an 82% reduction in mortality for those with QRS of at least 150 ms and 78% reduction in those with left bundle branch block (LBBB) conduction disturbance. However, for female patients with non-LBBB, rates of death or HF (HR=1.97; 95% CI, 0.40-9.64), as well as HF alone (HR=1.95; 95% CI, 0.40-9.53), were nearly two times greater.

Significant differences in baseline characteristics between women and men, the researchers wrote, could explain part of the observed findings because a greater proportion of women had a substrate of nonischemic cardiomyopathy and an underlying LBBB pattern.

“It is possible that among patients with heart disease, the risk of HF is greater for women than for men, resulting in a greater benefit from preventive CRT-D therapy in women,” they said.

Cardiology Today’s initial coverage of MADIT-CRT can be viewed here. – by Brian Ellis

Dr. Arshad and her colleagues report that women in the MADIT-CRT trial obtained significantly greater reductions in death or HF, HF alone, and all-cause mortality with CRT-D therapy than men. Although these findings were associated with greater echocardiographic evidence of reverse remodeling in women compared with men, the differences were small. Furthermore, female patients were more likely to have nonischemic cardiomyopathy and LBBB and less likely to have renal dysfunction than men; these factors are known to be associated with improved outcomes. Conversely, men had more ischemic heart disease, prior revascularization and renal dysfunction. Thus, the overall findings are not surprising.

On the other hand, it is notable that women with ICDs rather than CRT-Ds had worse outcomes than men, and women had a significantly overall higher likelihood of device-related adverse events than men. Despite these findings, just as in the case of atrial fibrillation and age, male gender should not be taken to mean that men should not receive CRT-D therapy, since the subset is less likely to respond. Patients who are male, the elderly and those with atrial fibrillation simply have blunting of beneficial responses, not absent response. Why women with nonischemic cardiomyopathy seem to be more responsive to CRT than are men remains unknown.
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LEAPS: Locomotor training not superior to home-based therapy post-stroke

International Stroke Conference 2011

Results from the LEAPS trial have indicated that a locomotor training program featuring body weight-supported treadmill training did not produce superior outcomes in patients post-stroke when compared with a rigorous home-based physical therapy, although both did produce improvements in mobility at 1 year.

“The important message [of this study] is that patients do change and they improve over time. What we found is that the more high-tech intervention didn’t help them walk any better [and that] the home-based exercise program works as well,” Pamela W. Duncan, PhD, professor and research fellow at Duke University School of Medicine, Durham, North Carolina, and investigator on the trial, said in an interview with Cardiology Today.

The Multi-site Phase III Randomized Trial of Physical Therapy Interventions to Improve Walking Recovery Post-stroke (LEAPS) was the largest randomized controlled trial performed in rehab, including 408 patients following stroke. The patients were randomly assigned to three groups: early locomotor training program (LTP; n=139) at two months post-stroke, late LTP (n=143) at 6 months post-stroke and home-based therapy (n=126) 2 months post-stroke.

At 1 year following stroke, the researchers found that functional outcome did not differ significantly between groups, with improved functional walking ability reported in 50.4% of the early-LTP group, 53.8% of the late-LTP group and 51.6% of the home-based therapy arm. Additionally, those in the early LTP group did not have improved change in comfortable walking speed at 1 year when compared with the late-LTP group (0.23 ± 0.20 m/s vs. 0.24 ± 0.23 m/s).

In the study’s secondary outcome, Duncan and fellow colleagues found that when compared to usual care at 6 months, those who received more structured, progressive interventions recovered twice as well.

“So, in stroke as in heart disease, exercise and maintaining your strength and mobility is extremely important and we have to figure out ways to do this more effectively,” Duncan said. – by Brian Ellis

We know that recovery and rehabilitation post-stroke is very important. We are looking for new approaches to improve outcomes in our stroke survivors. Walking and mobility are two of the biggest things that affect quality of life in a stroke survivor.

Although [the LEAPS researchers] hoped that this innovative approach to improving walking would be beneficial they weren’t able to show that. However, they were able to show that if you do home-based physical therapy at 2 months post the usual time period for rehab you had some very important recovery in terms of walking and mobility at 6 months and a year. This is important to us because sometimes the early acute rehab period passes and both patients and physicians neglect the longer-term importance of physical therapy and rehab. I try to emphasize it to my patients but sometimes insurance doesn’t cover it and other things kick in. I think this implies that home-based physical therapy started two months after stroke could still be very important for improving long-term outcomes.

So I think this shows us that sometimes the more innovative, possibly more costly approach isn’t always better than old-fashioned home-based physical therapy which I think that this trial shows is a very important rehabilitation opportunity for us to improve outcomes.

I think the LEAPS result is a transformative result. It shows us that intensive and prolonged therapy to improve gait is better than our usual care of only short and modest intensity therapy. It didn’t really matter which way we delivered the intensive and prolonged therapy, whether it was home-based physical therapy or a sophisticated locomotor weight elevation program. But we didn’t know for the lower extremity and for gait whether intensive therapy was better than standard care. We knew that for upper extremity before and this means that we need to change the way we’re taking care of patients. We need to have them engage much more often in prolonged therapy so that they can gain all the benefit they can while their brain is plastic and responsive to change after a stroke

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‘Ideal’ CV health extremely low among the middle-aged
Bambs C. Circulation. 2011;doi:10.1161/CIRCULATIONAHA.110.980151.

Less than 10% of a new study’s participants met at least five of the seven “ideal” CV health components stated in the American Heart Association’s 2020 Impact Goal.

The 2020 Impact Goal was designed to improve CV health of all Americans by 20% and reduce CVD and stroke mortality by 20%. The AHA’s definition of ideal CV health encompasses four health behaviors, which are smoking status, BMI, physical activity, and fruit and vegetable consumption, and three health factors, including total cholesterol, BP and fasting plasma glucose.

The researchers used the criteria to evaluate 1,933 participants (mean age, 59 years; 44% blacks, 56% whites; 66% women) of the community-based Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study.

Overall, only one participant met all seven components of the AHA definition, whereas less than 10% met at least five. Further, only 2% had all four components of the ideal health behaviors index and 1.4% had all three of the health factors’ index. After adjustment for age, sex and income level, blacks had significantly lower odds of having at least five ideal CV health components than whites (OR=0.18; 95% CI, 0.10-0.34).

Additionally, men had significantly worse status regarding smoking, BP, BMI and fasting plasma glucose, whereas women had poorer total cholesterol and physical activity status.

“Because of the comprehensive nature of the new AHA construct of CV health, we anticipated a low prevalence of ideal categories,” the researchers wrote. “However, the fact that only one out of 1,933 participants met the definition of ideal CV health and that the indices of ideal health behaviors and factors were only met by 2% and 1.4% of the participants, respectively, is especially concerning because of the participatory nature of our project, the use of a community-based recruitment strategy and the inherent healthy volunteer bias that we expected to be associated with more favorable findings.”

This large gap separating the prevalence of ideal CV health from AHA’s goals, the researchers said, suggests that the attainment of the stated goals for the next decade may be much more challenging than originally conceived.

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CDC survey: Statin use increased 23% over past two decades

A CDC survey found that the percentage of adults 45 years and older who use statins increased from 2% between 1988 and 1994 to 25% between 2005 and 2008. Further findings from the study indicated that half of men aged 65 to 74 years had taken a statin in between 2005 and 2008 compared with more than one-third of women in the same age group.

The 34th annual report of the national health survey was released last week CDC’s National Center for Health Statistics. Entitled “Health, United States, 2010,” the report compiled health data from federal and state health agencies, and included an in-depth feature on death and dying.

While not exclusively focused on cardiology, this year’s report included a number of CV highlights. For example, in 2007, the report found that heart disease was the leading cause of the death in the United States, followed by cancer. Exactly one quarter of all death in America in 2007 due to heart disease.

Despite being the leading cause of death, the heart disease death rate for adults 65 years of age and older decreased by 26% to 1,309 deaths per 100,000 population. Heart disease accounted for 28% of deaths for adults in this age group in 2007.

The report also observed that hypertension, defined as either having high BP or as taking antihypertensive medications, increased with age. Between 2005 and 2008, roughly 34% of adults aged 45 to 54 years had hypertension, vs. 67% of men and 80% of women aged 75 years and older.

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Updated guidelines for CVD prevention in women encompass clinical practice findings
Mosca L. Circulation. 2011;doi:10.1161/CIR.0b013e31820faaf8

The 2011 update to the American Heart Association’s guidelines for the prevention of CVD in women has incorporated benefits and risks associated with clinical practice findings, besides those observed in clinical research. Further, the guidelines also feature changes regarding the CVD risk classification threshold.

The AHA first published women-specific clinical recommendations for prevention of CVD in 1999. One of the major changes with the present guidelines compared with earlier ones, executive writing committee and expert panel members of the guidelines wrote, was that the benefits and risks observed in clinical practice of preventive therapies were strongly considered, and recommendations were not limited to evidence of benefits observed in clinical research.

“Hence, in the transformation from ‘evidence-based’ to ‘effectiveness-based’ guidelines for the prevention of CVD in women, the panel voted to update recommendations to those therapies that have been shown to have sufficient evidence of clinical benefit for CVD outcomes,” the writing committee and panel members wrote.

The updated guidelines now include modifications to the risk classification algorithm that acknowledge several 10-year risk equations for predicting 10-year global CVD risk, such as the updated Framingham CVD risk profile and Reynolds risk score for women. The new threshold for defining high risk is at least a 10% 10-year risk of all CVD, instead of an at least 20% Framingham 10-year predicted risk for CHD alone, which had previously identified women at high risk in the 2007 update.

“Indeed, it is difficult for a woman<75 years of age, even with several markedly elevated risk factors, to exceed a 10% (let alone a 20%) 10-year predicted risk for CHD with the Adult Treatment Panel III risk estimator,” the guideline authors wrote.

Besides recognizing the importance of racial, ethnic and socioeconomic traits in determining a patient’s risk for CVD, the guidelines also include several illnesses that put a woman at risk, including gestational diabetes, preeclampsia and pregnancy-induced hypertension, as well as those that put her at high risk, including clinically manifest CHD and diabetes.

Because most of the data used to develop these guidelines was based on trials of CHD prevention, the authors said future guidelines “should consider recommendations for specific outcomes of particular importance to women, such as stroke.” This, they said, is particularly critical because 55,000 more women die of stroke than men every year before they reach the age of 75 years
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Resource use increased among Medicare beneficiaries with HF at end of life
Unroe K. Arch Intern Med. 2011;171:196-203.

During the last 6 months of life, days of intensive care, hospice use and cost all increased for Medicare beneficiaries with HF during an 8-year period, according to findings from the Archives of Internal Medicine.

“Heart failure is listed on one in eight death certificates in the United States. Although some people live with HF for years, more than one-quarter of Medicare beneficiaries die within 1 year of the incident diagnosis, and 36% die within 1 year of a HF–related hospitalization,” the researchers wrote. “In this longitudinal analysis … we found that most patients [with HF] frequently accessed the health care system and spent some time in the hospital.”

The retrospective cohort study featured 229,543 Medicare beneficiaries with HF who died from 2000 to 2007. Investigators analyzed the beneficiaries’ resource use during the last 180 days of life, including all-cause hospitalizations, hospice, home health, ICU days, skilled nursing facility stays, durable medical equipment, outpatient physician visits and cardiac procedures.

Throughout the study period, about 80% of beneficiaries were hospitalized in the last 6 months of life. Investigators found that days in intensive care rose (3.5 to 4.6; P<.001), as did use of hospice (19% to 40%; P<.001) and unadjusted mean cost per beneficiary (26% increase; $28,766 to $36,216; P<.001).

When age, race, sex, geographic region and comorbid conditions were adjusted for, cost still increased by 11%. Renal disease, black race and chronic obstructive pulmonary disease were each independent predictors of higher costs, whereas increasing age was a strong independent factor for lower costs. Additionally, regional differences remained after adjustment, with higher costs of care found in the Northeast and West vs. the South.

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Referral strategy led to high rate of cardiac rehabilitation use
Grace S. Arch Intern Med. 2011;171:235-241.

Automatic referral combined with a liaison referral resulted in the highest rates of cardiac rehabilitation use among patients in a prospective controlled study.

Researchers in the Canadian study enrolled 2,635 inpatients with CAD from 11 Ontario hospitals and referred them to one of 52 cardiac rehabilitation programs. Patients were asked to complete a sociodemographic survey, and clinical data were obtained from medical charts. After 1 year, patients were then sent a follow-up survey that assessed self-reported cardiac rehabilitation referral, enrollment and participation, of which 1,809 patients responded.

According to study data, adjusted analyses indicated that referral strategy was significantly related to cardiac rehabilitation referral and enrollment (P<.001), with the greatest cardiac rehabilitation use found in the combined automatic and liaison referral strategy (OR=8.41; 85.8% referral, 73.5% enrollment) when compared with usual referral (32.2% referral, 29% enrollment). Other strategies showing high cardiac rehabilitation use when compared with usual referral were automatic only (OR=3.27; 70.2% referral, 60% enrollment) and liaison only (OR=3.35; 59% referral, 50.6% enrollment).

The results of this study, when combined with the results of a recent systematic review of the field, the researchers wrote, suggest that wider adoption of combined automatic- and liaison-based referral strategies should be promoted.

“Discussion with health care providers involved in cardiac rehabilitation referral at participating institutions revealed that this combination of strategies may be most effective because it targets the health care provider and patient,” they said. “Implementation could potentially raise cardiac rehabilitation use 45% (range, 29.1%-74%), suggesting that major public health gains could be achieved in the population being treated for cardiac disease.”
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Prognostic impact of no-reflow following acute myocardial infarction
An article from the e-journal of the ESC Council for Cardiology Practice

Conclusion

Contrast-enhanced CMR is a useful non-invasive technique for assessing the presence and extent of microvascular obstruction. No-reflow phenomenon has important prognostic implications, and the use of CMR can help to identify and quantify areas of microvascular damage in patients with STEMI. It could become a powerful tool to stratify the risk of patients and in future to differentiate the effectiveness of different techniques of reperfusion.
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Extent of and Reasons for Nonuse of Implantable Cardioverter Defibrillator Devices in Clinical Practice Among Eligible Patients With Left Ventricular Systolic Dysfunction
LaPointe NM, Al-Khatib SM, Piccini JP, et al.
Circ Cardiovasc Qual Outcomes 2011;Feb 8:[Epub ahead of print].
Study Question: How often do eligible patients with heart failure (HF) not receive an implantable cardioverter-defibrillator (ICD) for the primary prevention of sudden cardiac death (SCD)?

Additional Ablation of Complex Fractionated Atrial Electrograms (CFAEs) After Pulmonary Vein Antral Isolation (PVAI) in Patients With Atrial Fibrillation: A Meta-Analysis
Li W, Bai Years, Zhang H, et al.
Circulation Arrhyth Electrophysiol 2011;Feb 8:[Epub ahead of print].
Study Question: Does ablation of complex fractionated atrial electrograms (CFAEs) improve the efficacy of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) when performed after pulmonary vein antrum isolation (PVAI)?

Effects of Aspirin Responsiveness and Platelet Reactivity on Early Vein Graft Thrombosis After Coronary Artery Bypass Graft Surgery
Gluckman TJ, McLean RC, Schulman SP, et al.
J Am Coll Cardiol 2011;57:1069-1077.
Study Question: What parameters of platelet function following coronary artery bypass graft surgery (CABG) in patients on aspirin (ASA) are predictive of early bypass graft failure?

Association of Myocardial Enzyme Elevation and Survival Following Coronary Artery Bypass Graft Surgery
Domanski MJ, Mahaffey K, Hasselblad V, et al.
JAMA 2011;305:585-591.
Study Question: What is the relationship between peak post-coronary artery bypass grafting (CABG) elevation of biomarkers of myocardial damage and early, intermediate-, and long-term mortality?

Prenatal Ultrasound Screening of Congenital Heart Disease in an Unselected Population: A 21-Year Experience
Marek J, Tomek V, Škovránek J, Povýšilová V, Šamánek M.
Heart 2011;97:124-130.
Study Question: What is the prevalence of congenital heart disease and the impact of a national prenatal ultrasound screening program on outcomes in a discrete patient population?

Use of Intensive Insulin Therapy for the Management of Glycemic Control in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians
Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P, on behalf of the Clinical Guidelines Committee of the American College of Physicians.
Ann Intern Med 2011;154:260-267.
Perspective: The following are 10 points to remember about these guidelines on the use of intensive insulin therapy (IIT) for the management of glycemic control in hospitalized patients

5-Year Follow-Up After Primary Percutaneous Coronary Intervention With a Paclitaxel-Eluting Stent Versus a Bare-Metal Stent in Acute ST-Segment Elevation Myocardial Infarction: A Follow-Up Study of the PASSION (Paclitaxel-Eluting Versus Conventional Stent in Myocardial Infarction With ST-Segment Elevation) Trial
Vink MA, Dirksen MT, Suttorp MJ, et al.
JACC Cardiovasc Interv 2011;4:24-29.
Study Question: What are the long-term outcomes of the PASSION (Paclitaxel-Eluting Versus Conventional Stent in Myocardial Infarction With ST-Segment Elevation) trial?

Timeliness of Tissue-Type Plasminogen Activator Therapy in Acute Ischemic Stroke: Patient Characteristics, Hospital Factors, and Outcomes Associated With Door-to-Needle Times Within 60 Minutes
Fonarow GC, Smith EE, Saver JL, et al.
Circulation 2011;123:750-758.
Study Question: What were the presenting characteristics of acute ischemic stroke patients treated with intravenous tissue-type plasminogen activator (tPA) within 3 hours of symptom onset in whom a door-to-needle time ≤60 minutes was achieved, hospital-level variation in door-to-needle times, in-hospital clinical outcomes, and temporal trends in timely thrombolytic care?

Relationship Between Risk Stratification at Admission and Treatment Effects of Early Invasive Management Following Fibrinolysis: Insights From the Trial of Routine Angioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI)
Yan AT, Yan RT, Cantor WJ, et al.
Eur Heart J 2011; Feb 8:[Epub ahead of print].
Study Question: Does risk stratification using the Global Registry of Acute Coronary Events (GRACE) influence effectiveness of early routine percutaneous coronary intervention (PCI) after fibrinolysis for ST-segment elevation myocardial infarction (STEMI)?

Compelling Evidence of Long-Term Outcomes in Pulmonary Arterial Hypertension? A Clinical Perspective
Gomberg-Maitland M, Dufton C, Oudiz RJ, Benza RL.
J Am Coll Cardiol 2011;57:1053-1061.
Conclusions: The following are 10 points to remember from a review of clinical trials in pulmonary arterial hypertension (PAH).

Quantitative Troponin and Death, Cardiogenic Shock, Cardiac Arrest and New Heart Failure in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes (NSTE ACS): Insights From the Global Registry of Acute Coronary Events
Jolly SS, Shenkman H, Brieger D, et al., on behalf of the GRACE Investigators.
Heart 2011;97:197-202.
Study Question: What is the implication of the absolute level of troponin elevation in patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS)?

Cost-Utility of Aspirin and Proton Pump Inhibitors for Primary Prevention
Earnshaw SR, Scheiman J, Fendrick AM, McDade C, Pignone M.
Arch Intern Med 2011;171:218-225.
Study Question: What is the cost-utility of aspirin treatment with or without a proton pump inhibitor (PPI) for coronary heart disease (CHD) prevention among men at different risks for CHD and gastrointestinal (GI) bleeding?

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Researchers document post-transplantation mortality rates in adults with congenital heart disease
Davies R. Circulation. 2011;123;759-767.

Following a high short-term mortality, patients with congenital heart disease had better late survival after heart transplantation, according to researchers.

The study involved 41,849 patients older than 18 years who were listed for primary transplantation between 1995 and 2009. Investigators compared patients with a history of congenital heart disease (CHD; n=1,035) with those with non-CHD causes (n=40,814). Of the study patients, 26,055 reached transplantation, with 10,484 having and 15,571 not having prior sternotomy.

According to study data, survival was comparable between CHD and non-CHD arms, although among CHD patients, mechanical ventricular assistance was not linked with superior survival to transplantation. Also reported among CHD patients was a higher likelihood of having a BMI of less than 18.5 at transplantation, fewer comorbidities and a younger age.

Researchers looked at early mortality rates and found a significantly higher rate among patients with CHD in both the reoperation arm (18.9% vs. 9.6%; P<.0001) and the non-reoperation arm (16.6% vs. 6.3%; P<.0001), despite a nearly equal mortality rate at 10 years (CHD, 53.8% vs. non-CHD, 53.6%).

In the study’s clinical perspective, the researchers wrote that improving the understanding of the differences between CHD and non-CHD patients may enable improvements in the outcomes of this increasingly important population.

“The increasingly common transplantation of patients with complex CHD may result in particularly high post-transplantation mortality, and centers performing these transplantations should proceed with caution,” they said. “Collection of data specific to the CHD population, including accurate congenital diagnoses, is essential to better understand and improve the outcomes with transplantation in this population.”

The paper by Davies and colleagues is a significant review of over 1,000 congenital heart disease patients who develop advanced HF that requires cardiac transplantation. This is the first look into these patients in a large registry from the United Network for Organ Sharing. It is noteworthy that patients with CHD are living longer and as many as 10-20% of CHD patients will eventually require cardiac transplantation. As seen in previous smaller studies, early mortality after transplant is high but it is comforting to know (from this study) that late survival is better than that among non-CHD patients. The CHD patients are, in general, younger and I believe they are more resilient to recover from complications. A major limitation from this study is that the specific CHD abnormality was not available through the UNOS Registry. Therefore, accurate outcomes of specific CHD diagnoses was not possible to determine. This will be important for future studies as specific CHD diagnoses may have different outcomes.
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Registry data highlight importance of clinical conditions in treating CTO lesions

Cardiovascular Research Technologies 2011
Cardiovascular Research Technologies 2011

New one-year data from the IRCTO registry have suggested that outcome of treatment of chronic total occlusion lesions was related to patient clinical conditions as opposed to strategy of treatments in Italy where prevalence of these lesions is roughly 12%.

According to presenter Alfredo R. Galassi, MD, director, Diagnostic and Cardiovascular Interventional Laboratory, Ferrarotto Hospital University, Catania, Italy and investigator on the trial, the incidence and prevalence of coronary chronic total occlusion [CTO] lesions, as well as the demographic characteristics of patients affected by CTO’s, are unknown.

“The aim [of the study] was to assess the prevalence, demographics, clinical characteristics and therapeutic strategy of patients with CTOs in order to improve the management of patients with chronically occluded coronary arteries,” he said.

The study included 1,777 patients from 12 centers throughout Italy from the Italian Registry on Chronic Total Occlusion (IRCTO). The patients had at least one CTO in a main coronary artery for greater than 3 months duration with vessel size greater than >2.5 mm at coronary angiography.

Overall, investigators reported 1,968 CTOs among patients. One month unadjusted clinical outcome did not result in a statistically significant difference in death, stroke or MI, among patients treated with percutaneous coronary intervention, CABG or optimal medical therapy. However, at 12 months, compared with optimal medical therapy, rates of death and acute MI but not stroke were significantly less in patients treated with PCI.

According to univariate analysis, predictors of hard events included ejection fraction <35% (OR=1.76; 95% CI, 1.12-2.77), multivessel disease (OR=2.07; 95% CI, 1.13-3.80) and age (OR=1.06; 95% CI, 1.04-1.08).

Additionally, concluded Galassi, patients with a successful PCI had a better outcome than those without one (P=.03). – by Brian Ellis

For more information:
Galassi A. Presented at: Cardiovascular Research Technologies 2011. Feb. 27-March 1, 2011; Washington, D.C. .

There is now a remarkable consistency from data from Italy. In fact, this represents, by my count, the 12th study that would suggest through indirect comparison and minding the biases both with regard to treatment and selection of these patients that there is a consistency across these observational studies demonstrating improved survival and freedom from adverse events over an immediate long-term follow-up—follow-up, in some observation studies, that extends now beyond many years.

That said, however, we still need a large randomized trial that would help refine the benefit of CTO revascularization from hard clinical endpoints. However, to design a trial based on hard clinical endpoints like mortality, you have to think about the limitations of sample size and statistical power. And probably what is more relevant is a composite that would reflect not only mortality in itself but avoidance of future ischemic events and rehospitalization and very importantly a benefit with regard to quality of life.

It is noteworthy, however, that in this Italian registry there is a lower representation of patients with multivessel disease and patients with reduced left ventricular function in part reflecting clinicians’ discretion to refer patients to surgery or to treat them with medical therapy alone. But it’s important to realize that these are some of the patients who derive the greatest relative treatment effect from CTO revascularization.

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FDA approves azilsartan medoxomil tablets for hypertension treatment

The FDA today announced the approval of azilsartan medoxomil, an angiotensin II receptor blocker, for the treatment of hypertension in adults.

Azilsartan medoxomil tablets (Edarbi, Takeda Pharmaceuticals) will be made available in 80 mg and 40 mg doses. The agency approved the drug based on data from more than 5,900 patients showing that azilsartan medoxomil was more effective at lowering 24-hour BP than valsartan (Diovan, Novartis) and olmesartan (Benicar, Daiichi Sankyo).

The 40 mg dose, according to a press release, will be available for patients taking high-dose diuretics.

“High BP is often called the ‘silent killer’ because it usually has no symptoms until it causes damage to the body,” Norman Stockbridge, MD, PhD, director of the Division of Cardiovascular and Renal Drugs Products at the FDA’s Center for Drug Evaluation and Research, said in the press release. “High BP remains inadequately controlled in many people diagnosed with the condition, so having a variety of treatment options is important.”

The boxed warning that accompanied azilsartan medoxomil specified that the drug not be used in pregnant women during the second or third trimester.
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Stroke and death rates similar in stenosis patients undergoing stenting or endarterectomy
Silver F. Stroke.2011;42:675-680. S

Researchers have found no significant difference in stroke and death rates in patients with carotid stenosis treated with carotid artery stenting or with carotid endarterectomy; however, periprocedural stoke and death rates were much lower in symptomatic patients who received stents.

The Carotid Revascularization Endarterectomy Vs. Stenting Trial (CREST) was a randomized endpoint trial that compared the safety and efficacy of carotid artery stenting (CAS) vs. carotid endarterectomy (CEA) in patients with high-grade carotid stenosis. The study was supported by the National Institute of Neurological Disorders and Stroke and the NIH, with additional funding from Abbott Vascular Solutions Inc.

Patients were defined as symptomatic if they exhibited relative symptoms up to 180 days of randomization. A total of 1,321 symptomatic patients and 1,181 asymptomatic patients were enrolled at 117 sites throughout the United States and Canada. The primary endpoint included stroke, MI, death within the periprocedural period or ipsilateral stroke within 4 years.

Operators included surgeons who performed 12 or more CEAs per year; interventionalists were experienced in CAS and received hands-on training using the stenting and embolic-protection devices being observed in the study.

In both arms, the periprocedural aggregate of stroke, MI and death were similar (5.2% vs. 4.5%; HR=1.18; 95% CI, 0.82-1.68). The stroke and death rate was higher for CAS than for CEA (4.4% vs. 2.3%; HR=1.90; 95% CI, 1.21-2.98). For symptomatic patients, the periprocedural stroke and death rates were 6 ± 0.9% for CAS and 3.2 ± 0.7% for CEA (HR=1.89; 95% CI, 1.11-3.21). For asymptomatic patients, stroke and death rates were 2.5 ± 0.6% for CAS and 1.4 ± 0.5% for CEA (HR=1.88; 95% CI, 0.79-4.42). Rates were lower in patients aged younger than 80 years.

“CREST has demonstrated that, with experienced surgeons and interventionalists, both CEA and CAS are viable options for carotid revascularization because the overall complication rates for both procedures are within current treatment guidelines,” researchers wrote.
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Low, high BMI increased mortality in Asians
Zheng W. N Engl J Med. 2011;364:719-729.

A study involving more than 800,000 East Asians has shown that both low and high BMI increased the likelihood of death from any cause, as well as cause-specific death.

However, researchers looked at nearly 300,000 Indians and Bangladeshis and found that only low BMI elevated the risk for death.

The more than 1.14 million participants who comprised the study were recruited in 19 Asian cohorts. Investigators defined 10 BMI levels, ranging from lowest (≤15) to highest (>35) and carried out pooled analyses of individuals to determine the association between BMI (mean 22.9 ± 3.6) and mortality risk.

During a mean follow-up of 9.2 years, approximately 120,700 cohort members died, with CVDs reported as the main cause of death (35.7%), followed by cancer (29.9%). For East Asians, or those from China, Japan or Korea, the lowest risk for death was among those with a BMI between 22.6 and 27.5. The risk was elevated for those with a BMI of 15 or less by a factor of 2.8 and for those with a BMI of more than 35 by a factor of 1.5.

For the cohorts composed of Indians and Bangladeshis, the risk for death from any cause was increased among those with a BMI of 20 or less vs. those with a BMI between 22.6 and 25, but not for those with a higher BMI.

“Overall, the risk of death among Asians, as compared with Europeans, seems to be more strongly affected by a low BMI than by a high BMI,” the researchers concluded. “Given the limitations of the current study, in which the risk of death was used as the outcome, additional studies are needed to quantify the association between BMI and the incidence of disease, in order to better define BMI criteria for overweight and obesity in Asians.” – by Brian Ellis

This is an interesting study. The “obesity paradox“ in Western countries is already known. Although obesity is a risk factor for diabetes, hypertension, CAD and premature death, in the systolic HF (stage C ) population, higher BMI is associated with a better prognosis. Similarly, in patients undergoing CABG, higher BMI is associated with a better prognosis. Cardiac cachexia (increased tumor necrosis factor-alpha) is associated with poor prognosis in systolic HF and in cancer.

Based upon my personal knowledge about Asian Indians, Bangladeshis and Pakistanis, the life expectancy is lower due to a variety of causes in urban people. In rural areas, even though the people are thinner, they live longer. I think lifestyles play an important role in regulating BMI in every country.

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Long-Term Implications of Cumulative Right Ventricular Pacing Among Patients With an Implantable Cardioverter-Defibrillator
Barsheshet A, Moss AJ, McNitt S, et al.
Heart Rhythm 2011;8:212-218.
Study Question: Does the burden of right ventricular (RV) pacing impact long-term survival in patients with implantable cardioverter-defibrillators (ICDs) placed for primary prevention?

Comparison of Voltage Map-Guided Left Atrial Anterior Wall Ablation Versus Left Lateral Mitral Isthmus Ablation in Patients With Persistent Atrial Fibrillation
Pak HN, Oh YS, Lim HE, Kim YH, Hwang C.
Heart Rhythm 2011;8:199-206.
Study Question: Is mitral isthmus (MI) block achieved more effectively by voltage-guided left atrial anterior wall (LAAW) radiofrequency ablation (RFA) than by left lateral mitral isthmus (LLMI) ablation?

National Trends in Utilization and Postprocedure Outcomes for Carotid Artery Revascularization 2005 to 2007
Eslami MH, McPhee JT, Simons JP, Schanzer A, Messina LM.
J Vasc Surg 2011;53:307-315.
Study Question: What are the trends in utilization, mortality, and stroke after carotid angioplasty and stenting (CAS) and carotid endarterectomy (CEA) from 2005 to 2007?

Impact of Early Surgery on Survival of Patients With Severe Mitral Regurgitation
Samad Z, Kaul P, Shaw LK, et al.
Heart 2011;97:221-224.
Study Question: Is there an association between the timing of surgery and long-term survival in patients with severe degenerative mitral regurgitation (MR)?

Relationship Between Left Ventricular Mass, Wall Thickness, and Survival After Subaortic Septal Myectomy for Hypertrophic Obstructive Cardiomyopathy
Brown ML, Schaff HV, Dearani JA, Zhuo L, Nishimura RA, Ommen SR.
J Thorac Cardiovasc Surg 2011;141:439-443.
Study Question: Following septal myectomy, do measures of left ventricular (LV) wall thickness (WT) and LV mass impact late survival in patients with hypertrophic cardiomyopathy (HCM)?

β-Blockade With Nebivolol for Prevention of Acute Ischemic Events in Elderly Patients With Heart Failure
Ambrosio G, Flather MD, Bohm M, et al.
Heart 2011;97:209-214.
Study Question: Does nebivolol, a beta-blocker with B-1 selectivity and nitric oxide modulating properties, reduce ischemic events in elderly patients with heart failure (HF)?

Progestogen-Only Contraceptives and the Risk of Acute Myocardial Infarction: A Meta-Analysis
Chakhtoura Z, Canonico M, Gompel A, Scarabin PY, Plu-Bureau G.
J Clin Endocrinol Metab 2011;Feb 2:[Epub ahead of print].
Study Question: Do progestogen-only contraceptives (POCs) increase the risk for myocardial infarction (MI)?
Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women—2011 Update: A Guideline From the American Heart Association
Mosca L, Benjamin EJ, Berra K, et al.
Circulation 2011;Feb 16:[Epub ahead of print].
Perspective: The following are 10 points to remember from the American Heart Association guidelines on the prevention of cardiovascular disease in women.

Efficacy and Safety of Glycoprotein IIb/IIIa Inhibitors During Elective Coronary Revascularization: A Meta-Analysis of Randomized Trials Performed in the Era of Stents and Thienopyridines
Winchester DE, Wen X, Brearley WD, Park KE, Anderson RD, Bavry AA.
J Am Coll Cardiol 2011;57:1190-1199.
Study Question: What is the efficacy and safety of glycoprotein IIb/IIIa inhibitors (GPIs) during elective percutaneous coronary intervention (PCI) in the contemporary era?

Total Arch Replacement Combined With Stented Elephant Trunk Implantation: A New “Standard” Therapy for Type A Dissection Involving Repair of the Aortic Arch?
Involving Repair of the Aortic Arch?
Sun L, Qi R, Zhu J, et al.
Circulation 2011;123:971-978.
Study Question: What is the appropriate approach for patients with type A dissection involving the aortic arch?

Effect of Cardiac Rehabilitation Referral Strategies on Utilization Rates: A Prospective, Controlled Study
Grace SL, Russell KL, Reid RD, et al., on behalf of the Cardiac Rehabilitation Care Continuity Through Automatic Referral Evaluation (CRCARE) Investigators.
Arch Intern Med 2011;171:235-241.
Study Question: What is the optimal strategy to maximize cardiac rehabilitation’s (CR) referral, enrollment, and participation?

Effectiveness of a Barber-Based Intervention for Improving Hypertension Control in Black Men. The BARBER-1 Study: A Cluster Randomized Trial
Victor RG, Ravenell JE, Freeman A, et al.
Arch Intern Med 2011;171:342-350.
Study Question: How effective are barbershop-based hypertension (HTN) outreach programs for black men in improving HTN control?

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Update on Venous Thromboembolism: Risk Factors, Mechanisms, and Treatments
Arteriosclerosis, Thrombosis, and Vascular Biology
Journal of the American Heart Association
Deep vein thrombosis (DVT) and pulmonary embolism, collectively called venous thromboembolism (VTE), are a public health crisis. The number of incident and recurrent VTE events are estimated at more than 1 million per year. Beyond the initial risk of death, estimated at greater than 30% within 30 days of the event, one third to one half of surviving patients develop recurrent thrombosis or long–term morbidity associated with post–thrombotic syndrome.
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Direct association between dietary cholesterol intake and blood pressure: too good to be 'entirely' true
Journal of Hypertension
Official Journal of the International Society of Hypertension and the European Society of Hypertension
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A Novel Design of Posterior Leaflet Butterfly Resection for Mitral Valve Repair
Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery
Official Journal of the International Society for Minimally Invasive Cardiothoracic Surgery
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Mechanisms and consequences of salt sensitivity and dietary salt intake
Current Opinion in Nephrology & Hypertension
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Cardiovascular Imaging for Assessing Cardiovascular Risk in Asymptomatic Men Versus Women: The Multi-Ethnic Study of Atherosclerosis (MESA)
Circulation: Cardiovascular Imaging
Journal of the American Heart Association
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Progress in Prevention: Motivating Our Patients to Adopt & maintain Healthy Lifestyles
Journal of Cardiovascular Nursing
Official Journal of the Preventive Cardiovascular Nurses Association and Australasian Cardiovascular Nursing College
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From the American College of Cardiology... Cilostazol Reduces Repeat Revascularizations for Long Lesions
Mar 7 - In patients implanted with long zotarolimus eluting stents, triple antiplatelet therapy including cilostazol safely reduces 8 month late loss and restenosis...
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From JACC... 'Valve-in-Valve' Technique Effective in Treating CoreValve Leaks
Mar 7 - Implanting a second CoreValve device inside a first one is an effective means of treating paraprosthetic leakage in patients undergoing transcatheter...
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From Circulation: Cardiovascular Interventions... 'Mother-Child' Technique Improves Success for PCI in Challenging Lesions
Mar 4 - Inserting a 4 Fr catheter into a 6 Fr guiding catheter—the so called mother child technique—greatly improves the success rate for treating lesions...
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From the American Journal of Cardiology... Meta-analysis: Multivessel PCI Comparable to Culprit-Only Approach in STEMI
Mar 4 - A strategy of multivessel percutaneous coronary intervention (PCI) performed at the time of culprit revascularization or during the same hospital stay...
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From the American Journal of Cardiology... Early Bolus of Sodium Bicarb Reduces Contrast Nephropathy in Emergent PCI
Mar 3 - A rapid bolus injection of sodium bicarbonate immediately before contrast use drastically reduces the rate of contrast induced nephropathy (CIN) compared...
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From JACC... Autopsy Study: About One-Third of DES Contain New Atherosclerosis
Mar 2 - Neoatherosclerosis frequently develops in drug eluting stents (DES) within 2 years after implantation, according to a pathology study published online...
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From the Archives of Internal Medicine... Mental Outlook Linked to Long-term Survival After CHD Hospitalization
Mar 2- Patients hospitalized for coronary heart disease (CHD) who express high expectations for recovery later see their positive outlook come to fruition...
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From Circulation: Cardiovascular Quality and Outcomes... Many Cardiovascular Devices Approved by FDA Without Sex-Specific Data
Mar 1 - Most applications for high risk cardiovascular devices such as heart valves and stents that are eventually approved by the US Food and Drug Administration...
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CVD medication usage of older patients heavily influenced by adverse effects
Fried T. Arch Intern Med. 2011;doi:10.1001/archinternmed.2011.32.

Researchers of a new study have found that the willingness of older patients to take medication for primary CVD prevention was highly sensitive to the medication's potential adverse events and relatively insensitive to its benefits.

“The findings in this study regarding variability in willingness to take medication according to its benefit are consistent with the results of earlier investigations,” the researchers wrote. “This study further demonstrated that changing the absolute benefit provided by the medication affected the willingness only of a small proportion of people unless the change in absolute benefit was substantial.”

The study involved 356 community-dwelling older participants (mean age, 76 years) who were questioned in a face-to-face interview about their willingness to medication to prevent MI. All volunteers were included in the study without exclusion.

According to study data, most participants (88%) were willing to take a medication that provided a 30% relative reduction in MI risk (six fewer people with MI out of 100) if there were no adverse events, with the percentage of willing patients increasing as the absolute benefit of the medication increased. The reasons those in the initial scenario turned down medications included the belief that the benefit was too small (n=13), belief that medication would have adverse effects (n=13) and an overall dislike of medications (n=7).

Of those who would take medication, 82% remained willing if the absolute benefit was decreased to three fewer people with MI. Conversely, medications with average benefit but that caused mild fatigue, fuzzy thinking and nausea would be turned down by 48% to 69% of the study population, whereas only 3% would take medications with severe enough effects to affect functioning.

These results, the researchers concluded, “suggest that clinical guidelines and decisions about prescribing these medications to older persons need to place emphasis on both their benefits and harms.”
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Recovery expectations for patients with CAD reflect long-term survival
Barefoot J. Arch Intern Med. 2011;doi:10.1001/archinternmed.2011.41.

The baseline recovery expectations of patients with coronary artery disease were shown to positively correlate with long-term survival and functioning in a new study.

Researchers from Duke University Medical Center and Duke Clinical Research Institute, Durham, N.C., enrolled patients (n=2,818) who underwent diagnostic coronary angiography at the medical center from 1992 to 1996. All patients were found to have clinically significant CAD (>75% diameter stenosis of >1 coronary artery).

At the 15-year follow-up, 1,637 deaths were reported, 885 of which were from CV causes. CABG was performed at some point during this period on 1,277 participants (45.3%), and percutaneous transluminal coronary angioplasty was performed on 1,156 participants (41%), whereas those who were not treated with one or both procedures received medical treatment (n=781; 27.7%).

Overall, expectations were positively associated with survival regarding total mortality (HR=0.76; 95% CI, 0.71-0.82) and CV mortality (HR=0.76; 95% CI, 0.69-0.83). After further adjustments for demographic and psychosocial covariates, the relationships remained but to a lesser extent for both total mortality (HR= 0.83; 95% CI, 0.76-0.91) and CV mortality (HR=0.79; 95% CI, 0.70-0.89). Similar associations (P<.001) were also found regarding functional status.

As potential mechanisms for explaining the observed benefits, the researchers said the predisposition of optimists makes their coping more effective in reducing risk factor levels and improving levels of life satisfaction, whereas pessimists tend to experience more tension and negative emotions during recovery, thereby heightening stress reactions.

These study’s findings, they wrote, “argue for expanded efforts to understand the influence of recovery expectations and the potential benefits of attempts to modify them. The potential feasibility of altering specific aspects of patient beliefs provides a promising avenue for intervention if the importance of expectations is confirmed.”

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FDA: Long-term proton pump inhibitor use linked with hypomagnesemia

The FDA has issued a public safety communication warning that the long-term use of prescription proton pump inhibitors is potentially associated with low magnesium levels.

Citing a review of 38 cases from the Adverse Event Reporting System and 23 cases from medical literature, the agency determined there was an association between hypomagnesemia-related adverse events in adult patients who had been taking proton pump inhibitors (PPIs) for at least 3 months. Most of the events occurred after 1 year of taking PPIs, and approximately one quarter of the cases required the discontinuation of PPI treatment (as well as magnesium supplementation). The agency also noted that since hypomagnesemia is likely under-reported and under-recognized, available data was insufficient to quantify an incidence rate.

Among the clinically serious events reported in the review were tetany, seizures, tremors, carpo-pedal spasm, atrial fibrillation, supraventricular tachycardia and abnormal QT interval.

The FDA communication said that the mechanism responsible for the association was not known, and recommended that patients on PPIs exhibiting symptoms of hypomagnesemia first talk to their health care providers before discontinuing any prescription PPI regimens.

“Health care professionals should consider obtaining serum magnesium levels prior to initiation of prescription PPI treatment in patients expected to be on these drugs for long periods of time, as well as patients who take PPIs with medications such as digoxin, diuretics or drugs that may cause hypomagnesemia,” the agency wrote in the announcement. “For patients taking digoxin, this is especially important because low magnesium levels increase the likelihood of serious side effects.”
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Antihypertensive treatment improved outcomes in non-hypertensive patients with CVD

Thompson A. JAMA. 2011;305:913-922.
Ventura H. JAMA. 2011;305:940-941.

Rates of all-cause mortality, stroke, congestive HF and composite CVD events were reduced in CVD patients without hypertension who were treated with antihypertensive medication, meta-analysis data suggested.

In the analysis, investigators searched databases for randomized controlled trials that analyzed the use of antihypertensive treatment for the prevention of CVD events in those with systolic BP of less than 140 mm Hg or diastolic BP of less than 90 mm Hg. The final group of studies included in the analysis (n=25) featured 64,162 patients without hypertension.

Researchers found that compared with controls, participants who received antihypertensive medications had pooled RR reductions in stroke (RR=0.77; 95% CI, 0.61-0.98), congestive HF (RR=0.71; 95% CI, 0.65-0.77), MI (RR=0.80; 95% CI, 0.69-0.93), CVD mortality (RR=0.83; 95% CI, 0.69-0.99), composite CVD events (RR=0.85; 95% CI, 0.80-0.90) and all-cause mortality from random-effects models (RR=0.87; 95% CI, 0.80-0.95). This translated to an absolute risk reduction per 1,000 people of –7.7 for stroke, -43.6 for chronic HF events, -13.3 for MI, -27.1 for composite CVD events, -15.4 for CVD mortality and -13.7 for all-cause mortality.

“Our results show that persons with a history of CVD but with BPs in the normal and prehypertensive ranges can obtain significant benefit from antihypertensive treatments,” the researchers wrote. “Additional randomized trial data are necessary to assess these outcomes in patients without CVD clinical recommendations.”

In an accompanying editorial, Hector O. Ventura, MD, with the John Ochsner Heart and Vascular Institute, New Orleans, and Carl J. Lavie, MD, with the University of Queensland School of Medicine, Brisbane, Australia, said this study adds to the understanding of treatment benefits with agents designed to lower BP among patients with CVD.

“The clinical importance of this study is clear: Pharmacological intervention in patients with CVD and BP levels less than 140/90 mm Hg is associated with a decreased risk of CV morbidity and mortality,” they said. “However, this study does not determine whether lowering BP levels is the reason for improved clinical outcomes. These agents may improve clinical outcomes through multiple other mechanisms (eg, hemodynamic effects unrelated to BP, neurohormonal effects and tissue-level effects).”
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Meta-analysis: Glycoprotein IIb/IIIa inhibitors linked with reduced nonfatal MI in elective PCI

Bhatt D. J Am Coll Cardiol. 2011;57:1200-1201.
Winchester D. J Am Coll Cardiol. 2011;57:1190-1199.

Results from a meta-analysis suggested that glycoprotein IIb/IIIa inhibitors are associated with reduced nonfatal MI and a nonsignificant increase in major bleeding in patients undergoing elective percutaneous coronary intervention.

Researchers identified 22 studies from a search of Medline, Cochrane and ClinicalTrials.gov databases that included patients undergoing elective PCI who were randomly assigned to glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors vs. controls. The 22 study populations yielded 10,123 patients. They then looked at 30-day outcomes and used a DerSimonian-Laird model to construct random effects summary RRs and CIs.

According to the results, the incidence of MI with GPIIb/IIIa inhibitors was 5.1% vs. 8.3% with controls (RR=0.66; 95% CI, 0.55-0.79) across the studies, and the results were no different when the analysis was restricted to placebo-controlled trials. The incidence of major bleeding was 1.2% with GPIIb/IIIa inhibitors vs. 0.9% with controls (RR=1.37; 95% CI, 0.83-2.25), and this failed to attain statistical significance. The difference in minor bleeding was more significant, however (3% with GPIIb/IIIa inhibitors vs. 1.7% with controls; RR=1.70; 95% CI, 1.28-2.26). All-cause mortality within 30 days did not differ between the two populations (0.3% with GPIIb/IIIa inhibitors vs. 0.5% with controls; RR=0.70; 95% CI, 0.36-1.33).

“In the current era of elective PCI performed with stents and thienopyridines, [GPIIb/IIIa inhibitors] reduced nonfatal MI without a notable increase in major bleeding,” the researchers concluded. “However, these agents increase minor bleeding and thrombocytopenia. Overall, the use of [GPIIb/IIIa inhibitors] during elective modern PCI seems to be safe and effective.”

In an accompanying editorial, Deepak L. Bhatt, MD, of the VA Boston Healthcare System and Brigham and Women’s Hospital, said the necessity of the routine use of GPIIb/IIIa inhibitors has been challenged in the context of stenting with adenosine diphosphate receptor antagonists, but the potential role of GPIIb/IIIa inhibitors in patients undergoing non-urgent PCI was far from outdated.

“This meta-analysis demonstrates that even on a background of aspirin, standard thienopyridine regimens and heparin — the PCI cocktail most commonly used worldwide — [GPIIb/IIIa inhibitors] continue to have an important potential role,” Bhatt wrote. “Notably, this data set further validates the concept that additional platelet inhibition is warranted beyond that provided by aspirin and standard-dose thienopyridines. Whether this in fact will be [GPIIb/IIIa inhibitors] or one of the other novel antiplatelet regimens remains to be seen.”

[Chevychelov]

Mandatory Electrocardiographic Screening of Athletes to Reduce Their Risk for Sudden Death: Proven Fact or Wishful Thinking?
Steinvil A, Chundadze T, Zeltser D, et al.
J Am Coll Cardiol 2011;57:1291-1296.
Study Question: Does preparticipation screening of athletes with a strategy including resting and exercise electrocardiography (ECG) reduce their risk for sudden death?

Real-Time 3D Echo in Patient Selection for Cardiac Resynchronization Therapy
Kapetanakis S, Bhan A, Murgatroyd F, et al.
JACC Cardiovasc Imaging 2011;4:16-26.
Study Question: What is the utility of three-dimensional transthoracic echocardiography (3DE) for quantifying left ventricular (LV) mechanical dyssynchrony as a predictor of clinical and anatomical success of cardiac resynchronization therapy (CRT)?

Early Diagnosis of Acute Myocardial Infarction in the Elderly Using More Sensitive Cardiac Troponin Assays
Reiter M, Twerenbold R, Reichlin T, et al.
Eur Heart J 2011;Feb 28:[Epub ahead of print].
Study Question: What is the diagnostic accuracy of high-sensitivity troponin (cTn) assays in elderly patients with chest pain?

Antihypertensive Treatment and Secondary Prevention of Cardiovascular Disease Events Among Persons Without Hypertension: A Meta-Analysis
Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, Bazzano LA.
JAMA 2011;305:913-922.
Study Question: Does treatment with antihypertensive medications among patients with a history of cardiovascular disease (CVD), but not hypertension reduce the risk of death and future CVD events?
The Effect of Mediterranean Diet on Metabolic Syndrome and Its Components: A Meta-Analysis of 50 Studies and 534,906 Individuals
Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA, Panagiotakos DB.
J Am Coll Cardiol 2011;57:1299-1326.
Study Question: Does a Mediterranean diet affect components of the metabolic syndrome?

Diabetes Mellitus, Fasting Glucose, and Risk of Cause-Specific Death
The Emerging Risk Factors Collaboration.
N Engl J Med 2011;364:829-841.
Study Question: What are the associations of baseline diabetes and fasting blood glucose level with the risk of cause-specific death?

Exceptions to Outpatient Quality Measures for Coronary Artery Disease in Electronic Health Records
Kmetik KS, O’Toole MF, Bossley H, et al.
Ann Intern Med 2011;154:227-234.
Study Question: Are outpatient quality measures for coronary artery disease (CAD) accurate based on electronic health records?
Long-Term Effects of Intensive Glucose Lowering on Cardiovascular Outcomes
The ACCORD Study Group.
N Engl J Med 2011;364:818-828.
Study Question: What are the 5-year outcomes of intensive glucose lowering on mortality and key cardiovascular events?

Functional Variants of the HMGA1 Gene and Type 2 Diabetes Mellitus
Chiefari E, Tanyolac S, Paonessa F, et al.
JAMA 2011;305:903-912.
Study Question: Is variation in a gene (HMGA1) resulting in reduced insulin receptor (INSR) expression associated with type 2 diabetes mellitus (T2DM)?

Diuretic Strategies in Patients With Acute Decompensated Heart Failure
Felker GM, Lee KL, Bull DA, et al., on behalf of the NHLBI Heart Failure Clinical Research Network.
N Engl J Med 2011;364:797-805.
Study Question: How does intravenous furosemide given as a bolus every 12 hours compare with continuous infusion and at either a low dose (equivalent to the patient’s previous oral dose) or a high dose (2.5 times the previous oral dose) in acute decompensated heart failure (ADHF)?

Low-Dose Computed Tomography Coronary Angiography With Prospective Electrocardiogram Triggering: Feasibility in a Large Population
Buechel RR, Husmann L, Herzog BA, et al.
J Am Coll Cardiol 2011;57:332-336.
Study Question: What is the feasibility of prospective electrocardiogram (ECG) triggering for low-dose computed tomographic coronary angiography (CTCA)?

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EARLY ACS: Routine vs. delayed provisional use of eptifibatide may improve patient outcomes
Wang T. Circulation. 2011;123;722-730.

New data have shown that patients with non–ST-elevation acute coronary syndrome who used early eptifibatide besides clopidogrel before angiography had lower rates of 30-day mortality and MI compared with those who used eptifibatide on a delayed provisional basis.

Investigators of the Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome (EARLY-ACS) trial included 9,166 patients with non–ST-elevation ACS who underwent angiography, of which 7,068 patients received upstream clopidogrel (Plavix, Sanofi-Aventis).

At 96 hours after invasive strategy, 9.2% of patients who received early eptifibatide (Integrilin, Millennium/Schering) vs. 9.6% of patients treated with the delayed provisional strategy experienced the primary endpoint of death, MI, recurrent ischemia requiring urgent revascularization or thrombotic bailout, whereas at 30 days, the difference in the secondary endpoint in death or MI was slightly more pronounced in favor of early use (10.9% vs. 12.1%; adjusted HR=0.90).

Furthermore, a significant reduction in death or MI at 30 days was reported in patients receiving upstream clopidogrel who also received early eptifibatide vs. delayed provisional (adjusted OR=0.85, 95% CI 0.73-0.99), but not in patients without intended upstream clopidogrel use.

“These findings lend support to the concept of enhanced value for additive antiplatelet therapies,” the researchers concluded. “Future investigations are needed to identify those patients who may benefit from more intensive platelet inhibition without a significant excess in bleeding risk.”

EARLY ACS was funded by research grants from Schering-Plough and Merck Pharmaceuticals.
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CONNECT: Wireless remote monitoring ICDs, CRT-Ds significantly lowered length of hospital stay
Crossley G. J Am Coll Cardiol. 2011;57:1181-1189.

When compared with standard in-office care, patients treated with implantable cardioverter defibrillators or cardiac resynchronization therapy defibrillators that featured wireless remote monitoring with automatic clinician alerts had significantly reduced mean length of hospital stay and time to a clinical decision, new data suggested.

As a result of these findings, the researchers wrote, “Clinics employing wireless remote monitoring may expect fewer total clinic visits per year while not increasing the rate of ED visits or CV hospitalizations for their patients.”

The Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision (CONNECT) trial included 1,997 patients from 136 clinical sites enrolled between November 2006 and May 2008. Each patient underwent insertion of an ICD or cardiac resynchronization therapy defibrillator (CRT-D) and were randomly assigned to either the remote monitoring arm (n=1,014) that utilized the Medtronic CareLink Network or the in-office arm (n=983).

During a follow-up of 15 months, the median time from clinical event to clinical decision was substantially reduced in the remote monitoring arm compared with the in-office arm (4.6 days vs. 22 days; P<.001). Also reduced in the remote monitoring group was the mean length of stay per CV hospitalization visit (3.3 days vs. 4 days; P=.002). Due to the reduction in length of stay, the estimated mean cost of hospitalization was considerably lower in the remote arm ($8,114 vs. $9,822).

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One-minute CPR training video improved attempt rate, skill of nonprofessionals

Bobrow B. Circ Cardiovasc Qual Outcomes. 2011;4:220-226.

Individuals who were trained with a 60-second hands-only CPR training video had significantly higher rates of average compression and compression depth vs. a control group that did not view the video.

Investigators of the prospective study enrolled adults (n=336) who had not received previous CPR training and randomly assigned them into four training groups: no training (control; n=51); 60-second video training (n=95); 5-minute video training (n=99); and 8-minute video training that included mannequin practice (n=91). Participants had their CPR performance ability tested during an adult out-of-hospital cardiac arrest scenario using a CPR-sensing mannequin and computer software (Laerdal PC SkillReporting, Laerdal Medical).

After training, participants were randomly assigned to be tested either immediately or after a 2-month delay. Regardless of experimental group, researchers reported that, compared with control, video training had a significant effect on increasing average compression rate closer to the recommended 100/minute (P<.001 for all), as well as increasing the average compression depth (>38 mm; P<.0001 for all).

These findings, the researchers wrote, add to the current understanding of the effectiveness of CPR training, showing how adults without previous formal CPR training can learn, demonstrate and retain effective hands-only CPR skills with a single viewing of an ultra-brief, 60-second training video.

“Because of its brevity, the ultra-brief hands-only CPR video creates opportunities for frequent, recurrent training in multiple venues and the potential to increase the likelihood of lay citizens being recurrently and effectively trained in this technique,” they said. – by Brian Ellis

This article is very interesting. Out-of-hospital cardiac arrest at present has a miserable prognosis. In those reaching the hospital, only a very small number survive to leave the hospital without significant neurologic damage. Eventual return of spontaneous circulation is more likely if cardiac resuscitation is begun immediately, but as stated in the article, there are many barriers to the bystanders delivering effective CPR. Chief among them is the fear of performing mouth-to-mouth breathing.

There has for years been evidence from Gordon Ewy, MD, of University of Arizona, that cardiac compression was the effective activity in resuscitation (and that ventilation was less important). Now, the American Heart Association has adopted the change so that instead of ABC (airway, breathing, compression), the motto is now CAB. The study presented shows in an artificial, non-emergency setting that with extremely minimal training of hands-only resuscitation, the essential aspects of CPR can be learned. It also shows that for at least 2 months, the technique can be retained. Whether more people witnessing a real cardiac arrest will immediately perform CPR as a result is still an open question. If there is a significant increase in out-of-hospital resuscitations by this hands-only technique, the results will likely be similar to those with the old ABC technique as demonstrated by Svensson et al (N Engl J Med. 2010;363:434-442), but whether this will yield a better eventual prognosis for these patients has yet to be proved.
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Imaging modality may detect abnormal resting coronary blood flow

Chow B. J Am Coll Cardiol. 2011;57:1280–1288.

Rybicki F. J Am Coll Cardiol. 2011;57:1289-1290.

Changes in corrected coronary opacification within the coronary lumen detected by computed tomographic coronary angiography were predictive of abnormal resting coronary blood flow, suggested a new study.

The Canadian researchers conducted this proof-of-concept study by assessing 104 coronary arteries from 52 patients (mean age, 60 ± 9.5 years) via computed tomographic coronary angiography (CTA). All patients were without a history of revascularization, congenital heart disease and heart transplantation, and had obstructive CAD in at least one vessel and at least one major epicardial vessel for use as a “normal” reference artery.

According to data, differences in corrected coronary opacification (CCO) were greater in arteries with CTA diameter stenoses ≥ 50%, as were the CCO differences in arteries with thrombolysis in MI flow grade ≤3 (0.406 ± 0.226) vs. TIMI flow grade 3 (0.078 ± 0.078; P<.001). With regard to CCO differences, CTA detected abnormal coronary flow (TIMI flow grade <3) with a sensitivity of 83.3%, specificity of 91.2%, accuracy of 88.5%, positive predictive value of 83.3% and negative predictive value of 91.2%.

“The ability of CTA to estimate coronary blood flow and to assess for functional coronary stenosis would be extremely desirable,” the researchers wrote of their findings. “Such a technique might prove to be useful in settings of unevaluable coronary segments, perhaps by improving the diagnostic accuracy of CTA. Equally important would be its potential applicators to measure stress coronary blood flow, thus permitting the assessment of hemodynamic significance of a lesion.”

Frank J. Rybicki, MD, PhD, with the Brigham and Women’s Hospital and Harvard Medical School, Boston, commented in an accompanying editorial that “Coronary imaging will define the next generation of ‘state-of-the-art’ in CT, and future generations of hardware technology are likely to change the way we think about image acquisition. While we collectively study these gains and new applications, it is essential to recognize, optimize and study the properties of coronary artery enhancement to maximize our understanding of CT angiography and optimally use it for patient care.”

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ACTIVE I: Irbesartan failed to lower CV events in patients with AF
Yusuf S. N Engl J Med. 2011;364:928-938.

Among patients with atrial fibrillation, irbesartan, an angiotensin-receptor blocker, did not reduce the occurrence of CV events, including MI and death from vascular causes, compared with placebo, according to randomized, clinical trial data.

In the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-I) trial, investigators enrolled patients (n=9,016; mean age, 69.6 years) who had permanent AF or at least two episodes of intermittent AF in the previous 6 months. Patients were then randomly assigned to receive either irbesartan (Avapro, Sanofi-Aventis/Bristol-Myers Squibb) or placebo. The first coprimary outcome was defined as MI, stroke or death from vascular causes, and the second was this composite outcome plus hospitalization for HF.

During a mean follow-up of 4.1 years, patients taking irbesartan had a mean reduction in systolic BP of 2.9 mm HG and diastolic BP of 1.9 mm Hg. There was no difference in the first coprimary endpoint between groups (5.4% each per 100 patient years), and only nonsignificant reduction in the second coprimary endpoint in the irbesartan group (7.3% vs. 7.7% per 100 patient years; P=.12).

When rates of hospitalization were looked at individually, researchers found that patients given irbesartan had a nominally significant reduction in first hospitalization for HF (HR=0.86; 95% CI, 0.76- 0.98), but not in the risk of hospitalization for AF (HR=0.95; 95% CI, 0.85-1.07).

“Among patients with AF, most of whom had well-controlled hypertension and 60% of whom were receiving an ACE inhibitor, the addition of irbesartan did not reduce the risk of death from CV causes, stroke or MI or this composite outcome plus hospitalization for HF,” the researchers wrote, later adding that it remains to be seen whether more aggressive lowering of BP would be effective in patients with AF.
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Mandatory ECG screening in Israel failed to lower sudden death, cardiac arrest risk

Bove A. J Am Coll Cardiol. 2011;57:1297-1298.
Steinvil A. J Am Coll Cardiol. 2011;57:1291-1296.

Twelve years after Israel enacted the National Sport Law, which mandates electrocardiographic screening and exercise stress testing of all athletes, the incidence of cardiac arrest or sudden death did not change compared with 12 years before the law went into effect.

The National Sport Law requires that a medical questionnaire, physical examination, baseline ECG and exercise stress testing be completed by all athletes. Data for the current study were compiled by researchers during a systematic search of two main Israeli newspapers, which provided the yearly number of cardiac arrests among competitive athletes, whereas the Israel Sport Authority provided the size of the population at risk.

Between 1985 and 2009, 24 documented sudden death or cardiac arrest events occurred to competitive athletes, with 11 events reported 12 years before and 13 events reported 12 years after legislation. This resulted in an average yearly incidence of 2.6 events per 100,000 athlete years. Specifically, before legislation, the mean yearly incidence was 2.54 events per 100,000 athlete years vs. 2.66 events per 100,000 athlete years after legislation (P=.88).

“Sudden death among athletes is a very rare phenomenon,” the researchers wrote. “When the prevalence (or pretest probability) is so low, it is inevitable that many people with abnormal test results (abnormal ECG results) will represent false positive results. Of note, disqualification from participation in sports because of abnormal ECG results obtained during an obligatory (often unsolicited) screening has profound implications for the asymptomatic athlete. Therefore, before mandatory ECG screening is endorsed universally, it is reasonable to request additional proof that such a strategy actually saves lives.”

In an accompanying editorial, Alfred A. Bove, MD, PhD, with the Temple University School of Medicine, Philadelphia, said disqualifying athletes based on false positive ECG findings is a concern, and he made a suggestion on how physicians can limit the occurrence.

“At present, cardiologists who evaluate athletes should be familiar with the normal variants in echocardiography and ECG results and should incorporate the 12 questions posed by the American Heart Association for screening so that young athletes are not disqualified based on variant ECG results or normal cardiac adaptations to exercise,” Bove said.
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AHA publishes transition guidelines for adolescent congenital heart disease patients
Sable C. Circulation. 2011;doi:10.1161/cir.0b013e3182107c56.

The American Heart Association has issued a scientific statement outlining best practices for the transition of young patients with congenital heart disease into adulthood, the first step of which is to begin the process in early adolescence, between the ages of 12 and 14 years.

“It’s not as simple as getting the name of a new doctor and going to see them when a patient turns 18,” Craig Sable, MD, AHA statement committee co-chair, said in a press release. “There are multiple steps associated with the transition process that need to be started at a very young age.”

The AHA’s statement was based on a review of transition literature conducted by Sable and his team, beginning in 2008.

To provide uninterrupted medical care, the AHA recommends that the transition should be a joint effort between the patient, the patient’s family and the health care provider, who is usually a pediatric heart specialist. Critical steps for the patient and his or her team to consider on behalf of the patient, according to the statement, are:
Selecting an adult care physician to provide coordinated comprehensive care.
Receiving reproductive, genetic and career counseling.
Obtaining health insurance.
Educating adult care providers on congenital heart disease management.
Maintaining communication between patients, families and health care professionals.

Less than one-third of adults with congenital heart disease receive specialist care, Sable said.

“The vast majority of the patients we see are not necessarily the most severe, so there’s a real concern that some of the patients who really need care are not seeking it. The bottom line is to ensure that, as patients grow up, they receive the necessary care,” he said.

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Early Detection and Prediction of Cardiotoxicity in Chemotherapy-Treated Patients
Sawaya H, Sebag IA, Plana JC, et al.
Am J Cardiol 2011;Mar 7:[Epub ahead of print].
Study Question: What is the predictive ability of more sensitive echocardiographic measurements and biomarkers on future cardiac dysfunction in chemotherapy-treated patients?

Effect of Obesity and Overweight on Left Ventricular Diastolic Function: A Community-Based Study in an Elderly Cohort
Russo C, Jin Z, Homma S, et al.
J Am Coll Cardiol 2011;57:1368-1374.
Study Question: What is the effect of increased body size on left ventricular (LV) diastolic dysfunction?

Pro–B-Type Natriuretic Peptide1-108 Circulates in the General Community: Plasma Determinants and Detection of Left Ventricular Dysfunction
Macheret F, Boerrigter G, McKie P, et al.
J Am Coll Cardiol 2011;57:1386-1395.
Study Question: What is the ability of circulating pro-B-type natriuretic peptide (proBNP1-108) to detect left ventricular (LV) dysfunction in the general population?

Irbesartan in Patients With Atrial Fibrillation
The ACTIVE I Investigators.
N Engl J Med 2011;364:928-938.
Study Question: What are the effects of irbesartan on the risk of cardiovascular events and maintenance of sinus rhythm in patients with atrial fibrillation?

Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes
Haller H, Ito S, Izzo JL Jr, et al., on behalf of the ROADMAP Trial Investigators.
N Engl J Med 2011;364: 907-917.
Study Question: What is the effect of treatment with olmesartan on the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria?
Preventing Weight Gain by Lifestyle Intervention in a General Practice Setting: Three-Year Results of a Randomized Controlled Trial
Ter Bogt NC, Bemelmans WJ, Beltman FW, Broer J, Smit AJ, van der Meer K.
Arch Intern Med 2011;171:306-313.
Study Question: Can an intervention implemented in a general office practice prevent weight gain among adults?

Association Between Body-Mass Index and Risk of Death in More Than 1 Million Asians
Zheng W, McLerran DF, Rolland B, et al.
N Engl J Med 2011;364:719-729.
Study Question: Is body mass index (BMI) associated with increased mortality risk among Asian men and women?

Effect of Nitroglycerin Ointment on Bone Density and Strength in Postmenopausal Women: A Randomized Trial
Jamal SA, Hamilton CJ, Eastell R, Cummings SR.
JAMA 2011;305:800-807
Study Question: What is the effect of nitroglycerin on bone mineral density (BMD) in postmenopausal women?

Improving Safety in the Electrophysiology Laboratory Using a Simple Radiation Dose Reduction Strategy: A Study of 1007 Radiofrequency Ablation Procedures
Rogers DP, England F, Lozhkin K, Lowe MD, Lambiase PD, Chow AW.
Heart 2011;97:366-370.
Study Question: How effectively do radiation dose-reduction maneuvers (RDRMs) decrease radiation exposure in the electrophysiology laboratory?

Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT)
Zareba W, Klein H, Cygankiewicz I, et al.
Circulation 2011;123:1061-1072.
Study Question: Is the response to cardiac resynchronization therapy (CRT) affected by QRS morphology in patients enrolled in the MADIT-CRT trial?

Permanent Pacemaker Insertion After CoreValve Transcatheter Aortic Valve Implantation: Incidence and Contributing Factors (the UK CoreValve Collaborative)
Khawaja MZ, Rajani R, Cook A, et al.
Circulation 2011;123:951-960.
Study Question: What are the incidence and determinants of permanent pacemaker (PPM) need in patients undergoing transcatheter aortic valve implantation (TAVI) using CoreValve?

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Progress in hypertrophic cardiomyopathy has saved lives, but knowledge gaps exist

As the main cause of sudden cardiac death in the developed world for people younger than 35 years, it is perhaps not surprising that hypertrophic cardiomyopathy is most often regarded as a disease that strikes without warning and leaves family members and friends reeling from the loss of a loved one.

However, although unpredictable sudden death is a characteristic of hypertrophic cardiomyopathy (HCM), it does not represent the overall outlook for patients with this disease today, more than 50 years since it was first recognized in a patient.

Barry J. Maron, MD, said despite the complexity and unpredictability of HCM, substantial progress has been made in the diagnosis and treatment of the disease.

“After 50 years, we have arrived at a different place, where this is a treatable disease, compatible with a normal life expectancy, and sometimes without the necessity of treatment because probably the vast majority of affected people live their lives without any major complications from HCM and may not even know they have it,” Barry J. Maron, MD, director, Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, told Cardiology Today.

Still, Maron said more must be done to increase the awareness of this disease.

“Time to time, there have been misunderstandings about what [HCM] is and how it’s treated and what patients can expect from a diagnosis,” he said. “So that continues to be an obstacle for the patient population because HCM is relatively uncommon in CV practice, making it easy to understand why rapid developments in this disease may not immediately penetrate the knowledge of everyone practicing cardiology.”

Locating the source of the disease

Despite its first modern description in a patient in 1957, the cause of HCM remained much a mystery for more than 3 decades until Seidman and colleagues began to unravel the genetic foundation of the disease. Their findings showed a mutation in the MYH7 gene in a family with HCM. After this discovery, more than a dozen genes were also implicated in HCM, with MYH7 and MYBPC3 now regarded as the most common causal genes, accounting for approximately 50% of all HCM cases.

Currently, the gene for HCM occurs in at least one of every 500 people. The disease, with complications ranging from angina and dyspnea to arrhythmia, is clinically diagnosed based on the detection of cardiac hypertrophy via an echocardiogram. This detection method, however, is not without shortcomings, as the likelihood of patients with a clinical diagnosis of HCM being misdiagnosed because of phenocopy conditions may be as high as 10%, said A. J. Marian, MD, professor and director, Center for Cardiovascular Genetics with The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston.

“There are conditions, such as storage diseases, that can cause cardiac hypertrophy. Clinically, they may be similar to true HCM, but they have different mechanisms involved,” Marian said, adding that the consequence of mistaking the disease is that the patient will be given the wrong treatment.

Although this discrepancy opens the door for more precise genetic testing, this method too has its share of challenges to overcome, said James B. Young, MD, professor of medicine of the Cleveland Clinic Foundation and Cardiology Today Section Editor.

“Physicians are often unclear on how to use molecular diagnostic tools, when to order genetic and genomic testing, and when to search for various mutations. There is just a lot of confusion out there regarding this strategy,” Young said in an interview, further noting that HCM “often isn’t at the top of somebody’s differential diagnosis. A patient comes in with atypical symptoms, chest discomfort, particularly in a young individual, and [physicians] may not list this high in their differential diagnosis because perhaps we haven’t educated folks enough about the frequency of the problem and the importance of the problem.”

During the past decade, patients with HCM at high risk for sudden death have benefited from the use of implantable cardioverter defibrillators. One study that tested the device in a high-risk population was conducted by Maron and colleagues and published in a 2007 issue of the Journal of the American Medical Association. According to their results, ICD interventions in 506 patients up to a 17-year interval terminated ventricular fibrillation and ventricular tachycardia in 20% of the study population, with only one sudden cardiac death, which was attributed to an ICD malfunction.

“The importance of the study is that it shows that sudden death [associated with HCM] is preventable, and that the ICD is the only treatment for HCM known to prolong life,” Maron said.

ICD therapy, as well as surgical myectomy surgery, transplantation and alcohol ablation for HF, represent dramatic hits regarding how to approach patients with the disease, but the role of drug treatment in HCM still remains uncertain.

“One persistent problem is how do you treat these patients with medications? We have not had a good clinical trial that has given us insight,” said Robert Roberts, MD, president and CEO of the University of Ottawa Heart Institute and Cardiology Today Editorial Board member. “There are several drugs people use, like beta-blockers, calcium-channel blockers and disopyramide (Norpace, Pfizer), but those are directed more toward the symptomatic patient population rather than patients with HCM having hypertrophy without symptoms.”

Currently, Marion said, pharmaceutical treatment in HCM is empiric. “In adults, no treatment has been shown to reverse or prevent the evolution of cardiac hypertrophy or fibrosis in HCM,” he said. “However, prevention of cardiac hypertrophy and fibrosis through pharmacological interventions could possibly reduce the risk of sudden cardiac death and perhaps even eliminate it.”

In addition, Roberts said there have been several animal models that have explained numerous findings of HCM, which may have future consequence in the treatment of this disease. These include studies that have shown use of a statin drug, an ACE inhibitor, an aldosterone inhibitor and N-acetylcysteine in mice and rabbits given the human HCM gene to be able to significantly ameliorate the disease.

“Unfortunately, we have never been able to get funding to do the trial in humans,” Roberts said. “Despite it being a common cause of sudden death, it is still a rare disease. In order to do a clinical trial, you would have to find a large number of centers. But, so far, drug companies have not been keen on doing such a study, in part because they are looking at a small population.”

The role of molecular biology in the treatment of HCM for Maron, however, remains unclear and unlikely to be the ultimate answer. “The whole idea of some sort of molecular ‘cure’ ignores one important point: This is a very powerful and heterogeneous genetic heart disease that will be very difficult to reverse in its entirety. It’s unlikely that it will ever be reversible by molecular biology,” he said.

Nevertheless, obtaining funding for research into HCM to try to answer these questions remains paramount.

“There has been very little if any funding available from NIH for clinical research related to genetic diseases, such as HCM,” Maron said. “In my view, it is unfair that our major granting institutions do not put much weight in these less common diseases. For people with HCM, it’s the most common disease in the world.”

“This is a disease in which we know an awful lot and we’re ready to do clinical trials,” Roberts said. “Given the devastating nature of the disease, it would be most unfortunate if we cannot find funding to do that.”

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Screening tool improved appropriate referrals for ICD implant
Gravelin L. Circ Cardiovasc Qual Outcomes. 2011;4:152-156.

The use of a screening tool increased the likelihood of referral to an electrophysiologist among patients in whom an implantable cardioverter defibrillator would help prevent sudden cardiac death, a new study suggested.

Laura M. Gravelin, MD, and investigators examined screening tools from medical records of patients from two outpatient cardiology offices. The screening tool analyzed in this study questioned general cardiologists as to whether their patients’ ejection fraction was 35% or less, and if so, the physician was then asked whether the patients were referred to an electrophysiologist for an ICD. Appropriate referrals in the screening group were then compared with similar data before screening tool implementation.

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Researchers reported that significantly more eligible patients were offered a referral during the screening period vs. pre-implementation at both sites. Specifically, at site one, the referral rate was 80% (eight of 10 eligible patients) vs. 33% (five of 15; P<.02 for trend) in favor of the screening period, whereas at site two, it was 100% (44 of 44 eligible patients) vs. 60% (21 of 35; P<.001 for trend) in favor of screening. Among all patients referred, 41% accepted. No sex-specific differences were reported in this study.

Besides these findings, researchers said barriers to referral include physicians’ understanding and recollecting the importance of ICD therapy for primary prevention, as well as patients’ willingness to undergo evaluation.

“Verification of these findings on a larger scale, as well as studies defining the foundation of these barriers, may further improve use of ICDs in patients for whom their mortality benefit is well described,” they said. – by Brian Ellis



The study by Gravelin et al illustrates the potential for integrating guidelines into daily clinical practice, ideally through use of an electronic medical record, which can alert clinicians to the potential for life-saving treatments such as an ICD. Guidelines are not recipes or mandates for care, but are rather useful "check lists" of factors to be considered. Alerting clinicians to factors such as a low ejection fraction is similar to highlighting abnormal lab values such as a high potassium or low blood sugar.

Whether or not to implant an ICD is a complex decision, however, and one that should be made by an expert clinician who considers more than just the ejection fraction, which is only the beginning of the story. An opportunity exists to glean additional information from the medical record that would complement and improve on a simple ejection fraction measurement to select patients who would benefit from an ICD, to uncover new, real-time, real-world data that could be used to improve the guidelines.

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Researchers examine CV risks related to chronic kidney disease treatments
Kestenbaum B. JAMA. 2011;305:1138-1139.
Palmer S. JAMA. 2011;305:1119-1127.

In a recent study, researchers were unable to find a correlation between serum levels of calcium and parathyroid hormone and the risk for CV mortality or all-cause death in patients with chronic kidney disease, although higher serum phosphorus in this population was linked with increased mortality risk.

This systematic review and meta-analysis included 47 cohort studies with a total of 327,644 patients. All studies measured the association between death and CV events and serum levels of phosphorus, parathyroid hormone or calcium, which are recommended in clinical practice guidelines for the management of mineral and bone disorders related to chronic kidney disease (CKD).

According to data, the risk for all-cause mortality increased with each 1-mg/dL increase in serum phosphorus (RR=1.18), but the likelihood of death remained largely unchanged with increased serum levels of parathyroid hormone (per 100-pg/mL increase, RR=1.01) and calcium (per 1-mg/dL increase, RR=1.08). Similarly, rates of CV mortality were only slightly affected with increased levels of serum phosphorus (RR=1.10), parathyroid hormone (RR=1.05) or calcium (RR=1.15).

These data, the researchers wrote, do not support the hypothesis that individuals with CKD should have treatment to achieve targeted levels of serum parathyroid hormone or calcium to reduce mortality or CV morbidity, “except at extreme levels in which hypocalcemia and hypercalcemia result in immediate, clinically apparent adverse events such as tetany and seizures,” they said. “Furthermore, treating high phosphorus levels is linked to a substantial pill burden that is associated with lower quality of life in individuals with CKD. While we do not conclude that normalizing serum levels of calcium or phosphorus or avoiding upper or lower extremes of serum level of parathyroid hormone is futile, high-quality evidence is required before specific treatment should be advocated strongly.”

However, extrapolating this research into clinical guidelines currently, wrote Bryan Kestenbaum, MD, with the University of Washington, Seattle, in an accompanying editorial, remains premature.

“Placebo-controlled clinical trials are the necessary next step to determine the risks and benefits of treatments that target mineral metabolism disturbances in patients with CKD as a means to improve their health,” he said.

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SYNTAX: Angina slightly improved in CABG vs. PCI patients
Cohen D. N Engl J Med. 2011;364:1016-1026.

A new quality-of-life substudy of the SYNTAX trial has shown that among patients with three-vessel or left main coronary artery disease, there was greater angina relief in those treated with CABG compared with percutaneous coronary intervention at 6 and 12 months.

In the Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) trial, a group of investigators allocated 1,800 patients (mean age, 65 years) with three-vessel disease or left main CAD to be treated with either PCI with paclitaxel-eluting stents (Taxus, Boston Scientific; n=903) or CABG (n=897). Using the Seattle Angina Questionnaire (SAQ) and the Medical Outcomes Study 36-Item Short-Form Health Survey, they then assessed health-related quality of life at four intervals: baseline, 1 month, 6 months and 12 months.

At 6 and 12 months vs. baseline, both groups had significantly higher scores with both surveys, indicating better health status. A greater improvement on the angina-frequency subscale of the SAQ, however, was reported in the CABG group at 6 (P=.04) and 12 (P=.03) months, yet the differences between groups were small and did not reach 2 points for either periods. Although freedom from angina assessed by SAQ was similar for both procedures at 1 and 6 months, there was a trend toward an improvement in the CABG group at 1 year (P=.05).

In the conclusion of the study, the researchers said the symptomatic benefits of CABG were counterbalanced by the more rapid recovery and improved short-term health status achieved with PCI.

The study was funded by Boston Scientific. Previous coverage of the SYNTAX trial can be accessed here.
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Menopausal symptoms reported at onset of menopause not associated with increased risk for CVD events
Szmuilowicz ED. Menopause. 2011;doi:10.1097/gme.0b013e3182014849.

Vasomotor symptoms that occur early in menopause do not appear to be associated with increased risk for CVD and are instead associated with decreased risks for total CVD events, stroke and all-cause mortality. Symptoms that occur late in menopause, however, are linked to increased coronary heart disease risk and all-cause mortality, researchers reported in a new study.

Emily D. Szmuilowicz, MD, MS, and colleagues conducted a study to investigate associations between menopausal vasomotor symptoms, clinical CVD events and all-cause mortality in a group of more than 60,000 women from the Women's Health Initiative (WHI) Observational Study. Their study focused on incident CVD events and all-cause mortality in four groups of women:

Women with no vasomotor symptoms at menopause onset and no symptoms at WHI enrollment (reference group; n=18,799).
Women with vasomotor symptoms at menopause onset but not at WHI enrollment (early symptoms; n=24,753).
Women with vasomotor symptoms at menopause onset and at WHI enrollment (persistent symptoms; n=15,084).
Women with vasomotor symptoms at WHI enrollment but not at menopause onset (late symptoms; n=1,391).

"Our study is the first to investigate the relationships between menopausal symptoms and CV events, and the first to examine the timing of menopausal symptoms," Szmuilowicz, a clinical instructor of medicine at Northwestern University, said in an interview. "The key finding of the study is that the menopausal symptoms experienced by the majority of women at mid-life do not indicate an increased risk for CVD in the future."

Compared with women who had no vasomotor symptoms, women who exhibited early symptoms had a HR of 0.94 for major coronary heart disease, 0.83 for stroke, 0.89 for total CVD and 0.92 for all-cause mortality. Women who had late vasomotor symptoms had HRs of 1.32 for major CHD, 1.14 for stroke, 1.23 for total CVD and 1.29 for all-cause mortality compared with women who had no symptoms. The researchers found no significant association with clinical CVD events among women who had persistent vasomotor symptoms.

"The predictive value of vasomotor symptoms for clinical CVD events may vary with the onset of vasomotor symptoms at different stages of menopause," the researchers concluded. “Future studies will also be necessary to investigate whether vasomotor symptoms that develop for the first time in later postmenopausal years represent a pathophysiologic process distinct from the classic perimenopausal vasomotor symptoms."

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Troponin I assay improved detection of MI in patients with suspected ACS
Mills N. JAMA. 2011;305:1210-1216.

In a patient population with suspected acute coronary syndrome, a sensitive troponin I assay was able to increase the prognosis of MI and further identified patients at high risk for death and MI.

Researchers from Edinburgh, Scotland, performed this study using a sensitive troponin I assay (Abbott Architect assays, Abbott Laboratories) to detect cardiac injury in patients with suspected ACS who were admitted to the Royal Infirmary of Edinburgh.

The study was split into two phases: validation (n=1,038), or before lowering the threshold of detection of myocardial necrosis from 0.2 to 0.05 ng/mL with the assay; and implementation (n=1,054), or after lowering the threshold. The patients were then stratified into three groups based on myocardial necrosis concentration: less than 0.05 ng/mL (n=1,340); 0.05 to 0.19 ng/mL (n=170); and at least 0.2 ng/mL (n=582).

During the validation phase, event-free survival, which incorporated rates of recurrent MI and death, at 1 year was worse in patients with plasma troponin levels from 0.05 to 0.19 ng/mL, resulting in a death and MI rate of 39% vs. 7% in those with troponin assay concentrations of less than 0.05 ng/mL (P<.001) and 24% in those with concentrations of 0.2 ng/mL or more (P=.007).

However, lowering the diagnostic threshold to 0.05 ng/mL in patients with troponin concentrations of 0.05 to 0.19 ng/mL correlated with a reduced risk of mortality and recurrent MI from 39% to 21% (P=.01).

“In patients presenting with suspected ACS, the use of a sensitive troponin I assay increased the detection of MI by 29% and identified patients who were at the highest risk of recurrent MI and death,” the researchers wrote, later adding that the percentage “may increase further with future improvements in assay performance allowing the 99th percentile to be used as the diagnostic threshold. This greater diagnostic performance will have implications for public health targets, government statistics, health care resources, and on the employment prospects and insurance policies of our patients.” – by Brian Ellis

Clinicians have been reluctant to use the proper cutoff values with sensitive assays because they more often see elevations that are difficult to explain. However, when they do, they realize that they have been missing large numbers of patients who do poorly if not treated, but benefit substantially from appropriate therapy.

However, in this study, the 10% CV value was used. This was still a big jump from the prior standard, but it would be of interest to see if using the 99th percentile value of 0.012 ng/mL would have identified still more patients at risk. It is this value that we [in the joint task force] advocate using in the definition of acute MI, something that is misstated by the authors. The fact that the group with values <0.05 ng/mL had a much lower event rate does not exclude the likelihood that there was a group between the values of 0.012 and 0.05 ng/mL that was at risk and could also have been helped by more aggressive therapy. The authors mention this but do not provide any data about this group.
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Transient ischemic attack doubled risk for MI
Burns J. Stroke. 2011;doi:10.1161/STROKEAHA.110.593723.

Those who experience a transient ischemic attack have twice the annual incidence of MI compared with the general population. This risk proved to be especially high in those who were younger than 60 years of age, new data suggest.

“CAD is the leading cause of death after TIA,” the researchers wrote. “Despite the key role played by CAD … reliable estimates of the risk of MI after TIA and the excess risk of MI in those who have had a TIA compared with the general population are lacking.”

This led the group of researchers from the Mayo Clinic in Rochester, Minn., to cross-reference pre-existing incidence cohorts from the Rochester Epidemiology Project for TIA and MI. The final study population included 388 patients who were at risk for incident MI after TIA. These data were then compared with MI incidences in the general population.

During a median follow-up of 10.2 years, the mean annual occurrence of MI after TIA was 0.95%, with an RR compared with the general population of 2.09 (95% CI, 1.52-2.81). This risk proved to be highest among patients aged younger than 60 years (RR=15.1; 95% CI, 4.11-38.6). For those who had an MI after TIA, the risk for death was more than three times higher than those who did not have an MI after TIA (HR=3.19; 95% CI, 2.19-4.66).

Additionally, researchers reported the following independent risk factors for MI after TIA: use of lipid-lowering therapy at the time of TIA (HR=3.1; 95% CI, 1.2-8); male sex (HR=2.19; 95% CI, 1.18-4.06); and increasing age (per 10 years, HR=1.51; 95% CI, 1.14 -2.01).

“Given that CAD plays an important role in the mortality of patients after TIA, these data support the existing concept that careful attention to the primary prevention of CAD is warranted in all patients who have had TIA and that screening for asymptomatic CAD may be useful in select TIA patients,” the researchers concluded.

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Recent MI possible significant risk factor for postoperative MI, death
Livhits M. Ann Surg. 2011;doi:10.1097/SLA.0b013e3182125196.

Patients who experienced an MI within 30 days of an operation had higher rates of MI 30 days after the procedure, as well as mortality at 1 year, according to a new study in the Annals of Surgery.

Christian de Virgilio, MD, principal investigator at Los Angeles Biomedical Research Institute and the study’s corresponding researcher, told CARDIOLOGY TODAY that this study “provides contemporary data regarding the risk of postoperative MI in patients who have had a recent prior MI, across a broad spectrum of surgical procedures.”

In the study, de Virgilio and colleagues utilized the California Patient Discharge Database to retrospectively analyze patients (n=563,842) who underwent cholecystectomy, colectomy, hip surgery, elective abdominal aortic aneurysm repair and lower extremity amputation from 1999 to 2004. They compared rates of postoperative 30-day MI, 30-day mortality and 1-year mortality between patients with and without a recent MI.

Results showed that postoperative MI rate among patients with a recent MI decreased substantially over time (0-30 days, 32.8%; 31-60 days, 18.7%; 61-90 days, 8.4%; 91-180 days, 5.9%), with rates of 30-day mortality sharing a similar trend (0-30 days, 14.2%; 31-60 days, 11.5%; 61-90 days, 10.5%; 91-180 days, 9.9%). Additionally, MI within 30 days of an operation correlated with a higher risk for postoperative MI (RR range, 9.98-44.29), 30-day mortality (RR range, 1.83-3.84) and 1-year mortality (RR range, 1.56–3.14).

For de Virgilio, these findings should increase awareness of the importance of a recent MI as a major predictor of having another MI and of perioperative death.

“In light of these data, patients with a recent MI who are being considered for elective surgery should carefully weigh the risks and benefits of the procedure and, if at all possible, delay surgery for at least 2 months — if not longer,” he said. “They should [also] be evaluated by a cardiologist to determine whether further intervention is needed prior to surgery.” – by Brian Ellis

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Asthma may be linked to increased incidence of diabetes, heart disease

Asthmatics were more than twice as likely to develop diabetes mellitus as non-asthmatics, according to findings presented at the 2011 Annual Meeting of the American Academy of Allergy, Asthma & Immunology in San Francisco.

The retrospective population-based study aimed to evaluate potential associations between asthma and proinflammatory conditions, including inflammatory bowel disease, rheumatoid arthritis, diabetes mellitus and coronary artery disease, in 2,392 patients with asthma and 4,784 matched controls.

The incidence rates of proinflammatory conditions were calculated per 100,000 population. The incidence of inflammatory bowel disease was 16.7 in the non-asthmatic cohort and 21.2 in the asthmatic cohort. For rheumatoid arthritis, the incidence increased from 55.3 among non-asthmatics to 81.8 among asthmatics. The incidence of diabetes mellitus increased from 104 in the non-asthmatic group to 138.4 in the asthmatic group. Asthma also was associated with an increased incidence of coronary artery disease, 134 vs. 188.6.

The HR for developing diabetes mellitus among asthmatics compared with non-asthmatics was 2.11 (95% CI, 1.43-3.13). The risk for coronary artery disease also was significantly increased (HR=1.43; 95% CI, 1.02-2.01).

The risks for inflammatory bowel disease (HR=1.31) and rheumatoid arthritis (HR=1.42) were not significantly higher in the asthma cohort.

“Given that coronary artery disease and diabetes mellitus are major morbidities in adults, we believe that clinicians need to be aware of our findings,” Young Juhn, MD, associate professor of medicine at the Mayo Clinic in Rochester, Minn., said of the findings in a press briefing. “Symptoms of coronary artery disease and diabetes should be assessed during routine follow-up care.”

Juhn said the patient and control populations were individuals from the Rochester, Minn., area who were diagnosed or contacted between 1964 and 1983. “Asthma diagnosis was based on clinical criteria for asthma, not physician diagnosis,” he said. “Outcome events were also based on clinical criteria or ICD code.”

Asthma increased the risk for the studied proinflammatory conditions by about 50%, Juhn said.

“Rheumatoid arthritis and inflammatory bowel disease did not reach statistical significance,” he said. “This could be explained by limited statistical power, meaning a small sample size. However, it should be noted that rheumatoid arthritis and inflammatory bowel disease have lower incidence than the other diseases.”

Juhn said more focus should be placed on surveillance of asthma status. “It might be prudent to monitor the impact of asthma epidemiology on the epidemiology of these proinflammatory conditions, given that they have increased over the last 2 decades,” he said.

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ACCF/AHA/HFSA 2011 Survey Results: Current Staffing Profile of Heart Failure Programs, Including Programs That Perform Heart Transplant and Mechanical Circulatory Support Device Implantation
[Ссылки могут видеть только зарегистрированные и активированные пользователи]

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PARTNER A: Mortality comparable between TAVR and AVR procedures

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS – New results from the PARTNER A cohort have indicated that despite a higher rate of stroke among patients treated with transcatheter aortic valve replacement compared with aortic valve replacement, rates of mortality were similar between both procedures at 1 year.

The trial included 699 high-risk older patients (median age, 84.1 years) with severe aortic stenosis who were randomly assigned to receive either transcatheter aortic valve replacement (TAVR; Sapien, Edwards Lifesciences; n=348) or aortic valve replacement (AVR; n=348). The primary endpoint was all-cause mortality at one year, with stroke and major vascular and bleeding events serving as additional endpoints.

Despite a more favorable outcome for TAVR in mortality (3.4% vs. 6.5%) and symptoms at one month, by one year both rates were similar between the two procedures. Important differences, however, were reported in rates of stroke at one year (TAVR, 5.1% vs. AVR, 2.4%), vascular complications at one month (TAVR, 11% vs. AVR, 3.2%), major bleeding (TAVR, 9.3% vs. AVR, 19.5%) and new-onset irregular heart rhythms of atrial fibrillation (TAVR, 8.6% vs. AVR, 16%).

“This opens up a new set of patients who may very well benefit as much by TAVR as by conventional the gold standard surgery,” said Craig R. Smith, MD, chief, division of cardiothoracic surgery, New York-Presbyterian Hospital, Columbia University Medical Center, New York, and the study’s co-principal investigator, in a press conference. “As everyone knows no one wants surgery — no one should want surgery — and an equivalent therapy is always a good thing.”

Upcoming for the PARTNER trial is the recently approved PARTNER II trial which will pair the next generation of TAVR and a different catheter-based delivery system against the valve and delivery method used in the first trial. – by Brian Ellis

For more information:
Smith C. LBCT I, Session 3010. Presented at: ACC 60th Annual Scientific Sessions; April 2-5, 2011; New Orleans.

You are all witnessing history in the making. Those of you who saw Dr. Smith’s presentation really did see history unfolding. I think it probably will be seen as one of the biggest steps in CV medicine as far as intervention is concerned potentially in our lifetime. If we look back to balloon angioplasty, the advent of stents, and then drug-eluting stents, probably on the life-scale of the calendar [percutaneous valve intervention ] will be seen as the next major turning point.

These extraordinary results are accomplished because of an unprecedented team work between a cardiologist, cardiac surgeon and the associate care givers. I just want to emphasize that if we fail to not pay equal attention to what we have done in this trial after this device is approved, I don’t think we will be able to replicate these results. The cardiac surgeon profession and the cardiology profession, particularly interventional cardiologists, had a sometimes not easy relationship over the past 50 years, but now over the past 5 years as evidenced by this trial on how we interact with each other, how we perform as a single team, are really diametrically opposite … So I think it is critical to emphasize that.
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PARTNER B: Data reveal TAVR cost-competitive in elderly, inoperable patients

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS – Transcatheter aortic valve replacement proved to be cost-effective when compared with standard care for patients with severe aortic stenosis who were not candidates for surgery, according to PARTNER cohort B data.

Researchers of the PARTNER trial randomly assigned patients (mean age, 83 years) to receive either transcatheter aortic valve replacement (TAVR; n=179) or standard non-surgical care (n=179) that included medication and balloon aortic valvuloplasty. They derived the one-year cost-effectiveness data on all patients from medical resource utilization data, as well as hospital billing for a sub-set of patients, and then projected long-term survival from this data.

Initially, the cost of TAVR, including care before and after the procedure, was roughly $78,000, with the cost of the system estimated at $30,000. During the first year, those in the standard care group were more than twice as likely to be hospitalized for CV reasons, which resulted in follow-up costs being $23,000 more expensive at one year when compared with the TAVR group, which partially offset initial costs of TAVR.

According to estimates, there was a gain in life expectancy of approximately 1.9 years with the TAVR approach (3.1 years vs. 1.2 years). Each year of life gained corresponded with an incremental cost-effectiveness ratio of roughly $50,200, or approximately $62,000 per each quality-adjusted life year gained.

In a press conference, Matthew R. Reynolds, MD, director, economics and quality of life research at Harvard Clinical Research Institute, Boston, explained that “These life-time projections are necessary to understand the return on the upfront investment because most of the cost is incurred at the beginning … Based on lifetime projections, we estimated an $8,000 difference for incremental cost associated with TAVR which is significant. We also estimated a survival gain which is also quite significant… of almost 2 years in this extremely high risk and elderly population.”

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Target BP levels for patients with diabetes, high-risk hypertension remain debatable

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — The amount and quality of evidence indicating ideal target BP levels in patients with diabetes or high-risk hypertension was up for discussion at the American College of Cardiology 60th Annual Scientific Sessions.

“The current ACCORD trial was designed to answer the question of optimal BP control,” Stanley S. Franklin, MD, of the University of California, Irvine Heart Disease Prevention Program, said during a presentation here. “But targeting systolic BP to 119 mm Hg vs. 133.5 mm Hg did not reduce composite rate of CV events in ACCORD, so the crux of this debate is: Should office systolic BP be less than 140 mm Hg, less than 135 mm Hg or lower?”

Contradictory evidence

Franklin, who spoke in support of targeting BP below 130/80 mm Hg, cited population studies from the Prospective Study Collaboration Oxford Group that show that systolic BP correlates with cardiovascular risk to as low as 115 mm Hg at all ages. He also noted that the Framingham Heart Risk Equations indicate an additive effect of combining diabetes with hypertension and an even higher risk when combining with other risk factors, suggesting that BP levels are “only one part of global risk of assessment.”

In addition, Franklin said, stages of CV disease may yield different endpoints for therapy. “Indeed, the wide spectrum of disease over time may require different treatment thresholds and different treatment goals.”

Accuracy of BP measurements must also be taken into consideration, according to Franklin. The 11-country International Database on Ambulatory BP monitoring in relation to CV Outcomes (IDACO) study revealed that researchers found sustained hypertension in a little less than 50% of patients, white coat hypertension in more than 50% of patients and approximately 10% of clinic-normotensive patients had masked hypertension. About 73% of middle-aged to older patients, however, were misdiagnosed by clinic measurements, spurring Franklin to question whether a high rate of misclassification by office assessment played a role in recruitment for the ACCORD study.

Furthermore, another study denoted only a 5-mm Hg difference between patients with masked hypertension and normotensive patients. Results also revealed a statistically higher percentage of target organ damage, kidney disease or left ventricular hypertrophy in patients with masked hypertension, according to Franklin.

“Perhaps the question is not whether lower is better but if whether the earlier you diagnose and treat, the better,” he said.

Franklin stressed the importance of measuring standing BP and nocturnal dipping as well, highlighting one study that indicated a correlation between postural hypertension and increased stroke risk in certain patients, such as the elderly, patients with type 2 diabetes or those with peripheral neuropathy. He pointed out that, because of high rates of misclassification by clinic or office BP measurements, the American Heart Association and the American Society of Hypertension recommend beginning therapy with raised office BP, borderline or prehypertension in the presence of organ damage. In the absence of organ damage, home BP measurement can be valuable, Franklin said, noting that treatment may also be initiated if daytime ambulatory BP exceeds 135/85 mm Hg. Nevertheless, he warned against lowering BP too much in frail patients with diabetes.

The need for more data

In response, William C. Cushman, MD, chief of preventive medicine section at Veterans Affairs Medical Center in Memphis, Tenn., explained that no data confirm the benefits of targeting a BP of 130/80 mm Hg in patients with diabetes or high-risk hypertension. The ACCORD trial, he noted, afforded robust data in a high-risk population of more than 4,700 participants. The systolic BP was lower than 140 mm Hg in the majority of participants in the standard BP goal group, which targeted a systolic BP goal of less than 140 mm Hg, he said. In the intensive therapy group, which targeted a systolic BP of less than 140 mm Hg, the average number of drugs required to achieve a systolic BP of 119.3 mm Hg was 3.4, and slightly more than two drugs in the regular therapy group, which averaged systolic BP of 133.5 mm Hg, according to Cushman. The benefits of attaining this target, however, did not reach statistical significance.

“Results of ACCORD and previous studies provide no conclusive evidence that BP should be reduced with antihypertensive drugs below 120 mm Hg or 130 mm Hg,” Cushman said. “These trials also do not conclusively prove that we shouldn’t aim for less than 120 mm Hg, but they provide the best evidence to date, and, therefore, do not offer conclusive evidence that we should do it.”

Moreover, Cushman emphasized that lowering BP targets would potentially mean millions of new diagnoses of hypertension. These “new” patients will require therapy and monitoring, and those patients already diagnosed with hypertension will need more drugs and monitoring, and those patients already diagnosed with hypertension will need more drugs and monitoring to reach desired BP levels. This may also have a negative effect in the form of a J-curve, Cushman said, and if treatment is neither harmful nor beneficial, then that poses other problems. Monitoring would become more frequent and costly while adverse event would also become more common.

“It could waste patients’ and payers’ resources and time, and possibly deflects us away from something we have the resources to do,” he said.

Adherence may also decline, according to Cushman. Patients who are already taking eight to 10 drugs, for example, may decide to stop buying certain medications to alleviate cost or just because they want to take fewer pills. Nevertheless, they may be making the wrong choices, he said.

Both Cushman and Franklin acknowledged that more research is needed in this area and expressed hope that future trials will provide more conclusive data. – by Melissa Foster

Disclosures: Dr. Cushman has served as a consultant for Takeda Pharmaceuticals, Sanofi Aventis, Bristol Meyers-Squibb, Novartis, Daiichi Sankyo and Theravance. Dr. Franklin reports no relevant financial disclosures. Dr. Vongpatanasin reports no relevant financial disclosures.
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Abnormal glucose tolerance linked with endothelial dysfunction in setting of CAD

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS – According to new research, endothelial dysfunction was associated with abnormal glucose tolerance in patients who had coronary artery disease and unknown diabetes mellitus.

Researchers from Kokura Memorial Hospital in Japan enrolled 95 consecutive patients with CAD (37 with ACS and 58 with stable angina), normal fasting glucose levels (<110 mg/dL and HbA1c <6.5%) who underwent successful PCI between March and September 2010. They then assessed glucose metabolism and endothelial function using a 75 g oral glucose tolerance test and flow-mediated dilatation of the brachial artery.

Results from the 75-g oral glucose tolerance test separated the patients into those with normal glucose (n=25), those with impaired glucose tolerance (n=43) and those with diabetes (n=27). Flow-mediated dilatation in the diabetes group was lower (3.8% ± 1.3%) than that reported in both the normal (5.0% ± 2.1%) and the impaired glucose tolerance (5.2% ± 2.5%) groups. The researchers reported that only 2-hour postload glucose level was associated with flow-mediated dilatation (r=.10, P=.007).

“Endothelial dysfunction is associated with abnormal glucose tolerance, especially 2-hour post-load glucose level,” the researchers wrote in their abstract. “It indicates that early diagnosis and intervention for abnormal glucose tolerance may improve the endothelial dysfunction in patients with CAD and unknown diabetes mellitus.”

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Acute MI rates lower in men, women since Red Dress Campaign

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS – Since its inception in 2002, the National Heart, Lung and Blood Institute’s Red Dress Campaign has been associated with a decreased incidence of acute MI among both men and women, according to data presented here.

“Over the last few years there’s been a lot of awareness of women in public health and cardiovascular disease. Some research has been done to demonstrate the increase, and we wanted to see if this increase translated into improved outcomes in treatment patterns in women,” Liana M. Spano-Brennan, DO, cardiology fellow, told Cardiology Today.

Using the New Jersey Myocardial Infarction Data Acquisition System database, Spano-Brennan and colleagues at the University of Medicine and Dentistry of New Jersey’s Robert Wood Johnson Medical School identified 315,246 patients who presented to hospitals in New Jersey for acute MI between 1986 and 2007. Almost half (40.9%) of patients identified were female. The researchers examined the effect the campaign has had on acute MI incidence, management and outcomes.

The overall incidence of acute MI (per 100,000) decreased between 1986 and 2007, with the most notable decline observed in men (women: 321 to 197; P<.0001 and men: 598 to 311; P<.0001). According to the researchers, after 2002, the trend increased.

Over the observed period of 22 years, though the rate of left heart catheterization increased 5-fold for women and 3-fold for men, the likelihood of left heart catheterization was still low among women (OR=0.78; 95% CI, 0.77-0.79). The percent difference between men and women undergoing percutaneous coronary intervention increased from 2.2% in 1986 to 9.4% in 2007 (P<.0001), among those who received left heart catheterization.

Both in-hospital and one-year mortality was higher among women compared with men (OR=1.30; 95% CI, 1.27-1.34 for in-hospital and OR=1.10; 95% CI, 1.08-1.13 for one-year). However, the mortality rate did not decrease significantly after 2002.
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Combination ezetimibe, simvastatin plus niacin may benefit patients with hyperlipidemia

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Treatment with combination ezetimibe and simvastatin plus extended-release niacin may aid patients with hyperlipidemia in achieving target LDL cholesterol, non-HDL cholesterol and apolipoprotein B levels, according to data presented here.

To compare the efficacy of combination ezetimibe and simvastatin plus extended-release niacin with either treatment alone, researchers conducted a randomized, double blind study involving patients with type IIA and IIB hyperlipidemia.

“What we looked at in this combination with ezetimibe and the statin along with extended-release niacin how that supports the attainment of recommended LDL, non-HDL and apolipoprotein B goals and showing that the combination allows you in this patient population to get to significantly more patients to get to those goals,” Andrew M. Tershakovec, MD, MPH, researcher for Merck, told Cardiology Today.

Patients were randomly assigned to one of the following regimens:
10 mg/20 mg of combination ezetimibe and simvastatin plus up to 2 g of niacin for 64 weeks.
10 mg/20 mg of combination ezetimibe and simvastatin alone for 64 weeks.
Up to 2 g of niacin for 24 weeks then 10 mg/20 mg of combination ezetimibe and simvastatin plus up to 2 g of niacin for 40 weeks or more.
Up to 2 g of niacin for 24 weeks then 10 mg/20 mg of combination ezetimibe and simvastatin alone for 40 weeks or more.

Tershakovec and colleagues also assessed lipid outcomes in subgroups of patients with high risk for coronary heart disease, diabetes, metabolic syndrome and those without diabetes or metabolic syndrome.

Results revealed that considerably more patients receiving combination ezetimibe and simvastatin plus niacin reached concomitant LDL cholesterol, non-HDL cholesterol and apolipoprotein B levels when compared with those receiving niacin and combination ezetimibe and simvastatin at 24 weeks and combination ezetimibe and simvastatin at 64 weeks. In all subgroups, attainment rates remained higher for patients receiving the combination treatment plus niacin vs. niacin alone at 24 and 64 weeks. In addition, rates were generally greater with combination ezetimibe and simvastatin plus niacin vs. the combination treatment alone. Concomitant attainment of all three target lipid levels was most consistent with the single level attainment of non-HDL cholesterol.

“What this shows is that the combination of ezetimibe/statin and niacin is a very potent,” Tershakovec said. “I think niacin-based therapy has been around a long time, but the outcomes data are relatively limited. However, the data that do exist are positive.”

He noted that two large outcome studies examining the use of extended-release niacin will also provide physicians with more insight into how to implement these treatments into clinical practice.

“Seeing those outcomes data would be very informative on what the utility of therapies like this really are,” Tershakovec said. – by Melissa Foster

Disclosure: Dr. Tershakovec is an employee for Merck as well as a company stockholder.

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STICH: CABG plus medical therapy yields marginal benefit in patients with HF, CAD

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS – The addition of CABG to a regimen of optimal medical therapy in patients with HF and coronary artery disease was not associated with a significant benefit, but surgery was linked with lower risk for death from heart disease, results from the STICH trial suggested.

Researchers for the randomized Surgical Treatment of Ischemic Heart Failure trial enrolled 1,212 patients from 99 centers in 22 countries and randomly assigned them to either optimal medical therapy (n=602) or medical therapy plus CABG (n=610). Average follow-up was 56 months. The trial represented the largest randomized, controlled study comparing CABG plus optimal medical therapy to medical therapy alone in this patient population conducted to date.

According to the study data, the death rate in the CABG group was 36% vs. 41% with medical therapy alone, but the finding did not reach statistical significance (P=.12). However, CABG was linked with lower rates of CV death (28% vs. 33% with medical therapy alone; P=0.05) and lower rates of the combined endpoint of death from any cause plus hospitalization for heart disease (58% vs. 68% with medical therapy alone; P<.001). The researchers noted that 55 patients assigned to the surgery group did not undergo surgery, and 100 patients assigned to medical therapy alone ended up undergoing CABG. When looking specifically at the patients who had received their assigned treatments, however, CABG reduced any-cause death by 25% (P=0.005).

While the survival benefit of CABG was apparent after 2 years, the researchers cautioned that there was a higher up-front risk with CABG than with medical therapy alone.

“CAD should continue to be assessed among all patients presenting with HF, and in HF patients with CAD on medical therapy, CABG should now be considered to reduce CV mortality and morbidity,” Eric J. Velazquez, MD, associate professor of medicine and director of the cardiac diagnostic unit and echocardiography laboratories at Duke University Medical Center in Durham, N.C., said in a presentation. “The durability of CABG benefits will be tested in the STICH Extension Study, which is ongoing.” – by Eric Raible

Disclosure: Dr. Velazquez reports no relevant financial disclosures.
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Study: Myocardial viability imaging, CABG effectiveness not linked

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS – Myocardial viability imaging was not associated with the effectiveness of CABG, results from a viability substudy of the STICH trial indicated.

Researchers for the substudy recruited 601 patients from the STICH study and assigned them to undergo either nuclear perfusion scanning or dobutamine echocardiography. Of those, 487 were determined to have myocardial viability (243 assigned to medical therapy and 244 to CABG) and 144 patients did not have myocardial viability (60 assigned to medical therapy and 54 to CABG).

Although the death rate was 37% among patients with myocardial viability (P=0.003) and 51% among patients without myocardial viability, the association became statistically insignificant when baseline characteristics were adjusted for (P for interaction=0.528).

“Imaging may be important in individual patients, but there are many other factors that contribute to outcomes in patients with CAD and HF with or without surgery,” Robert O. Bonow, MD, professor of medicine and director of the Center for Cardiovascular Innovation at Northwestern University in Chicago, told Cardiology Today. “These include comorbidities like kidney failure, diabetes and overall left ventricular function that are more important factors in a multivariable analysis than just the myocardial viability data alone.” – by Eric Raible
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EVEREST II: Safety, efficacy remain stable at 2 years

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Two-year data from the EVEREST II trial indicate that percutaneous repair with MitraClip is as effective as surgery in select patients with mitral regurgitation. Updated study results were presented here by study author Ted Feldman, MD, director of the cardiac catheterization laboratory at NorthShore University HealthSystem in Illinois.

Initial results from EVEREST II demonstrated that the safety of MitraClip (Abbott Vascular) was greater compared with surgery, but also that MitraClip was inferior to surgery in reducing mitral regurgitation. One-year results were presented at the ACC 59th Annual Scientific Sessions in 2010. The current results suggest that at 2 years, 78% of patients who received the MitraClip device (Abbott Vascular) did not need surgery.

“The fundamental finding is that everything was very stable between 1 and 2 years. The Kaplan-Meier curves for mortality and reoperation remain, literally, completely flat through that time period. Gains in left ventricular performance and clinical outcome were very stable,” Feldman said during a press conference.

The study included 279 patients with grade 3+ or 4+ mitral regurgitation who were randomly assigned at 2:1 to receive the MitraClip (n=184) or standard surgery (n=95). Treatment efficacy was measured by freedom from death, absence of new mitral valve surgery and mitral regurgitation lower than grade 3+. Results were similar between the two groups: 62.7% of patients in the MitraClip group met this endpoint vs. 66.3% in the surgery group.

Major adverse events were significantly lower in the MitraClip group compared with surgery: 15% vs. 47.9% (P<.001). This difference is mainly explained, Feldman said, by the percentage of patients requiring a blood transfusion at ≥2 units (13.3% in the MitraClip arm vs. 44.7% in the surgery arm).

At 2 years, the researchers report no device embolization, fracture, erosion or migration. In addition, the occurrence of single leaflet device attachment remained unchanged between 1 and 2 years.

Primary effectiveness results were similar between years 1 and 2: 55.2% at 1 year vs. 51.7% at 2 years in the MitraClip group and 73.0% at 1 year vs. 66.3% at 2 years in the surgery group.

According to Feldman, both treatment strategies reduced mitral regurgitation and showed clinical benefit through 2 years, which includes significantly improved LV volumes and NYHA functional class. Follow-up will continue for 5 years. - Stacey L. Fisher

Disclosures: The EVEREST II study received funding from Evalve Inc. Dr. Feldman is a consultant for Abbott, which acquired Evalve in 2009.

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PRECOMBAT: Sirolimus-eluting stent non-inferior to CABG in patients with unprotected left main CAD

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Data from the PRECOMBAT trial have suggested that angioplasty with a sirolimus-eluting stent was noninferior to CABG in a composite endpoint of major adverse cardiac or cerebrovascular events at 1 year among patients with unprotected left main coronary artery disease.

The Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-eluting Stent in Patients with Left Main Coronary Artery Disease (PRECOMBAT) trial included 600 patients who were randomly assigned to either CABG (n=300) or angioplasty with a sirolimus-eluting stent (SES; Cypher, Cordis; n=300). All patients of the prospective, open-label trial had unprotected left main coronary artery (ULMCA) stenosis. The primary outcome was a composite of major adverse cardiac or cerebrovascular events that included all-cause mortality, stroke, MI and ischemia-driven target vessel revascularization (TVR) at 12 months.

According to results, the primary outcome was 8.7% in the CABG arm vs. 6.7% in the SES arm (P=.39), which remained similar at 24 months (SES, 12.2% vs. CABG, 8.1%; P=.12). Rates of death, MI or stroke at 2 years (CABG 4.7% vs. 4.4% SES) did not differ to a statistically significant extent, although ischemia-driven TVR did favor CABG (CABG, 4.2% vs. SES, 9.0%; P=.022).

“We didn’t find any hard endpoint concern in MI, stroke or all-cause death, just a difference in ischemia-driven TVR. The TVR concern is of frequent clinical relevance, however it is not such a strong one,” Seung-Jung Park, MD, PhD, professor of medicine, University of Ulsan College of Medicine, Seoul, Korea and lead study author, told Cardiology Today, later adding that he is anticipating large numbers of upcoming prospective, randomized studies that will give clearer answers on these hard endpoints in percutaneous coronary intervention vs. CABG procedures. – by Brian Ellis

Disclosure: Dr. Park has received consulting fees/honoraria as well as research grants from Cordis.
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RAPS: Better graft closure reported in radial artery vs. saphenous vein grafts

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Among patients with three-vessel disease who underwent CABG, those who received radial artery grafts compared with saphenous vein grafts had lower rates of occlusion after more than 7 years following the procedure.

“The study we’ve presented is the first multi-institutional, longitudinal, randomized comparison, so this is fairly unique data,” said Stephen E. Fremes, MD, MSc, study lead author and head of the division of cardiac and vascular surgery, Schulich Heart Centre, Sunnybrook Health Sciences Centre, Toronto, in a press conference. “Hopefully it will be persuasive and won’t detract from the use of radial arteries.”

In the randomized Radial Artery Patency Study (RAPS), investigators enrolled 561 patients who underwent CABG for three-vessel disease at 13 Canadian centers. Patients were treated with both a saphenous vein graft and a radial graft at two different diseased vessel sites. The primary endpoint was functional graft occlusion at least five years after surgery, while the secondary endpoint was complete graft occlusion.

During a mean of 7.6 years following procedure in 269 patients, researchers found substantially fewer radial arteries were occluded vs. saphenous vein grafts (12% vs. 18.8%; P=.05). Similarly, rates of complete occlusion were lower in radial arteries (8.9% vs. 17.8%; P=.004), as were rates of functional graft occlusion (12% vs. 18.8%; P=.05). Furthermore, graft stenosis of greater than 25% or occlusion was also lower in the radial arm (21.9% vs. 33.8%; P=.004). – by Brian Ellis

For more information:
Fremes S. LBCT II, Session 3013. Presented at: ACC 60th Annual Scientific Sessions; April 2-5, 2011; New Orleans.

It has pretty much fallen out of favor using the radial artery and yet since vein grafts are perceived to be so inferior to internal mammary grafts you look for something else and maybe new things will come in the future. But the RAPS trial was counter to the VA trial, which showed at one year 89% patency for veins and 89% for radial artery. Here with a longer follow-up and with a little different way the trial was done, this looks a little better. So I think this is going to reinvigorate surgeons to use radial arteries more. I would expect this will have a clinical impact.
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Meta-analysis: Lipid-lowering therapy may be most beneficial when started early

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — The mortality benefits afforded by lipid-lowering therapy persist after trial randomization in clinical trials where both arms receive active therapy, according to data from a meta-analysis.

William J. Kostis, PhD, MD, of Massachusetts General Hospital in Boston, and colleagues aimed to determine whether the mortality benefit bestowed by lipid-lowering therapy persists after the end of clinical trials when both treatment and placebo groups are advised to take active therapy.

The researchers used Medline, the Cochrane Library, Web of Science and ClinicalTrials.gov to identify eight randomized trials of lipid-lowering medications (including 5 statin trials); all trials included secondary reports describing the results observed at study completion. They then calculated odds ratios for all-cause and cardiovascular mortality for both the randomized and open-label follow-up phases of each trial trial (when all patients were advised to take active therapy). The results were compared using a random-effects meta-analysis.

Data for 44,255 patients and 8,144 deaths were included. According to Kostis, during the randomized phase, patients randomly assigned to active therapy were about six-and-a-half-times more likely to receive it compared with those assigned to placebo.

“The ratio of the percentage of patients receiving active therapy among the group randomized to receive it to the percentage of those receiving active therapy among those randomized to placebo (AMR) was 6.52 (inter quartile ratio (IQR)= 4.88-10.11),” the researchers wrote.

In the open-label phase, the proportion of patients originally assigned to placebo who were administered active therapy was nearly identical to those initially randomly assigned to active therapy (AMR=1.02; IQR=0.92-1.14).

Mortality rates – both all-cause (OR=0.84; 95% CI, 0.76-0.93) and CV (OR=0.72; 95% CI, 0.63-0.82) – were lower in the group assigned to active therapy during the randomization phase. This decrease in mortality continued when both groups received active therapy in the open-label phase (all-cause mortality: OR=0.90; 95% CI ,0.84-0.97; and CV mortality: OR=0.82; 95% CI, 0.73-0.93).

Kostis told Cardiology Today that the results of this analysis demonstrate that patients should be treated earlier, and that long-term statin therapy may not always be necessary. - Stacey L. Fisher

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ACC 2011
Diastolic Heart Failure: Beyond Recognizing a Preserved Ejection Fraction
By Jeffrey Hertzberg, MD, MS | 4 Апрель 2011 г.

Diastolic heart failure (or HFPEF—heart failure with preserved ejection fraction) is characterized by inadequate myocardial relaxation and diastolic filling ("stiff ventricle"), with heart failure signs and symptoms despite normal ejection fraction. The most common cause is long-standing hypertension. Current thinking regarding the underlying pathophysiology stresses poor diastolic reserve that is inadequate to meet the demands of exercise in HFPEF, in contrast with early studies which focused on the "stiff" ventricle in resting subjects. During exercise in normal subjects, rapidly relaxing ventricles "suck" blood out of the atria; in HFPEF, ventricular filling during exercise is markedly impaired, with cardiac output inadequate to meet demand. Other recent studies have revealed additional layers of complexity:

•Systolic abnormalities are part of HFPEF: despite grossly preserved systolic ejection fraction, systolic reserve is inadequate—systolic contractility doesn’t adequately increase with exercise. This research has shed new light on the functional limitations present in HFPEF patients.
•Poor vasodilator reserve function: normal subjects experience peripheral vasodilation with exercise; this afterload decrease enhances cardiac output to meet demand. Endothelial dysfunction in patients with HFPEF prevents this response.

Therapy: No therapy has demonstrated clear evidence for improved outcomes in diastolic heart failure. Aggressive use of beta blockers has fallen out of favor for most HFPEF patients because it can exacerbate chronotropic incompetence (inability to increase heart rate to meet cardiac output demands seen in HFPEF). The primary approach in the treatment of HFPEF remains aggressive treatment of controllable risk factors, and the use of cardiac rehabilitation to improve exercise tolerance through conditioning of peripheral tissue oxygen extraction. HFPEF and ischemic heart disease can present as comorbid conditions with four primary risk factors that can all be present in the same patient: hypertension, advanced age, renal insufficiency, and diabetes.

Diabetes appears to be a powerful independent risk factor for HFPEF, associated with abnormal left ventricular filling even in the absence of hypertension. Diastolic dysfunction is seen in 30% to 70% of patients with type 2 diabetes; the likely mechanisms include altered endothelial function, defective energy metabolism, and microvascular disease—diabetes is associated with left ventricular hypertrophy as an independent risk factor. Given that worldwide diabetes prevalence will increase from 135 million in 1995 to 300 million in 2025, primary care physicians can expect to treat an enormous number of new HFPEF patients in the coming years.

Regarding ischemic syndromes and HFPEF, it is paradoxically observed that:

•Chest pain can occur in the setting of HFPEF and relatively normal coronary arteries.
•Unstable angina is more prevalent in heart failure patients with preserved EF than with garden variety systolic dysfunction.

Echocardiography and other functional studies can help distinguish ischemic heart disease from symptomatology related to diastolic dysfunction, and is important because patients with HFPEF can present with chest pain unrelated to coronary artery disease. The lack of wall motion abnormalities or other functional changes indicative of ischemia can help avoid unnecessary angiography in this cohort.

Current Concepts in Diastolic Heart Failure: Highlights from "Diastolic Heart Failure, Beyond Recognizing a Preserved Ejection Fraction," a panel presentation at ACC.11, April 3, 2011. New Orleans, La.
Co-chairs: Anita Deswal, MD, Christopher O’Connor, MD
Synthesizing material from presenters: Eric Veslazquez, MD (Duke University), Barry Borlaug, MD (Mayo Clinic), Michael Fowler, MD (Stanford), and Carolyn Lam, MD (Mayo Clinic).

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RIVAL: More favorable outcomes documented for radial vs. femoral access

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — New data presented here from the largest randomized trial to date comparing radial and femoral access for coronary angiography and intervention have revealed radial access to be superior in vascular complications while still leading to a similar success rate compared with femoral access.

The international, multicenter RIVAL trial was designed to help answer the question as to which access site is the most optimal for coronary angiography and intervention in patients with acute coronary syndromes. The trial included 7,021 patients who were randomized to receive either radial (n=3,507) or femoral (n=3,514) access. Investigators defined the primary outcome as incidence of death, MI, stroke or non-CABG-related major bleeding at 30 days.

At follow-up, both access sites produced comparable results in the primary outcome (radial, 3.7% vs. femoral, 4%; P=.50). Similarly, angiographic success rates were even between arms (radial, 95.4% vs. femoral, 95.2%; P=.83).

Significant differences, however, were reported with major vascular access site complications, which favored the radial cohort (1.4% vs. 3.7%; P<.001). These complications, according to Sanjit S. Jolly, MD, study investigator and assistant professor of medicine, McMaster University, Hamilton, Ontario, Canada, in a press conference, included large hematomas at the access site, pseudoaneurysms, arteriovenous fistulas as well as other vascular site surgical repair.

“The implications for practice [of this study] are that both approaches are safe and effective in the coronary,” he said. “We believe that the more you do the better you get, which is an important phenomenon [showing] that volume is important, particularly in radial access. And, finally, both patients and physicians may end up choosing the radial approach because of its similar efficacy and reduced vascular complications.” – by Brian Ellis
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RESOLUTE US: TLF lowered at 1 year with Resolute vs. Endeavor stent

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS – Compared with a historical cohort treated with the Endeavor zotarolimus-eluting stent, patients who received the Resolute zotarolimus-eluting stent had significantly improved target lesion failure at one year, according to results of the RESOLUTE US trial.

Researchers in this trial enrolled 1,402 patients from 116 sites in the United States and split them into two cohorts: clinical (n=1,242) and angiographic (n=160). Patients received revascularization with the Resolute zotarolimus-eluting stent (Medtronic) either due to stable or unstable angina, while 34.4% of the population presented with diabetes at baseline.

At 1 month, target lesion failure (TLF) of all patients, which was defined as MI, cardiac death or clinically-driven target lesion revascularization, was 1.4% with one death reported due to cardiac causes, whereas at 12 months the rate of TLF was 4.7% with 18 deaths reported (9 due to cardiac causes).

The researchers then compared the main analysis cohort of this trial (n=1,001; evaluable n=982), which utilized 2.5 mm to 3.5 mm stents in single lesions only, to historical control patients (n=1,076) that received the Endeavor zotarolimus-eluting stent (Medtronic). The primary endpoint of TLF at one year was 3.7% in the Resolute group vs. 6.5% in the Endeavor group (P-noninferiority <.001; post-hoc P-superiority=.002).

“I think this study provides interesting additional information, certainly on effectiveness, in particular on some lingering safety issues with a stent thrombosis rate of 0.1% [that included] only two episodes both occurring in patients that received 2.25 stents and in patients that did not receive dual antiplatelet therapy fairly early after treatment,” said Martin B. Leon, MD, professor of medicine, Columbia University/New York Presbyterian Hospital, and trial researcher, in a press conference. “So I think we come away feeling that the composite of the data indicates a very effective and safe device, now finally treated in a US population. Tthis will hopefully lead to an FDA consideration for availability of this stent in the United States.” – by Brian Ellis

For more information:
Leon M. LBCT III, Session 3014. Presented at:ACC 60th Annual Scientific Sessions; April 2-5, 2011; New Orleans.

The Resolute stent is a further refinement of a second generation drug-eluting stent (DES). I think the most interesting part is that the Resolute stent changed the elution characteristics of the same drug used in the Endeavor stent. There is really no other DES that has done this iteration, so we can now understand what changing the elution profile does. What we found was that Resolute stent lowers the TLF rate as compared to the Endeaver stent. Prolonging the drug elution profile can indeed help reduce intimal proliferation resulting in better clinical outcome.

The Resolute stent, hopefully when it gets approved by the FDA, will add another new third generation DES to treat complex patients. We currently only have only two second generation DES, but adding another with a prolonged drug elution profile will help treat patients with complex disease.
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ISAR-CABG: DES superior to BMS in saphenous vein graft lesions

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — In what researchers called the largest randomized, multicenter trial comparing stents in saphenous vein graft lesions, drug-eluting stents were found to led to a lower composite rate of death, MI and repeat revascularization.
“Usually, all randomized trials comparing drug-eluting stents [DES] and bare-metal stents [BMS] have excluded lesions located in the saphenous vein grafts,” Julinda Mehilli, MD, director, clinical research and data coordinating, Intracoronary Stenting and Antithrombosis Research (ISAR) Center, German Heart Center, Munich, and study investigator, said in a press conference, later adding that the two trials comparing both stents in this indication included only 160 patients and produced incomplete results. “Thus the aim of the ISAR-CABG study was to have a study adequately powered for clinical endpoints to compare DES and BMS.”

The German researchers of the ISAR-CABG trial enrolled 610 patients who had undergone CABG and had ischemic symptoms or evidence of myocardial ischemia in the presence of at least 50% de novo stenosis in saphenous vein grafts. The patients were then randomly assigned to receive either drug-eluting (DES; n=303; mean age, 71.4 years) or bare metal (BMS; n=307; mean age, 71.5 years) stents. DES used in the study included the sirolimus-eluting (Cypher, Cordis), biodegradable polymer sirolimus-eluting and paclitaxel-eluting (Taxus, Boston Scientific) stents.

The study’s primary endpoint was defined as the composite of major adverse cardiac events (MACE) including death, MI and target lesion revascularization (TLR) at 1-year, while the secondary endpoints were individual rates of death, MI, ARC [Academic Research Consortium]-definite thrombosis and the need for TLR over one year.

Early data at 30 days indicated MACE rates of 5.9% in the BMS arm vs. 2.6% in the DES (P=.05). Similarly, researchers found that the primary endpoint occurred more frequently in the BMS group compared with the DES (22.1% vs. 15.4%; P=.03). The only secondary endpoint to differ to a statistically significant extent was TLR, which favored the DES group (7.2% vs. 13.1%; P=.02).

Following the conference, Mehilli spoke with Cardiology Today and explained that prior to these findings people were afraid of DES because the risk of more and longer stent thrombosis compared with BMS, not to mention the high risk of occlusion at long-term with saphenous vein grafts.

“This randomized controlled trial, the first with such a large number of patients powered for clinical endpoints, gives a definite answer: DES are safe. They don’t increase mortality, MI or stent thrombosis rate, and instead reduce the revascularization rate in bypass lesions,” she said. - by Brian Ellis

For more information:
Mehilli J. LBCT III, Session 3014. Presented at: ACC 60th Annual Scientific Sessions; April 2-5, 2011; New Orleans.

The reason trials like this are important is because the interventional community has been criticized for putting in DES off-label. Be that as it may, there are some safety concerns about that practice and those concerns seem to have been supported by the R-RISK trial which showed that patients who had drug-coated stents as opposed to uncoated seemed to have higher mortality. That was a small trial and I think it was largely driven by the fact that the patients who had the non-coated stents placed had a 0% observed mortality which is somewhat implausible. Patients who’ve had bypass surgery before develop new blockages. Those patients tend not to be immortal to say the least. So I think that is an example of a type-1 statistical error.

That’s why we needed to do a larger, more adequately powered trial. To the credit of this ISAR group, this is a very helpful trial showing that these devices seem to be both safe and efficacious in this “off-label” indication.

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REMEDIAL II: Contrast-induced acute kidney injury lowered with RenalGuard System

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Compared with conventional hydration treatment, use of the RenalGuard System in patients with chronic kidney disease improved the safety of image-guided cardiology procedures, which led to fewer cases of contrast-induced acute kidney injury, according to findings presented here.

“This trial demonstrates that the RenalGuard System [PLC Medical Systems] is very good device to prevent contrast-induced acute kidney injury in high-risk patients,” said Carlo Briguori, MD, PhD, lead study author and director, Laboratory of Interventional Cardiology, Clinica Mediterranea, Naples, in a press conference.

The Italy-based study was conducted at four interventional cardiology centers and included 292 patients with chronic kidney disease. Patients were scheduled for coronary and/or peripheral angiography and/or angioplasty between January 2009 and December 2010. They were randomized to receive either conventional hydration that included a combination of N-acetylcysteine (NAC) and sodium bicarbonate solution or hydration with normal saline plus NAC and low-dose furosemide controlled by the RenalGuard System. Biomarkers such as serum creatinine (sCr) and cystatin C were assessed the day before and up to 1 week following the procedure.

The researchers reported that the primary endpoint of the development of contrast-induced acute kidney injury CI-AKI (sCr increase ≥0.3 mg/dL at 48 hours) was nearly two times higher in the conventional treatment group (20.5% vs. 11%; P=.025). Non-statistically significant more patients experienced stage 2 or 3 damage in the conventional arm (23% vs. 6%; P=.14) as well.

Additional analysis revealed that a lower rate of in-hospital renal failure requiring dialysis occurred in the RenalGuard System group (0.7% vs. 4.1%; P=0.056), although rates of in-hospital stay and major adverse events were similar between groups.

For Briguori, the rate of dialysis was the most important clinical finding, because it shows the possibility to prevent this very improbable complication. – by Brian Ellis
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Platinum chromium stent performance comparable to cobalt chromium stent at 1 year

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Results from the PLATINUM trial indicated that the safety and efficacy of the platinum chromium everolimus-eluting stent were noninferior to those of a cobalt chromium everolimus-eluting stent at 1 year.

Researchers for the trial enrolled 1,530 patients undergoing angioplasty between January and September 2009 and randomly assigned them to receive either a platinum chromium stent (n=768) or a cobalt chromium stent as a control (n=762). The composite primary endpoint consisted of target vessel-related cardiac death, target vessel-related MI or ischemia-driven target lesion revascularization (TLR).

According to the results, the platinum chromium stent was noninferior to the cobalt chromium stent (3.4% vs. 2.9%; P=.001 for noninferiority). There were also no differences between the groups for other safety and efficacy measures, including stent thrombosis (0.4% vs. 0.4%) and TLR (1.9% vs. 1.9%). There were no differences in all-cause mortality between the two groups (3.0% in cobalt chromium group vs. 2.4% in platinum chromium; P=.049).

“A novel platinum chromium everolimus-eluting stent has been developed which has been shown to be noninferior to the predicate cobalt chromium everolimus-eluting stent for target lesion failure, with nonsignificant differences in measures of safety and efficacy demonstrated through 12-month follow-up after PCI,”Gregg W. Stone, MD, professor of medicine and director of CV research at New York Presbyterian Hospital/Columbia University Medical Center, said in a presentation.

Stone pointed out that the study’s limitations included the exclusion of patients with acute MI, chronic total occlusion, bifurcation, left main coronary artery lesions, saphenous vein graft lesions, ostial lesions or lesions with thrombus or excessive tortuosity or calcification. The trial was also not designed to assess differences in deliverability, acute performance or ease of use. – by Eric Raible
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EXCELLENT: Guidelines may have overestimated length of DAPT after DES

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Instead of the 12 months currently recommended by guidelines for dual antiplatelet therapy following drug-eluting stent insertion, new data from the EXCELLENT trial have suggested that 6 months of therapy may be all that is necessary to produce equivalent results.

In order to generate these findings, researchers conducted a 19-center trial in which 1,443 patients were randomly assigned to 6 or 12 months of dual-antiplatelet therapy (DAPT) in addition to aspirin following insertion of a drug-eluting stent. Inclusion criteria of the prospective, open-label trial included >50% stenosis by visual estimation, evidence of myocardial ischemia and location of target lesion in a native coronary artery. The patients were then followed for at least 2 additional years.

Among the 1,428 patients in which 12-month data was available for, target vessel failure – cardiac death, MI and target vessel revascularization – occurred in 4.7% of patients in the 6-month group and 4.4% in the 12-month group. This primary endpoint, according to analysis, showed non-inferiority between 6-month and 12-month groups with a pre-specified non-inferiority margin of 40 percent (P=0.0031).

Additionally, the safety endpoint, which was a composite of death, MI, cerebrovascular accident, stent thrombosis and thrombolysis in MI bleeding, was 3.4% in the 6-month group vs. 3.1% in the 12-month group (P=.678).

“At least in low-risk patients, [those] non-diabetic and treated with second generation DES, we may safely discontinue clopidogrel [Plavix, Sanofi-Aventis] at about 6 months, especially in patients that are at high-risk of bleeding,” concluded Hyeon-Cheol Gwon, MD, PhD, with the department of cardiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, and study researcher, in a press conference. - by Brian Ellis
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MAGELLAN: Rivaroxaban efficacy comparable to enoxaparin in acutely ill

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Results of the MAGELLAN trial demonstrate that, when used as thromboprophylaxis in acutely ill hospital patients, rivaroxaban was not inferior to enoxaparin when used short-term and was slightly superior to enoxaparin followed by placebo when used long-term. However, compared with enoxaparin, rivaroxaban was associated with an increased rate of bleeding.

“Not only did we show that rivaroxaban was effective in this setting, but we also showed that at 35 days patients are still at risk for venous thrombosis,” Alexander T. Cohen, MD, of the department of surgery at King's College Hospital, London, said during a press conference. “We had a 5.7% frequency in the control arm, which was higher than the benchmark data of about 4%.”

The phase 3 trial compared oral rivaroxaban with subcutaneous enoxaparin (Lovenox, Sanofi-Aventis) in patients admitted to the hospital for acute HF, acute infectious disease and acute respiratory insufficiency or other acute medical conditions. Patients from 52 countries (n=8,101) were randomly assigned to rivaroxaban for 35 days (n=4,050) or enoxaparin for 10 days (n=4,051); both groups received placebo. The primary endpoint was a composite of asymptomatic proximal deep vein thrombosis, symptomatic deep vein thrombosis, symptomatic non-fatal pulmonary embolism and venous thromboembolism-related death. The primary safety outcome was a composite of treatment-related major bleeding and clinically relevant non-major bleeding.

At 10-days follow-up, the primary endpoint was similar between both groups: 2.7% of patients in both arms experienced the primary endpoint (relative risk ratio=0.968; P=.0025 for non-inferiority, one-sided).

At 35-days follow-up, researchers documented superiority in the rivaroxaban arm compared with enoxaparin followed by placebo: 4.4% of patients in the rivaroxaban group experienced the primary endpoint vs. 5.7% in the enoxaparin group (relative RR=0.771; P=.0211 for superiority, two-sided).

Conversely, enoxaparin was superior to rivaroxaban in reducing the rate of bleeding at both 10 and 35 days: at 10-days 1.2% of patients in the enoxaparin arm experienced clinically relevant bleeding vs. 2.8% of patients in the rivaroxaban group (relative RR=2.3; P<.0001). Similarly at 35 days, 1.7% of patients in the enoxaparin group had clinically relevant bleeding vs. 4.1% of patients in the rivaroxaban group (relative RR=2.5; P<.0001). According to Cohen, rates of liver and CV events were similar in both groups.

“We’ve shown that we have an effective drug; we have an ongoing problem and we have to look carefully at the bleeding and see if we can work out why this occurred and whether there are any groups that can benefit,” Cohen said. – by Stacey L. Fisher

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OSCAR: Olmesartan improves outcomes in patients with diabetes

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Combination therapy with olmesartan and a calcium antagonist was associated with similar rates of CV events and mortality when compared with a high-dose angiotensin II receptor antagonist alone in patients with CVD. However, dual therapy appeared inferior to AII receptor antagonist monotherapy in patients with diabetes, according to results of the OSCAR study.

High-dose AII receptor antagonists are more effective than low-dose AII receptor antagonists for the prevention of CVD in patients with diabetic nephropathy or heart failure; however, the question of whether combination therapy with an ARB plus a calcium antagonist is superior to AII receptor antagonist monotherapy remains unanswered.

Hisao Ogawa, MD, PhD, professor in the department of CV medicine at Kumamoto University in Japan, and colleagues aimed to address this question by initiating the Olmesartan and Calcium Antagonists Randomized (OSCAR) study.

“The OSCAR Study is the first single trial in the world to examine the effect of high-dose AII receptor antagonist and AII receptor antagonist plus calcium antagonist in high-risk elderly patients,” Ogawa said during a press conference here.

Between June 2005 and May 2007, Ogawa and colleagues recruited 1,164 high-risk patients aged 65 to 84 years from 134 institutions in Japan. To qualify for inclusion, patients had to have uncontrolled blood pressure despite receiving treatment with the AII receptor antagonist olmesartan (Benicar, Daiichi Sankyo) and CVD or type 2 diabetes. The study’s primary endpoint was a composite of CV events, including cerebrovascular disease, coronary artery disease, HF, other atherosclerotic diseases, diabetic microvascular diseases and renal dysfunction, as well as all-cause mortality.

Patients were randomly assigned to receive daily high-dose olmesartan (40 mg) or a calcium antagonist plus olmesartan (20 mg). At 36 months, adequate blood pressure control was observed in both treatment groups. However, compared with monotherapy, combination therapy induced considerably greater decreases in BP, according to the researchers. Mean systolic BP was a mean 2.4 mm Hg lower and mean diastolic BP 1.7 mm Hg lower.

The researchers noted no significant differences between the two treatment arms in the number of primary endpoints. Fifty-eight events occurred in the monotherapy group vs. 48 in the combination group (HR=1.31; 95% CI, 0.89-1.92).

Results of a subgroup analysis, however, revealed a statistically significant difference between treatment groups in patients with pre-existing CVD. Patients assigned to combination therapy experienced considerably fewer CV events and death compared with those assigned monotherapy (24 vs. 51; HR=1.63; 95% CI, 1.06-2.52).

In addition, a second subgroup analysis indicated a higher rate of the primary outcome between treatment arms in patients with diabetes only, with 14 events occurring in the combination group and seven occurring in the AII receptor antagonist monotherapy group (HR=0.52, 95% CI, 0.21-1.28). The researchers also noted a significant treatment-by-subgroup interaction for the primary endpoints between patients with CVD and patients with diabetes only.

These results suggest that the relative effect of the two therapies is dependent on the presence of CVD or diabetes, according to the researchers. – by Melissa Foster
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NAGOYA HEART: ARB, calcium antagonist equally effective in patients with diabetes, hypertension

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Valsartan, an angiotensin II receptor blocker, and amlodipine, a calcium antagonist, comparably reduced adverse CV events in hypertensive patients with diabetes or glucose intolerance, according to data presented here.

“Many hypertension treatment guidelines recommend angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) as first-line treatment for hypertensive patients with diabetes, especially for prevention of major CV events,” Toyoaki Murohara, MD, PhD, lead researcher of the NAGOYA HEART Study, said during a press conference. “But some clinical trials show that calcium antagonists are almost equally effective in reducing the risk of CV disease as compared to ARBs.”

The NAGOYA HEART Study is the first randomized trial comparing the efficacy of an ARB with a calcium antagonist, according to Murohara. For the trial, Murohara and colleagues recruited 1,150 hypertensive patients with diabetes or glucose intolerance at 46 facilities in Japan. Between October 2004 and July 2010, the researchers randomly assigned patients to receive valsartan (Diovan, Novartis) or amlodipine (Norvasc, Pfizer) as first-line treatment. The study’s primary outcome measure was a composite of CV events, including acute myocardial infarction, stroke, coronary revascularization, hospital admission resulting from congestive heart failure (CHF) and sudden cardiac death. Blood pressure and HbA1c levels were also monitored.

Follow-up lasted a median of 3.2 years, with analysis occurring every month for the first 3 months and then every 1 to 3 months thereafter. Results revealed that 54 patients (9.4%) assigned to valsartan and 56 (9.7%) assigned to amlodipine experienced the primary outcome (HR=0.97; 95% CI, 0.66-1.4), suggesting no significant differences between treatment groups. Analysis of individual components of the primary outcome, however, indicated that the incidence of hospital admission for CHF was higher in the amlodipine group, with the event occurring in three patients (0.5%) in the valsartan arm vs. 15 patients (2.6%) in the amlodipine arm (HR=0.2; 95% CI, 0.06-0.69).

BP and HbA1c levels also appeared similar between the groups, the researchers said. At 54 months, BP decreased to 131/73 mm Hg in the valsartan group and 132/74 mm Hg in the amlodipine group. HbA1c levels were lowered to 6.7% in both groups.

“Our present paper shows that ARB is superior to a calcium antagonist in HF, and clinical trends already show ACE inhibitors slow [the development of] some of the complications of diabetes,” Murohara said. “Our study results support the current guidelines recommending ARB and ACE inhibitors for first-line treatment in diabetic patients with hypertension.”
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Specialized clinic improved outcome in patients with AF

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS – Rates of CV-related mortality and hospitalization were improved in patients with atrial fibrillation treated in a specialized clinic that adheres to AF guidelines when compared with usual care, according to new data.

“In order to improve outcomes in our patients, we developed a AF clinic which was characterized by substation of care by specialized nurses and they also delegated a software program … which stays with you and warns you in case you’ve made the wrong decision and it also suggests the most appropriate therapy,” said Robert G. Tieleman, MD, PhD, study investigator and cardiologist at the Martini Hospital, Groningen, the Netherlands, in a press conference. “We believed that doing this approach would improve outcome in these patients.”

Tieleman and fellow researchers tested this theory by analyzing the outcomes of patients (n=712) who were newly diagnosed with AF referred to the specialized AF clinic (n=356) or usual care (n=356). Baseline data revealed similar rates of CV conditions including hypertension, stroke, coronary artery disease and HF between the AF clinic and usual care arms. The primary endpoint was a composite of CV mortality, life-threatening effects of drugs, and hospitalization due to HF, stroke, acute MI, systemic embolism, bleeding and arrhythmic events.

After a mean 22-month follow-up, the primary endpoint was reported in 14.3% of the AF clinic arm vs. 20.8% of the usual care arm (HR=0.65; 95% CI, 0.45-0.93). Lower rates were also found in the AF clinic arm regarding deaths (1.1% vs. 3.9%; HR=0.28, 95% CI 0.09-0.85) and hospitalizations (13.5% vs. 19.1%; HR=0.66; 95% CI 0.46-0.96).

In his concluding remarks, Tieleman said that this study is at least the first step towards treating more patients with this approach, “but we also have to improve cost-effectiveness,” he said. “But I think these are very promising data.” – by Brian Ellis

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Patients may benefit from lower recommended BMI targets

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Recommended normal BMI parameters may be higher than necessary, as new data indicate that CV risk factors increase as BMI increases, beginning with a BMI of 20.

Glenn Lee, MBBS, and colleagues from the National University Health System and Khoo Puat Hospital in Singapore studied more than 3,000 adults who were referred for routine employment health screening for traditional CV risk factors. The mean age of the cohort was 38.9 years; mean BMI was 25.2; and 89.9% were men. The researchers excluded patients with diabetes and vascular disease.

According to the results, the overall prevalence of new diabetes cases was 2.4%. The majority of patients (84.5%) were classified as low risk, using the Framingham Risk Score.

The mean BMI of the cohort was 25.2. Analysis indicated a strong association between BMI and blood pressure, HDL and LDL levels; HDL and LDL levels were significantly worse with a BMI greater than 20. Systolic and diastolic BP rose significantly with a BMI greater than 22. The researchers noted a dose-response relationship for all risk factors, with the exception of LDL levels. Instead, these levels plateaued with a BMI greater than 26.

"Significant dose-response increases in traditional risk factors occurred at a BMI that is well within the normal range. Given the step-wise and additive nature of CV risk factors and the consistent correlation with a rising BMI of above 20, this calls into question what can be considered a truly normal BMI," Lee told Cardiology Today. "That's our major concern. Are we really being too lenient with these recommended guidelines for Caucasian populations (25) and Asian populations (23) or should we lower it?"

Lee also noted that several other studies support their findings, with one trial, which was published in Circulation in 2007 by Razak et al, suggesting that Asians may benefit from lowering the recommended BMI to 21. Another study conducted by Odegaard et al and published in PLoS One also suggested that the normal BMI for nonsmokers aged younger than 65 years should range from 18.5 to 21.4. Lee said this area requires further investigation.

"We would like to investigate and follow this cohort to see if this trend between CV risks and BMI persists as they age, and if these trends translate into increased cardiovascular event and mortality rates," Lee said. – by Melissa Foster

For more information:
Lee G. Poster 1079-304. Presented at: ACC 60th Annual Scientific Sessions; April 2-5, 2011; New Orleans.
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Aspirin use in patients with diabetes requires careful consideration
American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Aspirin has been proven to be effective in reducing the risk for CV events; however, patients with diabetes are a unique population that requires special considerations before treatment. While aspirin therapy is recommended, further exploration into dosing strategies, stronger antiplatelet therapy and the clinical interaction between aspirin and patients with diabetes is essential, a speaker said here.

“A landmark stage published in 1990 really set the stage as to why diabetics are different and why antiplatelet therapy may be effective in this population,” Jeffrey S. Berger, MD, of the NYU Cardiac and Vascular Institute at the NYU Langone Medical Center in New York, said during a presentation. “Compared with nondiabetics, diabetics had greater platelet activity.”

Berger noted that one study currently being conducted at NYU suggests that markers of platelet activity correspond well with an increasing prevalence of diabetes, even in patients without CVD. Data from other trials support this association, and these results raised an important question: Can measuring platelet activity prevent a future event? At present, this question remains unanswered but warrants further investigation, he said.

In addition, physicians must consider dosing when treating with aspirin. Berger explained that aspirin inhibits COX-1 and, thus, reduces amounts of platelet activation and vascular constriction. However, aspirin at higher doses also reportedly inhibits prostacyclin, which causes an effect opposite of thromboxane. Therefore, Berger emphasized that physicians be careful not to prescribe too much aspirin, even among patients with diabetes.

Many physicians believe that patients with diabetes have a different clinical response to aspirin than those without the disease. Berger pointed out that this is a misconception, however, and cited data from a large meta-analysis that indicated no significant differences in aspirin’s effect on decreasing myocardial infarctions, stroke or all-cause mortality in patients with diabetes compared with those without the disease. Most importantly, he said, research showed no significant interaction in how aspirin prevents CV events between patients with the diabetes and those without.

Despite aspirin’s efficacy in decreasing CV benefits, the medication has been linked with serious adverse events, such as major bleeding, with research showing a low number needed to treat and a low number needed to harm.

“Thinking about it this way, for every 1,000 patients treated for 5 years, three ischemic events are avoided, but three major bleeds are caused,” Berger said. “So when you’re thinking about who should get aspirin, you should think about the absolute benefit and the absolute risk.”

Future studies

Because patients with diabetes are a special population, researchers and physicians should consider whether stronger antiplatelet therapies are required. Berger said future studies must take other medications into account. Statins, fish oil and ACE inhibitors, for example, have antiplatelet activity and this effect may attenuate some of aspirin's effect for patients with diabetes. He also noted that dosing strategies may have to be altered, such as administering aspirin twice a day instead of once daily. Additionally, improved tools for monitoring aspirin’s effect on preventing CV events would also be extremely valuable, according to Berger.

“There is no significant clinical interaction between diabetics and nondiabetics regarding the effect of aspirin. If remains uncertain if diabetics may need a different strategy of dosing or a stronger antiplatelet therapy, and I think future clinical trials should address these issues,” Berger said. – by Melissa Foster
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New analyses yield insufficient data on safety of rosiglitazone

American College of Cardiology 60th Annual Scientific Sessions

NEW ORLEANS — Current evidence remains insufficient to incriminate or exonerate rosiglitazone, on the basis of recent analyses, according to Sanjay Kaul, MD, and George A. Diamond, MD.

The safety of rosiglitazone was questioned in 2007 after a meta-analysis by Steven E. Nissen, MD, and Kathy Wolski, MPH, of the Cleveland Clinic, was published in The New England Journal of Medicine. The original meta-analysis, which included 56 trials of more than 35,000 patients, found a 43% increased risk for myocardial infarction and a 64% increased risk for CV death among rosiglitazone users. Nissen and Wolski recently updated their meta-analysis, and found that rosiglitazone was associated with a 28% greater risk for MI and no associated with CV death.

Because the updated analysis excluded 15 trials on MI and 29 trials on CV death, Kaul and Diamond, both from Cedars-Sinai Medical Center, sought to determine whether these exclusions biased the updated results on the CV safety of rosiglitazone (Avandia, GlaxoSmithKline). They compared the index study with meta-analyses of the 56 trials that were originally included and used different pooling methods.

According to the results, ORs ranged from 1.17 to 1.28 for MI and from 0.94 to 1.03 for CV death.

“Corrected models resulted in smaller ORs and narrower confidence intervals than did uncorrected models,” Kaul and Diamond wrote in their study abstract. “Although corrected risks remain elevated, none are statistically significant, except for the ‘treat as one trial’ method employed by the authors that is prone to bias.”

Further, ORs were nonsignificant when Kaul and Diamond excluded results of the DREAM trial or the seven trials in which rosiglitazone is not indicated or is contraindicated.

“Given the fragility of the data … additional data will be required to adjudicate these inconclusive results,” Kaul and Diamond said. - by Katie Kalvaitis

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Antiarrhythmics After Ablation of Atrial Fibrillation (5A Study): Six–Month Follow-Up Study
Circulation: Arrhythmia and Electrophysiology
Journal of the American Heart Association
The authors previously demonstrated that treatment with antiarrhythmic drugs (AADs) during the first 6 weeks after atrial fibrillation (AF) ablation reduces the incidence of clinically significant atrial arrhythmias and need for cardioversion or hospitalization for arrhythmia management. Whether early rhythm suppression decreases longer-term arrhythmia recurrence is unknown. The authors now report the 6–month follow-up data from this study.
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Multivessel Awake Off–Pump Coronary Bypass Grafting Using Median Approach: Technical Considerations
Innovations
Official Journal of the International Society for Minimally Invasive Cardiothoracic Surgery
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Permanent Pacemaker Insertion After CoreValve Transcatheter Aortic Valve Implantation: Incidence and Contributing Factors (the UK CoreValve Collaborative)
Circulation
Journal of the American Heart Association
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Acute Coronary Syndrome Pathways: Alignment With a Bundled Care Reimbursement Model
Critical Pathways in Cardiology
Official Journal of the Society of Chest Pain Centers
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Is there a role for surgeons in transcatheter mitral valve procedures?
Current Opinion in Cardiology
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Preventing Heart Disease Today & Tomorrow in Youth
Nutrition Today
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Wrist circumference in obese children may predict CVD
Capizzi M. Circulation. 2011;123:1757-1762.

A manual measure of wrist circumference was more closely linked to insulin parameters than BMI in a cohort of overweight or obese children and adolescents, according to new study results published in Circulation.

The trial involved 477 overweight or obese children and adolescents aged 10.31 ± 2.80 years from Rome. Each participant’s wrist was manually measured. The researchers also evaluated standard deviation score BMI, fasting biochemical parameters and homeostasis model assessment of insulin resistance in the study population.

A subcohort of 51 randomly selected participants underwent a wrist MRI to assess transversal wrist area at the Lister tubercle level.

Wrist circumference was significantly linked with the parameters of insulin levels (β=0.34) and homeostasis model assessment of insulin resistance (β=0.35), according to the results (P<10-5 for both comparisons).

Standard deviation BMI score yielded a statistical association of β=0.12 with insulin levels and β=0.10 with homeostasis model assessment of insulin resistance (P≤.02 for both comparisons).

In the MRI cohort, the link between wrist circumference and insulin levels was further clarified. Wrist circumference was associated insulin levels or homeostasis model assessment of insulin levels in bone tissue-related areas (P≤.01 for both comparisons) but not in adipose tissue areas (P>.05). MRI explained 20% of the variances in insulin levels and 17% of the variances in homeostasis model assessment of insulin levels.

The researchers noted that excess fat is a key determinant of insulin resistance which representing the metabolic basis for developing future CVD. The aim of the study, they said, was to find a clinical marker of insulin resistance to identify young individuals at increased risk for CVD.

“Our findings suggest a close relationship among wrist circumference, its bone component, and insulin resistance in overweight/obese children and adolescents, opening new perspectives in the prediction of CVD,” the researchers wrote.
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Serum alpha-carotene inversely associated with death from CVD, all-causes
Li C. Arch Intern Med. 2011;171:507-515.

Increasing levels of serum alpha-carotene had an inverse association with rates of death due to CVD and all-cause mortality among participants of the Third National Health and Nutrition Examination Survey.

These findings help to elucidate the role of carotenoids on CVD, as previous research had primarily involved beta-carotene, according to study investigators.

The current analysis included 15,318 US adults aged at least 20 years from the NHANES III, which was conducted from 1988 to 1994. Patients were considered ineligible if they had a follow-up of 1 month or less, missing data on covariates or insufficient identifying information.

The study’s findings revealed a mean alpha-carotene concentration of 4.79 mcg/dL for the entire cohort (men, 4.22 mcg/dL; women, 5.31 mcg/dL). A statistically significant association was found between increasing serum alpha-carotene levels and lower CVD-related mortality (P=.007), which included ischemic heart disease (P=.21), stroke (P=.84), as well as other CVDs (P=.06).

Overall, increasing levels of serum alpha-carotene compared with those in the reference group (0-1 mcg/dL) resulted in a lower risk for death from all-causes: 2 to 3 mcg/dL (RR=0.77; 95% CI, 0.68-0.87), 4 to 5 mcg/dL (RR=0.73; 95% CI, 0.65-0.83), 6 to 8 mcg/dL (RR=0.66; 95% CI, 0.55-0.79) and at least 9 mcg/dL (RR=0.61; 95% CI, 0.51-0.73).

According to researchers, this inverse association was independent of demographic characteristics, lifestyle habits and traditional health risk factors.

“Our results, if replicated in other studies and populations, suggest a need for clinical research into the health benefits of serum alpha-carotene,” they said.
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Combined diet, exercise more beneficial in older obese adults than either intervention alone
Villareal DT. N Engl J Med. 2011;364:1218-1229.

A combination of weight loss and exercise significantly improved physical function of obese older adults vs. either intervention alone, according to 1-year, randomized trial data.

The trial included 107 participants who were aged at least 65 years and considered obese. They were randomly assigned to either a control group (n=27), a weight-management (diet; n=26) group, an exercise group (n=26), or a diet-plus-exercise (diet-exercise; n=28) group. Among these participants, 93 finished the study.

At 1 year, the researchers reported that the study’s primary outcome, the change in Physical Performance Test score, was higher, thus indicating better physical status in individuals from the diet-exercise group (21%) vs. either diet (12%) or exercise (15%) groups, although all three were better than the control group (1%; P<.001 for between group differences).

Similarly, peak oxygen consumption was better in the diet-exercise (increase of 17%) arm compared with diet (10%) or exercise (8%) participants, as were scores on the Functional Status Questionnaire with the diet-exercise arm vs. the diet arm (increase of 10% vs. 4%; P<.001). Conversely, the greatest decrease in body weight was documented in the diet arm compared with those in the diet-exercise group (10% vs. 9%; P=.67), whereas no decreases were found in either the control or exercise arms.

“Our findings suggest that weight loss alone or exercise alone improves physical function and ameliorates frailty in obese older adults; however, a combination of weight loss and regular exercise may provide greater improvement in physical function and amelioration of frailty than either intervention alone,” the researchers concluded. “Therefore, weight loss combined with regular exercise may be beneficial in helping obese older adults maintain their functional independence.”

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Reduced physician work hours did not adversely affect patient safety
Moonesinghe S. BMJ. 2011; 342:d1580.

A systematic review published in the British Medical Journal found that reducing doctors’ working time to less than 80 hours a week does not seem to adversely affect patient safety and has limited impact on post-graduate medical training in the US, according to a press release.

The study, led by S. Ramani Moonesinghe, an anesthesiology consultant and honorary senior lecturer at the University College Hospital in London, and colleagues sought to evaluate the impact of work reduction on educational and clinical outcomes by reviewing 72 studies published in the UK and US.

“The impact of reducing hours to less than 56 or 48 a week in the UK has not been sufficiently evaluated in high-quality studies,” the researchers wrote. “Further work is required, particularly in the European Union, using large, multicenter evaluations of the impact of duty hours’ legislation on objective educational and clinical outcomes.”

Of the studies reviewed, 38 reported on training outcomes, 31 noted patient outcomes and three studies reported on both types of outcomes.

The maximum hours per week for trainees can range from 37 hours in Denmark to 80 hours in the US. The European Working Time Directive, initiated in 2004, restricted the weekly training period for doctors in Europe to 48 hours. Since that time, there has been concern in the medical profession about potential adverse effects on postgraduate training for junior doctors and the provision of high-quality care for patients, according to the release.

The authors noted that more high-quality studies are needed to evaluate the impact of restricting work hours using objective measures of medical training and patient safety, particularly in the European Union, according to the release. “Only then can both the public and the profession be reassured that the standard of medical training, and therefore the future care of patients, is of the highest possible quality and will be maintained or improved over time,” they concluded.
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Exclusion of older patients prevalent among trials testing HF treatments

Cherubini A. Arch Intern Med. 2011;171:550-556.
Gurwitz J. Arch Intern Med. 2011;171:557-558.

More than one-quarter of clinical trials that investigated treatment for HF excluded patients with an upper age limit, despite recommendations issued by national and international regulatory agencies against the practice.

The new study appearing in the Archives of Internal Medicine also found that upper age restrictions were significantly more common in the European Union than the United States.

To generate these data, Antonio Cherubini, MD, PhD, and colleagues scrutinized ongoing clinical trials regarding HF registered in the WHO database. Trials were excluded if they were observational in design; did not have HF as the main target condition; did not propose any treatment; involved children; or were registered twice. The final analysis included 251 trials.

Overall, 64 trials (25.5%) excluded patients by what researchers termed an “arbitrary upper age limit,” which varied between 65 and 95 years of age (median age, 80 years). They also found that 109 trials (43.4%) had poorly justified exclusion criteria that may negatively affect inclusion of older individuals in HF trials.

Compared with the trials conducted in the United States, those performed in the European Union more often excluded older patients (32.3% vs. 16.2%; P=.007). Upper age restrictions were also more common in trials sponsored by public institutions vs. private entities (35.6% vs. 13.9%; P=.02).

“Despite the recommendations offered by the Helsinki Declaration of the World Medical Association and by several national and international regulatory agencies … and the best efforts of physicians caring for older patients, the exclusion of older individuals in clinical trials regarding HF continues to be widespread in pharmacologic and nonpharmacologic trials currently ongoing,” Cherubini and colleagues wrote. “To improve care of elderly patients, more older individuals need to be included in clinical trials investigating conditions of relevance to members of this fast-growing age group.”

In an accompanying editorial, Jerry H. Gurwitz, MD, and Robert J. Goldberg, PhD, with the Meyers Primary Care Institute, Worcester, Mass., said the guidelines have been ineffective in enhancing the participation of older individuals in clinical trials. As a way to improve the evidence base to guide the care of older patients with CVD, they proposed a multifaceted approach. The four initial steps include:

Eliminating arbitrary age-based exclusions in CV clinical trials.
Requiring strong justification for exclusion criteria that could adversely affect the inclusion of older individuals, including those criteria relating to comorbidity, medication use, and functional and cognitive impairment.
Encouraging the design and conduct of randomized controlled trials specific to older individuals through targeted funding.
Reporting and publicizing trends in the inclusion of elderly patients in CV clinical trials to assess progress in improving the generalizability of research findings to this high-risk population.

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ACTIVE I: Irbesartan failed to lower CV events in patients with AF
Yusuf S. N Engl J Med. 2011;364:928-938.

Among patients with atrial fibrillation, irbesartan, an angiotensin-receptor blocker, did not reduce the occurrence of CV events, including MI and death from vascular causes, compared with placebo, according to randomized, clinical trial data.

In the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-I) trial, investigators enrolled patients (n=9,016; mean age, 69.6 years) who had permanent AF or at least two episodes of intermittent AF in the previous 6 months. Patients were then randomly assigned to receive either irbesartan (Avapro, Sanofi-Aventis/Bristol-Myers Squibb) or placebo. The first coprimary outcome was defined as MI, stroke or death from vascular causes, and the second was this composite outcome plus hospitalization for HF.

During a mean follow-up of 4.1 years, patients taking irbesartan had a mean reduction in systolic BP of 2.9 mm HG and diastolic BP of 1.9 mm Hg. There was no difference in the first coprimary endpoint between groups (5.4% each per 100 patient years), and only nonsignificant reduction in the second coprimary endpoint in the irbesartan group (7.3% vs. 7.7% per 100 patient years; P=.12).

When rates of hospitalization were looked at individually, researchers found that patients given irbesartan had a nominally significant reduction in first hospitalization for HF (HR=0.86; 95% CI, 0.76- 0.98), but not in the risk of hospitalization for AF (HR=0.95; 95% CI, 0.85-1.07).

“Among patients with AF, most of whom had well-controlled hypertension and 60% of whom were receiving an ACE inhibitor, the addition of irbesartan did not reduce the risk of death from CV causes, stroke or MI or this composite outcome plus hospitalization for HF,” the researchers wrote, later adding that it remains to be seen whether more aggressive lowering of BP would be effective in patients with AF.

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APEX-AMI: Age strongest predictor of 90-day mortality
Gharacholou S. Arch Intern Med. 2011;171:559-567.

Patients aged 75 years or older had nearly three times the rate of 90-day mortality after primary percutaneous coronary intervention compared with patients who were aged 65 to 74 years and more than five times the rate found in patients aged younger than 65 years. As a result, age was the strongest predictor of death at 90 days in this study’s population.

Among the patients (n=5,745) in the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial, 3,410 were aged younger than 65 years, 1,358 were aged 65 to 74 years, and 977 were aged 75 years or older. Ninety-day mortality and a composite of congestive HF, shock and 90-day death were defined as the study’s main outcome measures.

At baseline, patients aged 75 years or older had higher rates of hypertension, angina, stroke, chronic HF and chronic obstructive pulmonary disease. Overall, 90-day mortality rates were 2.3% in patients aged younger than 65 years, 4.8% in those aged 65 to 74 years and 13.1% in those aged 75 years or older. Composite outcomes shared a similar increase by age group (5.9%, 11.9% and 22.8%, respectively). After adjustment, age was the strongest independent predictor of 90-day mortality with an HR of 2.07 (95% CI, 1.84-2.33) per 10-year increase.

“Despite optimal mechanical reperfusion and high rates of adjunctive medical treatment, age remains the main predictor of 90-day mortality in STEMI patients treated with primary PCI,” the researchers wrote. “Efforts to attenuate this risk and understand reperfusion factors that increase age-associated outcomes are needed.”

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Cardiac Imaging after Myocardial Infarction
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In the acute phase of MI, an echo should be obtained as early as possible to assess regional and global left and right ventricular function and to rule out acute mechanical complications; urgent echocardiography is mandatory for patients who experience sudden deterioration, hypotension or shock, acute heart failure, a new murmur, or otherwise experience sudden deterioration. Cardiac imaging after the acute phase of MI has a wealth of valuable information to offer to inform and guide patient management. Given the variety of imaging options for nearly all clinical questions, a rational choice must factor in reliability of a method, potential therapeutic consequences, cost and availability, and finally the risks involved, e.g. radiation exposure and contrast application (Table 1and Table 2). The clinical choice will therefore differ depending on local expertise and resources, patient characteristics and, last but not least, individual experience of the physician. The following recommendations are therefore based on and perhaps to some degree biased by our practice:

An echo should be performed as quickly as possible in every patient with the acute coronary syndrome. As long as reperfusion therapy is not delayed, this may include ST elevation infarction infarction, but requires an immediately available, trained echocardiographer performing a limited emergency study while the patient is prepared for primary intervention. The rationale is that echo allows assessment of regional and global left and right ventricular function and recognition of critical complications, e.g. pericardial effusion possibly signalling impending rupture, papillary muscle rupture, right ventricular infarction, or may alert to unsuspected differential diagnoses such as Type A aortic dissection (e.g. in the presence of aortic regurgitation and a pericardial effusion). While the echo on admission is often performed under emergency conditions and focuses on left ventricular function and potential MI complications, a full echocardiographic examination should be performed during the following weeks to guide further therapy and to serve as a baseline for future comparison. Besides documenting global systolic function (ejection fraction), regional wall motion abnormalities and mitral regurgitation, signs of increased left ventricular filling pressures should be identified, in particular the restrictive mitral inflow pattern. Global strain measurements may be a useful supplement of ejection fraction with some evidence of a lower observer variability. Subtle markers of increased diastolic pressures such as an increase in left atrial size, of the E/e′ ratio or of systolic pulmonary pressure may indicate that the patient perhaps needs more aggressive treatment and a closer follow-up. If large akinetic or dyskinetic left ventricular regions are present, thrombi and spontaneous echo contrast should be identified or excluded.
If identification of inducible ischaemia is clinically warranted, typically in a patient who did not undergo coronary angiography or who has intermediate coronary non-culprit lesions on the acute coronary angiogram, a stress test should be performed after the acute phase of MI once the patient is stable. Imaging stress tests offer substantial advantages over classic ECG and symptom-based exercise tests, which are still the first-line recommendation of current guidelines. However they involve higher costs, higher demands on reader expertise, and, in the case of nuclear perfusion imaging, expose the patient to radiation. Strengths and weaknesses of stress echo, nuclear perfusion imaging, and stress MRI are well documented and should be considered individually according to patient characteristics. The most important point, though, is local availability and expertise, outweighing the modest differences in diagnostic accuracy.
If identification of viable myocardium is of concern, typically in a patient with impaired global left ventricular systolic function and coronary anatomy which is either unknown or amenable to revascularization, the choice is between MRI (with late contrast-enhancement and/or wall motion assessment under dobutamine stimulation), nuclear perfusion imaging, and (usually dobutamine) stress echocardiography. The interpretation of these tests in conjunction with the coronary angiogram to arrive at the decision whether to revascularize or not is frequently very difficult, unless findings are clear cut (transmural scar/no contractile reserve or minimal scar/well-preserved contractile reserve). The test should be performed after the acute phase of MI. In the infarct area, especially after reperfusion therapy, stunned myocardium may be present which will recover spontaneously over the following days and weeks; however, there seems to be a fluid transition between repetitive stunning and classic myocardial hibernation, and the ideal timing of the test is unclear. Similar to the detection of ischaemia, the most crucial issue is local availability and expertise, again outweighing the differences in diagnostic accuracy of the individual test.

[Chevychelov]

Combination therapy plus LVAD not validated in multicenter trial

ISHLT 31st Annual Meeting and Scientific Sessions

SAN DIEGO – Despite a previous single-center trial indicating sustained survival for patients with nonischemic dilated cardiomyopathy who were treated with a left ventricular assist device plus optimal medical therapy followed by clenbuterol, a new multicenter study showed that this combination treatment in the same population did not confer the same benefit on myocardial recovery.

For Keith D. Aaronson, MD, medical director of the Heart Failure Program at the University of Michigan in Ann Arbor, and study researcher, the study began with some skepticism about whether there was any potential for clinical recovery with this treatment in patients with chronic HF.

“At this point, while I don’t know how much this [treatment] brings out recovery or who will recover, I have to concede that this is a real phenomenon worth pursuing clinically and certainly warrants further study,” Aaronson said in a presentation.

The five-center, US-based study included nonischemic dilated cardiomyopathy bridge-to-transplant patients (n=17; median age, 57 years) who had received HeartMate XVE (Thoratec) and target or maximum tolerated angiotensin receptor antagonist, beta-blocker, ACE inhibitor, digoxin and aldosterone antagonist therapy. Patients were then given clenbuterol and beta-1 selective betablockers for 3 months following either plateau in reverse remodeling or 16 weeks.

Researchers withdrew four patients due to complications before treatment with clenbuterol. Following 4 months of LVAD therapy, the remainder of patients received clenbuterol for a median of 7 months.

Among the 13 patients that entered phase II of the study, 12 had an adverse event, which included muscle spasms and pain, supraventricular tachycardia and sustained ventricular tachycardia requiring cardioversion. Of these 12, three had a reduction in clenbuterol dose.

According to data, at the start of clenbuterol usage, LV ejection fraction was 42.5%, which decreased markedly at 6 months (31%). However, at 18 months, LVEF rose to 45%. Overall, one of the 13 patients were explanted, while two of the 10 evaluable patients without device complication requiring study withdrawal had marked myocardial recovery.

Significant limitations of the study highlighted by Aaronson included the very small sample size as well as loss of patients due to complications unrelated to clenbuterol or study procedures. – by Brian Ellis
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REVEAL registry: PAH exacerbated by presyncope, syncope

ISHLT 31st Annual Meeting and Scientific Sessions

SAN DIEGO – For patients with pulmonary arterial hypertension, a history of presyncope and syncope worsened the severity of disease, according to data from the REVEAL registry.

What this indicates, according to researchers, is the importance of validating the prognosis and effect of syncope among patients with pulmonary arterial hypertension (PAH) as treatment guidelines continue to be defined.

The study featured patients (n=70) who had both PAH and a history of either presyncope or syncope at initial prediagnosis of symptoms (IS) and first PAH-clinic visit from the REVEAL registry, which was a 55-center, observational, US-based longitudinal registry. The study’s objective was to both define the significance of presyncope and syncope in newly diagnosed patients with PAH and determine whether it is linked with clinical and or hemodynamic parameters.

Inclusion criteria for the study was that all patients with PAH must be characterized by having each of the following: mean pulmonary artery pressure <25 mm Hg at rest or <30 mm Hg with exercise; pulmonary capillary wedge pressure or left ventricular end-diastolic pressure no greater than 18 mm Hg; and pulmonary vascular resistance of at least 240 dyn/s/cm-5. Patients were then followed for at least 5 years.

The researchers reported that patients with PAH and a history of presyncope and syncope were younger; had higher mean pulmonary artery pressure and right atrial pressure; had more functional class IV disease; had more right ventricular chamber enlargement; and had higher percent predicted diffusing capacity of carbon dioxide. They also found that 3-year survival was worse for the IS group despite these patients being characterized as younger and having a better capacity for exercise.

“Presyncope/syncope is associated with markers of increased disease severity in newly diagnosed PAH patients. However, it was not predictive of unadjusted survival,” said Rachel Le, MD, with the Mayo Clinic, Rochester, Minn., and investigator on the study, in her presentation.

As directions for future research, Le and colleagues suggested determination of the prognosis of presyncope or syncope as evidence-based PAH treatment guidelines are established; separating out the differences between presyncope or syncope; accessing whether treatment will affect prognosis in these patients; the effect of resolution of these symptoms with therapy; and differentiating pediatric vs. adult patients. – by Brian Ellis
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Elevated adolescent BMI may predict diabetes in adults
Tirosh A. N Engl J Med. 2011;364:1315-1325. S

Individuals with elevated adolescent BMI were at a nearly threefold increased risk for developing diabetes as adults, according to study results.

The prospective study involved 37,674 young men who were apparently healthy. The men were followed for incident angiography-proven CHD and diabetes during 650,000 person-years of follow-up (mean follow-up, 17.4 years). Height and weight measurements were taken at regular intervals starting at age 17 years.

There were 1,173 incident cases of type 2 diabetes and 327 cases of CHD reported.

A multivariate analysis accounted for age, family history, BP, lifestyle factors and biomarkers in blood.

Results indicated that elevated adolescent BMI — the mean range of which, for the first through last deciles, was 17.3 to 27.6 — was significantly linked to diabetes (HR for the highest vs. the lowest decile, 2.76; 95% CI, 2.11-3.58). Elevated adolescent BMI was also associated with angiography-proven CHD (HR=5.43; 95% CI, 2.77-10.62).

The link between BMI and diabetes disappeared when the participants reached adulthood (HR=1.01; 95% CI, 0.75-1.37). However, adult BMI was associated with CHD (HR=6.85; 95% CI, 3.30-14.21).

Results of a further adjustment in which BMI was evaluated as a continuous variable indicated that adult BMI was the only factor significantly associated with diabetes (P=.003).

Angiography-proven coronary heart disease was independently linked to BMI in adolescence (P=.004) and adulthood (P=.03).

“An elevated BMI in adolescence — one that is well within the range currently considered to be normal — constitutes a substantial risk factor for obesity-related disorders in midlife,” the researchers wrote.

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Sudden cardiac death risk may be underestimated in NCAA athletes
Harmon K. Circulation. 2011;123:1594-1600.

Sudden cardiac death accounted for more than half of the medical-related fatalities in a cohort of collegiate student-athletes in the US, according to study results.

Researchers from two US sites reviewed all cases of sudden cardiac death among National Collegiate Athletic Association (NCAA) student-athletes from January 2004 to December 2008. The NCAA database was used, as were public media reports and catastrophic insurance claims.

There were 273 deaths in 1,969,663 athlete participant-years. Sixty-eight percent of those deaths were attributed to nonmedical or traumatic causes, 29% were due to medical causes and 2% were the result of unknown causes.

Among the medical cases, CV-related sudden death was the most frequently reported cause, accounting for 56% of the fatalities. CV-related sudden deaths also accounted for 75% of medical-related sudden deaths during exertion.

Sudden cardiac death had an incidence rate of 1:43,770 participants per year, according to the results. That rate was 1:3,100 per year among NCAA Division I male basketball players.

Among the 45 cardiac cases reported, 87% were identified through the NCAA database, 56% were identified through public media reports and 20% were found via catastrophic claims data.

The study was conducted to determine the true incidence of sudden cardiac death among NCAA student-athletes and to assess the accuracy of data collection methods on sudden cardiac death.

“[Sudden cardiac death] is the leading medical cause of death and death during exercise in NCAA student-athletes,” the researchers wrote. “Accurate assessment of [sudden cardiac death] incidence is necessary to shape appropriate health policy decisions and develop effective strategies for prevention.”
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Private-Practice Cardiology is Dead and Mr. Obama Wasn’t the Killer
by L. Samuel Wann, MD
by L. Samuel Wann, MD

OK, the private practice of cardiology certainly isn’t dead or even dying, but it has suffered some serious wounds in the past couple of years. An estimated 50% to 60% of cardiology practices in this country have now been sold to hospitals. This trend toward hospital employment is particularly noticeable for larger cardiology groups, and there is considerable geographic variation in the phenomenon. However, if you are a cardiologist younger than 45 years old living in a medium-sized urban community outside of the South or California, you are probably an employed physician or about to be.
L. Samuel Wann

This is an enormous change from how your father practiced cardiology, and these changes began when Mr. Obama was still living in Indonesia. The past 50 years have brought enormous technical advances to the practice of cardiology, from the introduction of coronary angiography to echocardiography to bypass surgery, as well as stents, statins, SPECT, CTA, CMR, genomic medicine — and on and on. The positive and negative economic impact of these advances has been enormous. While we may have been indiscriminate in adopting some of these expensive technologies before proving their true value to our patients, we owe much of our success to the medical–industrial complex. As we mature as clinician scientists, we are more appreciative of the demands for cost consciousness and appropriate, evidence-based utilization of medical technology.

But this isn’t what broke the bank for traditional private practice, nor was it conflicts of interest due to physician ownership of imaging equipment, nor was it the fear of malpractice litigation. Conflicts of interest are inseparable from life itself. Physician ownership of equipment can have positive implications for patient service and focus on high-quality diagnostics with direct impact on patient care. Divorcing imaging from users and patients does not automatically reduce waste or inappropriate utilization, but it surely does reduce revenues in many private practice offices that have come to depend on technical fees to support the less remunerative office visits. Moving imaging to the hospital makes it even easier to order more imaging procedures to counter the perceived threat of malpractice litigation. Or, because the hospital electronic medical record doesn’t extend to the private office and the hospitalist in charge, it simply becomes easier to order another study than to track down the old one.

So we hear from politicians of all stripes that the government is out of money and current spending rates can’t continue. Is this what killed private cardiology practice? I don’t think so. We are a wily bunch and can hold our own in a free-for-all if given a chance. Small business — which at some level is what private practice comes down to — is remarkably resilient and continues to provide much of the growth and progress in this country and elsewhere. Larger is not always better. Given that more than half of us are now employed, it is time to take the many good aspects of old-fashioned private practice with us to the new setting and help the professional administrators create something newer and better. Not all private practices will sell, but they will adapt to the new environment by practicing smarter and by creating mutually beneficial relationships with hospitals that allow the physician groups to retain autonomy.

What is the fundamental change taking us away from 100 years of independent practice to the employment model? The cardiologist in the mirror is the real reason traditional private cardiology practice is declining in market share (“declining market share” is the verbiage they use in business school instead of the simpler term “dead” used in the title of this entry). Many of us baby boomers who are thinking of cutting back or retiring, as well as the new crop of female and male cardiologists who have had protected work hours during their residencies and fellowships, simply don’t want to work as hard as the traditional private-practice cardiologist has worked in the past. We do not want the financial responsibility of running a small business that is becoming increasingly complex with the coming of electronic records, accountable care organizations, pre-authorization, accreditation, the need to employ more support personnel, and topped off by negative innuendo related to self-referral. Add to this our desire to practice high-quality subspecialty cardiology in a sophisticated environment of team players, to have a decent family life, to get home before dark and go to a baseball game with the kids on Saturday instead of going to the hospital.

Others have gone there before us. EDs were once covered by rotating medical staff, not specialized ED physicians working a shift. Likewise, hospitalists and extended-practice nurses and physician assistants are doing much of the inpatient hospital work that used to occupy the off-hours of primary care physicians. ED and PCPs also want a better life.

So blame the decline in traditional cardiology private practice on the hope for a sane and balanced life, devotion to family and desire for some life outside medicine. The traditional private practice of cardiology is dead. May it rest in peace.

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Calcium supplements implicated in increased risk for CV events
Bolland M. BMJ. 2011;doi:10.1136/bmj.d2040.

Calcium supplements, taken with or without vitamin D, have been shown to modestly increase the risk for CV events, including MI and stroke.

These results, reported in a new study published by the British Medical Journal, incorporated findings from a re-analysis of the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD), as well as a meta-analysis of several additional trials.

Initially, results from WHI CaD, which was a 7-year, randomized, placebo-controlled trial with 36,282 postmenopausal women, showed no adverse effect of calcium and vitamin D on any CV endpoint. The results were obscured, however, because participants had free access to those supplements, according to the researchers. Specifically, at randomization, 54% of the participants were taking personal calcium supplements and 47% personal vitamin D supplements, which researchers said rendered the trial a comparison of higher- and lower-dose calcium and vitamin D for most of those participating.

According to results of their re-analysis, the 46% (n=16,718) of women not taking personal calcium supplements had an HR of 1.13 for any CV endpoint and 1.20 for total MI (P=.07 for both). Results on the other endpoints, including revascularization and stroke, were similar, with the exception of all-cause mortality (HR=0.99). Designation to calcium and vitamin D among women taking personal calcium supplements did not change CV risk.

“By restricting the analyses to women not taking personal calcium supplements, we were able to estimate the effect of calcium and vitamin D on CV events, observing increased risks of these events with calcium and vitamin D,” the researchers wrote.

To gain further insight into this issue, investigators then supplemented these results with data from placebo-controlled trials that examined CV events among individuals taking calcium or calcium and vitamin D. The complete trial-level data were obtained from 28,072 individuals from eight trials, as well as the WHI CaD participants who did not take personal calcium supplements.

Overall, 1,835 died during the mean trial duration of 5.7 years, which was weighted by study size. Researchers reported that 1,384 individuals had an incident MI or stroke, which resulted in RRs of 1.24 (P=.004) for MI and 1.15 (P=.009) for the composite of MI and stroke.

“When [WHI CaD] results are taken together with the results of other clinical trials of calcium supplements, with or without vitamin D, they strongly suggest that calcium supplements modestly increase the risk of CV events, particularly MI,” the researchers concluded. “These data justify a reassessment of the use of calcium supplements in older people.”

The situation seems quite complex to me because there are different reasons to supplement with calcium. For example, there are people who have conditions like osteoporosis, renal disease, and who are receiving treatment under clinical supervision. There are people at varying levels of osteoporosis risk, some of whom take calcium with or without vitamin D on their own prophylactically, and some who take it under clinical supervision based on recommendations from their physicians. There are people who take calcium and other supplements for general health reasons with the belief that anything natural must be good. Some people take calcium as part of antacid preparations — it is not clear to me how this is captured in the studies included in this meta-analysis. It is also unclear to me how antacid use was cross-referenced with calcium use in WHI.
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ICD nonuse in eligible patients may be lower than previously estimated
LaPointe N. Circ Cardiovasc Qual Outcomes. 2011;4:146-151.

Detailed analysis showed that rates of underutilization of implantable cardioverter defibrillators among eligible patients decreased from 41% to 13%, according to newly published data.

“To date, several analyses of claims or registry data have indicated high rates of underutilization of this evidence-based therapy in clinical practice, as well as age, sex and racial disparities in ICD use,” the researchers wrote. “Although we initially identified similar rates of ICD underutilization and disparities within our health care system, after detailed medical record abstraction, we discovered that a majority of those not receiving an ICD had an identified contraindication or patient refusal.”

Their analysis included patients (n=542) with a diagnosis of HF and left ventricular ejection fraction of no more than 30% at a tertiary care center from Jan. 1, 2007, to Aug. 30, 2007. With the use of medical records, researchers determined reasons for nonuse among patients without an ICD.

Overall, 224 eligible patients (41%) did not receive an ICD. Adjusted analysis comparing all ICD recipients with all nonrecipients revealed absence of ventricular arrhythmia or cardiac arrest (OR=3.17; 95% CI, 2.14-4.68), index hospitalization on a noncardiology service (OR=2.64; 95% CI, 1.65-4.21) and female sex (OR=1.90; 95% CI, 1.28-2.81) as being the factors most associated with nonuse.

After performing a detailed chart review on the eligible patients, researchers observed that 117 patients (52%) were ineligible for the device and 38 (17%) refused it, leading to only 69 (13%) patients eligible for an ICD who failed to receive one.

Furthermore, analysis comparing all ICD recipients with nonrecipients without contraindications indicated the following characteristics of nonuse: absence of ventricular arrhythmias (OR=4.93; 95% CI, 2.56-9.5), noncardiology hospital service (OR=3.73; 95% CI, 1.98-7.04) and no health insurance (OR=3.10; 95% CI, 1.48-6.46).

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Omega-3 fatty acid yielded significant reductions in triglycerides

A 4-g daily formulation of omega-3 fatty acid AMR101 was linked to decreases in triglyceride levels of more than 20% compared with placebo, according to recent results.

The aim of the ANCHOR trial was to determine the efficacy of AMR101 (Amarin) in reducing triglyceride levels without increasing LDL cholesterol in 702 individuals with high triglycerides who had experience with background statin therapies, including simvastatin (Zocor, Merck), atorvastatin (Lipitor, Pfizer) or rosuvastatin (Crestor, AstraZeneca). High triglycerides were defined as 200 mg/dL to 500 mg/dL. Eligible participants had mixed dyslipidemia, and 73% were diabetic.

Four grams of AMR101 was associated with a 21.5% decrease in triglyceride levels (P<.0001). The 2-g formulation reduced triglycerides by 10.1% (P=.0005).

Both doses of the drug yielded decreases in LDL that met predetermined noninferiority criteria. Compared with placebo, a 6.2% decrease in LDL was observed from baseline among patients receiving the 4-g dose. Among patients receiving 2 g per day, LDL was reduced by 3.6% compared with placebo (P=.0867).

Secondary endpoint results indicated that, compared with placebo, non-HDL cholesterol decreased by 13.6% in the 4-g per day group (P<.0001) and by 5.5% in the 2-g per day group (P =.0054).

Adverse event profiles were similar between treatment and placebo groups, and no drug-related adverse events were reported.

The primary outcome measure was the percentage change in triglyceride levels from baseline among patients on the AMR101 compared with placebo after 12 weeks. The trial was also powered to demonstrate a lack of LDL-elevating effect of the study drug compared with placebo. Secondary endpoints included the difference in other lipid and biomarker levels between treatment and placebo groups.
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Racial disparity observed in survival after heart transplantation
Liu V. Circulation. 2011;123:1642-1649.

During a 22-year interval, black recipients of a heart transplant had higher rates of mortality compared with white recipients, according to retrospective cohort study data.

The study included 39,075 adult recipients of a heart transplant between 1987 and 2009. Among this population, 79.3% of the recipients were white and 12.8% black, with the remaining 7.9% either Latino, Asian, American Indian or Alaskan native, Pacific Islander or multiracial; although the number of nonwhite recipients increased over time.

Overall, median waiting list time was 66 days for nonwhite recipients vs. 92 days for white recipients. There were 16,880 total deaths after transplantation during the study period.

After multivariate adjustment for recipient, socioeconomic and transplant factors, only blacks had an increased mortality risk compared with whites (HR=1.34; 95% CI, 1.21-1.47). This equated to a 5-year mortality rate of 35.7% (95% CI, 35.2-38.3) among blacks and 26.5% (95% CI, 26-27) among whites.

Also, blacks were more likely to die of graft failure or a CV cause than whites (57.9% vs. 37.8%) or other nonwhites (44.1%), but they were less likely to die of an infection or malignancy than whites (19.9% vs. 33%) or other nonwhites (28.2%).

“Although long-term survival has improved for all recipients, the racial gap in survival among blacks has persisted over 2 decades, and may be related in inadequate immunosuppression,” the researchers concluded. “Additional research aimed at identifying the source of this disparity is necessary.”

These are extremely interesting observations. The difference in outcomes between white and black heart transplant recipients is substantial. Moreover, graft failure and CV causes appear to be the cause although the mechanism(s) involved remain speculative. Given the high and increasing number of blacks who receive heart transplants in the US each year, these results provide strong motivation for further research efforts directed at identifying the cause of the higher rate of graft failure in blacks and, most importantly, providing direction for new treatment algorithms to solve this problem.
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Screen time shown harmful on retinal microvascular structure of children
Gopinath B. Arterioscler Thromb Vasc Biol. 2011;doi:10.1161/ATVBAHA.110.219451.

Among 6-year-old students in Australian schools, screen time was found to have a negative effect on their retinal microvascular structure, whereas physical activity had a positive influence.

The random sample of 34 schools in Sydney, Australia, featured 1,492 6-year-old students. Researchers collected data during a pre-organized visit to each school and excluded children if they had missing or incomplete data or retinal conditions. Afterward, parents completed a comprehensive questionnaire that assessed the physical and sedentary activities of their children.

Researchers reported that the children spent a mean of 1.9 hours per day of screen time — which incorporated TV viewing, using a computer or playing a videogame — whereas only 36 minutes per day were spent in physical activity.

After adjustment for variables, including age, ethnicity, eye color, axial length, BMI and mean arterial BP, children in the highest tertile of outdoor sporting activity had a wider mean retinal arteriolar caliber by 2.2 mcm compared with those in the lowest tertile (P=.004). When researchers increased quartiles of time spent watching TV, the result was a narrower mean retinal arteriolar caliber of roughly 2.3 mcm (P=.003).

“We show for the first time that engaging in higher levels of outdoor activity is associated with modestly wider retinal arterioles in children. However, increased screen time was associated with narrowing of retinal arteriolar caliber,” the researchers wrote. “As retinal arteriolar narrowing could be a potential subclinical marker of future CVD risk, the presence of this risk factor may indicate a need for closer monitoring and lifestyle modifications to decrease the time schoolchildren spend watching the TV and increasing the time they spend in physical activity.”

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Study: CABG use decreased between 2001 and 2008
Epstein A. JAMA. 2011;305:1769-1776.

Results from an analysis published in JAMA suggested that CABG use decreased between 2001 and 2008, but also that percutaneous coronary intervention remained at stable levels.

Researchers for the cross-sectional study examined time trends in patients undergoing CABG or PCI between 2001 (n=77,952 for CABG; n=55,483 for PCI) and 2008 (n=151,893 for CABG; n=153,800 for PCI) in the Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample. The data were supplemented by Medicare outpatient hospital claims.

According to the results, there was a 15% decrease in coronary revascularizations, from 5,569 (95% CI, 5,315-5,835) procedures/million-adults in 2001-2002 to 4,748 (95% CI, 4,532-4,975) procedures/million-adults in 2007-2008 (P<.001). Annual rates of annual CABG surgery decreased by 38%, from 1,742 (95% CI, 1,663-1,825) procedures/million-adults in 2001 to 1,081 (95% CI, 1,032-1,133) procedures/million-adults in 2008 (P<.001). The decreases were observed across sex, age racial and regional subgroups.

By contrast, annual rates of PCI decreased by 4%, from 3,827 (95% CI, 3,578-4,092) procedures/million-adults in 2001-2002 to 3,667 (95% CI, 3,429-3,922) procedures/million-adults in 2007-2008 (P=.74).

“Although the total rate of US coronary revascularization decreased modestly between 2001 and 2008, there was a substantial decrease in the CABG surgery rate,” the researchers concluded. “Between 2001 and 2008, the rate of PCI did not significantly change; however, there were continual changes in the frequency of stent types used for PCI.”

As we move forward into an era of limited health care resources, it will become increasingly important to have an accurate estimation of the clinical need and utilization of medical procedures. This information will enable forecasting of needs for resource allocation and decision-making about future investments in clinical infrastructure and training of future physicians.

In the study published by JAMA, Epstein et al estimate that rates of CABG have declined steadily by 15%, while PCI rates have declined only slightly, with a non-significant 4% decrease in 2008 compared with 2001. Although they claim that PCI volumes remained steady, their data show PCI procedures increased from 2001 to 2004, but decreased by 10% from 2005 to 2008.

Our similar study published in Circulation: Cardiovascular Quality and Outcomes also found a steady decrease in CABG, but a more complicated trend in PCI procedures. We reported annual CABG and PCI revascularization rates in the entire Medicare population from the beginning of 2000 through the end of 2009 and found an early increase in PCI procedures from 2000 to the end of 2004, but a steady decrease in PCI procedures from 2004 through 2009. Epstein et al also suggest a rise in multivessel stenting. Our data show that any increase multivessel stenting peaked in 2006, before publication of the SYNTAX study, and has since declined. Based on the rate of decrease in PCI, we concluded the decrease in CABG volume could not be entirely accounted for by a preferential use of PCI.

Epstein et al’s conclusion that PCI rates have remained unchanged must be evaluated closely. Both their study and ours show the changes in PCI volume were not steady over the 2000 to 2008 time period. However, their comparison between the 2001 and 2008 data assumes a linear change and, therefore, does not accurately reflect the trends that occurred in the intervening years.

The minor differences in the procedure rates published in our study result from use of different billing datasets and methodology. We utilized nearly complete Medicare physician billing data on inpatient and outpatient procedures, whereas Epstein et al evaluated all insurance types, but did not have data on outpatient procedures and made estimations of rates for their sample based on the US population, rather than the number of patients actually eligible for treatment in this subset of hospitals.

Importantly, Epstein et al acknowledge that the present study does not provide sufficient patient-level data to form any conclusions regarding procedural appropriateness. These revascularization rates may reflect changing patient demographics and clinical comorbidity within this sample of hospitals, rather than operator or patient preferences. An increase in acute coronary syndromes in numbers of patients with inoperable/high-risk surgical disease or low-risk non-surgical disease or the migration of patients from one hospital to another may explain their findings.
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FDA committees evaluate recent safety data on contrast agents

Members of the Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee met today to interpret and discuss safety data for the two approved ultrasound contrast agents, Definity and Optison, as well as the investigational agent SonoVue. The FDA was not seeking advice on a vote to approve or revoke any of the agents but a discussion on current labeling.

The Cardiovascular and Renal Drugs Advisory Committee (CRDAC) had previously gathered in 2008 to examine efficacy and safety issues of those three agents.

According to background provided by the FDA, despite the appearance of a low overall adverse event rate with ultrasound contrast agents, serious adverse events and even fatalities still persist with all three agents. Although the organization noted the difficulty in distinguishing adverse events related to ultrasound contrast agents from concomitant medications and complications due to underlying comorbidities, it also said there is reason to believe ultrasound contrast agents play a contributory role.

In today’s meeting, both the CRDAC and the Drug Safety and Risk Management Advisory Committee convened at the request of the FDA to discuss in detail the safety data that have come to light in the 3 years since the meeting.

During the morning session, industry members from Lantheus Medical Imaging (Definity), GE Healthcare (Optison) and Bracco Diagnostics (SonoVue) presented post-marketing results on the safety studies performed on their respective agents. All of the studies presented showed minimal risk for serious adverse events related to usage of the agents, while also being consistent with the data presented at the previous meeting. As a result, both GE and Lantheus requested changes to the black box warnings, which they said are a barrier to use. The requested changes were either to remove the black lines or remove the warning completely.

Responding to this concern, Allan Coukell, BScPharm, director of medical safety, the Pew Health Group, Washington DC, said during the meeting, “It does seem there was a dip in use [of contrast agents] after the black box warning, but it’s come back up. It also seems clear that these agents are going to be used in ever-expanding settings by more and more people using them for the first time. So it seems to me that you would want them to know there is this [risk for a] rare but potentially very serious event.”

This led to one of the main issues discussed in the afternoon portion of the meeting which was the extent to which the new safety information presented justified modification of the boxed warnings. A consensus was not reached among members.

“The most positive thing I’ve heard today is of the impact of the black box warnings, in that it actually did something, maybe, which is unusual compared to drugs,” said Brian Strom, MD, MPH, chair and professor of biostatistics and epidemiology, University of Pennsylvania, Philadelphia. “But it’s important to keep in mind that black box warnings do not prohibit use. They are simply a way to clarify the risk/benefit balance. We are also in a climate now when more and more black box warnings are being added. Clearly, if you look at now, as opposed to five years ago, there is a lot more of them. To take it away now sends a clear message that we’ve seen data that changes the risk/benefit from what it was before seeing the data, and we haven’t. We’re all very clear on that. So if we haven’t seen anything to change it, it would send a really bad message that these agents are safer than we thought.”

However, Henry Black, MD, clinical professor of medicine, New York University School of Medicine, New York, was still not convinced there was a need for the warning and questioned why the black boxes were even added in the first place.

“It’s like an inflation creep, a grade creep. That’s why there are more black box warnings and why their impact becomes less and less; because they are not used appropriately,” he said. “I wasn’t at the 2008 meeting, [but the labeling’s] already been softened and there isn’t anything here. And I think it has an impact based on what we saw. I don’t think it’s going to affect things very much except in the legal environment we’re in where risk management to a hospital’s lease is so important that they are not going to go against this for obvious reasons that I think we ought to take this away.” – by Brian Ellis

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Shocks for AF, ventricular rhythms increased risk of death

Heart Rhythm Society 32nd Annual Scientific Sessions

SAN FRANCISCO – Among patients with an implantable cardioverter defibrillator or cardiac resynchronization therapy-defibrillator, those who received shocks for atrial fibrillation and ventricular rhythms had a significantly greater likelihood of death compared with those who did not receive a shock, according to data presented here.

“The overall findings suggest that the increased risk of death after inappropriate shock is related to the underlying arrhythmia and the associated disease process with it as opposed to a adverse effect from the shock itself,” said Brian Powell, MD, electrophysiologist at the Mayo Clinic, Rochester, Minn., and the study’s primary investigator, in an interview with Cardiology Today.

In the study, all ICD and cardiac resynchronization therapy-defibrillator (CRT-D) patients (n=3,809) involved were enrolled in the Latitude remote monitoring system (Boston Scientific) through January 1, 2010. A group of seven electrophysiologists adjudicated the first shock episode rhythms for these patients and matched them to patients without a shock (n=3,630).

During a mean follow-up of 25 ± 17 months after the first shock, 36% experienced a shock as the result of sustained monomorphic ventricular tachycardia (SMVT), 18% resulted from atrial fibrillation/flutter, 17% from sinus tachycardia/supraventricular tachycardia (SVT), 5% from noise/artifact/oversensing, and 1% from non-sustained ventricular tachycardia (NSVT).

Overall, mortality in the shock group was significantly higher compared with the no shock group for ventricular fibrillation/polymorphic ventricular tachycardia (PMVT; HR=2.10, P<.0001), SMVT (HR=1.65; P<.0001), SMVT and PMVT (HR=2.77; P<.0001) and AF (HR=1.61; P=0.003). No difference in mortality was reported among those who received a shock for sinus tachycardia/SVT (HR=0.97; P=0.86) or noise/artifact/oversensing (HR=0.91; P=0.76) when compared with those who did not experience a shock.

As a result of these findings, Powell said that electrophysiologists can have some reassurance that the shock itself may not affect the patient’s survival. “This is something that electrophysiologists have been concerned about based on previous studies,” he said. “This is the first study that is large enough to look at the subgroups within the inappropriate shock category to see what exactly is driving that increased risk of death among patients who receive inappropriate shocks. It appears that AF and its associated comorbidities account for the increased risk of death after an inappropriate shock.” – by Brian Ellis
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CRT found superior to right ventricular apical pacing in patients with permanent AF

Heart Rhythm Society 32nd Annual Scientific Sessions

SAN FRANCISCO – Patients with permanent atrial fibrillation who, on top of atrioventricular junction ablation, were treated with cardiac resynchronization therapy had lower rates of worsening HF and hospitalizations for HF compared with those treated with right ventricular apical pacing, according to new data presented at the Heart Rhythm Society’s 32nd Annual Scientific Sessions.

According to Michele Brignole, MD, the study’s primary investigator andhead of the department of cardiology, Ospedali del Tigullio, Lavagna, Italy, the prospective study began as an attempt to add to the current level of understanding of right ventricular apical pacing vs. cardiac resynchronization therapy (CRT) in patients with AF, which he said only consisted of a few small short-term trials.

“So there is a lack of knowledge,” Brignole told Cardiology Today. “For this reason, current guidelines in America (2008) and Europe (2010) on CRT have ranked CRT pacing as Class IIa level of evidence B and only for a subgroup of patients with AF, specifically the subgroup of patients with large QRS, low ejection fraction and NYHA Class 3 or 4.”

To bring further clarification to this issue on a larger scale, Brignole and fellow researchers randomly assigned 186 patients from 19 hospitals to receive either optimized echo-guided CRT (n=97) or right ventricular apical pacing (n=89). All patients had previous atrioventricular junction and CRT implantation performed successfully. The study’s primary endpoint was a composite of death from HF, hospitalization due to HF or worsening HF.

During a median follow-up of 20 months, the primary endpoint proved to be significantly lower in the CRT group vs. those in the right ventricular group (11% vs. 26%; sub-HR=0.37; 95% CI, 0.18-0.73). This was due primarily to significantly lower rates of worsening HF (sub-HR=0.27; 95% CI, 0.12-0.58) and hospitalizations for HF (sub-HR=0.20; 95% CI, 0.06-0.72) in the CRT group because the rates of mortality between groups were similar. As a result, the CRT mode was an independent predictor of the absence of clinical failure (OR=0.19; 95% CI, 0.05-0.67).

For Brignole, two important implications can be taken from this trial. “The first is that this trial confirms the Class IIa indication of the most recent guidelines,” he said. “This indication was mainly based on an expert consensus opinion, rather than based on real studies. This is the first study that gives evidence of clinical benefit of therapy in patients who already have a IIa indication. In other words, this study could serve to upgrade the current recommendation from IIA to Class I.”

The second implication, however, according to Brignole, is even more important. “This study, if confirmed by others, would expand the indication of guidelines to all patients with severe symptomatic AF, independently for ejection fraction, length and duration of QRS and so on,” he said, but adding that this study must be regarded as somewhat preliminary. – by Brian Ellis

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CRT found superior to right ventricular apical pacing in patients with permanent AF

Heart Rhythm Society 32nd Annual Scientific Sessions

SAN FRANCISCO – Patients with permanent atrial fibrillation who, on top of atrioventricular junction ablation, were treated with cardiac resynchronization therapy had lower rates of worsening HF and hospitalizations for HF compared with those treated with right ventricular apical pacing, according to new data presented at the Heart Rhythm Society’s 32nd Annual Scientific Sessions.

According to Michele Brignole, MD, the study’s primary investigator andhead of the department of cardiology, Ospedali del Tigullio, Lavagna, Italy, the prospective study began as an attempt to add to the current level of understanding of right ventricular apical pacing vs. cardiac resynchronization therapy (CRT) in patients with AF, which he said only consisted of a few small short-term trials.

“So there is a lack of knowledge,” Brignole told Cardiology Today. “For this reason, current guidelines in America (2008) and Europe (2010) on CRT have ranked CRT pacing as Class IIa level of evidence B and only for a subgroup of patients with AF, specifically the subgroup of patients with large QRS, low ejection fraction and NYHA Class 3 or 4.”

To bring further clarification to this issue on a larger scale, Brignole and fellow researchers randomly assigned 186 patients from 19 hospitals to receive either optimized echo-guided CRT (n=97) or right ventricular apical pacing (n=89). All patients had previous atrioventricular junction and CRT implantation performed successfully. The study’s primary endpoint was a composite of death from HF, hospitalization due to HF or worsening HF.

During a median follow-up of 20 months, the primary endpoint proved to be significantly lower in the CRT group vs. those in the right ventricular group (11% vs. 26%; sub-HR=0.37; 95% CI, 0.18-0.73). This was due primarily to significantly lower rates of worsening HF (sub-HR=0.27; 95% CI, 0.12-0.58) and hospitalizations for HF (sub-HR=0.20; 95% CI, 0.06-0.72) in the CRT group because the rates of mortality between groups were similar. As a result, the CRT mode was an independent predictor of the absence of clinical failure (OR=0.19; 95% CI, 0.05-0.67).

For Brignole, two important implications can be taken from this trial. “The first is that this trial confirms the Class IIa indication of the most recent guidelines,” he said. “This indication was mainly based on an expert consensus opinion, rather than based on real studies. This is the first study that gives evidence of clinical benefit of therapy in patients who already have a IIa indication. In other words, this study could serve to upgrade the current recommendation from IIA to Class I.”

The second implication, however, according to Brignole, is even more important. “This study, if confirmed by others, would expand the indication of guidelines to all patients with severe symptomatic AF, independently for ejection fraction, length and duration of QRS and so on,” he said, but adding that this study must be regarded as somewhat preliminary. – by Brian Ellis
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Infection incidence for pacemaker implants increased from 1993 to 2008

Heart Rhythm Society 32nd Annual Scientific Sessions

SAN FRANCISCO — The burden of infection among recipients of cardiac implantable electronic devices has increased between 1993 and 2008 for pacemakers, but not for implantable cardioverter defibrillators, according to new research.

Researchers for the study reviewed data from the National Inpatient Sample to identify patients receiving pacemakers and ICD between 1993 and 2008. They used ICD-9-CM procedure codes to identify the specific patients, including the codes for primary pacemaker, primary ICD, pacemaker removal and ICD removal. Patient comorbidities and the national incidence for pacemakers and ICDs were evaluated.

A total of 3.2 million patients received pacemakers and 1.1 million received ICDs from 1993 to 2008, and a total of 73,000 of them were diagnosed with infection (1.88% for pacemakers and 1.13% for ICDs). A 224% increase in the infection rate was reported in pacemaker patients from 1993 (1.6%) to 2008 (3.5%), while ICD infection rates remained constant over time. The incidence of infection was also 75% higher in patients with pacemakers vs. those with ICDs (P<.001). The incidence in infection rose in ICD patients with HF (OR=1.28), renal failure (OR=2.18) and respiratory failure (OR=1.30), while pacemaker infection rose in patients with diabetes (OR=1.12), HF (OR=1.46), renal failure (OR=2.38) and respiratory failure (OR=2.25).

The researchers also noted that in 2008, over 32% of patients with infected ICDs or pacemakers were diagnosed with renal failure, which was an increase from 1993.

“The dimensions of the national cardiac implantable electronic device infection burden are changing due to the increasing prevalence of comorbidities, particularly renal failure,” the researchers concluded in their abstract. “Strategies for decreasing cardiac implantable electronic device infection should include a better understanding of periprocedural risk factors.”
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Primary prevention ICD yielded higher overall mortality in women than men

Heart Rhythm Society 32nd Annual Scientific Sessions

SAN FRANCISCO — Women who received an implantable cardioverter defibrillator for primary prevention of sudden death experienced a similar arrhythmic death rate but a mortality rate nearly 10% higher than in men, according to findings presented at the Heart Rhythm Society’s 32nd Annual Scientific Sessions.

Data on the survival benefit of ICD for women with cardiomyopathy to prevent sudden death are unclear. The current retrospective analysis measured the effect of gender on the appropriate use of ICD therapy and associated mortality rates in 525 consecutive patients. Eligible patients had ischemic or nonischemic cardiomyopathy and had undergone ICD implantation for primary prevention of sudden death.

Overall, there were 160 deaths. The mortality rate was 38.9% among 121 women and 30% among 404 men.

Appropriate ICD therapies were administered to 14.9% of women and 17.1% of men. Four-year survival rates were different between the groups (P=.039), but there was no difference in the rate of appropriate ICD therapy, according to results of a Kaplan-Meier analysis.

Mortality was the primary endpoint, along with appropriate ICD therapy at the 4-year mark. The mean duration of follow-up was 3.8 years.

The researchers assessed demographic information and data for comorbid illnesses and medications for all patients. The 121 women in the study accounted for 23.1% of the population and had similar baseline characteristics as men. Women were aged 61 years and men were aged 62.5 years. Women also had similar ejection fraction (25%) and comorbidities and medication use as men.

Regarding baseline characteristics that were not similar, 81% of men were white vs. 63% of women (P<.001). The tobacco use rate was 63% among men and 43% among women (P<.001). Fifty percent of men had undergone prior coronary bypass surgery vs. 26% of the women (P<.001).

“Women who received an ICD for prevention of [sudden death] had a similar arrhythmic event rate as men,” the researchers wrote. “However, the impact of primary prevention ICD therapy is attenuated by increased mortality rate in female patients.”
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SCD-HeFT: Frequency of non-sustained ventricular tachycardia associated with mortality

Heart Rhythm Society 32nd Annual Scientific Sessions

SAN FRANCISCO — The number of non-sustained ventricular tachycardia episodes that patients with HF experience is linked with mortality, results from a study presented at the Heart Rhythm Society’s 32nd Annual Scientific Sessions indicated.

Researchers for the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) enrolled 2,521 patients with NYHA Class II or III HF and with an ejection fraction of at least 35%, of whom 2,040 had readable 24-hour Holter monitoring data. Holter monitoring data were obtained 2 weeks before randomization to placebo, amiodarone or an implantable cardioverter defibrillator. The researchers evaluated the Holter data and characterized non-sustained (≥3 beats in <30 seconds) ventricular tachycardia (NSVT), identifying it as at least 120 beats/minute. Holter staff and physician readers were blinded to clinical parameters, randomization and status outcomes. Cox regression models were used to identify prognostic baseline covariates such as age, ejection fraction and NYHA Class.

According to the researchers, no NSVT was observed in 1,367 (67%) patients on baseline monitoring; at least one 1 episode was seen in 673 (33%) patients; at least two episodes were seen in 402 (20%) patients; and at least three episodes in 291 patients (14%). The mean NSVT rate was 155 beats/minute, with a mean duration of 4.5 beats. They determined that at least two NSVT episodes were predictive of overall mortality.

“The presence of only one episode of NSTV on the baseline Holter monitoring did not confer an increase in overall mortality, whereas >2 NSVT episodes did confer increased overall mortality compared to less frequent NSVT episodes,” the researchers concluded in an abstract.

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Time of day of acute MI shown influential on infarct size
Suárez-Barrientos A. Heart. 2011;doi:10.1136/hrt.2010.212621. S

Researchers have found that the time of day of acute MI had a significant effect on infarct size in patients with STEMI, with 6 a.m. to noon associated with the largest infarct size.

All patients (n=811) in the study were admitted to the coronary care unit of Hospital Clínico San Carlos in Madrid, Spain, for STEMI between March 2003 and September 2009. Investigators split patients into one of four groups depending on occurrence of infarction — midnight to 6 a.m. (n=141), 6 a.m. to noon (n=269), noon to 6 p.m. (n=240) and 6 p.m. to midnight (n=161) — and estimated infarct size by peak enzyme release.

According to their results, there was a circadian variation in infarct size across time of day as determined by concentrations of troponin I (P=.012) and peak creatine kinase (P=.015). Similar curves were found with both biomarkers and showed a global maximum from the 6 a.m. to noon and a local minimum from noon to 6 p.m.

To further support this, researchers conducted additional analysis and found the largest infarct size in those who experienced STEMI during the dark-to-light transition period (6 a.m.-noon), as evidenced by increases in concentrations of peak troponin I of 24.6% (P=.033) and peak creatine kinase of 18.3% (P=.031) compared with the three other time periods.

“Overall, there is an expected increase of about 20% in infarct size in patients with STEMI onset in the dark-to-light transition period compared with any other time of day,” the researchers wrote, adding that these results “advocate the inclusion of ‘time of acute MI onset’ as an important variable in clinical trials testing novel cardioprotective strategies with MI size as an endpoint.” – by Brian Ellis

Circadian rhythms are biologic clocks that regulate body processes over a 24-hour cycle in response to daylight or darkness. In recent years light stimulated alterations in gene expression and protein translation have been identified that cause neurohumoral alterations highly relevant to human physiology and pathophysiology. Some of these are relevant to CVDs. These include circadian variations in proteins critical to fibrinolysis, regulation of BP and heart rate, and modulation of lipid and glycogen metabolism.

It has been known for many years that MIs are most common in the early morning hours. This is likely due to a predisposition due to circadian changes. Results of a recent study done in mice exposed to ischemia and reperfusion have supported the concept that myocardial infarct size may be dependent on time dependent light and darkness alterations.

Lawrence Horwitz, MD

The clinical study by Suarez-Barrientos et al in Heart this year retrospectively examines infarct size, estimated by cardiac enzyme levels, according to time-of-day in 811 patients, most of whom were treated with percutaneous coronary intervention. They concluded that the largest infarcts occurred between 6 AM and noon, which is often termed the “light-to-dark transition period.” There was a relatively small difference in infarct size between 6 a.m. to noon and 6 p.m. to midnight periods, but infarcts during the other two time periods were substantially less. There was some inconsistency between the estimates of infarct size and measurements of left ventricular ejection fraction among groups. These discrepancies; the many other factors that may influence infarct size; the limitations of the enzyme technique for estimating infarct size; and the relatively small population examined in this study limit the strength of its conclusions.

Nevertheless, it offers some support to the concept that in addition to the well-established circadian variation in the timing of MIs, there may be a similar variation in the severity of the infarctions. The existence of such variations raise the issue of whether preventive measures focused on the timing of neurohumoral changes could decrease incidence or improve outcomes of MIs. For example, could certain drugs be more effective given in the evening than in the morning, or could drugs that alter the photosensitivity of the biological clock decrease time-of-day dependent increases in the incidence or severity of MI?
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Low health literacy cause for concern among patients with HF
Peterson PN. JAMA. 2011;305:1695-1701.

Retrospective cohort study data have shown that among patients with HF, low health literacy correlated with a significantly higher risk for all-cause mortality. This, however, did not translate to an increased risk for hospitalization.

Pamela N. Peterson, MD, MSPH, and a group of researchers conducted the study by surveying outpatients with HF enrolled at Kaiser Permanente of Colorado. All patients (n=2,156) were diagnosed from 2001 to 2008 and were mailed a survey that consisted of three brief questions assessing health literacy skill, from which they were graded on a five-point scale.

Of those surveyed, 1,547 responded and 1,494 were included in the final analysis. Overall, 262 patients had low health literacy. Characteristics that identified patients as having low health literacy included old age, higher rates of coexisting illnesses and low socioeconomic status.

During the 1.2-year median follow-up, 124 deaths were reported, with a significantly higher rate found in the low health literacy group vs. the adequate health literacy group (17.6% vs. 6.3%; adjusted HR=1.97; 95% CI, 1.3-2.97). Despite this finding, rates of hospitalization were only modestly higher in the low literacy group and did not reach statistical significance (30.5% vs. 23.2%; adjusted HR=1.05, 95% CI, 0.8-1.37).

According to the researchers, the study’s finding “supports efforts to determine whether interventions to screen for and address low health literacy can improve important health outcomes in patients with HF.”

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HIV infection may elevate risk for HF
Butt A. Arch Intern Med. 2011;171:737-743.

Among more than 8,000 male veterans, HIV infection proved to be an important risk factor for HF, even after adjusting for traditional risk factors, according to a study appearing in the Archives of Internal Medicine.

In the study, researchers examined 8,486 participants (28.2% HIV-infected; median age, 48 years) who were enrolled in the Veterans Aging Cohort Study Virtual Cohort and the 1999 Large Health Study of Veteran Enrollees from January 2000 to July 2007. Participants were excluded if they were diagnosed with cancer, with the exception of non-melanoma skin cancer, or if they were female, due to the small number of women enrolled (n=276).

Adeel A. Butt, MD, MS

Over the study’s median follow-up of 7.3 years, 286 incident HF events were reported. After adjusting for age, race and ethnicity, the incidence of HF was 7.12 per 1,000 person-years among those infected with HIV and 4.82 per 1,000 person-years among those not infected. This led to a notably higher risk for HF among those with HIV infection (HR=1.81; 95% CI, 1.39-2.36), which remained similar among veterans who did not have a CHD event or alcohol dependency before the incident HF event.

Additionally, compared with HIV-uninfected participants, ongoing viral replication (HIV-1 RNA level ≥500 copies/mL) among those with HIV infection was linked with a higher risk for developing HF (HR=2.28; 95% CI, 1.57-3.32), whereas infected veterans with baseline and recent HIV-1 RNA level of less than 500 copies/mL did not have an increased risk for HF.

For future research, the study authors suggested that additional work be done to fully characterize the association between HIV infection and HF, and to understand the underlying mechanisms.
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Particle traps benefited CV health in men exposed to diesel exhaust
Lucking A. Circulation. 2011;123:1721-1728.

Exhaust particle traps, which are used to reduce particle emissions from diesel engines, are not only beneficial to the environment but may even confer a health benefit by reducing CV events among those exposed to the exhaust, a new study suggested.

“There is a robust and consistent association between air pollution and CV morbidity and mortality,” the researchers wrote. “Using complementary and relevant measures of CV health, we have reconfirmed the adverse effects of exposure to diesel engine exhaust on endothelial function and ex vivo thrombosis.”

The randomized, double blind study involved 19 healthy male volunteers (mean age, 25 years). Researchers used an exposure facility led by technical staff to expose participants for 1 hour to filtered air and diesel exhaust in either the presence or absence of a particle trap. Investigators then measured forearm blood flow and plasma fibrinolytic factors and assessed ex vivo thrombus formation.

They found that diesel exhaust compared with filtered air correlated with increased ex vivo thrombus formation and reduced vasodilatation under both low- and high-shear conditions. Overall, diesel exhaust particulate number and mass were substantially reduced with the particle trap (P<.001 for both), which resulted in reduced thrombus formation, increased vasodilatation and an increase in tissue-type plasminogen activator release.

This led the researchers to conclude by supporting the application of particle traps to diesel-powered vehicles for reducing urban particulate concentrations, as well as limiting a range of adverse CV effects related to exposure to traffic-derived air pollution.

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Treatment with angiotensin receptor blockers before stroke could exert a favourable effect in acute cerebral infarction
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Left atrial appendage closure with Amplatzer Cardiac Plug for prevention of stroke in atrial fibrillation: in-vivo imaging
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Community Stroke Prevention Programs: An Overview
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The Effect of Balance Training on Balance Performance in Individuals Poststroke: A Systematic Review
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Heterogeneity of the Phenotypic Definition of Coronary Artery Disease and Its Impact on Genetic Association Studies
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Short-term high-dose atorvastatin for periprocedural myocardial infarction prevention in patients with renal dysfunction
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Simple or Complex Stenting for Bifurcation Coronary Lesions
A Patient-Level Pooled-Analysis of the Nordic Bifurcation Study and the British Bifurcation Coronary Study
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In-vivo detection of the frequency and distribution of thin-cap fibroatheroma and ruptured plaques in patients with coronary artery disease: an optical coherence tomographic study
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Neurologic and Cardiac Benefits of Therapeutic Hypothermia
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HERCULES: BNP not predictive of reduced systolic BP in stented renal artery stenosis patients

Society for Cardiovascular Angiography and Interventions 2011 Scientific Sessions

BALTIMORE — Results presented in a late-breaking trial session demonstrated that elevated pretreatment brain natriuretic peptides were not predictive of reduction in systolic BP in patients treated with renal artery stenting.

“The results are disappointingly negative,” said HERCULES trial investigator Michael R. Jaff, DO, medical director of the Vascular Center at Massachusetts General Hospital in Boston, and a member of the Cardiology Today Editorial Board, while presenting the findings at the 2011 Society for Cardiovascular Angiography and Interventions Scientific Sessions. “I must tell you, this is a field struggling for predictive help,” Jaff said, “but we weren’t able to find it.”

The prospective, multicenter trial evaluating the safety and effectiveness of the RX Herculink Elite Renal Stent System (Abbott Vascular) reviewed outcomes for 202 patients (241 lesions, 39 bilateral lesions) with uncontrolled hypertension who were treated with a renal artery stent between August 2007 and October 2009.

The primary endpoint was a 9-month binary restenosis rate as determined by duplex ultrasound or angiographic analysis; the performance goal was 28.6%. Secondary endpoints were changes in systolic BP, antihypertensive medications and renal function between baseline and 9 months. Measurements of brain natriuretic peptide (BNP) were taken at baseline, 24 hours and 30 days’ post-procedure.

The investigators found that systolic BP decreased after stenting with no adjustment to medications. A BNP level of more than 80 pg/mL was found in 66% of patients; baseline serum creatinine was 1.2 ± 0.4; 61.5% of participants had an estimated glomerular filtration rate (eGFR) of less than 60. At 9 months, eGFR was stable. Despite a reduction in mean systolic BP, mean BNP levels remained elevated at 1 month.

There was no correlation between BNP levels at baseline and systolic BP reduction, nor between BNP reduction and systolic BP response. The restenosis rate was 10.5% at 9 months (P<.0001). The study device, procedure and clinical success rates were 96%, 99.2% and 98%, respectively. Freedom from medical error and reintervention was 94.8%.

“The clinical results are promising, as we found very low restenosis rates and a significant drop in BP following renal artery stenting,” Jaff said in a press release, but because the study’s goal was to help predict which patients will have the best outcomes after the procedure, “the search must continue.” – by Whitney McKnight
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ST-DETECT: High-risk patients with ICDs show low spontaneous coronary event rate

Society for Cardiovascular Angiography and Interventions 2011 Scientific Sessions

BALTIMORE — The addition of high-fidelity intracardiac electrogram signals in implantable cardioverter defibrillators provided data indicating that high-risk CVD patients experienced low rates of spontaneous coronary events.

“The events are shockingly low,” said study investigator Timothy D. Henry, MD, of the Minneapolis Heart Institute at Abbott Northwestern Hospital. “The results suggest that the [patients’] disease was well managed by a combination of medical therapy and revascularization.” Henry made his remarks while presenting the results of the ST Segment Detection Study (ST-DETECT) at the 2011 Society for Cardiovascular Angiography and Interventions Scientific Sessions.

After implantation of an ICD programmed with high-fidelity intracardiac electrogram (EGM) signals, 175 patients from 32 participating centers were monitored for 24 months. Investigators in this prospective, non-randomized study evaluated whether spontaneous coronary events and exercise-induced cardiac ischemia precipitated detectable changes on the intracardiac EGM signals.
Patients qualified if they had experienced an MI in the previous 6 months, had previously undergone stenting or a percutaneous coronary intervention procedure, had multivessel disease (>1 coronary arteries, >60% stenosis) or had a recent positive stress test with suspected CAD. Antiplatelets were in use by 93% of the study group; 88% were using anti-hyperlipidemia medication; 93% were using beta-blockers; 84% were using ACE inhibitors/angiotensin receptor antagonists; 60% were using diuretics; and 35% were using vasodilators/nitrates.

A blinded, external endpoint committee determined that of the 361 recorded adverse events, based on 174.7 patient-years from 121 patients, 181 were CV-related. The trial, which was based on a 4% annual acute MI rate, was discontinued early.

“This trial illustrates that to implement the potential of this new technology, we need to further study the complex relationship between clinical events, surface ECG and EGM changes,” Henry said. – by Whitney McKnight

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New hemodynamic device improved outcomes for high-risk PCI patients

Society for Cardiovascular Angiography and Interventions 2011 Scientific Sessions

BALTIMORE — An analysis of data showed that the Abiomed Impella 2.5 device offered better hemodynamic support than the intra-aortic balloon pump traditionally used in high-risk percutaneous coronary intervention patients.
William O’Neill, MD, executive dean for clinical affairs at the University of Miami Miller School of Medicine, presented data from the aborted PROTECT II trial during the Society for Cardiovascular Angiography and Interventions 2011 Scientific Sessions. After the trial was halted, investigators continued to follow the population for 90 days. They determined that in the Impella arm (n=213), 21.6% experienced major adverse events compared with 31% in the balloon device arm (n=210).

Between November 2007 and November 2010, 452 of an intended 654 patients were prospectively enrolled in a multicenter, randomized trial to determine the type of hemodynamic support that provides the best clinical outcomes during high-risk PCI. Patients with three-vessel disease and left ventricular ejection fraction <30% or with unprotected left main or last patent conduit and LVEF <35% during PCI were included. Prophylactic support was initiated before the intervention and halted as soon as it was efficacious after the procedure. The revascularization procedure was at the discretion of the clinician. The primary endpoint was a composite of major adverse events at 30 days; the primary endpoint follow-up was assessed at 90 days.

Due to futility on the primary analysis at the first interim mark, the Data Safety Monitoring Board recommended the study be terminated. The patient population (n=452) at interim was 66 ± 10 years of age and included those with diabetes (52%), active angina (66%) and renal insufficiency (25%). Class NYHA III/IV patients numbered 56%; 67% were not candidates for surgery. Patients had syntax scores of 31 ± 14 and their LVEF was 24 ± 6%.

O’Neill also presented data on the effect of operator learning curve: 90-day outcomes in the intent-to-treat population (n=447) saw a major adverse event rate for the Impella device of 47.8% in 2008; 39.1% in 2009; and 37.3% in 2010. “I can’t fault the Data Safety Monitoring Board for halting the trial,” O’Neill said. “The thing we didn’t take into full consideration was the learning curve of the trial.”
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Prevalence of wake-up strokes found in large population
Mackey J. Neurology. 2011;76:1662–1667.

Almost 15% of all strokes that occurred in a recent study were found to be wake-up strokes. This study, according to researchers, was the first large and population-based study to examine the event rate of wake-up strokes.

Jason Mackey, MD, and fellow colleagues studied all first-time and recurrent ischemic strokes among 1.3 million residents of the Cincinnati/northern Kentucky region in 2005. Only patients aged at least 18 years who were evaluated in an ED were included in the analysis.

Overall, 1,778 residents were identified with 1,854 first-ever and recurrent ischemic strokes. Of these, 273 (14.3%) were wake-up strokes, resulting in an adjusted wake-up stroke event rate of 26 per 100,000 people. Among those who experienced a wake-up stroke, at least 35.9% would have been eligible for thrombolysis had arrival time not been a factor.

Additional analysis also revealed that those who had wake-up strokes tended to be older (72.3 ± 0.83 years vs. 70 ± 0.48 years; P=.01) and had a higher baseline retrospective NIH Stroke Scale score (median interquartile ratio,4 vs. 3; P=.004).

Despite these factors, study researchers said there were no obvious features distinguishing between wake-up and nonwake-up strokes.

In addition, they said: “Wake-up strokes constitute a significant percentage of ischemic strokes and are ineligible for thrombolytic therapy due to the current time-based restrictions, which is unfortunate because it is likely that some of these events occurred immediately prior to awakening. Efforts are ongoing to develop better methods of identifying those patients most likely to benefit from treatment while at the same time minimizing exposure to undue risk.”
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FDA approves carotid stenting system in standard-risk patients

The FDA has recently approved the use of the RX Acculink carotid stenting system for patients at standard surgical risk for carotid endarterectomy, expanding the use of the system beyond the former indication of those who are at high risk with the procedure.

This approval follows the FDA advisory panel’s 7-3 vote in January that the benefits of an expanded indication of the RX Acculink system (Abbott Vascular) outweigh the risks. Both the advisory panel and the FDA’s vote were based on the findings of the 10-year Carotid Revascularization Endarterectomy Vs. Stenting Trial (CREST), which demonstrated similar results among patients treated with carotid stenting vs. carotid endarterectomy.

According to a press release, a condition of this approval is that Abbott will conduct a post-approval study on the device, following new patients treated with the system for at least 3 years to confirm the results of CREST. Also stated in the release, this upcoming study will be consistent with recommendations made by the panel and will evaluate how patients aged at least 80 years respond to the treatment, as well as whether success is affected by physician experience and whether those with symptoms before treatment have a different outcome compared with those who are asymptomatic.

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REVEAL: Epoetin alfa potentially harmful in patients with STEMI after PCI

Najjar S. JAMA. 2011;305:1863-1872.
Bhatt D. JAMA. 2011;305:1908-1909.

Epoetin alfa administered to patients with STEMI within 4 hours of successful percutaneous coronary intervention was shown to increase the rate of adverse CV events while having no benefit on infarct size.

The Reduction of Infarct Expansion and Ventricular Remodeling with Erythropoietin after Large Myocardial Infarction (REVEAL) trial was a phase 2 study that included 222 patients with STEMI who were successfully treated with PCI. Patients were randomly assigned to either treatment with IV epoetin alfa or matching placebo delivered within 4 hours of the procedure. Physicians then measured infarct size with cardiac MRI between 2 to 6 days after drug administration and then again 12 weeks later, and they expressed findings as percent of left ventricular mass.

According to results, infarct size at both first (epoetin alfa, 15.8% vs. placebo, 15%) and second (epoetin alfa, 10.6% vs. placebo, 10.4%) MRI scan did not differ between those given 60,000 units of epoetin alfa and placebo. However, for patients aged at least 70 years, mean infarct size in the first week was larger among those in the epoetin alfa group (19.9% vs. 11.7%; P=.03).

The researchers then performed safety analysis, which included a dose escalation of epoetin alfa (15,000 units, 30,000 units and 60,000 units), which revealed a higher rate of any adverse event in those who received epoetin alfa (55.2% vs. 41.2%; P=.04), which was also true of serious adverse events (20% vs. 10.3%; P=.05). Furthermore, the composite outcome of death, MI, stroke or stent thrombosis occurred only in the epoetin alfa group (4% vs. 0%; P=.04).

Considering the results of this study, Deepak L. Bhatt, MD, MPH, with the VA Boston Healthcare System, wrote in an accompanying editorial that it may not be worth taking epoetin alfa into phase 3 trials.

“Several compounds to limit infarct size or to mitigate reperfusion injury have appeared promising in animal models, only to fail when tested in humans,” Bhatt said. “Use of cardiac MRI may allow screening of several future candidate compounds in studies with reasonable sample sizes and may reveal those that appear most promising for reducing infarct size. Investigators can then conduct large clinical trials to evaluate those approaches that are likely to yield benefit and not cause harm.”
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CONFIRM: Novel ablation approach promising treatment for AF

Heart Rhythm Society 32nd Annual Scientific Sessions

SAN FRANCISCO — Compared with conventional ablation alone, patients who had focal impulse and rotor modulation ablation followed by conventional ablation had improved freedom from atrial fibrillation at 2 years, suggested new data.
The Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation (CONFIRM) included 103 patients with AF, of which 67% had persistent AF, which, according to Sanjiv Narayan, MD, PhD, study researcher and associate professor of medicine in residence at the University of California, San Diego School of Medicine, is a more difficult disease to treat and makes the present study different from some previous research which included mostly earlier stage disease. The patients were either treated with focal impulse and rotor modulation (FIRM) ablation prior to conventional ablation for pulmonary vein isolation (n=32) or conventional ablation alone (n=71).

According to results, rotors and focal drivers were observed in 98% of AF patients. FIRM ablation led to termination of or substantially slowed AF within 10 minutes of ablation when preceding conventional ablation. FIRM also dramatically improved two-year freedom from AF when compared with conventional ablation alone (84% vs. 50%).

“The promising results of the CONFIRM study show that with a single procedure we can improve the success rate of conventional ablation,” said Narayan in a press conference. “This means we should reevaluate the way we are thinking about AF as a rhythm and potentially ablating it.”

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Ambulatory blood pressure monitoring in diabetic patients: new data, new questions
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Cardiovascular Outcomes in Framingham Participants With Diabetes
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Have You Checked Your Blood Pressure Today?
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Prevalence and Risk Factors Associated With Prehypertension: Identification of Foci for Primary Prevention of Hypertension
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Cardiometabolic Risk in Community-Dwelling Persons With Chronic Spinal Cord Injury
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Influence of COURAGE trial on optimal medical therapy use small

Borden WB. JAMA. 2011;305:1882-1889.

During the years after the publication of the COURAGE trial results, few changes were observed in the practice patterns of optimal medical therapy use among patients with stable coronary artery disease undergoing percutaneous coronary intervention, according to a new study.

In 2007, Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) data indicated that PCI and optimal medical therapy (OMT) did not improve survival or prevent MI in patients with stable CAD compared with OMT alone.

In the current analysis, researchers set out to find the influence of these results on clinical practice. The observational study featured 467,211 patients (37.1% before, 62.9% after COURAGE publication) with stable CAD undergoing PCI from the National Cardiovascular Data Registry between Sept. 1, 2005, and June 30, 2009. Researchers defined OMT as either being prescribed or having a documented contraindication to medicines, including antiplatelet agents, beta-blockers and statins.

Overall, 206,569 patients were treated with OMT before PCI and 303,864 were treated at discharge after PCI. Before the COURAGE trial, OMT before PCI was used in 43.5% of patients (n=75,381), whereas after the trial, it was used in 44.7% of patients (n=131,188). Additionally, OMT use at discharge after PCI was 63.5% before the COURAGE trial and 66% after the trial.

“Collectively, these findings suggest a significant opportunity for improvement and a limited effect of an expensive, highly publicized clinical trial on routine clinical practice,” the researchers wrote, later concluding that the results “support a call for innovations in how OMT is incorporated into interventional strategies and for improving the translation of clinical evidence into practice.” – by Brian Ellis

It is a paper of some interest. It would appear to be disappointing that the rates of OMT were low and little affected by COURAGE trial results. However, there are significant limitations beyond those reported. The institutions reporting were not constant. Also the purpose of the NCDR CathPCI database is primarily to examine PCI outcomes. The medications and contraindications to medications may not have been as complete or careful as one would hope. Also, while these patients did not have acute coronary syndromes, there may have been some urgency to their care, limiting ability to place patients on OMT prior to their procedures. We should be glad to see a 20% absolute increase in OMT after the procedure given that these patients generally have a length of stay of 1 day and are often not even formally hospital admissions. So, while we should not be complacent and need to do better, let us also not overestimate the problem
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Cardiac rehabilitation improved mortality in patients after PCI

Goel K. Circulation. 2011;doi:10.1161/CIRCULATIONAHA.110.983536.

Findings from a retrospective study have suggested that patients who participated in cardiac rehabilitation within 3 months of percutaneous coronary intervention had a decreased rate of mortality. However, rates of MI and revascularization were not influenced by participation.

“Our results provide supportive evidence for the decision by Centers for Medicare and Medicaid Services to cover cardiac rehabilitation in PCI patients and for the recommendations in clinical practice guidelines and performance measures that support cardiac rehabilitation for all PCI patients,” the researchers wrote.

In the study, investigators from the Mayo Clinic in Rochester, Minn., examined consecutive patients (n=2,395) from a prospectively collected registry who underwent PCI in Olmsted County, Minnesota. During the 3 months after PCI, 964 patients (40%) participated in at least one outpatient cardiac rehabilitation session.

During a median follow-up of 6.3 years, 503 deaths (199 cardiac-related), 394 MIs and 755 revascularization procedures were reported. Patients who took part in cardiac rehabilitation had a noted reduction in all-cause mortality by all three statistical techniques employed, including propensity score-matched analysis (HR=0.54), propensity score stratification (HR=0.53) and regression adjustment with propensity score in a 3-month landmark analysis (HR=0.55; P<.001 for all three). A trend toward a reduction in cardiac-related mortality among those participated was also reported; however, only propensity score stratification documented a significant reduction (P=.016).
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Mortality, adverse events found higher in patients with elevated biomarkers after nonemergent PCI

Feldman D. Catheter Cardiovasc Interv. 2011;doi:10.1002/ccd.22962.

Elevation of cardiac troponin I and troponin T among patients who underwent nonemergent percutaneous coronary intervention was predictive of long-term all-cause mortality and a composite of adverse events in a new study.

All patients (n=22,353) in the analysis were compiled from 22 studies published between 1998 and 2009 that reported on the prognostic effect of cardiac troponin I (cTnI) and troponin T (cTnT). All-cause mortality was defined as the study’s primary endpoint.

In all, post-PCI cTnT or cTnI was elevated in 32% of patients. During a mean follow-up of 17.7 months, the primary endpoint was noticeably higher for patients with cTnI or cTnT elevation after PCI compared with patients without cTnI or cTnT elevation (OR=1.45; 95% CI, 1.22–1.72). Similarly, the composite of adverse events of all-cause mortality and MI in patients with cTnI or cTnT elevation was also higher (OR=1.77; 95% CI, 1.48-2.11).

“Our meta-analysis supports the ACC/AHA recommendation to monitor cTn markers post-PCI as to assess long-term clinical outcomes and to identify patients with high-risk coronary artery features,” the researchers wrote. “Further studies are needed to determine if peri-procedural efforts to minimize cTn elevations and more intensive outpatient monitoring/treatment of patients with elevated cTn levels after nonemergent PCI will result in improved long-term outcomes.” – by Brian Ellis

Meta-analyses can be very valuable but can also be misleading. One of the major problems with almost all of the studies in this area is that they use a baseline value that with rare exception is markedly above the recommended cut off value of the 99th percentile. When one does this one ignores the prognostic significance of the baseline value and also fails to understand that the values are most often rising. Thus, the results post procedure are substantially more elevated. Some would say most of the increase is due the natural rise of the elevated baseline value and most often not the procedure. If one uses the 99th percentile value as to define normality at baseline, it turns out that most if not all of the prognostic significance resides in the baseline value and there is modest or perhaps no additional contribution of the post-intervention values either short- or long- term. Lack of attention to this critical metric has confounded all of the meta-analyses and most of the studies. If one uses the 99th percentile value to define a normal baseline as in the Prasad study, there is no additional prognostic value in the post-PCI values. Unfortunately, that is the only study that uses that value at baseline. Thus, one needs to consider this meta-analysis with great caution.

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Genetic defects predictive of adverse events in patients with long QT syndrome

Jons C. Sci Transl Med. 2011;3:76ra28.

Mutations that caused a slow activation of the potassium current channel strongly correlated with an increased risk for cardiac events in patients with long QT type 1 syndrome, one of the most common forms of long QT syndrome.

In a recent study, Coeli M. B. Lopes, PhD, and fellow researchers examined 17 mutations found in 387 patients with long QT type 1 (LQT1) syndrome from four long QT syndrome international registries. They correlated the clinical phenotype of patients (n=314) with cellular electrophysiological characteristics resulting from an array of mutations in the slow potassium current channel alpha-subunit KCNQ1 to determine whether there was an association between channels with a decreased rate of current activation and an increased risk for cardiac events, which included syncope, aborted cardiac arrest requiring defibrillation and sudden cardiac death.

They found there was a direct association between channels with a decreased rate of current activation and an increased risk for events (HR=2.02). This association was independent of the clinical parameters used for risk stratification.

Furthermore, for patients with moderate QT prolongation, which was defined as a QT interval of less than 500 ms, slower activation independently predicted an increased risk for cardiac events (HR=2.10), although length of QT interval did not.

“The appropriate clinical care for LQT1 patients with modest corrected QT prolongation is not well established, with many patients remaining untreated,” Lopes and colleagues wrote. “Identification of high-risk mutations in this population could lead to more aggressive treatment in the population at risk and better patient care.”
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Prescription adherence with CVD medications complex process in US

Choudhry N. Arch Intern Med. 2011;171:814-822.
Salanitro A. Arch Intern Med. 2011;171:822-823.

A new study appearing in the Archives of Internal Medicine has highlighted the complexity involved with prescription adherence with CVD medications in the United States, leading researchers to conclude that it may be necessary to reduce this complexity to improve adherence.

“Because nonadherence is associated with excess morbidity and mortality, our findings suggest that therapeutic complexity may undermine the goals of chronic disease management,” they wrote. “In addition, these results highlight an essential aspect of the therapeutic cascade that may be particularly burdensome and which few clinicians likely consider when making prescribing decisions.”

Researchers used prescription claims data from CVS Caremark, a pharmacy benefit manager in Rhode Island with more than 50 million beneficiaries in the United States, to generate these results. The study population consisted of individuals who were prescribed a statin (n=1,827,395) or an ACE inhibitor or renin angiotensin receptor blocker (n=1,480,304) from June 1, 2006, to May 30, 2007. Complexity was determined by measuring the number of medications, pharmacies, pharmacy visits, prescribers and refill consolidation for 3 months after first prescription.

Overall, 80% of medication users in both cohorts were prevalent users, meaning they had received a prescription for a member of the therapeutic class within the prior 12 months. During a 1-year period, researchers found that statin users (mean age, 63 years; 51% female) filled 11.4 prescriptions for 6.3 different medications, had prescriptions written by two prescribers and made five visits to the pharmacy. Data for angiotensin receptor blocker and ACE inhibitor users was similar.

According to adjusted models, patients who had the least refill consolidation, which was determined by measuring the number of visits per fill, had 8% lower adherence rates in the year than patients with the greatest refill consolidation.

For Amanda H. Salanitro, MD, and Sunil Kripalani, MD, with the department of medicine, Vanderbilt University, Nashville, Tenn., and authors of the accompanying editorial, even with the study’s limitations, they wrote that it provides a valuable step forward in measuring the complexities of prescription medication management, as well as its effect on adherence.

“Based on the results of this study, additional research is needed to determine if a reduction in therapeutic complexity (ie, fewer prescribers and/or pharmacies or maximal refill consolidation) positively affects adherence,” they said. “Few published adherence interventions have addressed complexity comprehensively. Such programs are most likely to benefit patients with multi-morbidity and complex medication regimens.”

Disclosures: Dr. Kripalani is a consultant to and holds equity in PictureRx, LLC, and has served as a consultant to Pfizer and Bristol-Myers Squibb/Sanofi-Aventis. Dr. Salanitro reports no relevant financial disclosures.

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New combination therapy offers promising approach for hypertension management

American Society of Hypertension 2011 Annual Scientific Meeting

NEW YORK — Among patients with stage II systolic hypertension, azilsartan medoxomil, a newly approved angiotensin II receptor antagonist, plus chlorthalidone led to greater reductions in systolic BP compared with olmesartan plus hydrochlorothiazide, according to findings presented here at the American Society of Hypertension 2011 Annual Scientific Meeting and Exposition.

According to study investigator William C. Cushman, MD, of the University of Tennessee College of Medicine in Memphis, this was the first large, forced titration study of an angiotensin II receptor blocker fixed-dose combination.

“This [study] gives the maximum comparison in terms of the effectiveness of these products … and demonstrates superior efficacy of the [azilsartan medoxomil-chlorthalidone] fixed-dose combinations compared with [olmesartan-hydrochlorothiazide],” Cushman said in a press conference.

In the phase 3, multicenter, double blind, randomized study, the effects of two doses of azilsartan medoxomil (AZL-M; Edarbi, Takeda Pharmaceuticals) plus chlorthalidone (CLD) were compared with olmesartan (OLM) plus hydrochlorothiazide (HCTZ). The study design called for force titrating to maximum doses for all three arms during a 12-week interval: 20 mg AZL-M/12.5 mg CLD to 40 mg AZL-M/25 mg CLD (n=355); 40 mg AZL-M/12.5 mg CLD to 80 mg AZL-M/25 mg (n=352); and 20 mg OLM/12.5 mg HCTZ to 40 mg OLM/25 mg HCTZ (n=364). Only patients aged at least 18 years and with post-washout clinic systolic BP of between 160 mm Hg and 190 mm Hg were included.

At 12 weeks, the study’s primary endpoint of change in clinic systolic BP favored both the 40/25-mg (–42.5 mm Hg) and 80/25-mg AZL-M arms (–44 mm Hg) vs. the OLM arm (–37.1 mm Hg; P<.001 for both comparisons). Similarly, change in 24-hour mean systolic BP also favored the 40/25-mg (–33.9 mm Hg) and 80/25-mg AZL-M arms (–36.3 mm Hg) compared with the OLM arm (–27.5 mm Hg; P<.001 for both).

Overall, adverse events appeared more frequently in the 40/25-mg (71.3%) and 80/25-mg (70.7%) AZL-M groups vs. the OLM group (60.2%). However, serious adverse events were least common in the 40/25-mg group (0.3%), followed by OLM (2.2%) and ALZ 80/25 mg (2.8%).

The study was sponsored by Takeda. – by Brian Ellis

Disclosure: In the past 12 months, Dr. Cushman reports receiving grant/research support from Merck, GlaxoSmithKline and Novartis and has consulted for Takeda, Novartis and Noven.

For more information:
Cushman W. LB-OR-03. Presented at: American Society of Hypertension 2011 Annual Scientific Meeting and Exposition; May 21-24, 2011; New York.

This certainly is an impressive study. AZL-M as mono-therapy seems to be an absolutely superb angiotensin II receptor blocker. It has been shown to lower BP more efficaciously than 40 mg of OLM, which is a very good angiotensin II receptor blocker as we know. However, why AZL-M is so much better than the others is not entirely clear.

It is important to consider, though, that there was no placebo in this study. There would certainly be a placebo reduction [in systolic BP] of about 10 mm HG. Therefore what you would then see when you then look at 24-hour BP is much more realistic, but still extremely good.

Another point is that we have shown that CLD is absolutely more powerful than HCTZ. It has been established in quite a few studies, though never in a combination, so we cannot say this is a good way of comparing the two. But it is my suspicion that the good anti-hypertensive effects of AZL-M and CLD are obviously synergistic and will beat the competition.
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High prevalence of masked hypertension confirmed among blacks

American Society of Hypertension 2011 Annual Scientific Meeting

NEW YORK — New research presented here has confirmed previous data that indicated a high prevalence of masked hypertension among blacks and further reinforces the importance of ambulatory BP monitoring to help identify patients with high BP who do not present as such at doctors’ office visits.

The preliminary study included 38 black patients (mean age, 51 years; 86.8% women) from the Philadelphia region who were sedentary, nondiabetic, nonsmoking, not on antihypertensive medication and did not have CVD. Office BP measurements were taken during three visits on an average of three readings per visit, whereas ambulatory BP monitoring was performed on a typical day of the patient and was set to go off at 30-minute intervals during the day (6 a.m. to 10 p.m.) and 60-minute intervals during the night (10 p.m. to 6 a.m.).

According to study data, the BP measurements at the office were 124.4 mm Hg/79.1 mm Hg for the first visit, 126.4 mm Hg/80.1 mm Hg for the second visit 1 week later and 128.7 mm Hg/79.7 mm Hg for the third, whereas the mean ambulatory BP monitoring for 24 hours was 126.7 mm Hg/78.5 mm Hg (daytime, 128.4 mm Hg/80.2 mm Hg; nighttime, 116.8 mm Hg/68.6 mm Hg). The prevalence of masked hypertension decreased with each visit, from 59% on the first visit to 40% on the second visit and 38% on the third visit. Additionally, as an average for all three BP office measurements, roughly 45% of the population consistently had masked hypertension.

“The take-home message is office BP may not be sufficient, especially in this cohort,” study researcher Praveen Veerabhadrappa, MD, MS, research fellow, International Society of Hypertension Doctoral Candidate, Hypertension Molecular & Applied Physiology Lab, said in a press conference. “Close to 45% had masked hypertension, and they were not even aware they had hypertension. They may require some kind of intervention, whether it be nonpharmacological or pharmacological.” – by Brian Ellis

If you look at end-organ damage for African Americans compared with whites for the same level of office BP, African Americans have significantly higher rates of stroke, kidney disease and HF. This is probably the reason (for reasons that we don’t quite understand yet) that African Americans have higher BP outside the office than inside the office. The implication then is we can’t be complacent with a normal BP for an African American in the office. We are going to have to do more ambulatory BP monitoring and home monitoring.

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FDA panel advises clinical trial, revised labeling of fenofibric acid

The FDA Endocrinologic and Metabolic Drugs Advisory Committee unanimously recommended a clinical trial to assess the cardiovascular benefits of adding fenofibric acid to statin treatment in high-risk men and women with high triglycerides and low HDL.

The panel also narrowly advised for revision of the fenofibric acid (Trilipix, Abbott) drug labeling regarding co-administration to include recent data from the Action to Control Cardiovascular Risk Diabetes (ACCORD) Lipid Trial.

Results of two subgroup analyses conducted during the ACCORD-Lipid trial were at the center of the panel discussion. One analysis revealed a higher rate of CV events, especially myocardial infarction, in women taking fenofibrate plus statin vs. men taking the same combination (HR=1.38 vs. HR=0.82). Henry Ginsberg, MD, lead research for the ACCORD-Lipid trial and director of the Irving Institute for Clinical and Translational Research at Columbia University, noted no difference in baseline lipids or lipid response after 48 months between men and women. He said this issue warrants further investigation.

A second subgroup analysis of patients with dyslipidemia revealed a lower rate of major adverse cardiac events among participants with triglycerides in the highest tertile and HDL in the lowest tertile compared with the entire study cohort.

Despite the results of the ACCORD-lipid analyses, as a whole, the panel was hesitant to make recommendations for subgroups because ACCORD-Lipid was a negative trial overall. Consequently, the panel unanimously voted for a clinical trial to be conducted using major adverse cardiac events as an endpoint to test the benefit of adding fenofibrate to statin therapy in high-risk patients with high triglycerides and low HDL.

"In reviewing the data for fibrates, it's not clear to me if these drugs are beneficial or not," William R. Hiatt, MD, professor of medicine at the University of Colorado Denver, said at the meeting.

The committee was divided regarding fenofibric acid's labeling indication for co-administration with a statin. Three members voted to continue marketing and maintain the current indication; four voted to withdraw that particular indication; and six voted to revise the indication for co-administration to incorporate the principal findings from ACCORD.

Edward W. Gregg, PhD, from the division of diabetes translation at the CDC, voted to revise the indication. he said the available evidence indicates potential negative effects, but the data are not strong enough to warrant complete removal. Nevertheless, he said, "I think there should be a more specific indication to prevent overmarketing to people who may not benefit."

In response to the committee's decision, Eugene Sun, MD, vice president of Global Pharmaceutical Clinical Development of Abbott, said in a press release: "We also appreciate the request for more clinical data and look forward to further discussions with the FDA."

ACCORD-Lipid is a randomized, double blind, placebo-controlled, add-on trial that evaluated the efficacy and safety of adding fenofibrate to simvastatin (Zocor, Merck) therapy in more than 5,500 patients with type 2 diabetes. During an average 4.7 years, researchers found no significant difference in the proportion of patients treated with simvastatin plus placebo (11.3%) vs. simvastatin plus fenofibrate (10.5%) who experienced a major adverse cardiac event (HR=0.92; 95% CI, 0.79-1.08).

Fenofibric acid is the active ingredient of fenofibrate. Fenofibrate is a peroxisome proliferator-activated receptor-alpha agonist (PPAR-alpha) that was approved for the treatment of hypertriglyceridemia in 1993. In 2009, the FDA approved the new drug application for fenofibric acid in combination with a statin.

While the FDA is not required to follow the recommendations of the advisory committee, it usually does. - by Melissa Foster
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Echocardiographic measurements promising for predicting improvement after elective PCI
Djordjevic-Dikic A. J Am Soc Echocardiogr. 2011;24:573-581.

Among patients with previous MI, evaluation of basal coronary blood flow pattern and diastolic deceleration time measurements were shown to predict myocardium improvement after elective percutaneous coronary intervention.

The study featured 50 patients (mean age, 53 years; 82% men) with previous MI who underwent elective PCI. Researchers measured their coronary flow using transthoracic Doppler echocardiography before PCI, as well as both 24 hours and 3 months after. Recovery from PCI was determined by an improvement in resting wall motion score index of more than 0.20.

Researchers reported that patients with recovered left ventricular function (n=32) had a longer diastolic deceleration time (DDT) before the procedure compared with patients without improvement in LV function (n=18; 841 ± 286 ms vs. 435 ± 80 ms; P<.001). Furthermore, coronary flow reserve 24 hours after PCI was higher in the recovered group (2.60 ± 0.70 vs. 2.16 ± 0.34, P=.034). Among the univariate predictors of LV functional recovery were end-diastolic and end-systolic volumes, global and regional wall motion scores, as well as DDT before PCI and coronary flow reserve 24 hours after PCI.

Additionally, multivariate analysis also indicated that DDT (P=.003) and regional wall motion score (P=.007) were independent predictors of LV recovery during follow-up.

Commenting on the clinical implications of the study, the researchers wrote that although transthoracic Doppler echocardiography could not be considered as a substitute for other techniques that can directly assess transmurality of myocardial viability, such as MRI or myocardial contrast imaging, it could be useful in providing additional information about coronary pathophysiology and prognosis, considering the broad availability and low cost of the method.

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Younger physicians may be more likely to prescribe CVD drugs

Tocci G. Int J Clin Pract. 2011;65:649-657.

In an analysis of the EFFECTUS trial, researchers observed that outpatients of younger physicians had a higher prevalence of vascular diseases and, as a result, were prescribed more medications for CVDs than patients of older physicians.

Investigators of the study, appearing in the International Journal of Clinical Practice, looked at data collected during the cross-sectional phase of the EFFECTUS program. The study population was composed of 9,904 outpatients (mean age, 67 years) observed by 1,078 physicians in Italy. The physicians were stratified into three age groups — no older than 45 years (n=219), 46 to 55 years (n=658) and older than 55 years (n=201) — and asked to provide clinical data on the first 10 adult outpatients seen in May 2006.

Investigators found higher rates of MI (P=.003), cerebrovascular disease, primarily stroke (P=.008) and transient ischemic attack (P=.031) in outpatients of physicians aged younger than 45 years vs. physicians aged older than 46 years. Physicians aged younger than 46 years were also more likely to prescribe several CVD medications, including ACE inhibitors (P=.006), antihypertensive drugs (P=.005), beta-blockers (P=.016), insulin (P=.005) and antiplatelet agents (P=.013), as opposed to older physicians who more commonly recommended lifestyle changes.

Additionally, information on CV risk factors were far more regularly recorded by physicians aged older than 45 years, whereas those who were younger provided more updated information on organ damage detection.

As a possible explanation for these discrepancies, the researchers wrote that the relatively low rate of data collection and registration found in younger physicians suggests a potential way to improve global CV risk management in the daily clinical practice.

“On the basis of these considerations, specific training and educational programs for specialized physicians should be carefully considered, to improve quality of care, reduce doctor’s inertia and ameliorate the clinical management of CVDs in Italy,” they said.
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Sleep-disordered breathing increased arrhythmias in patients with ICDs

Zeidan-Shwiri T. Heart Rhythm. 2011;8:657-662.

A study in the journal Heart Rhythm has found that patients with implantable cardioverter defibrillators who had sleep-disordered breathing were at significantly higher risk for ventricular arrhythmias compared with those without sleep-disordered breathing.

The prospective study involved 45 patients with an ICD who were enrolled from August 2007 to March 2009. Twenty-six of these patients had sleep-disordered breathing (SDB), defined as an apnea-hypopnea index of morethan 10 events per hour as determined by an overnight sleep study. The current study’s primary endpoint was appropriate ICD therapy during a 1-year follow-up.

During this time, 62% of patients had one or more episodes of ventricular fibrillation or ventricular tachycardia. Researchers reported a higher rate of appropriate ICD therapies in patients with SDB vs. those without (73% vs. 47%; P=.02), with further analysis proving SDB to be a predictor of any ICD therapy (OR=4.4; P=.01). Cited as the cause of the increased risk for ventricular arrhythmias in patients with SDB was the increase in events that occurred between midnight and 6 a.m. (OR=5.6; P=.001), which was not seen during non-sleeping hours.

“These findings provide a rationale for SDB screening in patients with appropriate ICD therapy if device interrogation reveals a predominance of nocturnal onset of arrhythmias,” the researchers concluded. “Future studies are warranted to evaluate whether treatment of SDB reduces the risk of appropriate ICD therapy.”

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EMPHASIS HF: eplerenone shown to reduce atrial fibrillation (AF)
EMPHASIS-HF trial was presented at the Heart Failure Congress 2011, organized by the Heart Failure Association of the European Society of Cardiology (ESC).

Topics: Heart Failure (HF)
Date : 22 May 2011
“This latest analysis makes an even stronger case for the use of eplerenone in patients with mild heart failure because in addition to reducing mortality it also reduces the incidence of AF. AF is a condition which both increases morbidity and complicates the care of patients with heart failure,” says Karl Swedberg, ESC spokesperson.

May 22, 2011- Gothenburg, Sweden : The aldosterone antagonist eplerenone (Inspra, Pfizer) significantly reduced the development of new onset atrial fibrillation and flutter (AFF) in patients with class 2 heart failure, concludes a sub-analysis of the EMPHASIS-HF trial, presented at the Heart Failure Congress 2011, organized by the Heart Failure Association of the European Society of Cardiology (ESC). The analysis, presented in Late Breaking Session 1, furthermore showed that the beneficial effects of eplerenone in reducing major CV events were similar in patients with and without AFF at the start of the study.

The Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure study (EMPHASIS-HF) - presented first at the American Heart Association Meeting in 2010 and published simultaneously on-line in the New England Journal of Medicine ¹ - showed that eplerenone in comparison to placebo produced a 37% reduction in the primary end point of the composite of death from cardiovascular causes or hospitalization for heart failure, a 24% reduction in cardiovascular death, and a 42% reduction in hospitalization for heart failure for patients with class 2 heart failure.

While previous studies had shown that aldosterone blockade delivered significant benefits in patients with class 3-4 heart failure (The RALES study) or in post MI patients with left ventricular dysfunction (The EPHESUS study), what had been unknown until EMPHASIS-HF was whether the benefits could be extended to the far larger population of patients with mild heart failure (class1-2). The RALES study used spironolactone, while the EPHESUS study used the newer, more selective eplerenone.

The EMPHASIS-HF trial - which involved 2737 patients from 278 centres with NYHA class 2 heart failure and ejection fractions of no more than 35% - set out to address the question of whether eplerenone was effective in patients with mild heart failure. Patients were randomized to receive eplerenone (25mg once daily, up titrated to 50 mg daily if required) or placebo in addition to recommended therapy. The trial was stopped after 21 months due to the significant benefits in the eplerenone group. In the current presentation, the investigators have re-analyzed the original data to explore the development of new onset atrial fibrillation or flutter (AFF) in patients who had no history of AFF at baseline. The study also set out to determine whether eplerenone worked as well in patients who already had AFF at baseline as those who did not.

Results at an average follow-up of two years showed that new onset AFF occurred in 25/911 (2.7%) of the patients in the group randomized to eplerenone versus 40/883 (4.5%) in the group randomized to placebo (hazard ratio (HR) 0.58 95% CI 0.35-0.96, p=0.034). The analysis also showed that the risk of cardiovascular (CV) death or hospital admission for worsening heart failure (the primary endpoint of the original study) was not significantly different in patients with and without AFF at baseline (P=0.33).

Commenting on the results study presenter Karl Swedberg, from the University of Gothenburg, Sweden, said, “This latest analysis makes an even stronger case for the use of eplerenone in patients with mild heart failure because in addition to reducing mortality it also reduces the incidence of AF. AF is a condition which both increases morbidity and complicates the care of patients with heart failure.”

Use of eplerenone in patients with mild heart failure, he added, will be considered for inclusion in the ESC guidelines when they are updated at the end of 2011.

Eplerenone
Eplerenone, which has been called a "cleaner, safer" version of spironolactone, is approved for hypertension and for use in addition to optimal medical therapy early after acute MI in patients with congestive heart failure (CHF), on the basis of the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) study. It has, however, yet to be approved for patients with mild HF.
While eplerenone is available generically in the US, the drug is still under patent in Europe and Canada.

Authors:
ESC Press Office
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References
Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. New Eng J Med 2011: 364:11-21. Available at: [Ссылки могут видеть только зарегистрированные и активированные пользователи]

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MADIT: study defines patient group most likely to benefit from cardiac resynchronisation therapy (CRT)
The CRT-MADIT-CRT trial - was presented at the Heart Failure Congress 2011, organized by the Heart Failure Association of the European Society of Cardiology (ESC) in Late Breaking Session 1.

Topics: Heart Failure (HF)
Date : 22 May 2011
Patients with dyssynchronous yet viable ventricles are most likely to benefit from cardiac resynchronization therapy combined with defibrillation, concludes the latest analysis of the MADIT CRT trial.

Patients with dyssynchronous yet viable ventricles are most likely to benefit from cardiac resynchronization therapy combined with defibrillation, concludes the latest analysis of the MADIT CRT trial. The CRT-MADIT-CRT trial - presented at the Heart Failure Congress 2011, organized by the Heart Failure Association of the European Society of Cardiology (ESC) in Late Breaking Session 1 - showed that CRT produced improvements in both synchrony and contractile function, and that the extent of this benefit relates to subsequent outcomes.

The Multicentre Automatic Defibrillator Implantation Trial-CRT (MADIT-CRT) set out to determine whether patients with mild heart failure (NYHA class I or II) would do better if they got implanted with a CRT-D device (which combines cardiac resynchronization therapy with defibrillation), than if they only received the traditional ICD defibrillation. In earlier studies CRT-D devices had been approved for use in patients with severe heart failure (NYHA class III/IV).

In the MADIT-CRT study, funded by Boston Scientific, 1820 patients with Class I and II heart failure, wide QRS and left ventricular dysfunction were randomized 3:2 to receive CRT-D (n=1089) or ICD alone (n=731). Results, presented at the 2009 ESC Annual Conference in Barcelona after a follow period averaging 2.4 years, demonstrated a greater than 40% reduction in the primary endpoint of death or heart failure in patients receiving CRT-D. However, in virtually all studies of CRT-D approximately 30% of patients do not respond to therapy.

In the current study, Dr Scott D Solomon (Brigham and Women’s Hospital, Boston, MA) and colleagues set out to investigate whether the degree of synchrony – the extent to which the walls of the left ventricle contract in unison – might influence the likelihood of patients responding to CRT-D. “It’s important to target patients in whom CRT-D works well because the technology is quite expensive,” explained Soloman.

In this latest analysis of MADIT-CRT, investigators analyzed echocardiograms from 1077 patients enrolled in MADIT-CRT (CRT-D n=66; ICD, n=416) who had echocardiographic images of sufficient quality to allow analysis of synchrony and contractile function. Researchers were blinded to the randomization and study outcomes.

Results showed that patients with mild to moderate dyssynchrony at baseline (defined as a time-to peak transverse strain SD of 142-230 ms) and greater baseline contractile function (longitudinal strain < -8.7%) improved to a greater extent when randomised to the CRT-D group than the ICD only group.

The study showed that over a year each 10 ms decrease in LV dyssynchrony was associated with a 3% reduction in the primary outcome of death or heart failure, and each 5 point absolute increase in LV strain was associated with a 75% reduction in the primary outcome.

“These results suggest that the patients who are most likely to benefit from CRT-D are those with at least some dyssynchrony who have relatively preserved contractile function,” said Solomon, adding that the observation that improvements in synchrony and contractile function were associated with reduced death and heart failure events, suggests that the benefits delivered by CRT relate to improvements in these factors. “Future studies will continue to try to identify the patients who are most likely to benefit from this expensive but highly effective therapy,” he said.

Authors:
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AIM-HIGH study halted prematurely by NIH

The NIH has stopped the AIM-HIGH trial 18 months earlier than planned due to a lack of efficacy in reducing CV events of a combined treatment of niacin and statin compared with statin alone.

In the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides (AIM-HIGH) trial, 3,414 patients from the United States and Canada with a history of CVD were either treated with a combination of a high-dose, extended release niacin and statin or stain therapy alone. Over the study’s 32 months of follow-up, patients who took the combined therapy had increased HDL cholesterol and lowered triglyceride levels. Despite this, the combination treatment failed to reduce fatal or non-fatal heart attacks, strokes, revascularization procedures or hospitalizations for acute coronary syndrome.

The FDA, in an official statement released in an email, noted that the role niacin may have played in the reported imbalance in ischemic stroke was not yet clear.

“At this time, FDA has made no new conclusions or recommendations regarding the use of extended-release niacin alone or in combination with simvastatin or other statins,” they wrote in the statement. “The Agency will conduct a comprehensive review of the AIM-HIGH trial data as soon as they become available to determine their impact on the approved indications for extended-release niacin.”

The study was funded by NHBLI with additional support from Abbott. The full NIH press release is available here.

I would hope that this information improves the quality of life for those patients who are repeatedly encouraged to continue to take these preparations despite their very annoying cutaneous side effects.
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Biomarkers associated with mortality in elderly patients with HF symptoms

Alehagen U. JAMA. 2011;305:2088-2095.

An increased concentration of copeptin, a surrogate marker for vasopressin, alone or combined with N-terminal pro–B-type natriuretic peptide was associated with an increased risk for all-cause mortality in elderly patients with symptoms of HF.

Researchers from Sweden and Denmark performed the study by looking at 470 elderly patients (mean age, 72.6 years) from the primary health care population in Sweden. All patients had HF symptoms, including shortness of breath, fatigue and/or peripheral edema during 1996. Physicians performed clinical examination, echocardiography and peptide measurements.

During follow-up, which lasted through December 2009, 226 all-cause and 146 CV-related deaths were reported. Patients with more than 18 pmol/L of copeptin (fourth quartile; n=118) compared with those with less than 5.70 pmol/L (first quartile; n=117) had a greater risk for both all-cause (HR=2.04; 95% CI, 1.38-3.02) and CV mortality (HR=1.94; 95% CI, 1.20-3.13).

When researchers looked at levels of copeptin combined with N-terminal pro–B-type natriuretic peptide (NT-proBNP), they found a similar correlation with all-cause mortality (copeptin fourth quartile, HR=1.63; 95% CI, 1.08-2.47; NT-proBNP fourth quartile, HR=3.17; 95% CI, 2.02-4.98). Furthermore, use of biomarkers simultaneously to evaluate CV mortality resulted in significant associations for both copeptin in the presence of NT-proBNP (P=.048) and for NT-proBNP (fourth quartile, HR=4.68; 95% CI, 2.63-8.34).

These results, the researchers concluded, suggest that vasopressin may be a potential target for therapeutic intervention.
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More primary care physicians yielded better patient outcomes

Chang C. JAMA. 2011;305:2096-2105.
Lower mortality rates were observed among a cohort of Medicare beneficiaries in areas of the US with more primary care physicians compared with areas with fewer primary care physicians, according to study results.

Researchers from several sites in the US attempted to outline clearer links between the adult PCP work force and individual patient outcomes.

The study population included 5,132,936 fee-for-service Medicare beneficiaries aged at least 65 years. The analysis involved 6,542 primary care service areas.

The researchers used two measures of adult PCPs (including general internists and family physicians): American Medical Association Masterfile nonfederal, office-based physicians per total population; and office-based primary care clinical full-time equivalents per Medicare beneficiary derived from Medicare claims.

Outcome measures included mortality, ambulatory care sensitive condition hospitalizations and Medicare program spending. These outcomes were adjusted for individual patient characteristics and geographic area variables.

Although there was variability in the PCP work force across geographical areas, low correlation was observed between the two primary care work force measures (Spearman rank correlation coefficient=0.056; P<.001).

Data from the AMA Masterfile counts indicated that beneficiaries in areas with the highest quintile of PCPs had fewer ambulatory care sensitive condition hospitalizations than those in areas in the lowest quintile, 74.9 vs. 79.61 per 1,000 beneficiaries (RR=0.94; 95% CI, 0.93-0.95). Lower mortality rates (5.38 vs. 5.47 per 100 beneficiaries; RR=0.98; 95% CI, 0.97-0.997) also were observed in the highest quintile compared with the lowest quintile.

No significant difference in total Medicare spending ($8,722 vs. $8,765 per beneficiary; RR=1.00; 95% CI, 0.99-1.00) was observed between the lowest quintile and the highest quintile.

In the analysis of primary care full-time equivalents per beneficiary, those residing in the highest-quintile areas had lower mortality rates compared with those residing in lowest-quintile areas, 5.19 vs. 5.49 per 100 beneficiaries (RR=0.95; 95% CI, 0.93-0.96). Also, in the full-time equivalents analysis, fewer ambulatory care sensitive condition hospitalizations (72.53 vs. 79.48 per 1,000 beneficiaries; RR=0.91; 95% CI, 0.90-0.92) and higher overall Medicare spending ($8,857 vs. $8,769 per beneficiary; RR=1.01; 95% CI, 1.004-1.02) were observed among beneficiaries residing in areas of the highest quintile compared with those in the lowest quintile.

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Patients with pneumonia at increased risk for early cardiac arrest

Patients hospitalized for pneumonia may be at increased risk for early cardiac arrest and may present with little or no warning symptoms, according to data presented at the American Thoracic Society 2011 International Conference.

“We found a compelling signal that some patients with pneumonia may develop cardiac arrest outside of the intensive care unit, without apparent shock or respiratory failure,” Gordon Carr, MD, pulmonary and critical care fellow at the University of Chicago Medical Center, said in a press release. “If this is true, then we need to improve how we assess risk in pneumonia.”

Carr and colleagues pooled data from the American Heart Association’s Get with the Guidelines database among 44,416 in-hospital cardiopulmonary arrest cases who went into early cardiac arrest within 72 hours of hospital admission. Of these, 5,367 patients had pre-existing pneumonia. The median time from hospital admission to in-hospital cardiopulmonary arrest was 20.7 hours.

Of these patients, 77.2% of cardiac arrests occurred in an ICU step-down unit, and 19.3% occurred in the general patient area. At the time of cardiac arrest, only 40% of patients with pre-existing pneumonia received mechanical ventilation, and 36.3% received infusions of vasoactive therapies, according to the study abstract.

Causes of in-hospital cardiopulmonary arrest included arrhythmia (65%), respiratory insufficiency (53.9%) and hypotension/hypoperfusion (49.8%).

“While our study design precluded definitive analyses of incidence or cause and effect, our main finding was that some patients with pneumonia and cardiac arrest did not appear to experience a premonitory period of overt critical illness,” Carr said. “There appears to be an important group of patients with pneumonia who develop cardiac arrest without respiratory failure or shock.”

Carr said future studies should “examine the incidence and cause of sudden, early cardiovascular collapse in patients with pneumonia and other forms of sepsis, and address ways to measure and mitigate this risk. In the meanti
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Polypill linked with improved BP, LDL levels

PILL Collaborative Group. PLoS One. 2011;doi:10.1371/journal.pone.0019857.

A pill containing aspirin plus BP- and cholesterol-lowering agents was linked to reductions in systolic BP and LDL, according to recent results.

The pill contains 75 mg of aspirin, 10 mg of lisinopril, 12.5 mg of hydrochlorothiazide and 20 mg of simvastatin. There were 378 eligible participants who had no indication for any component of the pill but who had an estimated 5-year CVD risk of more than 7.5%.

Baseline data indicated that the mean BP was 134 mm Hg/81 mm Hg and the mean LDL cholesterol was 3.7 mmol/L.

A 9.9 mm Hg reduction in systolic BP (95% CI, 7.7-12.1) was linked to polypill treatment at 12 weeks’ follow-up. The pill also was associated with a reduction in LDL cholesterol of 0.8 mmol/L (95% CI, 0.6-0.9).

Patients in the treatment group discontinued at a rate of 23% vs. an 18% discontinuation rate in the placebo group (RR=1.33; 95% CI, 0.89-2.00).

Adverse events were reported in 58% of recipients and 42% of placebo recipients (P=.001). These events were evident early on in the trial but generally did not warrant cessation of treatment, according to the researchers.

The primary outcomes of the randomized, double blind, placebo-controlled trial were systolic BP, LDL cholesterol and tolerability (proportion discontinued randomized therapy) by 12 weeks.

“This polypill achieved sizeable reductions in [systolic] BP and LDL cholesterol but caused side effects in about one in six people,” the researchers wrote. “The halving in predicted cardiovascular risk is moderately lower than previous estimates and the side effect rate is moderately higher. Nonetheless, substantial net benefits would be expected among patients at high risk.”

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Racial disparity in quality of PCI hospital observed among Medicare beneficiaries
Popescu I. Circulation. 2011;doi:10.1161/circulationaha.110.973628.

Researchers of a study appearing in Circulation have found that black Medicare beneficiaries are significantly less likely to undergo percutaneous coronary intervention in high-quality and revascularization hospitals compared with white beneficiaries.

The California and Iowa-based researchers performing the analysis pooled data from 1,244 US hospitals that had at least 50 black admissions in 2005. The 65,633 patients included in the study were either black (n=8,291) or white (n=57,342) and all had acute MI. Hospital quality was determined by a composite score composed of hospital risk-adjusted 30-day mortality and acute MI performance measures, with the top 20% designating high quality and the lowest 20% representing low quality.

Overall, blacks lived closer to revascularization (3.8 vs. 6.8 miles), high-quality (5.6 vs. 9.7 miles) and low-quality hospitals (25.5 vs. 36.9 miles; P<.001 for all three). After adjustment for distance, blacks had a significantly lower likelihood of being admitted to revascularization (RR=0.87) and high-quality hospitals (RR=0.88) while also having a higher likelihood of being admitted to low-quality hospitals (RR=1.17; P<.001 for all three).

Despite the study having several limitations, including lack of data on patient preferences and the inclusion of only white and black Medicare beneficiaries, the researchers wrote that the findings provide important information on factors contributing to racial disparities in acute MI treatment.

“The study confirms the role of differential access to hospitals with revascularization services and high quality of care as a plausible source of disparity,” they said. “However, racial differences in access to high-quality hospitals appear to be primarily driven not by race in itself, but by differences in where the majority of blacks and whites live and seek care. Effective policy recommendations aimed at reducing disparities need to take local socioeconomic and health care system factors into consideration.”
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Tonsillectomy and appendectomy as a child may increase MI risk

Janszky I. Eur Heart J. 2011;doi:10.1093/eurheartj/ehr137.

A link may exist between undergoing a tonsillectomy or appendectomy as a child and an increased risk for MI as an adult, results of a new study indicate.

Although the tonsils and appendix are not considered vital to the body, Swedish researchers have found that those who had them removed before the age of 20 years may have a slightly greater risk for premature acute MI.

“Given the strong biological and epidemiological evidence linking inflammation with coronary heart disease, one might anticipate that surgical removal of the tonsils and appendix, with their consequent effects on immunity, might also have a long-term effect on coronary heart disease,” Imre Janszky, MD, of the department of public health science at the Karolinska Institute in Stockholm, Sweden, said in a news release from the European Society of Cardiology. “However, we were aware of no studies evaluating the potential effects of appendectomy or tonsillectomy on atherosclerosis or coronary heart disease risk.”

For the prospective matched-cohort study, the researchers identified 54,449 appendectomies and 27,284 tonsillectomies performed on Swedish residents aged younger than 20 years; participants were born between 1955 and 1970. The patients were followed for an average of 23.5 years to determine how many would suffer fatal or non-fatal MIs.

Within the follow-up period, 89 of the participants who underwent appendectomies and 47 of those who underwent tonsillectomies experienced an acute MI, the investigators found.

The research team derived HRs from proportional hazard models adjusted for parental occupation and parental history of acute MI. Operations before the patient was aged 20 years were associated with an increased risk for acute MI (417 and 216 events in the appendectomy and tonsillectomy datasets, respectively), with adjusted HRs of 1.33 (95% CI, 1.05-1.70) for appendectomy and 1.44 (95% CI, 1.04-2.01) for tonsillectomy.

“These results are consistent with the hypothesis that subtle alterations in immune function following these operations may alter the subsequent cardiovascular risk, but further studies are needed to confirm these findings and to explore possible mechanisms,” the researchers wrote.

Because the study was limited to childhood procedures and participants were relatively young during the follow-up period, the findings may not apply to older people at greater risk for heart disease, they concluded.

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Hypertension rate could be as high as 20% in young adults

Nguyen Q. Epidemiology. 2011;22:532-541.

New findings have revealed that rates of hypertension among young adults may be close to 20%, nearly five times the rate found among participants of the National Health and Nutrition Examination Survey.

Senior study researcher Kathleen Mullan Harris, PhD, and colleagues examined 14,252 participants from the National Longitudinal Study of Adolescent Health (Add Health), Wave IV study, and compared them with participants from NHANES 2007-2008 (n=733). All of the participants were aged 24 to 32 years and had BP of at least 140 mm Hg/90 mm Hg.

Overall, rates of hypertension were much higher for Add Health study participants (19% vs. 4%), although self-reported history was only slightly higher (11% vs. 9%). Among participants with self-reported hypertension, approximately 50% of those in Add Health vs. 20% in NHANES actually had elevated BP by study measurement.

Adjustments for differences in participant characteristics, use of antihypertensive medications, examination time, as well as the consumption of food, caffeine and cigarettes before BP measurement had little influence on these estimates.

“The large and unexplained differences between Add Health and NHANES merit further investigation,” the researchers wrote. “US CHD mortality and policy models rely heavily on NHANES systolic BP distributions and, in some cases, on optimistic assumptions regarding relatively small decreases of 0–1 mm Hg per year in population mean systolic BP.”

Also meriting further scrutiny, they wrote, is the prevalence of hypertension found among Add Health Wave IV participants, indicating an unexpectedly high risk for CVD among young adults in the United States.
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FDA: No increased risk for cancer with angiotensin receptor blockers

Angiotensin II receptor blockers do not increase the risk for cancer, despite a study from last year reporting a small increased risk for cancer among those taking the drug, according to a news release issued by the FDA.

The FDA’s finding was based on a review performed by the agency that began in July 2010, shortly after the study was published. The review looked specifically at 31 randomized controlled trials that compared those taking with those not taking angiotensin II receptor blockers (ARBs) to determine the incidence of cancer.

“The FDA has completed its review of controlled trial data on more than 155,000 patients randomized to ARBs or other treatments — the largest evaluation of such data to date — and finds no evidence of an increased risk of cancer in patients who take an ARB,” Mary Ross Southworth, PharmD, deputy director for safety in the Division of Cardiovascular and Renal Drugs of the FDA’s Center for Drug Evaluation and Research, said in the release.

As a result of these findings, the FDA concluded in the release that any concern about a link between ARB use and development of cancer has been resolved, and that patients currently taking any antihypertensive medication should continue to unless advised by a health care professional.

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New antiplatelet agents face hurdles in clopidogrel-dominated market

For the treatment of patients with acute coronary syndrome or percutaneous coronary intervention, the antiplatelet therapy of choice has been consistent among physicians since it was first approved in 1997 — clopidogrel.

“[Clopidogrel (Plavix, Sanofi-Aventis)] was the first safe thienopyridine in the marketplace, so in a sense, it had a huge head start over a lot of other drugs in the field that are now available or about to be available,” David P. Faxon, MD, vice chair of medicine for strategic planning at the Brigham and Women’s Hospital, Boston, and Cardiology Today Editorial Board member, said in an interview. “So, for that reason, there hasn’t been much competition for it, and it has taken over the marketplace.”

The substantial, high-level evidence that supports the use of clopidogrel for reduction of morbidity and mortality in patients with ACS, MI and many other indications has helped the drug develop its formidable presence, said Rhonda M. Cooper-DeHoff, PharmD, MS, associate professor in the colleges of pharmacy and medicine at University of Florida, Gainesville, and a Cardiology Today Editorial Board member.

“Additionally, its relative ease of use, good tolerability and low incidence of adverse reactions have made it the antiplatelet agent of choice for reduction of atherosclerotic events in patients with MI or stroke since its approval,” she said.

Yet, despite its strengths, shortcomings with clopidogrel are still hindering its use in all patients in need of therapy. At the top of this list, according to Cooper-DeHoff, is clopidogrel resistance, which is the result of a patient’s genetic makeup, “whereby they are not able to adequately convert the prodrug to the active metabolite, resulting in inadequate protection, or they over-convert to the active metabolite, resulting in increased risk of bleeding,” she said.

Other shortcomings, according to Gilles Montalescot, MD, PhD, professor of cardiology at the Pitié-Salpêtrière Hospital in Paris, include poor predictability of the effect, slow onset of action, possible interactions with proton pump inhibitors, as well as recent negative studies on double doses of clopidogrel, including the CURRENT and GRAVITAS trials.

In response to these limitations, new agents have and are continuing to be developed that could potentially change the paradigm of the antiplatelet market by providing answers to several of these concerns.

Adoption of prasugrel inhibited by risks

After its approval in 2009, prasugrel (Effient, Daiichi Sankyo/Eli Lilly) became the only other available thienopyridine compound, which is still true today. Similar to clopidogrel, prasugrel is an indirect platelet inhibitor. However, platelet inhibition with prasugrel is observed after only 15 or 30 minutes and at a significantly lower loading dose compared with clopidogrel (60 mg vs. 300 mg), which occurs within 1 to 2 hours after a single-loading dose.

“While both compounds are prodrugs, clopidogrel requires a two-step enzymatic conversion to the active metabolite, while prasugrel only has to undergo a single conversion,” Cooper-DeHoff said. “However, prasugrel must be used with caution in the very elderly and/or lean population.”

This issue with the elderly, Faxon said, stems from the risk for bleeding with the drug, which he cited as the greatest obstacle currently inhibiting its widespread use. “They say patients have to be off [prasugrel] for 7 days, even longer for surgery. For people who are older, with stroke risk and prior transient ischemic attacks, you get higher risk of intracranial bleeding. This is serious because half the patients with [intracranial bleeding] die and the other half are severally disabled,” he said.

There is even some concern stemming from a study that found a link between prasugrel use and cancer, but Faxon said the study was not powered to look at the connection, and as a result, the finding has not made a huge effect on the drug’s usage.

“It needs to be evaluated, but the incidence was tiny,” he said. “If you’re going to do a study to determine whether prasugrel has any relation to cancer, you need a study of 22,000 patients. You can forget about that. … Personally, I think it was purely by chance because there is no plausible explanation.”

Upcoming trials for prasugrel that will help expound upon current knowledge of the drug, according to Montalescot, include the TRILOGY trial, which will be looking at a new regimen of the drug in ACS, as well as the ACCOAST trial, which will examine pretreatment with the drug in non-STEMI.

Need for data halts ticagrelor

With the FDA panel’s vote of 7-1 in July to recommend approval of the direct-acting P2Y12 inhibitor ticagrelor (Brilinta, AstraZeneca) for the reduction of thrombotic events in patients with ACS, it seemed an almost sure thing that clopidogrel would soon face one of its greatest challenges yet. However, less than 5 months later, the momentum of the drug was halted when the FDA issued a complete response letter to AstraZeneca declining the approval of the drug without additional analysis of the PLATO trial.

“There are a certain number of questions around the [PLATO] results that need to be answered. They are different from country to country,” Montalescot said. “Even if the results look impressive, this is not a home run. Heterogeneity in the results, same safety issues (bleeding) as prasugrel, side effects, reality of the death effect … all this needs to be answered.”

Yet, as many cardiologists agree, even these obstacles seem to be only a temporary setback to the drug’s ultimate approval.

“Ticagrelor is the only one in the group that has shown a reduction in mortality, and I always put a lot of weight into that. Saving lives is what you want to do,” Faxon said. “The bleeding rates are probably more significant than the papers would have you realize, but it seems to have a better profile than prasugrel. It has a relatively short half-life. So you can administer the drug and it works right away, and you can stop it and it goes away very quickly.”

Other promising agents

Although prasugrel and ticagrelor may currently have most of the spotlight in the category of newer antiplatelet therapies, others have emerged that are giving physicians a reason to take notice, including cangrelor, an IV-administered thienopyridine that is a direct and reversible P2Y12 inhibitor. This drug has the advantage of having an even more rapid onset and offset than ticagrelor due to IV administration.

However, the 2009 CHAMPION-PCI trial showed that cangrelor did not reduce the primary endpoint of a composite of death, MI or ischemia-driven revascularization at 48 hours after PCI compared with clopidogrel.

Still, these findings should not rule out possible use, Faxon said. “In some instances, a patient comes in with unstable coronary syndrome and has to go right to the cath lab, and you don’t know if they are going to be a surgical candidate or not. Here’s a drug that you could give them intravenously, cath them and if they don’t have the procedure, you can stop the drug. It wears right off, and you can take them to surgery,” he said. “So, it has a potential place, but if the next trial is negative, then it should be written off. But not quite yet.”

Also of interest to Faxon are protease-activated receptor-1 (PAR-1) drugs, which go to work on the platelet’s thrombin receptor.

“PAR-1 drugs are going to be interesting. There are some big studies with PAR-1 antagonist, including the TRACER study,” he said. “You might think it would only be good by itself, but since it works differently, it might be useful to combine it with clopidogrel or ticagrelor. This is true in general, as it might be good to combine different drugs that work in different ways for patients who want to have the most powerful effect.” – by Brian Ellis

For more information:
Bellemain-Appaix A. J Am Coll Cardiol. 2010;56:1542-1551.
Wallentin L. Eur Heart J. 2009;30:1964-1977.

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Widespread Increase in Myeloid Calcifying Cells Contributes to Ectopic Vascular Calcification in Type 2 Diabetes
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SHIFT data reveal key improvements with ivabradine

Patients with chronic HF who were treated with ivabradine had improved quality of life at 2 years and lowered heart rate at 8 months, according to results from two substudies of the SHIFT trial presented at the Heart Failure Congress 2011.

In the quality-of-life substudy, patients with chronic HF (n=1,944) were randomly assigned to either ivabradine (Procoralan, Servier; n=968) or placebo (n=976). The Kansas City Cardiomyopathy Questionnaire (KCCQ) score was determined at baseline and at 4, 12 and 24 months after randomization.

Researchers found that the difference in KCCQ overall summary score — which included clinical summary score and quality of life — for surviving patients from baseline to last assessment was nearly two times greater in the ivabradine arm (5.3 vs. 3; P<.001). Although both arms reported decreases in overall summary score when researchers included death, the least reduction was found in the ivabradine group (–2.8 vs. –6.4; P=.004).

Similar but less significant results were also reported when researchers looked at clinical summary score alone for both scores including (P=.012) or not including (P=.015) death.

“In patients with HF and systolic dysfunction who are in sinus rhythm with HR >70 bpm, heart rate reduction with ivabradine was associated with improved health-related quality of life,” Inger Ekman, PhD, study investigator and director, University of Gothenburg Centre for Person-Centred Care (GPCC), Gothenburg, Sweden, said in her presentation. “This … benefit was seen in addition to reduction in the primary endpoint of CV death or hospitalization for worsening HF.”

Also presented at the Heart Failure Congress was the SHIFT ECG-Holter substudy, which looked at 501 patients of SHIFT to better understand the heart rhythm safety profile of ivabradine. All patients were given optimized HF therapy and ivabradine (n=254) or placebo (n=247).

At 8 months, 24-hour heart rate was significantly reduced in the ivabradine arm compared with placebo (P<.0001), and higher rates of at least one episode of heart rate less than 40 bpm were also reported in the ivabradine group (P<.0001). However, rates of atrial fibrillation were slightly higher in the ivabradine group (2.4% vs. 2%), whereas rates of second- or high-degree atrioventricular block were higher with those taking placebo (3.6% vs. 1.6%).
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SHARP: Simvastatin plus ezetimibe linked with fewer atherosclerotic events

Baigent C. Lancet. 2011;doi:10.1016/S0140-6736(11)60822-2.

In patients with chronic kidney disease, a combination of simvastatin 20 mg plus ezetimibe 10 mg given daily was associated with a significant reduction in atherosclerotic events, results from the SHARP study indicated.

Researchers for the study enrolled 9,270 patients with chronic kidney disease and a known history of MI or coronary revascularization. Patients were randomly assigned to receive either simvastatin (Zocor, Merck) 20 mg daily plus ezetimibe (Zetia, Merck) 10 mg daily (n=4,650) or matching placebo (n=4,620). The primary endpoint was the first major atherosclerotic event (nonfatal MI or coronary death, non-hemorrhagic stroke or any revascularization).

According to the results, patients in the combined therapy group had an average LDL difference of 0.85 mmol/L during the median follow-up of 4.9 years, which produced a 17% proportional reduction in major atherosclerotic events (11.3%) vs. placebo (13.4%, P=.0021). Fewer patients receiving the combined therapy died from CHD (4.6% vs. 5.0%), and there were also reductions in non-hemorrhagic stroke (2.8% vs. 3.8%) and arterial revascularization procedures (6.1% vs. 7.6%) vs. placebo, but these reductions did not attain statistical significance.

“The SHARP randomized trial has now shown that lowering of LDL cholesterol with simvastatin plus ezetimibe safely reduces the risk of major atherosclerotic events in a wide range of patients with chronic kidney disease,” the researchers wrote in their interpretation of the results. “When the SHARP results are compared with those of previous statin trials in renal patients, it appears that the absence of significant reductions in earlier trials could have been due both to the much smaller number and the much smaller proportion of vascular events in the primary outcomes that were related to atherosclerosis and, hence, preventable by lowering of LDL cholesterol.”

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Epidemiology of hypertension in low-income countries: a cross-sectional population-based survey in rural Uganda
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The next decade in mechanical assist: advances that will help the patient and the doctor
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Success in Implementing a Hospital-wide Evidence-based Clinical Pathways System for the Management of Cardiac Patients: The ACAP Program Experience
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MI rate fell nearly 75% in London cohort during 20-year period

Hardoon S. Eur Heart J. 2011;doi:10.1093/eurheartj/ehr142.

From 1985 to 2004, the rate of MI among participants of a cohort in London decreased 74%, with declining non-HDL cholesterol levels and increased HDL cited as the main reasons for the decline. However, the study, appearing in the European Heart Journal, also found that rising BMI could potentially reverse the trend in the future.

The researchers performing the study looked at men (n=6,379) and women (n=3,074) from the Whitehall II cohort. All participants were from 20 civil service departments in London between 1985 and 1988, aged 35 to 55 years and had clinic visits every 5 years. Participants completed questionnaires and examinations on health and lifestyle during four periods: 1985 to 1988, 1991 to 1993, 1997 to 1999 and 2002 to 2004.

During the 20 years, 256 first MI events were reported, of which 81.3% occurred in men. The age-sex adjusted hazard for MI decreased by 74% (95% CI, 48-87) during this time, which corresponded to a mean decline of 6.5% (95% CI, 3.2-9.7) per year.

According to the researchers, 56% of this decline could be attributed to percent decreases in non-HDL levels (34%), systolic BP (13%) and cigarette smoking (6%), as well as increases in HDL levels (17%) and fruit and vegetable consumption (7%). Also noteworthy, rising BMI reduced the scale of the decline by 11%.

These findings, the researchers wrote, highlight what can be achieved and emphasize the value of measures to reduce exposure to risk factors in the population.

“Further research is needed to determine whether the residual unexplained portion of the decline in MI may be explained by early treatment, underestimated contributions of the major risk factors (reflecting imprecision in the analyses) or the influence of other risk factors,” they said, while adding that the rising BMI in the UK and other countries still needs urgent attention.
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SPARCL: Statin treatment did not affect outcomes in patients with type 2 diabetes, metabolic syndrome

Callahan A. Arch Neurol. 2011;doi:10.1001/archneurol.2011.146.

A cohort of patients with type 2 diabetes mellitus or metabolic syndrome did not benefit from statin treatment, according to recent results.

The secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial aimed to determine whether treatment with atorvastatin (Lipitor, Pfizer) could reduce stroke in patients with type 2 diabetes or metabolic syndrome who had recently had a stroke or transient ischemic attack.

There were 794 patients with type 2 diabetes at enrollment; 642 patients retrospectively included in a metabolic syndrome cohort; and 3,295 patients in a reference group who belonged to neither category.

Compared with the reference group, those with type 2 diabetes were at an increased risk for stroke (HR=1.62; 95% CI, 1.33-1.98), major CV events (HR=1.66; 95% CI, 1.39-1.97) and revascularization procedures (HR=2.39; 95% CI, 1.78-3.19).

There was no increased risk for stroke (P=.78) or major CV events (P=.38) among patients with metabolic syndrome compared with those in the reference group. However, patients with metabolic syndrome were more likely to undergo revascularization procedures (HR=1.78; 95% CI, 1.26-2.5).

No significant treatment interactions were observed for the SPARCL primary endpoint (P=.47), according to the results.

The primary endpoint was combined risk for nonfatal and fatal stroke, and secondary endpoints included major coronary events, major CV events, any coronary disease event and any revascularization procedure. Regression analysis was conducted to determine whether the effect of treatment varied based on the presence of type 2 diabetes or metabolic syndrome.
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SIRTAX LATE: Comparable outcomes for sirolimus-, paclitaxel-eluting stents at 5 years

Räber L. Circulation. 2011;123:2819-2828. Su

New randomized trial data have indicated that patients treated with first generation sirolimus-eluting stents had no significant differences in clinical and angiographic outcomes at 5 years compared with patients receiving paclitaxel-eluting stents.

The Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX LATE) trial involved 1,012 patients randomly assigned to receive either sirolimus-eluting stents (SES; Cypher, Cordis; n=503) or paclitaxel-eluting stents (PES; Taxus, Boston Scientific; n=509). In addition, all patients had at leastone lesion in a vessel with a reference diameter between 2.25 and 4.00 mm.

At 5 years, 97.6% of SES and 96.1% of PES patients had obtainable clinical follow-up. Major adverse cardiac events (a composite of cardiac death, MI and ischemia-driven target lesion revascularization) occurred in 19.7% of SES patients and 21.4% of PES patients (HR=0.89; 95% CI, 0.68-1.17). Individually, there were no statistically significant differences in the rates of cardiac death (SES, 5.8% vs. PES, 5.7%), MI (SES, 6.6% vs. PES, 6.9%) or target lesion revascularization (TLR; SES, 13.1% vs. PES, 15.1%).

Also reported, the annual rate of TLR between 1 and 5 years was 2.0% for the SES group and 1.4% for PES group, while delayed lumen loss for those undergoing paired angiography between 8 months and 5 years was 0.37 ± 0.73 mm for SES and 0.29 ± 0.59 mm for PES patients.

Among the clinical implications of the study, the researchers wrote, were the low risk of repeat revascularization with first-generation drug-eluting stents (DES) and the observation that very late stent thrombosis remains an important liSIRTAX LATE: Comparable outcomes for sirolimus-, paclitaxel-eluting stents at 5 years

Räber L. Circulation. 2011;123:2819-2828.

New randomized trial data have indicated that patients treated with first generation sirolimus-eluting stents had no significant differences in clinical and angiographic outcomes at 5 years compared with patients receiving paclitaxel-eluting stents.

The Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX LATE) trial involved 1,012 patients randomly assigned to receive either sirolimus-eluting stents (SES; Cypher, Cordis; n=503) or paclitaxel-eluting stents (PES; Taxus, Boston Scientific; n=509). In addition, all patients had at leastone lesion in a vessel with a reference diameter between 2.25 and 4.00 mm.

At 5 years, 97.6% of SES and 96.1% of PES patients had obtainable clinical follow-up. Major adverse cardiac events (a composite of cardiac death, MI and ischemia-driven target lesion revascularization) occurred in 19.7% of SES patients and 21.4% of PES patients (HR=0.89; 95% CI, 0.68-1.17). Individually, there were no statistically significant differences in the rates of cardiac death (SES, 5.8% vs. PES, 5.7%), MI (SES, 6.6% vs. PES, 6.9%) or target lesion revascularization (TLR; SES, 13.1% vs. PES, 15.1%).

Also reported, the annual rate of TLR between 1 and 5 years was 2.0% for the SES group and 1.4% for PES group, while delayed lumen loss for those undergoing paired angiography between 8 months and 5 years was 0.37 ± 0.73 mm for SES and 0.29 ± 0.59 mm for PES patients.

Among the clinical implications of the study, the researchers wrote, were the low risk of repeat revascularization with first-generation drug-eluting stents (DES) and the observation that very late stent thrombosis remains an important liSIRTAX LATE: Comparable outcomes for sirolimus-, paclitaxel-eluting stents at 5 years

Räber L. Circulation. 2011;123:2819-2828. Submit a Comment Print Email


New randomized trial data have indicated that patients treated with first generation sirolimus-eluting stents had no significant differences in clinical and angiographic outcomes at 5 years compared with patients receiving paclitaxel-eluting stents.

The Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX LATE) trial involved 1,012 patients randomly assigned to receive either sirolimus-eluting stents (SES; Cypher, Cordis; n=503) or paclitaxel-eluting stents (PES; Taxus, Boston Scientific; n=509). In addition, all patients had at leastone lesion in a vessel with a reference diameter between 2.25 and 4.00 mm.

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At 5 years, 97.6% of SES and 96.1% of PES patients had obtainable clinical follow-up. Major adverse cardiac events (a composite of cardiac death, MI and ischemia-driven target lesion revascularization) occurred in 19.7% of SES patients and 21.4% of PES patients (HR=0.89; 95% CI, 0.68-1.17). Individually, there were no statistically significant differences in the rates of cardiac death (SES, 5.8% vs. PES, 5.7%), MI (SES, 6.6% vs. PES, 6.9%) or target lesion revascularization (TLR; SES, 13.1% vs. PES, 15.1%).

Also reported, the annual rate of TLR between 1 and 5 years was 2.0% for the SES group and 1.4% for PES group, while delayed lumen loss for those undergoing paired angiography between 8 months and 5 years was 0.37 ± 0.73 mm for SES and 0.29 ± 0.59 mm for PES patients.

Among the clinical implications of the study, the researchers wrote, were the low risk of repeat revascularization with first-generation drug-eluting stents (DES) and the observation that very late stent thrombosis remains an important limitation of first-generation DES, accounting for more than half of all MIs between 1 and 5 years.

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Late postoperative atrial fibrillation after cardiac surgery: a national survey within the cardiac rehabilitation setting
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Evaluation of the hypertensive state in treated patients: selection of appropriate blood pressure measurements per visit to the community pharmacy
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Core Competencies for Cardiac Rehabilitation/Secondary Prevention Professionals: 2010 Update: Position Statement of the American Association of Cardiovascular and Pulmonary Rehabilitation
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VALOR II: Thoracic stent graft safe, efficacious in patients with descending TAA

The Valiant thoracic stent graft produced favorable results at 1 year among patients with descending thoracic aortic aneurysms of degenerative etiology and proved to be noninferior to a predicate device, according to presented data.

The nonrandomized, prospective, pivotal VALOR II trial followed 160 patients with descending thoracic aortic aneurysms (TAA) of degenerative etiology who were treated with a thoracic stent graft (Valiant, Medtronic) at 24 US centers. Outcomes were compared with those obtained in the VALOR pivotal trial, a study that examined a precursor thoracic stent graft (Talent, Medtronic) among 195 patients with the same inclusion criteria.

Overall, 96.3% of VALOR II patients had successful stent graft delivery and deployment. At 30 days, perioperative mortality was 3.1% with a major adverse event rate of 38.1%. At 1 year, among 94.4% of patients from the VALOR II trial who were available for follow-up, rates of aneurysm-related mortality was 3.3%, 2.9% for stent-graft migration and 13% for endoleak, with no cases of rupture, conversion to open surgery or loss of stent-graft patency.

In all, the Valiant stent graft proved to be statistically noninferior to the Talent stent graft in 12-month all-cause mortality (12.6% vs. 16.1%) and exceeded the primary effectiveness goal of 12-month successful aneurysm treatment (97.4% vs. 80%), which was defined as the absence of aneurysm growth of more than 5 mm and of secondary procedures for type I/III endoleak.
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Sustained effectiveness of paclitaxel-eluting stent observed in patients with diabetes

For treating superficial femoral artery lesions in diabetic patients, the paclitaxel-eluting stent was shown to have sustained effectiveness at 1 and 2 years compared with percutaneous transluminal angioplasty, according to results of a late-breaking clinical trial presented at the 65th Vascular Annual Meeting of the Society for Vascular Surgery.

“Most superficial femoral artery interventions have worse outcomes in diabetics,” Sean P. Lyden, MD, with the Cleveland Clinic Foundation and researcher of the prospective, randomized trial, told Cardiology Today. “Diabetics do as well as nondiabetics with the paclitaxel-eluting [Zilver PTX, Cook Medical] stent.”

The trial involved 479 patients with symptomatic de novo or restenotic superficial femoral artery lesions who were treated at 55 institutions in the United States, Japan and Germany. All of patients were randomly assigned to receive a paclitaxel-eluting stent (n=241) or percutaneous transluminal angioplasty (PTA; n=238). In the event of acute PTA failure, defined as at least 30% residual stenosis, patients underwent secondary randomization to either provisional bare metal stent (Zilver) or provisional paclitaxel-eluting stent (Zilver PTX).

Overall, 118 patients had acutely successful PTA, and 120 did not. Of those 120 patients, 61 had provisional paclitaxel-eluting stent implantation vs. 59 who had provisional bare metal stent implantation. Among the 302 patients who received primary or provisional paclitaxel-eluting stent treatment, 48.3% had diabetes.

For patients with and without diabetes, demographics and lesion characteristics were similar. Event-free survival was comparable between groups, but slightly favored the nondiabetes group at both 1 year (93.5% vs. 89.2%) and 2 years (88.7% vs. 84.4%). Also similar were paclitaxel-eluting stent patency rates, which were nonsignificantly higher in nondiabetes patients at 1 year (85.2% vs. 83.9%) and 2 years (77.5% vs. 74.1%).

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ADDITION-Europe: Diabetes screening, early intensive intervention improved CV outcomes

SAN DIEGO — In patients who had their type 2 diabetes detected by screening in general practice, intensive multifactorial treatment led to small but significant improvements in risk factors when compared with usual care, including small reductions in mortality and cardiovascular events, researchers found in a new study.

Patients with longstanding diabetes will likely draw CV benefits from intensive multifactorial therapy, although how such treatment affects patients with diabetes found through screening is unclear. To answer this question, researchers conducted the multicenter Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care (ADDITION-Europe).

Routine vs. intensive multifactorial therapy

Between 2001 and 2006, patients were screened for type 2 diabetes at 343 general practices in Denmark, the Netherlands and the United States. The researchers then randomly assigned the centers to provide routine care or intensive multifactorial therapy to the 3,057 patients (mean age, 60 years) who were diagnosed with diabetes via screening.

“Practices in routine care were asked to follow national guidelines, whereas family physicians assigned to provide intensive care were urged to give intensive lifestyle advice, such as changing diet or physical activity level, and drug treatments for blood glucose, lipids and blood pressure,” Torsten Lauritzen, MD, chairman of the ADDITION-Europe steering committee and professor at the University of Arhus in Denmark, said at a press conference said.

After a mean follow-up of 5 years, the intensive therapy group had CV outcomes that were only slightly better than the routine care group, results showed. The incidence of first CV event was 7.2% in the intensive therapy arm and 8.5% in the routine care arm. The incidence of all-cause mortality was 6.2% in the intensive treatment group and 6.7% in the routine care group. The slight discrepancies between the two treatment groups linked the intensive therapy to a nonsignificant 17% reduction in incidence of CV events.

Likewise, improvements in CV risk factors were comparable. The decline in BP, from 150 mm Hg at baseline to 138 mm Hg at follow-up, in the routine care arm was on par with the decrease observed in the intensive therapy arm (149 mm Hg to 135 mm Hg). Similarly, cholesterol levels dropped from 5.6 mmol/L to 4.4 mmol/L in the routine care group and from 5.5 mmol/L to 4.2 mmol/L in the intensive treatment group.

“Family physicians in the routine care group did a much better job than we expected,” Lauritzen said in a press release. “Even in that group, there was a clinically significant reduction in BP and cholesterol levels, and small reductions in blood glucose levels and weight were maintained over 5 years.”

Lauritzen explained that the study results provide a basis for offering routine screening for type 2 diabetes. “This study adds to the evidence that early detection and treatment is beneficial and may be useful in terms of encouraging high risk screening in the general population,” he said.

In an accompanying editorial, David Preiss, MRCP, of the British Heart Foundation, and Naveed Sattar, MBChB, MRCP, of the University of Glasgow, remained cautious.

While they noted that the data indicate the benefits of early diagnosis and treatment of diabetes, they said this study cannot answer “whether screen detection of diabetes is clinically beneficial against the background of current clinical diagnosis and practice.

“The key questions now are whether a sizeable reduction in the lead time between diabetes onset and clinical diagnosis can be achieved by implementation of simpler diagnostic criteria and, if so, to what extent this development might further reduce CV and mortality risks in patients with diabetes,” Preiss and Sattar wrote in The Lancet editorial. – by Melissa Foster

For more information:
Lauritzen T. Joint ADA/The Lancet Symposium. Presented at: American Diabetes Association’s 71st Scientific Sessions; June 24-28, 2011; San Diego, Calif.
Griffin SJ. Lancet. 2011;doi:10.1016/S0140-6736(11)60698-3.
Preiss D. Lancet. 2011;doi:10.1016/S0140-6736(11)60819-2.

Disclosure: ADDITION-Europe received funding from several institutions, public health councils as well as Novo Nordisk, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue and Merck. Drs. Preiss and Sattar report no relevant financial disclosures.

You might look at this trial and say that it is a little disappointing that the researchers did not see a significant difference between the intensive care and the routine care groups, but there are a couple of things to consider. First, only 5 years of follow-up were done. I do not know that you would really expect to see a very significant difference in the sort of hard CV outcomes with only 5 years, especially when treating people with very early diabetes. It will be interesting to see how the long-term follow-up works out. Second, the kind-of-surprising thing is how well the routine care patients were treated. It is almost like there were not huge differences between the care. Overall, [the study] does suggest that screening, finding people early and treating them early does seem to have some benefits.

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Smoking during pregnancy could adversely affect children’s HDL levels

Ayer J. Eur Heart J. 2011;doi:10.1093/eurheartj/ehr174.

Data from a community-based longitudinal study have indicated that 8-year-old children whose mothers smoked during pregnancy had lower HDL levels while also having higher triglycerides and systolic BP.

“The prevalence of maternal smoking during pregnancy remains high, [about] 15% in many Western countries,” the researchers wrote. “The documented associations between smoking in pregnancy and childhood behavioral problems, neurocognitive deficits and sudden infant death syndrome highlight the potential for smoking to result in adverse fetal programming. The independent effect of prenatal exposure to cigarette smoke on the risk of future CVD, however, remains uncertain.”

Researchers performed a prospective analysis, culling data from questionnaires that were completed by face-to-face interviews of mothers soon after giving birth, which assessed their smoking status during the first, second and third trimesters. At the beginning of the study, 616 newborn infants were included in the analysis, and data on 405 of these children who reached 8 years of age were available.

Overall, women who smoked in pregnancy tended to have lower levels of education and shorter breast-feeding duration. At 8 years of age, children whose mothers smoked during pregnancy had lower levels of HDL (1.32 mmol/L vs. 1.50 mmol/L; P=.0005], as well as higher systolic BP (102.1 mm Hg vs. 99.9 mm Hg; P=.006) and triglycerides (1.36 mm Hg vs. 1.20 mmol/L; P=.04). However, no significant difference regarding carotid intima-media thickness was observed.

After multivariable adjustment, smoking during pregnancy remained predictive of lower HDL levels in children (P=.003), although not higher systolic BP (P=.07).

These data, the researchers concluded, “may be important for informing population-based prevention of atherosclerosis, as smoking in pregnancy remains common and HDL cholesterol has important atheroprotective functionality.”

This is a novel study of importance that extends our knowledge about long-term adverse effects on offspring of smoking during pregnancy. Lower levels of HDL that persist in childhood is clear evidence of formative pre-natal conditioning that has long-term consequences and while the mechanistic pathway(s) are not understood, the implications are clear - smoking during pregnancy sets the child up for CVD. Renewed efforts must address the smoking epidemic among younger women today.
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Intensive statin therapy may increase risk for new-onset diabetes

Preiss D. JAMA. 2011;305:2556-2564.

An analysis of data from previously published studies revealed an increased risk for new-onset diabetes with intensive-dose statin therapy as compared with moderate-dose therapy.

Pooled results from five statin trials indicated that, of 32,752 participants without diabetes, 8.4% developed diabetes during a mean follow-up of about 5 years. Diabetes developed in 1,449 of those assigned to intensive-dose statin therapy and 1,300 assigned to moderate-dose therapy.

The researchers calculated an OR of 1.12 (95% CI, 1.04-1.22) for new-onset diabetes in patients who received intensive statin therapy vs. moderate therapy. Data also showed that two more cases of incident diabetes occurred per 1,000 patient-years among those who received intensive treatment (18.9) compared with those who received moderate therapy (16.9). Consequently, the researchers found that the number needed to harm was 498 per year for intensive therapy as compared with moderate therapy.

In contrast, intensive therapy conferred cardiovascular benefits. In those who received intensive therapy, 3,134 patients experienced CV events compared with 3,550 who received moderate therapy. Compared with moderate therapy, the researchers calculated an OR of 0.84 (95% CI, 0.75-0.94) for CV events in patients who received intensive therapy. Further, 6.5 fewer first major CV events occurred per 1,000 patient-years in the intensive-dose group (44.5) vs. the moderate-dose group (51). These results suggested that the number needed to treat to prevent one CV event per year was 155.

According to other results, the risk for incident diabetes was similar among patients who received an 80-mg dose of simvastatin (Zocor, Merck) and those who received an 80-mg dose of atorvastatin (Lipitor, Pfizer), although high-dose atorvastatin was associated with greater reductions in risk for CV events.

“Our findings suggest that clinicians should be vigilant for the development of diabetes in patients receiving intensive statin therapy,” the researchers concluded.

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Multiple readings may be necessary for accurate BP measurement

Appel L. Ann Intern Med. 2011;154:838-839.
Powers B. Ann Intern Med. 2011;154:781-788.

The averaging of several BP measurements could have a substantial effect on reducing the variability in measurements witnessed among hypertensive patients, with the greatest benefit observed with five to six measurements, according to a new study.

In the study, 444 veterans (mean age, 64 years; 92% men) with hypertension from the Durham Veterans Affairs Medical Center, Durham, N.C., were followed for 18 months. Investigators obtained BP through three methods — clinic BP measurements obtained during outpatient visits; standardized research BP measurements every 6 months; and home BP measurements with a monitor transmitting measurements electronically. Controlled systolic BP was defined as a mean measurement of less than 140 mm Hg for clinic or research measurement and less than 135 mm Hg for home measurement.

During follow-up, a substantial variability in BP measurements was found among patients. Specifically, 28% of patients were designated as in control by clinic measurement, 47% by home measurement and 68% by research measurement. Variability was particularly apparent during the short-term for all methods, culminating with a mean within-patient coefficient of variation of 10%.

Overall, a single clinic systolic BP measurement from 120 mm Hg to 157 mm Hg was unable to classify patients as having BP in or out of control with 80% certainty. However, variability could be substantially reduced by averaging several measurements, the researchers said, with the most benefit detected at five to six measurements.

“Current treatment of patients with hypertension relies heavily on clinic measurement of BP, and the quality of this care is evaluated solely in this setting,” the researchers wrote. “For patients who visit their physician to receive personalized health recommendations, high-quality care should reflect good clinical decision-making based on adequate information. In hypertension, simple changes in the setting and number of BP measurements used for decision-making could greatly enhance the personalization of care.”

In an accompanying editorial, Lawrence J. Appel, MD, Edgar R. Miller III, MD, PhD, and Jeanne Charleston, BSN, RN,with Johns Hopkins University, wrote that previously, the importance of accurate and precise BP measurement had been largely ignored and that this study highlights the benefits of recording and averaging high-quality BP measurements across several visits.

“Given persistent problems in obtaining such measurements, a regulatory approach should be considered in which the Joint Commission, the National Committee for Quality Assurance and other organizations set standards and monitor compliance,” they said. “It is time to get serious about BP measurement.”

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Rivaroxaban Wins FDA Approval for DVT Prevention
By Peggy Peck, Executive Editor, MedPage Today
Published: July 01, 2011

WASHINGTON -- The FDA has approved rivaroxaban (Xarelto), an oral, once-daily, factor Xa inhibitor, for prevention of deep vein thrombosis in patients undergoing knee or hip replacement surgery, according to an announcement by Janssen Pharmaceuticals.

The drug is approved for use at a 10 mg dose, once a day for 35 days following hip replacement and for 12 days following knee replacement.

Rivaroxaban, which is also being developed for prevention of recurrent DVT and for prevention of stroke in patients with atrial fibrillation, is the second oral anticoagulant approved by the FDA within the last nine months.

Dabigatran (Pradaxa), a direct thrombin inhibitor, won FDA approval last October for prevention of stroke in patients with atrial fibrillation. It is not approved for DVT prophylaxis.

A third novel oral anticoagulant, apixaban (Eliquis), has also posted promising results in clinical trials and it is widely expected that an NDA for it will be submitted by year end.

Janssen said the FDA based its decision on data from the rivaroxaban phase III clinical development program in which the drug demonstrated greater efficacy than enoxaparin while demonstrating a similar safety profile "including low rates of major bleeding."

When compared with enoxaparin in EINSTEIN DVT, a study of more than 3,400 older adults with symptomatic DVT, rivaroxaban-treated patients had a significantly lower rate of recurrent DVT than warfarin-treated patients.

Likewise, in ROCKET-AF rivaroxaban was as effective as warfarin for preventing stroke in patients with Afib and boasted a slightly better safety profile.

[Chevychelov]

Low vitamin D increased risk for arterial stiffness, endothelial dysfunction
Mheid AL. J Am Coll Cardiol. 2011;58:186–192.

In a study of over 500 patients, low levels of the vitamin D marker 25-hydroxyvitamin D significantly increased the likelihood of arterial stiffness and endothelial dysfunction in the conductance and resistance blood vessels.

“Our findings … provide mechanistic explanation of how depressed vitamin D status, by precipitating vascular dysfunction, might predispose individuals to a higher risk for the development of CVD and adverse events,” the researchers wrote.

In the study, a group of researchers from Georgia and the United Kingdom measured 25-hydroxyvitamin D (25-OH D) in 554 subjects between the ages of 20 and 79. They then determined arterial stiffness as well as endothelial and microvascular function.

Overall, mean 25-OH D among the population was 31.8 ± 14 ng/ml. Following adjustment for several variables, including age, sex, race, BMI, medication use, total cholesterol, LDL, triglycerides and CRP, 25-OH D was associated with reactive hyperemia index (P<.001), subendocardial viability ratio (P=.001), flow-mediated vasodilation (P=.03), augmentation index (P=.03) and pulse wave velocity (P=.04).

Among those with vitamin D deficiency (n=42), 25-OH D normalization by 6 months resulted in increases in both reactive hyperemia index (P=.009) and subendocardial viability ratio (P=.04), and a decrease in mean arterial pressure (P=.02).

As a result of these findings, the researchers called for larger trials to assess the effect of vitamin D therapy on prevention of CVD in individuals with vitamin D insufficiency.
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Drug-, device-induced effects on HF markers did not predict mortality benefit
Wessler BS. Circ Heart Fail.2011;doi: 10.1161/circheartfailure.111.961573.

In an analysis of trial level data from different eras, the average drug- and device-induced effects on peak oxygen consumption, 6 minute walk distance and two biomarkers among patients with HF and reduced ejection fraction was not predictive of long-term therapeutic effects on mortality.

The study featured a total 20,820 patients from 109 trials that were published between January 1966 to September 2009. All trials determined the role of the functional markers peak oxygen consumption (VO2) and 6 minute walk distance, and natriuretic peptide biomarkers (BNP and NT-proBNP) in predicting mortality in patients with HF and left ventricular dysfunction. As a requisite, the trials were randomized controlled trials, and determined mortality in at least 500 patients over a period of at least 6 months.

Overall, there was no significant association between mortality and therapy-induced placebo-corrected change in peak VO2 or in natriuretic peptides. Researchers did observe a modest correlation between drug or device induced average change in 6 minute walk distance and an increased odds ratio for mortality (P= 0.036). However, with regards to the latter finding, James E. Udelson, MD, with Tufts Medical Center, Boston, and study investigator, told Cardiology Today that because the correlation was so weak, “it is clear that you could never really use change in 6 minute walk distance as a predictor of mortality in any clinical sense.”

As a result, Udelson and colleagues concluded in the study that while these markers may objectively reflect functional capacity and represent pathophysiologic changes that are seen in HF, “our findings do not provide support for their use as surrogates for an intervention’s effect on long-term mortality. Continued work is needed to validate potential markers and find novel surrogates for research trials of therapies in HF.” – by Brian Ellis

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Diastolic dysfunction predicted mortality in patients with normal systolic function

Halley CM. Arch Intern Med. 2011;171:1082-1087.
Piña IL. Arch Intern Med. 2011;171:1088-1089.

Diastolic dysfunction in the presence of impaired systolic dysfunction is associated with mortality, but a new study has found that diastolic dysfunction in patients with normal systolic function is also predictive of mortality.

In the study, researchers from the Cleveland Clinic found that both moderate and severe diastolic dysfunction as assessed by echocardiography among patients with normal systolic function was linked with mortality. However, mild diastolic dysfunction was not.

“This finding has important clinical implications, especially given the high prevalence of mild diastolic dysfunction in the population studied,” they wrote.

The study population included 36,261 patients (mean age, 58.3 years; 54.4% female) with normal ejection fraction (>55%) between January 1996 and December 2005. Researchers determined diastolic function on the basis of four echocardiographic Doppler variables: normal (n=12,603), mild dysfunction (grade 1; n=21,758), moderate dysfunction (grade 2; n=1,773) and severe dysfunction (grade 3; n=127).

Overall, patients who were male, obese (BMI >30) and older than 65 years were more likely to have diastolic dysfunction.

During a mean follow-up of 6.2 years, 5,789 deaths were reported. According to unadjusted analysis, survival was worse depending on the presence and degree of diastolic dysfunction (P<.001). The researchers then performed propensity matching and found that moderate (HR=1.58) and severe (HR=1.84; P<.001) diastolic dysfunction were significantly associated with an increased risk for mortality.

For Ileana L. Piña, MD, with Case Western Reserve University, Cleveland, and author of the accompanying editorial, these findings lend credence to the complexity of HF with preserved ejection fraction beyond only diastolic dysfunction and of the ways patients ultimately progress to frank HF.

“Halley et al provide an important piece of the puzzle (ie, that diastolic dysfunction is common and that physicians need to be aware of the prognostic value of moderate and severe diastolic dysfunction),” she wrote. “The missing link between diastolic dysfunction diagnosed via echocardiographic testing and the acute presentation of older women with HF with preserved ejection fraction is yet to be elucidated. Further work will help solve this puzzle.”
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Atherosclerotic plaque characteristics differ between black, white patients

Nance JW. Radiology. 2011;doi:10.1148/radiol.11110158.

Using coronary CTA, researchers were able to detect differences in atherosclerotic plaque burden and composition between black and white patients, which highlighted the presence of more non-calcified disease in blacks and more calcified disease in whites.

“For a long time, physicians have searched for explanations as to why African Americans have higher rates of heart disease and higher cardiac death rates, but less coronary artery calcium than Caucasians,” U. Joseph Schoepf, MD, director of CV imaging at Medical University of South Carolina, Charleston, and study investigator, said in a press release. “We show that one possible explanation for the discrepancy may be found in the higher rate of less stable, non-calcified plaque in the heart vessels of African Americans.”

All patients (n=301; 50.2% white, 49.8% black) in the analysis had acute chest pain and underwent coronary CT angiographic examination that included the evaluation of each coronary artery segment for the presence of atherosclerotic plaque, plaque composition and stenosis.

According to results, with the exception of diabetes, which was higher in blacks (P=.003), no other difference in a CV risk factor reached statistical significance between white and black patients. Overall, the presence of any plaque and stenosis did not significantly differ between white and black patients. However, other characteristics did, including higher rates in blacks of prevalence (64% vs. 41%; P<.001) and volume (2.2 mL vs. 1.4 mL; P<.001) of non-calcified plaque independent of CV risk factors, as well as a lower prevalence of calcified plaque (26% vs. 45%; P=.001).

“For African-American patients, coronary CTA may be a more appropriate screening tool for CV risk,” Schoepf said.

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Salt reduction initiatives around the world
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Depression and Cardiac Disease: A Review
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Impact of smoking on acute phase outcomes of myocardial infarction
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Varenicline linked to increased chance for serious CV events
Singh S. CMAJ. 2011;doi:10.1503/cmaj.110218.

The use of varenicline, a medication used for smoking cessation, was associated with an increased risk for serious adverse CV events, results from a meta-analysis suggested.

The researchers analyzed data from 14 double blind, randomized controlled trials that included 8,216 participants. The studies included smokers or users of smokeless tobacco who had reported CV events such as ischemia, arrhythmia, congestive HF, sudden death or CV-related death as serious adverse events linked with the use of the drug. The trials ranged in duration from 7 weeks to 1 year.

According to the results, the use of varenicline (Chantix, Pfizer) was associated with an increased risk for serious adverse CV events (52 of 4,908 patients) vs. placebo (27 of 3,308 patients; 1.06% vs. 0.82%; Peto OR=1.72; 95% CI, 1.09-2.71). The researchers said there were not enough patients in the analysis to allow meaningful comparisons of mortality.

“Our meta-analysis raises safety concerns about the potential for an increased risk of serious adverse CV events associated with the use of varenicline among tobacco users,” the researchers concluded. “Despite the limitations of our analysis, our findings have potential regulatory and clinical implications.”

In an addendum, the researchers said the FDA had announced the addition of a warning to the product label of varenicline regarding “the small increased risk of certain adverse CV events associated with the use of varenicline among smokers with CVD.”
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Recurrent stroke, vascular event rate on decline during past 50 years

Hong K. Circulation. 2011;123:2111-2119.

During a 50-year span, the annual event rate of strokes and major vascular events declined by roughly 1% per decade each, according to an analysis of nearly 60 secondary prevention trials.

The systematic review included only randomized controlled trials (n=59) published from 1960 to 2009 with a more than 6-month follow-up. Other inclusion factors were that most qualifying events were ischemic stroke or transient ischemic attack and intervention was a medical treatment. A total of 66,157 patients comprised the study population.

During the 50 years, annual event rates for recurrent stroke declined by 0.996% per decade (P=.001), with similar reductions also found for fatal stroke (0.282% decline per decade; P=.003). However, the greatest percent deduction was found with major vascular events, which declined by 1.331% per decade (P=.001).

The researchers then performed multiple regression analysis to determine the underlying causes of the decline in stroke and found that increasing use of antithrombotic agents and lowering systolic/diastolic BPs were the major contributors.

In the clinical perspective of the study, the researchers wrote on the influence of drug therapy, commenting that the introduction into practice of successive waves of therapies with proven efficacy in stroke prevention “has been notably successful, resulting in a substantial decline in the rate of recurrent vascular events in the control arms of secondary stroke prevention trials. Consequently, trials of new therapies are more arduous, requiring ever larger sample sizes to confirm treatment efficacy, and clinical investigators must cope with the paradox of progress.”

Other study data of interest showed that compared with the 3 decades before 1990, the past 20 years saw rises in hypertension, diabetes and hyperlipidemia, whereas smoking and transient ischemic attacks declined (P<.05 for all). – by Brian Ellis
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Therapeutic hypothermia yielded positive neurological outcomes among certain cardiac arrest patients

Mooney MR. Circulation. 2011;doi:10.1161/circulationaha.110.986257.

More than 90% of patients who had received therapeutic cooling as treatment for an out-of-hospital cardiac arrest survived with positive neurological outcomes, according to trial results.

There were 140 out-of-hospital cardiac arrest patients who participated in the trial between February 2006 and August 2009. Eligible patients had remained unresponsive after a return of spontaneous circulation. These patients were cooled and re-warmed with an automated, non-invasive cooling device.

Three-quarters of the patients (n=107) — including those with non-ventricular fibrillation arrest or cardiogenic shock — were transferred to a therapeutic hypothermia-capable hospital via referral from other hospitals within the participating network. Sixty-eight patients with concurrent STEMI received cardiac intervention and cooling simultaneously.

The overall survival to discharge rate was 56%. Ninety-two percent of survivors had a positive neurological outcome at discharge.

No differences in survival rates were observed between transferred and non-transferred patients. Non-ventricular fibrillation arrest and presence of cardiogenic shock were strongly linked to death. However, survivors with non-ventricular fibrillation arrest had a 100% positive neurological recovery rate, and survivors with cardiogenic shock present had an 89% positive neurological recovery rate.

For each hour of delay in initiating cooling, mortality risk increased 20% (95% CI, 4-39).

The endpoint of positive neurological outcome was defined as cerebral performance category 1 or 2 at discharge.

The researchers said therapeutic hypothermia is an underused treatment strategy despite showing signs that it improves survival and confers neuroprotection on patients who have a cardiac arrest outside of the hospital, and regional systems of care for these patients are necessary. A comprehensive protocol may result in further dispersion of this “essential therapy for [out-of-hospital cardiac arrest].”
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CAD affecting atrial branches predictive of AF development after MI
Alasady M. Heart Rhythm. 2011;8:955-960.

In a population of patients with acute MI, coronary artery disease was shown to be an independent determinant of atrial fibrillation after MI.

After examining patients (n=2,460) admitted to a cardiac care unit for MI between 2004 and 2009 and excluding patients with prior AF, pericarditis, severe valvular heart disease, left ventricular hypertrophy, LV dysfunction and recent CABG, the researchers ended up with a study population of 42 AF cases and 42 MI but no AF cases (control).

Overall, AF patients had a higher likelihood of presenting with an inferior MI (P=.002), but a lower likelihood of presenting with STEMI (P=.03) and undergoing early revascularization with primary angioplasty within 6 hours (P=.004).

Researchers also found the following variables associated with AF: indexed left atrial volume (P<.001), right atrial branch disease (P<.001), sinoatrial branch disease (P<.001), LV filling pressure (P=.001), time from onset of symptoms to coronary intervention (P=.002), left atrial branch disease (P=.009) and left main stem disease (P=.02). After multivariable analysis, they determined that both right and left coronary artery arterial branch disease predicted AF after MI (P=.02).

“With the angiographic data and echocardiographic findings, our results provide novel insight into the mechanisms underlying the development of AF in patients after they experience a heart attack,” study researcher Prashanthan Sanders, MBBS, PhD, of the Royal Adelaide Hospital, Australia, said in a press release. “The findings shed new light on how coronary disease affects the atrial branches after the trauma of a heart attack regardless of measurable effects such as a patient’s gender or age.”

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Reduced Dietary Salt for the Prevention of Cardiovascular Disease: A Meta-Analysis of Randomized Controlled Trials (Cochrane Review)
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SIRTAX LATE: Comparable outcomes for sirolimus-, paclitaxel-eluting stents at 5 years

Räber L. Circulation. 2011;123:2819-2828.

New randomized trial data have indicated that patients treated with first generation sirolimus-eluting stents had no significant differences in clinical and angiographic outcomes at 5 years compared with patients receiving paclitaxel-eluting stents.

The Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX LATE) trial involved 1,012 patients randomly assigned to receive either sirolimus-eluting stents (SES; Cypher, Cordis; n=503) or paclitaxel-eluting stents (PES; Taxus, Boston Scientific; n=509). In addition, all patients had at leastone lesion in a vessel with a reference diameter between 2.25 and 4.00 mm.

At 5 years, 97.6% of SES and 96.1% of PES patients had obtainable clinical follow-up. Major adverse cardiac events (a composite of cardiac death, MI and ischemia-driven target lesion revascularization) occurred in 19.7% of SES patients and 21.4% of PES patients (HR=0.89; 95% CI, 0.68-1.17). Individually, there were no statistically significant differences in the rates of cardiac death (SES, 5.8% vs. PES, 5.7%), MI (SES, 6.6% vs. PES, 6.9%) or target lesion revascularization (TLR; SES, 13.1% vs. PES, 15.1%).

Also reported, the annual rate of TLR between 1 and 5 years was 2.0% for the SES group and 1.4% for PES group, while delayed lumen loss for those undergoing paired angiography between 8 months and 5 years was 0.37 ± 0.73 mm for SES and 0.29 ± 0.59 mm for PES patients.

Among the clinical implications of the study, the researchers wrote, were the low risk of repeat revascularization with first-generation drug-eluting stents (DES) and the observation that very late stent thrombosis remains an important limitation of first-generation DES, accounting for more than half of all MIs between 1 and 5 years.
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VALOR II: Thoracic stent graft safe, efficacious in patients with descending TAA

The Valiant thoracic stent graft produced favorable results at 1 year among patients with descending thoracic aortic aneurysms of degenerative etiology and proved to be noninferior to a predicate device, according to presented data.

The nonrandomized, prospective, pivotal VALOR II trial followed 160 patients with descending thoracic aortic aneurysms (TAA) of degenerative etiology who were treated with a thoracic stent graft (Valiant, Medtronic) at 24 US centers. Outcomes were compared with those obtained in the VALOR pivotal trial, a study that examined a precursor thoracic stent graft (Talent, Medtronic) among 195 patients with the same inclusion criteria.

Overall, 96.3% of VALOR II patients had successful stent graft delivery and deployment. At 30 days, perioperative mortality was 3.1% with a major adverse event rate of 38.1%. At 1 year, among 94.4% of patients from the VALOR II trial who were available for follow-up, rates of aneurysm-related mortality was 3.3%, 2.9% for stent-graft migration and 13% for endoleak, with no cases of rupture, conversion to open surgery or loss of stent-graft patency.

In all, the Valiant stent graft proved to be statistically noninferior to the Talent stent graft in 12-month all-cause mortality (12.6% vs. 16.1%) and exceeded the primary effectiveness goal of 12-month successful aneurysm treatment (97.4% vs. 80%), which was defined as the absence of aneurysm growth of more than 5 mm and of secondary procedures for type I/III endoleak.

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Title: A New Risk Scheme to Predict Warfarin-Associated Hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study
Date Posted: July 12, 2011
Authors: Fang MC, Go AS, Chang Y, et al.
Citation: J Am Coll Cardiol 2011;58:395-401.

Related Resources
Clinical Trial
The Anticoagulation and Risk Factors In Atrial Fibrillation Study
Study Question:
Can we predict hemorrhage risk associated with warfarin use?
Methods:
The authors studied data from the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study, which followed 13,559 adults having nonvalvular atrial fibrillation who were enrolled in Kaiser Permanente of Northern California health care system. This included all subjects with International Classification of Diseases-Ninth Revision, Clinical Modification (ICD-9) diagnosis codes for atrial fibrillation between July 1, 1996 and December 31, 1997, with follow-up through September 30, 2003. The authors obtained data from clinical databases and identified hemorrhage events validated using a review of medical records. They then developed a hemorrhage risk stratification score using a Cox regression model with candidate variables selected using bootstrapping approaches. The final model was internally validated with split-sample testing, and compared to six previously published hemorrhage risk schemes.
Results:
The authors of this study followed 9,186 patients with atrial fibrillation, contributing 32,888 person-years of follow-up (median warfarin duration 3.5 years [interquartile range, 1.2-6.0 years]). During follow-up, they observed 461 first major hemorrhage events (1.4% annually). The final model included five independent variables, weighted by regression coefficients: anemia (3 points), severe renal disease–defined as glomerular filtration rate <30 ml/min or on dialysis (3 points), age ≥75 years (2 points), prior bleeding (1 point), and hypertension (1 point). Cumulative point score was associated with major hemorrhage rates ranging from 0.4% (at 0 points) to 17.3% (at 10 points). The c-index for the continuous risk score was 0.74 and it was 0.69 across three categories of risk (low risk 0-3 points; intermediate risk 4 points; high risk 5-10 points). This was higher than the other previously published risk schemes. There was a net reclassification improvement with this newly derived risk score compared with all six previously published schemes (ranging from 27-56%).
Conclusions:
The authors concluded that this simple five variable risk score is effective in quantifying the risk of warfarin-associated hemorrhage in this large community-based cohort of adult patients with atrial fibrillation.
Perspective:
As larger, more complex, and more detailed clinical databases become available, as well as improved statistical methods, better and more precise epidemiologic studies become possible. The authors of the current study have contributed significantly to the important clinical dilemma of assessing the potential harm of a medical therapy that has a quantifiable proven clinical benefit. Often, the clinical decision regarding the appropriateness of instituting warfarin therapy is made on the basis of an estimation of the potential clinical benefit. In the case of atrial fibrillation, this means an estimation of the patient’s risk of stroke without anticoagulation. Warfarin therapy is deemed appropriate when the risk of stroke without anticoagulation exceeds the risk of bleeding with anticoagulation. While increasingly precise tools have been developed and widely disseminated for estimating the risk of stroke without warfarin therapy, much less attention has been paid to the other side of the equation—estimating the risk of bleeding with warfarin therapy. The current study has developed, validated, and compared with prior schemes, a clinically useful and relatively easy to calculate tool for estimating the individualized risk of bleeding with warfarin therapy in adults with atrial fibrillation. This should greatly enhance clinical decision-making surrounding the use of warfarin therapy for stroke prophylaxis in atrial fibrillation.
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Title: Management and Outcomes of Cardiac Tamponade During Atrial Fibrillation Ablation in the Presence of Therapeutic Anticoagulation With Warfarin
Date Posted: June 28, 2011
Authors: Latchamsetty R, Gautam S, Bhakta D, et al.
Citation: Heart Rhythm 2011;8:805-808.

Study Question:
What are the outcomes among patients with and without a therapeutic international normalized ratio (INR) who developed cardiac tamponade (CT) as a complication of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF)?
Methods:
The subjects of this retrospective study were 40 consecutive patients who developed CT during RFCA of AF at three centers. The authors divided the patients into two groups: RFCA performed with INR <2 (group 1) and INR ≥2 (group 2). There were 23 patients in group 1 and 17 patients in group 2. Comparisons between the two groups were performed using the Student t-test for continuous variables and the Fisher exact test for categorical variables. The duration of pericardial drainage and the length of hospital stay were compared using the Wilcoxon signed-rank test.
Results:
Baseline clinical and procedure characteristics were not different between the two groups. Heparin was reversed by protamine in 83% and 94% of patients (p = 0.37), and warfarin was reversed by fresh frozen plasma or factor VIIa in 17% and 35% of patients (p = 0.27) in groups 1 and 2, respectively. All patients were successfully treated by percutaneous drainage, and none required surgical intervention. There were no significant differences in the amount of initial pericardial drainage (523 ± 349 ml vs. 409 ± 157 ml, p = 0.22) or the duration of drainage (p = 0.14) between the two groups. All patients survived to hospital discharge. Median length of hospital stay was 2 days longer in group 1 (p < 0.01).
Conclusions:
The authors concluded that CT is not more severe or difficult to manage in the presence of therapeutic anticoagulation with warfarin in patients undergoing RFCA of AF.
Perspective:
This study reports that the severity of CT was not affected by whether or not the INR was in the therapeutic range. Moreover, the length of hospital stay appeared to be shorter in patients undergoing RFCA with a therapeutic INR. Overall, the data suggest that the continuation of warfarin through the RFCA procedure to maintain a therapeutic INR is a safe strategy, but prompt recognition and management of CT during left atrial ablation is critical.

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Title: Esophageal Temperature Change and Esophageal Thermal Lesions After Pulmonary Vein Isolation Using the Novel Endoscopic Ablation System
Date Posted: June 23, 2011
Authors: Metzner A, Schmidt B, Fuernkranz A, et al.
Citation: Heart Rhythm 2011;8:815-820.

Study Question:
What is the risk of esophageal injury during pulmonary vein isolation (PVI) by laser ablation compared to radiofrequency catheter ablation (RFCA)?
Methods:
Sixty patients (mean age 59 years) with paroxysmal atrial fibrillation were assigned to undergo PVI using a laser balloon endoscopic catheter (n = 40) or an irrigated-tip RF ablation catheter (n = 20). With both catheters, individual lesions were created circumferentially until PVI was achieved. A temperature probe was placed in the esophagus and energy applications were discontinued whenever the esophageal temperature (ET) was ≥38.5ºC. All patients underwent endoscopy 2 days post-ablation and were treated with a proton pump inhibitor for 6 weeks.
Results:
PVI was successfully achieved in all patients in both groups. Ablation on the posterior left atrial wall resulted in an ET ≥38.5ºC in 70% of patients in the laser group and 90% of patients in the RFCA group. Endoscopy demonstrated minimal thermal lesions in 8% of patients in the laser group and 15% of patients in the RFCA group. Esophageal ulcerations were present in 10% of patients in the laser group and were not found in any of the RFCA patients. There was not a significant correlation between thermal lesions and the maximal ET in either group. No patient developed an atrioesophageal fistula.
Conclusions:
The authors concluded that risk of esophageal ulcerations is higher with laser ablation than RFCA in patients undergoing PVI.
Perspective:
The higher risk of esophageal injury with laser ablation is consistent with the deeper tissue penetration of laser energy than RF energy. Importantly, the ET data in the study confirm the limited value of luminal temperature monitoring for avoiding esophageal injury.

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After GRAVITAS: Is There a Future for Functional Platelet Testing?
Negative findings evoked multiple possible explanations
Much research needed before test-guided antiplatelet therapy enters the clinic
By Kim Dalton
Monday, July 18, 2011

In a 2-part series, TCTMD will explore how the GRAVITAS trial is influencing the field of functional platelet testing. Part 1 summarizes the trial and its aftermath, including explanations for the results and remaining issues. Next up, part 2 will address the risks of using platelet function tests to guide therapy in lieu of randomized trial data and discuss their future in clinical practice.

At the American Heart Association Scientific Sessions 2010 this past November in Chicago, one of the most keenly awaited late-breaking trials delivered a blow to the attractive concept of adjusting antiplatelet therapy following percutaneous coronary intervention (PCI) based on functional measurement of platelet reactivity.

GRAVITAS (Gauging Responsiveness with A VerifyNow assay—Impact on Thrombosis And Safety) promised to answer the question of whether a relatively straightforward strategy for managing the almost one-third of patients who have high platelet reactivity despite receiving standard dual therapy after PCI—and thus are at substantially increased risk of thrombotic events—was in fact effective.

The trial had the potential to change practice. After mixed signals from several small observational studies, here were data from the first large randomized trial to close the circle between pharmacodynamic and clinical data by rigorously testing whether adjusting clopidogrel dose based on results of a point-of-care functional test would improve patient outcomes.

The answer, reported by lead investigator Matthew J. Price, MD, of Scripps Clinic (La Jolla, CA), was no, bringing with it larger implications for the future of this nascent field.

Disappointing Results—and Plenty of Explanations

In the targeted cohort with high on-treatment reactivity, at 6 months rates of the primary endpoint, a composite of cardiovascular death, MI, or stent thrombosis, were identical for the high- and standard-dose clopidogrel groups: 2.3%.

For the trial, almost 5,500 patients with stable or unstable CAD underwent DES implantation and received a 600-mg loading dose of clopidogrel (if they were drug naïve). Testing 12 to 24 hours later using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) identified 2,214 patients (41%) with high residual reactivity, defined as a P2Y12 reaction unit (PRU) value equal to or above 230. That cohort was then randomized to continue on the standard 75-mg maintenance dose or receive another 600-mg loading dose and then 150 mg daily, both for 6 months.

While GRAVITAS is clearly not the final word on the use of functional testing to guide therapy, several commentators noted, at the least it invalidated the particular strategy tested and put routine point-of-care platelet testing on hold. Meanwhile, they said, it is important to try to understand why the trial was negative in order to move forward. And there has been no shortage of proposed explanations, with attention directed at nearly every aspect of the trial design, from the patients studied to the antiplatelet regimen used and the reactivity cutpoint chosen.

Analysis confirmed that the more aggressive antiplatelet regimen did in fact have a pharmacodynamic impact. At 30 days after PCI, platelet reactivity had decreased in both arms, but the decline was steeper in those who received the double clopidogrel dose, and the difference remained largely unchanged at 6 months. At 1 month, high residual reactivity persisted in only 40% of the high-dose group compared with 62% of the standard-dose group (P < 0.001), for an absolute reduction of 22%.

Significantly, however, even in the high-dose arm, the absolute reduction in PRU was modest, declining from a median of about 280 at baseline to about 200, Dr. Price reported. Moreover, the relatively small absolute difference in median platelet reactivity between the 2 arms—about 40 PRU—was reflected in the fact that rates of GUSTO severe and moderate bleeding were similar (1.4% in the high-dose arm vs. 2.3% in the standard-dose arm; P = 0.10).

The investigators’ power assumptions—a 5% event rate in patients on standard clopidogrel and a 50% risk reduction with high-dose drug—also came under fire as being overly optimistic. The low event rate observed in the standard-dose arm of only 2.3% set a near-impossible bar for double-dose patients to surpass, several commentators suggested. They added that increasing the sample size and/or lengthening follow-up might boost the event rate, improving the odds of seeing a difference between the treatment groups, but it would also expose even more patients to the possibility of bleeding when there was no hint of ischemic benefit.


In fact, after GRAVITAS, many experts were pinning their hopes on the more aggressive strategy of the TRIGGER-PCI trial. It not only set a PRU threshold of 208 but was testing the more potent antiplatelet agent prasugrel in elective PCI patients with high platelet reactivity on clopidogrel.

Nonetheless, other, ongoing randomized trials are exploring different approaches to test-guided therapy and may provide insights into the question of whether functional testing holds any future role. These include:
ARCTIC, in which clopidogrel dosage will be adjusted for elective patients with a suboptimal response to initial therapy based on a VerifyNow cutpoint of 235 PRU
DANTE, in which ACS patients will be randomized to a standard or double maintenance dose of clopidogrel based on VerifyNow-measured residual reactivity
TARGET PCI, in which PCI patients determined by genotyping or serial functional testing (230 PRU cutpoint) to have high residual platelet reactivity will be switched to prasugrel

Unresolved Issues

Supporting that view are results of a recent Italian trial (Campo G, et al. J Am Coll Cardiol. 2011;57:2474-2483) in which high on-clopidogrel platelet reactivity (defined as a PRU of ≥ 235) at baseline frequently fell below that threshold by 1 month. Moreover, 1-month reactivity levels were found to be stronger predictors of long-term outcomes.

Given this temporal variability, a proposed way to rescue a test-guided antiplatelet strategy is to treat patients to a target level of reactivity, adjusting therapy based on the results of serial testing. A hint that such an approach might work comes from a small, nonrandomized study of ACS patients undergoing PCI (Bonello L, et al. J Am Coll Cardiol. 2010;56:1630-1636). Among poor responders to a 600-mg loading dose (about one-third of whom carried at least 1 loss-of-function CYP2C19 allele), the loading dose was repeated up to 4 times—guided by reactivity monitoring—until 88% of them reached ‘adequate’ platelet inhibition (defined as a VASP [vasodilator stimulated phosphoprotein] index < 50%).

The larger hope of using testing to guide therapy, however, faces many hurdles. “I’ve always felt there will ultimately be some role for testing, but we need to wait for the evidence rather than just act on gut feelings,” Dr. Bhatt stressed, offering as a cautionary example the discredited therapy for premature ventricular contractions (PVCs). Suppressing these dangerous arrhythmias seemed to make sense, he explained. The only problem was that the drug used for that purpose ended up causing even worse arrhythmias.

Similarly, “it’s logical to think that responding to [inadequate] antiplatelet inhibition on a point-of-care assay [with higher antiplatelet doses or a more potent drug] should improve patient outcomes,” Dr. Bhatt said. “But it’s tricky, because more isn’t always better. There may also be more bleeding.” Furthermore, the risk-benefit ratio could vary widely based on patient presentation—for example, elective vs. urgent PCI with a DES, he added.

The second half of this feature, which will appear Monday, July 25, will discuss how these debates play out in clinical practice.



Sources:
1. Price MJ. Standard versus high-dose clopidogrel according to platelet function testing after PCI: Results of the GRAVITAS trial. Presented at: American Heart Association Scientific Sessions; November 16, 2010; Chicago, IL.

2. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention. JAMA. 2011;11:1097-1105.

3. Gurbel PA and Tantry US. An initial experiment with personalized antiplatelet therapy. JAMA. 2011;11:1136-1137.

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HORIZONS-AMI: Bivalirudin Reduces Cardiac Death in Diabetics

Key Points:
Cardiac mortality more than halved at 1 year with bivalirudin vs. heparin plus a GPI in diabetics with STEMI receiving primary PCI
Other endpoints including major bleeding, MACE, not reduced with newer agent
Interaction analysis shows bivaliridin benefits similar irrespective of diabetic status
By Jason Kahn
Monday, July 18, 2011

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The direct thrombin inhibitor bivalirudin results in significantly reduced rates of cardiac death compared with heparin and a glycoprotein IIb/IIIa inhibitor (GPI) in diabetics with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention, according to a substudy of the HORIZONS-AMI trial. But, according to 1-year results appearing in the July 2011 issue of JACC: Cardiovascular Interventions, bivalirudin may not reduce overall mortality or major bleeding in this population.

For the HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in AMI) trial, researchers led by Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), randomized 3,602 STEMI patients at 123 centers in 11 countries who were undergoing primary PCI to receive bivalirudin (n = 1,800) or heparin plus a GPI (n = 1,802). In a second randomization, 3,006 of the patients were assigned in a 3:1 ratio to receive a paclitaxel-eluting Taxus stent (n = 2,257; Boston Scientific, Natick, MA) or an otherwise identical BMS (n = 749).

At 3 years, bivalirudin significantly reduced major bleeding (non-CABG), reinfarction, cardiac death, and all-cause death compared with heparin plus a GPI, while Taxus patients experienced a 40% reduction in ischemic TLR compared with BMS patients.

Focus on Diabetics

In the new subanalysis, researchers led by Dr. Stone focused on the 593 patients from HORIZONS-AMI who were diabetic. Of these, 281 received bivalirudin and 312 received heparin plus a GPI. Baseline and procedural characteristics were similar between the 2 groups, although thienopyridine use prior to admission was higher in diabetics receiving heparin plus a GPI compared with those receiving bivalirudin (6.1% vs. 2.5%; P = 0.03).

At 30 days, the rate of cardiac death was reduced in patients receiving bivalirudin. However, noncardiac deaths were higher in these patients, rendering the endpoint of overall death equivalent in both groups. In addition, net adverse clinical events (major bleeding or MACE), MACE (death, reinfarction, TVR, or stroke), TVR, and major non-CABG bleeding all were equivalent (table 1).

Net adverse events also were similar at 1 year, though exact rates were not reported. Stent thrombosis rates were likewise equivalent between the bivalirudin (4.2%) and heparin plus GPI (3.8%; P = 0.85) arms. Breaking down the diabetes patients by insulin-treated and noninsulin-treated status, antithrombotic strategy made no difference in net adverse events, MACE, or stent thrombosis. However, among insulin-treated patients, bivalirudin was associated with a lower incidence of cardiac death at 1 year (1.4% vs. 9.4%; P = 0.04).

The current study “represents the largest analysis of diabetic STEMI patients treated by contemporary primary PCI to date and demonstrates that bivalirudin compared with heparin plus GPI significantly reduces cardiac mortality in the high-risk diabetic cohort as well as patients without diabetes,” Dr. Stone and colleagues conclude.

No Interaction with Diabetes Status Found

Because bleeding and overall mortality were not reduced as they were in the main cohort, the authors performed an interaction analysis, demonstrating that the favorable effects of bivalirudin were independent of diabetic status for the endpoints of major bleeding (P for interaction = 0.26), net cardiac events (P = 0.64), all-cause mortality (P = 0.55), and cardiac mortality (P = 0.19). This showed that “the most appropriate interpretation of these data is that the overall benefits of bivalirudin seen in the main trial seem to apply to patients both with and without diabetes,” the researchers write, although they could not rule out a “modest difference in the relative effect of bivalirudin versus heparin plus GPI in patients with, versus without, diabetes.”

According to Debabrata Mukherjee, MD, of Texas Tech University Health Sciences Center (Lubbock, TX), the interaction analysis was the most meaningful part of the substudy. “That’s very important [because] it means statistically, whether the patient has diabetes or not, they get benefit, and having diabetes shouldn’t factor into the decision to use bivalirudin or not,” he told TCTMD in a telephone interview. “This is very reassuring.”

Therefore, Dr. Mukherjee added, the subanalysis results should be viewed in the same context as the overall trial. “Based on the totality of the data, whether the patient has diabetes or not, bivalirudin appears to be the antithrombotic of choice. It’s pretty robust, strong evidence,” he said, adding that in his own practice, “we use bivalirudin irrespective of diabetes in the majority of patients.”

Change Is Slow, But Steady

Nevertheless, clinicians have not made a wholesale switch to bivalirudin. “Physician practice takes time to change. There’s a lot of bivalirudin use in the younger generation, newer physicians and people coming out of training,” Dr. Mukherjee said. “For people who have trained with unfractionated heparin, it takes time, sometimes years or decades, but bivalirudin use has gone up. It’s maybe 50%. It’s not 100%, but it will take time.”

Regarding the question of why the subanalysis failed to show differences in overall mortality, MACE, or major bleeding, Dr. Mukherjee said the answer may lie in the sample size. “If you did a several-thousand patient diabetic trial, I think you’d see a similar magnitude of bleeding reduction with bivalirudin as in the overall trial,” he added.

Note: Dr. Stone and several coauthors are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.



Source:
Witzenbichler B, Mehran R, Guagliumi G, et al. Impact of diabetes mellitus on the safety and effectiveness of bivalirudin in patients with acute myocardial infarction undergoing primary angioplasty. Analysis from the HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction) trial. J Am Coll Cardiol Intv. 2011;4:760-768.

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Prasugrel Fails to Tame Platelets in One-Quarter of ACS Patients Undergoing PCI

Key Points:
A quarter of ACS patients undergoing PCI show high on-treatment platelet reactivity after 60-mg prasugrel loading dose
High reactivity (≥ 50% VASP) predicts more MACE at 1 month
No difference in TIMI bleeding between those above or below VASP cutpoint
By Kim Dalton
Monday, July 18, 2011

Despite prasugrel’s greater potency and faster action compared with the older antiplatelet agent clopidogrel, platelet reactivity testing after a loading dose of the newer third-generation thienopyridine shows suboptimal inhibition in about 1 in 4 patients with acute coronary syndromes (ACS) following percutaneous coronary intervention (PCI). Furthermore, high on-treatment platelet reactivity leads to more thrombotic events at 30 days, according to a prospective multicenter study published in the July 26, 2011, issue of the Journal of the American College of Cardiology.

Laurent Bonello, MD, of Hôpital Universitaire Nord (Marseille, France), and colleagues enrolled 301 patients who underwent successful PCI for ACS (42.5% STEMI) and received prasugrel as antiplatelet therapy (60-mg loading dose and 10 mg daily for 1 year). Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) assay on blood drawn between 6 and 12 hours after drug loading.

High on-treatment platelet reactivity was defined as a VASP index of at least 50%. In the overall cohort, the mean VASP index was 34.3 ± 23.1%, but there was wide variability among individuals (1% - 82.8%). Although the majority of patients showed adequate inhibition, 25.2% were found to have high residual reactivity. On the other hand, about one-third had very low VASP values (< 20%).

High Reactivity Means More Thrombotic Events

At 30-day follow-up, more patients with high on-treatment reactivity met the primary composite endpoint (cardiovascular death, nonfatal MI, or Academic Research Consortium-defined stent thrombosis) than did good responders. In addition, 3 poor responders experienced nonfatal definite stent thrombosis. Although 4 good responders had TIMI bleeding events (2 major requiring transfusion and 2 minor) compared with only 1 minor bleed in patients with high reactivity, the difference was not significant (table 1).

VASP levels were higher in patients experiencing recurrent thrombotic events compared with those free of events at 1 month (64.4 ± 14.4% vs. 33.4 ± 22.7%; P = 0.001). In univariate analysis, the only factors significantly associated with thrombotic events were the VASP index (P = 0.001) and hypercholesterolemia (P = 0.032). No difference was seen in VASP index between patients with or without TIMI non-CABG-related bleeding (30 ± 17.8% vs. 34.3 ± 23.1%; P = 0.70).

Similarly, Kaplan-Meier analysis showed that patients with high on-treatment reactivity had worse 1-month outcomes than good responders (9.2% vs. 0.4%; log-rank P < 0.001). However, no difference emerged in TIMI bleeding between patients above or below the reactivity cutpoint of 50% (P = 1.00). Demographic, clinical, and angiographic factors were similar between the 2 groups, except for relatively fewer men in the high on-treatment reactivity group (81.6% vs. 92% in the good responders; P = 0.007).

The optimal cutoff value of the VASP index was determined to be 53.5%, yielding a positive predictive value of 10.4% and a negative predictive value of 99.6%.

Low Reactivity a Lingering Concern

The authors point out that although a sizable number of patients had very low platelet reactivity after prasugrel loading, no relationship emerged between reactivity level and bleeding risk. Nonetheless, they caution, previous studies involving clopidogrel have found an association between excessive inhibition and bleeding complications. “These findings suggest that there may [be] a therapeutic window of [thienopyridines] to reach to prevent thrombotic events and not increase the bleeding risk,” the investigators write.

Dr. Bonello and colleagues suggest that, based on the current findings, “prasugrel therapy may require [platelet reactivity] monitoring to enable optimal [platelet reactivity] inhibition to be achieved, which may lead to improved outcomes in all patients.”

In a telephone interview, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), told TCTMD that he was not surprised that one-quarter of prasugrel-treated patients showed high platelet reactivity. But many physicians may be, he said, since until now most attention in regard to poor response has focused on clopidogrel.

High Reactivity: It’s Not Just the Drug

Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), similarly observed in an e-mail communication with TCTMD that even with prasugrel, it increasingly seems that high on-treatment platelet reactivity “is an important variable to measure patient response to drug [therapy].”

“Unfortunately,” he added, “[reactivity] thresholds may vary by test, and the result is influenced by clinical syndrome, patient factors, and time of measurement, not just the antiplatelet drug.”

Dr. Bates also said he wished the researchers had continued platelet reactivity measurements for 4 days, as they did in an their study on repeat clopidogrel loading doses (Bonello L, et al. J Am Coll Cardiol. 2008;51:1404-1411). Such a protocol could have helped determine “whether there was earlier suppression [of reactivity] in low responders than there was with clopidogrel,” he noted.

Dr. Bhatt agreed that clinical setting plays a key role in platelet reactivity. He pointed out that, with the exception of genetic polymorphisms (which affect the bioavailability of clopidogrel but not prasugrel), all the factors that contribute to variability in platelet response to clopidogrel likely also apply to response to prasugrel—just to a lesser degree.

Moreover, Dr. Bhatt noted, “[y]ou would think that if someone had high on-treatment platelet reactivity, their risk of bleeding should be lower and risk of ischemic events should be higher. And vice versa. But that has not been consistently seen in studies. In fact, if anything, it seems like patients who bleed have a higher rate of ischemic events.

“It’s a very complex issue and shows we don’t really understand what predisposes patients to bleeding or ischemic events as precisely as we’d like to,” he commented.

Practicing in a ‘Gray Zone’

Dr. Bhatt said it is difficult to know whether the reactivity testing results are clinically important.

“As with clopidogrel studies, high on-treatment reactivity is associated with a high rate of ischemic events, so it’s certainly a marker of future risk. If your platelets are more reactive than other patients’, you are worse off regardless of whether you’re on clopidogrel or prasugrel,” he said. “But is it really the drug that’s at fault or the patient’s ‘angry platelets?’ I think what we’re identifying here is primarily high-risk patients.”

According to Dr. Bhatt, the key clinical question remains unanswered: Is there a way to alter therapy based on knowledge of platelet reactivity that improves patient outcomes? “To date, no one has shown that satisfactorily, and if anything, the negative findings of GRAVITAS would argue against it,” he noted.

“The study is something researchers can build on and leaves the door open for more potent periprocedural inhibition of platelet reactivity,” Dr. Bhatt acknowledged. But until a positive randomized study is reported, “we’re left in a kind of gray zone where we have provocative data [but no clear clinical strategy]. My fear is that some physicians might overinterpret this study and if a test shows high on-treatment reactivity double the prasugrel dose, for example. Not only might that not be helpful, it might be harmful. Especially when we’re talking about more potent agents, we have to be really cautious about the bleeding risk of an untested strategy.”

Study Details

The great majority of the study patients were men (88.7%), with a mean age of 58.1 years. Almost one-quarter (23.3%) had diabetes.

DES or BMS were used according to French Society of Cardiology guidelines. Functional testing was performed using Platelet VASP kits (Diagnostica Stago, Asnières, France).

Source:
Bonello L, Pansieri M, Mancini J, et al. High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. J Am Coll Cardiol. 2011;58:467-473.

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Higher sodium-potassium level linked to CVD risk

Yang Q. Arch Intern Med. 2011;171:1183-1191.

A higher ratio of sodium-potassium intake was linked to an increased risk for all-cause mortality of nearly 50%, according to study results.

Previous findings have indicated that higher sodium and lower potassium intakes may increase CVD risk, researchers from several sites in the US suggested. However, the impact of that ratio on mortality has not been explored.

Data for 12,267 adults from the 1988-2006 Third National Health and Nutrition Examination Survey Linked Mortality File were analyzed for associations between sodium-potassium intake ratios and all-cause, cardiovascular and IHD mortality. There were 2,270 deaths during a mean of 14.8 years of follow-up. There were 825 CVD deaths and 443 deaths attributed to IHD.

Multivariate analysis results indicated that higher sodium intake was linked to increased all-cause mortality (HR=1.20; 95% CI, 1.03-1.41 per 1000 mg/d) and higher potassium intake was linked to lower mortality risk (HR=0.80; 95% CI, 0.67-0.94 per 1000 mg/d).

The sodium-potassium ratios were broken down into quartiles. The adjusted HRs for the highest quartile compared with the lowest were 1.46 (95% CI, 1.27-1.67) for all-cause mortality, 1.46 (95% CI, 1.11-1.92) for CVD mortality and 2.15 (95% CI, 1.48-3.12) for IHD mortality, according to the results.

There were no significant differences in these findings with regard to demographic data, BMI, hypertension status or physical activity levels of the study population.

“Our findings suggest that a higher sodium-potassium ratio is associated with significantly increased risk of CVD and all-cause mortality, and higher sodium intake is associated with increased total mortality in the general US population,” the researchers wrote.
__________________________________________________ ___________________________
Torcetrapib raised HDL, may help control diabetes

An analysis of the ILLUMINATE trial data revealed new findings: Torcetrapib, a cholesteryl ester transfer protein inhibitor, may improve HDL levels and blood glucose in those with diabetes who are also taking a statin.

Researchers discovered the beneficial effects of torcetrapib while analyzing data from the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, which was halted in 2006 because patients with diabetes assigned to torcetrapib and atorvastatin (Lipitor, Pfizer) had more cardiovascular problems and a higher mortality rate vs. patients assigned to atorvastatin and a placebo. Researchers later determined that the adverse events were related to other effects of torcetrapib, not its cholesteryl ester transfer protein (CETP) inhibition, according to a press release from the American Heart Association.

Data from ILLUMINATE showed that after 3 months of treatment, more than 6,600 patients with diabetes who were taking torcetrapib and atorvastatin had lower fasting blood glucose levels (0.34 mmol/L) and fasting insulin levels (11.7 mcU/mL) than patients taking statin and placebo. Insulin resistance also improved in the investigational combination therapy group. After 6 months, average blood glucose levels were lower in the torcetrapib and atorvastatin group (7.06%) compared with the statin and placebo group (7.29%). Additionally, HDL levels improved 66.8% after 1 year with torcetrapib and atorvastatin compared with a minimal change with statin and placebo. Researchers said it is unclear whether torcetrapib’s effect on HDL may account, in part, for the improvement in diabetes control. Torcetrapib also improved glucose and insulin measurements in study participants without diabetes, although not as much.

“The possibility that CETP inhibitor drugs may not only reduce the risk of [myocardial infarction] and stroke, but may also improve the control of blood sugar in people with diabetes, is an exciting prospect that may translate into real health benefits for people with diabetes,” Philip Barter, MBBS, PhD, director of the Heart Research Institute at University of Sydney, Australia, said in a press release.

Although torcetrapib’s effect on diabetes was not as effective as other commonly used antidiabetic therapies, “inhibition of CETP has the potential to prevent a worsening of diabetic control that often occurs in people taking statin drugs,” Barter said.

ILLUMINATE included more than 15,000 participants aged 45 to 75 years with a history of MI, stroke, chest pain, peripheral vascular disease or cardiac revascularization, and all were taking antidiabetic therapies.

Although the development of torcetrapib was halted, researchers said two other CETP inhibitors that do not cause the adverse effects — dalcetrapib and anacetrapib — are in the drug approval pipeline.

In an accompanying editorial, Stephen D. Wiviott, MD, a member of the TIMI Study Group and from the CV division at Brigham and Women’s Hospital, Harvard School of Medicine, said “this analysis may provide additional insight into the relationships between two key risk factors for CV disease, lipids (in particular, HDL) and glycemia.”

However, Wiviott said the glycemic findings from ILLUMINATE may be due to chance, as is the case in some post hoc analyses.

“With these important reductions of key surrogate markers of the risk of CV disease, including LDL, HDL, triglycerides and glycemia, this seems like a drug that should be widely prescribed to those at risk for CVD. Of course, it is not now, and will never be, prescribed to our patients for these indications. The reason for this is that, despite the observed benefits on these key surrogates, patients treated with torcetrapib in ILLUMINATE had 25% more CV events, including 58% more total deaths than those treated with placebo,” Wiviott wrote.
__________________________________________________ ____________________________
Review: Testosterone therapy does not elevate CV event risk

Carson CC. J Sex Med. 2011;doi:10.1111/j.1743-6109.2011.02337.x.

A review of various meta-analyses and randomized controlled trials conducted in middle-aged and older men did not link testosterone therapy with elevated risk for cardiovascular events.

Cardiovascular risk has been a topic of concern for elderly men taking testosterone therapy. To evaluate the link, Culley C. Carson, III, MD, of the University of North Carolina School of Medicine, and Giuseppe Rosano, MD, of San Raffaele Pisana, Rome, Italy, conducted the review of trials examining testosterone administration in men aged 45 years and older.

“In clinical trials where testosterone has been used in patients with pre-existing CV conditions, the effect on disease symptoms has typically been either neutral or beneficial,” the researchers wrote. According to results of the review, testosterone treatment significantly improved exercise performance in hypogonadal and eugonadal men with heart failure. Therapy also had no significant effect on serum lipid profiles or C-reactive protein in hypogonadal men with HF and physiologic levels of testosterone; however, therapy did produce small increases in total body mass and reductions in body fat percentage.

Several meta-analyses also linked testosterone treatment with better metabolic parameters, including decreases in fasting plasma glucose, HbA1c, fat mass and plasma triglycerides in patients with type 2 diabetes. In addition, the researchers found that testosterone therapy had no impact or slightly beneficial effects on CV risk factors in hypogonadal men with diabetes or metabolic syndrome. The treatment appeared to improve insulin sensitivity, decreased central adiposity and did not negatively affect inflammation.

An exception was an increase in hematocrit in this patient population using testosterone therapy, the researchers said.

“Although an increase in hematocrit may be of concern in some conditions, patients with [HF] are often anemic; therefore, the effect of testosterone on [hemoglobin] levels may be regarded as beneficial,” the researchers wrote.

In patients with angina or coronary artery disease, hematocrit increased with testosterone treatment, but the therapy had no effect on C-reactive protein, plasminogen activator inhibitor-1 and fibrogen, and antithrombotic factor tissue plasminogen activator.

Although testosterone therapy did not have an effect on LDL and triglyceride levels, the treatment either did not change or considerably reduced total and HDL cholesterol, according to the results. The researchers noted, however, that decreases in total and HDL cholesterol were an inconsistent response among study participants.

Despite these encouraging conclusions, the researchers acknowledged the limitations of the studies analyzed.

“The majority of the randomized, blinded, placebo-controlled clinical trials of testosterone included in this analysis were small and of short duration,” the researchers wrote. “Obviously, outcomes of large, well-designed, prospective trials would be a more compelling proof of the benefit (or otherwise) of testosterone treatment in terms of CV safety.”

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The renaissance of the “J-shaped curve” for on-treatment low blood pressure values
An article from the e-journal of the ESC Council for Cardiology Practice

Grassi G.
Topics: Hypertension
Authors: Grassi G.
The so-called "J curve" paradox refers to the finding described in studies performed about 30 years ago suggesting that treatment-induced systolic blood pressure values below 120 or 125 mm Hg and diastolic blood pressure values below 75 mm Hg may be harmful for the heart. New evidence in favour of the existence of the “J curve” have been published in the context of some recent clinical trials.

The most recent guidelines for the management of essential hypertension, published jointly in the 2007 by the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC), recommend a blood pressure goal of 140/90 mmHg in the general hypertensive population and a lower goal of 130/80 mmHg or less in patients with type 2 diabetes and in high-risk individuals, such as those with a clinical history of an acute cerebrovascular or coronary event or with an evidence of target organ damage (1). Based on the information provided by recent clinical trials, however, the issue of the risk/benefit ratio of aggressive blood pressure-lowering interventions and the so-called “J-curve” phenomenon (2) have been a matter of academic and clinical debate. As a result, an ESH task force recently updated some of the recommendations for hypertension management, with special emphasis on the definition of the blood pressure goals (3).
1- The “J-Shaped Curve" Hypothesis: previous history

The first evidence in favour of the “J-curve” was provided in 1979 by Stewart who claimed in a retrospective analysis of 169 hypertensive patients that the risk of myocardial infarction was of greater magnitude in patients in whom the diastolic blood pressure was lowered to less than 90 mmHg compared with 100 mmHg to 109 mmHg (4).
In 1987, a group of british investigators published a retrospective analysis of 939 treated hypertensive patients (5). From this analysis, they claimed that lowering of the diastolic blood pressure to less than 85 to 90 mmHg was associated with an increase in fatal myocardial infarction in patients with pre-existing ischemic heart disease. Support for this view appeared to be provided by Alderman and coworkers (6), who observed a huge number of previously untreated hypertensive patients for about 4 years. They found that the 39 fatal and nonfatal myocardial infarctions that occurred in the study were significantly more common in patients with a small fall in diastolic blood pressure (=6 mmHg) or a large fall (=18 mmHg), whereas patients with a reduction of diastolic blood pressure between 7 and 17mm Hg had a significantly smaller risk. Studies supporting the "J-shaped curve" hypothesis have been mostly retrospective, often open, and commonly have included too few events to allow significant conclusions to be reached. Furthermore, “J-shaped" relationships between cardiovascular events and blood pressure have also been described in untreated or placebo-treated patients, which suggests that increased event rates at lower blood pressure may be a sign of poor health conditions, particularly in the elderly. However, the real issue is not whether the relationship between achieved blood pressure and cardiovascular risk is ‘“J-shaped" (as it must be), but whether there are additional benefits or risks in lowering the blood pressure of patients with hypertension to fully normotensive levels, that is, to diastolic blood pressure between 70 mmHg and 85 mmHg.

2 - The “J-Curve" Phenomenon: Recent Findings

The existence of a “J-curve” has been investigated for both systolic and diastolic blood pressure, on the assumption that a critical level of blood pressure (particularly diastolic) is of vital importance for maintaining coronary blood flow adequate to the physiological needs. The results of four recently published studies, looking separately at systolic blood pressure and at diastolic blood pressure (10) have concluded in favour of the existence of a “J-curve”. These data have led us to readdress the question of whether blood pressure is sometimes lowered too far, resulting in underperfusion of vital organs that increases cardiovascular risk, The issue is open to several considerations.
First, although there must be a blood pressure value below which organ perfusion is compromised, observational studies in patients initially free of cardiovascular disease show that the relationship between blood pressure and the cardiovascular event rate is substantially linear down to very low blood pressure values (about 110/70 mmHg), which are only exceptionally achieved during antihypertensive drug treatment. Second, It is possible that in patients with high cardiovascular risk, impairment of the mechanisms that guarantee blood flow autoregulation elevates the blood pressure threshold below which organ perfusion is reduced (2), However, the extent of this elevation (which may differ between patients in relation to the degree of organ damage and age) has never been unequivocally established by trials specifically designed to explore the advantages of more-intense versus less-intense blood pressure lowering. Third, despite adjustment for initial demographic and clinical differences between groups, post-hoc analysis of trial results cannot escape the problem that the members of the group with the lowest on-treatment blood pressure could have had the greatest initial cardiovascular risk, which caused both the excessive blood pressure reduction and the increased incidence of cardiovascular events. Indeed, this idea is supported by the evidence of a similar J-curve phenomenon in placebo-treated groups of several trials (2). Furthermore, the post hoc analyses have consistently showed that the nadir of cardiovascular outcome incidence occurred at a rather wide range of blood pressure values, between 120 mmHg and 140 mmHg systolic blood pressure and 70-80 mm Hg diastolic blood pressure, suggesting that within this low range, the differences in achieved cardiovascular protection are small (2-3). This finding is in line with the results of observational studies showing that the relationship between blood pressure and cardiovascular events is linear when cardiovascular events are quantified on a logarithmic scale, which implies smaller absolute differences at lower blood pressure values.
3 - Blood pressure goals

Based on the above mentioned clinical trials results, in the 2009 a reappraisal document of the European guidelines made a number of recommendations regarding blood pressure goals of antihypertensive drug treatment (3). These recommendations can be briefly summarized as follows. In the general hypertensive population the recommendation to decrease systolic/diastolic blood pressure below 140/90 mmHg in all hypertensive patients still remains valid and supported by a large amount of data. As far as diabetic hypertensive population is concerned, the results of The ADVANCE and ACCORD trial have raised the possibility that the benefits of lowering blood pressure gradually flattens at lower systodiastolic blood pressure values (11-12). This has led the ESH in the 2009 document to suggest less ambitious but safer blood pressure targets, i.e. 130-139 mmHg for systolic and 80-85 mmHg for diastolic (3). The same targets should be prudently valid also in hypertensive patients with a history of cardiovascular disease, given the evidence that many clinical trials have been unable to show benefits from more intense lowering of blood pressure. In patients with previous coronary disease, for example, the greater blood pressure reduction induced by active (or more active) treatment was accompanied by a beneficial effect on the primary end point in only two trials, whereas five trials did not show any consistent beneficial effect (2-3).

Conclusion

Critical analysis of the available data regarding which target blood pressure values should be achieved during antihypertensive treatment in current clinical practice allows the following recommendations to be issued:
There is enough evidence to recommend that systolic blood pressure should be lowered to 140 mmHg (and diastolic blood pressure below 90 mmHg) in all antihypertensive patients, both those at low to moderate risk and those at high risk.
The recommendation from previous guidelines to aim for a lower goal for systolic blood pressure values (<130 mmHg) in diabetic patients and in patients at very high cardiovascular risk (those with previous cardiovascular events) may be wise, but it does not appear to be consistently supported by trial evidence.

A “J-curve" phenomenon may indeed occur when lower blood pressure values are achieved, particularly in patients with advanced atherosclerotic arterial disease.

It is recommended to lower systolic and diastolic blood pressure to values within the range of 130-139/80-85 mm Hg in all hypertensive patients. The lower values in this range should be the goal of treatment in high risk patients.

[Chevychelov]

Echocardiographic Evaluation of Hemodynamics in Patients
With Decompensated Systolic Heart Failure
[Ссылки могут видеть только зарегистрированные и активированные пользователи]

Prompt Repeat Testing After Out-of-Range INR Values
A Quality Indicator for Anticoagulation Care
[Ссылки могут видеть только зарегистрированные и активированные пользователи]

Effects of Weight Loss on Structural and Functional
Alterations of Subcutaneous Small Arteries in
Obese Patients
[Ссылки могут видеть только зарегистрированные и активированные пользователи]

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FDA Okays New Drug to Prevent MI
WASHINGTON -- The third time proved to be the charm for the long-awaited new entry into the antiplatelet market as ticagrelor (Brilinta) today won FDA marketing approval for reducing thrombotic events in patients with acute coronary syndrome who are candidates for stenting.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]

Wednesday July 20, 2011

FDA Panel Backs Sapien Heart Valve

GAITHERSBURG, Md. -- An FDA advisory panel has voted 9 to 0, with one abstention, to recommend approval for Edwards Lifesciences’ Sapien transcatheter heart valve -- a novel device intended as an alternative for patients with severe aortic stenosis who are too frail for open-heart surgery.

FDA Panel Votes in Favor of Recommending Premarket Approval of Sapien Heart Valve

The US Food and Drug Administration (FDA) Circulatory System Devices Panel voted today in favor of recommending the premarket approval (PMA) application of the Edwards Sapien transcatheter heart valve for use in inoperable patients with severe aortic stenosis.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]

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Aspirin Holiday Is a Bad Idea

By Chris Kaiser, Cardiology Editor, MedPage Today
July 20, 2011

Explain that a case-control study found that patients taking low-dose aspirin for secondary prevention who had recently discontinued the drug had a higher risk of nonfatal myocardial infarction than those who continued to take the aspirin.

Note that the most common reason for discontinuing aspirin was lack of patient adherence.
Review

Those at risk of cardiovascular events who stop taking low doses of aspirin are at an increased risk of myocardial infarction (MI), a large case-controlled study found.

Compared with those taking aspirin, individuals prescribed aspirin for secondary prevention who had recently discontinued the drug had a significantly increased risk of nonfatal myocardial infarction or death from coronary heart disease combined (rate ratio 1.43, 95% CI 1.12 to 1.84) and nonfatal myocardial infarction alone (RR 1.63, CI 1.23 to 2.14), reported Luis Garcia Rodriguez, MD, from the Spanish Centre for Pharmacoepidemiologic Research in Madrid, and colleagues.

There were four more cases of nonfatal myocardial infarction among those who stopped aspirin for every 1,000 patients over a period of one year, according to the study published online in BMJ.

Researchers used the Health Improvement Network database in the U.K. to identify 39,513 participants ages 50 to 84 with a first prescription for aspirin for secondary prevention of cardiovascular outcomes from 2000 to 2007.

"Low dose" was defined as 75 mg to 300 mg/day. However, the current American Heart Association/American College of Cardiology practice guidelines recommend 75 mg to 162 mg of aspirin per day.

Researchers categorized those who discontinued low-dose aspirin therapy as recent (last prescription finished 31 to 180 days before the index date) and distant (last prescription finished 181 to 365 days before the index date). Rodriguez et al. also sampled 5,000 controls matched by age, sex, and calendar year.

The participants in the study were followed for a mean of 3.2 years. During that time, 876 nonfatal myocardial infarctions occurred, as well as 346 deaths from coronary heart disease.

Among the 1,222 cases of nonfatal myocardial infarction or death from coronary heart disease, 72% were still on aspirin therapy, 9% were recent discontinuers, and 3% were distant discontinuers.

Those numbers among the 5,000 controls were 76%, 7%, and 4%, respectively.

Most of those who discontinued aspirin were nonadherent (75% of all, 68% of recent discontinuers). Among the rest, 17% switched to another medication, 11% had safety concerns, and 4% were using over-the-counter low dose aspirin.

The increased risk of nonfatal myocardial infarction or death among those who recently discontinued aspirin was similar for different durations of aspirin therapy and for different indications.

"Despite the strong evidence supporting the protective effects of low-dose aspirin, discontinuation rates of around 50% have been reported in patients who have been taking this medication for several years," the authors wrote.

Furthermore, they said, it's been shown that discontinuation of oral antiplatelet therapy is an independent predictor of an increase in mortality after acute coronary syndromes.

"Does this evidence justify adding aspirin to tap water, as is the case with fluoride and has been suggested for statins?" asked Giuseppe Biondi-Zoccai, MD, from the University of Modena in Modena, Italy, and Giovanni Landoni, MD, from Università Vita-Salute San Raffaele in Milan, Italy, in an accompanying editorial.

Not yet, they stated, because the study by Rodriguez et al. "cannot be accepted uncritically."

Biondi-Zoccai and Landoni pointed out that the study was not randomized, and that it is impossible to know if discontinuation was "appropriate on personal or clinical grounds."

They also noted that there could have been a bleeding risk for some who discontinued aspirin, and the "risk-benefit ratio of aspirin in individual patients should always be considered."

The two editorialists mentioned two studies on the horizon that should help fill in the gaps.

PeriOperative Ischemic Evaluation-2 (POISE-2) study is randomizing 10,000 patients undergoing noncardiac surgery to aspirin or clonidine (or both) versus placebo, and the Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) study is randomizing 4,600 patients undergoing coronary artery bypass grafting to aspirin or tranexamic acid (or both) versus placebo.

Nevertheless, Rodriguez and colleagues called for additional research to figure out why patients discontinue aspirin "in the absence of a clinical reason."

Two people from Oxford PharmaGenesis provided writing support funded by AstraZeneca.

This study was funded by an unrestricted research grant from AstraZeneca Research and Development Mölndal. The sponsors played no part in the design or conduct of the study.

Rodríguez and co-author Elisa Martín-Merino's institution receives funding from AstraZeneca. The other co-author, Saga Johansson, is an employee of AstraZeneca.

Primary source: BMJ
Source reference:
Rodriguez, L, et al "Discontinuation of low dose aspirin and risk of myocardial infarction: case-control study in UK primary care" BMJ 2011; 343: d4094.

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ADA: FDA Unlikely to Zap Pioglitazone

By Crystal Phend, Senior Staff Writer, MedPage Today
Reviewed by
June 26, 2011

Review

SAN DIEGO -- Bladder cancer risks aren't likely to send the diabetes drug pioglitazone (Actos) down the same path as rosiglitazone (Avandia), according to this exclusive InFocus report from the American Diabetes Association meeting.

Earlier this month French and German regulators halted sales of pioglitazone over excess bladder cancer seen in a French epidemiologic study, which the FDA followed with a warning pending further review of the data.

Yet the situation may not be as dire as the cardiovascular risks that led the European Medicines Agency to take rosiglitazone off the market last year and the FDA to severely restrict access to it, as leading diabetes specialist John Buse, MD, PhD, explains in an interview with MedPage Today Senior Staff Writer Crystal Phend.

"I don't think it [pioglitazone] will be taken off the market in the United States," says Buse, director of the Diabetes Care Center at the University of North Carolina at Chapel Hill and a past president of the ADA.

The same kinds of studies that suggested an increase in bladder cancer showed a decrease in other more common types of cancers, he notes.

Pioglitazone also holds some unique benefits among anti-diabetic treatments that may argue for a clinical need to keep the drug on the market, Buse adds.

ADA: American Diabetes Association Meeting
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After Gravitas Part 2: Is There a Future for Functional Platelet Testing?

Key Points:
Multiple factors may underlie platelet reactivity levels, including noncompliance
Stent thrombosis may justify functional testing
Reactivity ‘sweet spot’ sought to balance ischemic, bleeding risks
By Kim Dalton
Monday, July 25, 2011

Part 1 addressed possible explanations for the negative findings of the GRAVITAS trial and the implications for current clinical practice. In Part 2, the story continues with a discussion of the limitations of functional platelet testing and the potential risk of using it to guide therapy as well as some arguments in favor of current testing and hints of a wider future role.

The failure of the GRAVITAS trial to support a strategy of intensified clopidogrel therapy to overcome high residual platelet reactivity following PCI prompted many experts to conclude that, for the time being, there is no justification for routine testing.

A key reason is that a host of factors may be contributing to a patient’s baseline platelet reactivity and response to antiplatelet therapy, including:
Comorbid conditions like diabetes
Age
Body weight
Smoking status
Compliance with the prescribed antiplatelet regimen
Concomitant medications such as proton pump inhibitors
Genotype (including complicated interactions between variant alleles and heterozygosity vs. homozygosity)

An underlying question, raised by Paul A. Gurbel, MD, of the Sinai Center for Thrombosis Research (Baltimore, MD), among others, is if ischemic events can occur even in patients with low platelet reactivity, is the latter truly a modifiable risk factor or is it more in the nature of a risk marker?

Numerous studies have shown that high on-treatment platelet reactivity as measured by functional testing correlates with increased thrombotic risk. But in the POPULAR trial (Breet NJ, et al. JAMA. 2010;303:754-762), a head-to-head comparison of 6 major assays, the predictive value of the 3 tests with validated cutpoints was relatively modest.

Exceptions to the ‘No Test’ Rule

Nonetheless, a recent white paper (Bonello L, et al. J Am Coll Cardiol. 2010;56:919-933) outlined certain situations in which it is appropriate to “consider” platelet function testing to help determine antiplatelet therapy: in patients with a history of stent thrombosis and prior to high-risk PCI.

The bottom line is that, for the most part, therapy should be guided by a patient’s presentation, not testing, Dr. Bhatt said, and he offered 2 scenarios from opposite ends of the risk spectrum to illustrate the point.

A Test-Guided Algorithm

At UCSD Medical Center (San Diego, CA), however, testing has been given a more liberal role. Several years ago, Ehtisham Mahmud, MD, and colleagues developed an algorithm to help make decisions about the best antiplatelet therapy for different patients. The algorithm is intended as a rough guide and has evolved as more trial data have become available, Dr. Mahmud said.

After PCI, all patients’ platelet reactivity is tested with the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA), he reported. If they are not already on a thienopyridine, patients with ACS and diabetics go straight to prasugrel, unless they have clinical characteristics that put them at increased bleeding risk (primarily age > 75, low BMI, a history of TIA or stroke).

Nondiabetic elective patients are given clopidogrel (600 mg loading dose, 75 mg daily). Among those who are clearly compliant with therapy yet do not respond (ie, show less than 30% platelet inhibition), a key factor in deciding whether or not to switch them to prasugrel is their angiographic characteristics, said Dr. Mahmud. “In patients with a straightforward focal lesion, and inhibition of 15% or 20%, in the past we would have switched them to prasugrel,” he observed. “Since GRAVITAS, I would probably keep them on clopidogrel. But if I don’t see any meaningful inhibition based on VerifNow measurement, I will switch these patients to prasugrel.”

On the other hand, compliant clopidogrel nonresponders who are undergoing high-risk PCI, such as for left main stenosis or multivessel disease, are candidates for prasugrel, Dr. Mahmud said. The same applies to patients who present with an event on clopidogrel or have had stent thrombosis, he added.

Another testing outpost is nearby Scripps Clinic in La Jolla, CA. There, Paul S. Teirstein, MD, says that even in the wake of GRAVITAS, he still tests nearly every PCI patient on standard-dose clopidogrel. “I might even start testing my prasugrel patients considering the new data that have come out,” he added in a telephone interview with TCTMD, alluding to the recent study showing that about one-quarter of ACS patients respond inadequately to prasugrel (Bonnello L, et al. J Am Coll Cardiol. 2011;58:467-473).

Limitations of Functional Testing

Beyond the issue of clinical validation, functional testing itself is far from straightforward. According to Dominick J. Angiolillo, MD, PhD, of the University of Florida College of Medicine-Jacksonville (Jacksonville, FL), to be useful in routine practice, a point-of-care test must:
Be simple to use
Provide quick results
Be easy to interpret
Be relatively inexpensive

Searching for a ‘Sweet Spot’

For most researchers, the holy grail of antiplatelet testing is identifying a therapeutic window—a range of platelet reactivity that will safeguard a patient between thrombotic risk on the high end of reactivity and bleeding risk on the low end.

Even more encouraging, a kind of therapeutic window of reactivity emerged from the study by Campo et al. Analysis showed that both ischemic and bleeding events were minimized when PRU values fell between 86 and 238.

However, a reactivity ‘sweet spot’ will likely vary not only with the specific functional test used but also with patients’ clinical presentation and the time from PCI, Dr. Angiolillo noted. For example, the low platelet reactivity required to prevent thrombotic events during the periprocedural period may be a liability 6 months later. And the optimal levels are likely to differ for elective and emergent PCI.

Nonetheless, if reliable therapeutic windows can be established, “the role of functional testing will be huge,” Dr. Mahmud commented. Furthermore, when in the near future clopidogrel becomes generic, platelet testing is likely to be used to show when a high-risk patient is responding to the drug and therefore does not need to be switched to a more potent—and more expensive—agent, he observed.

The Clinician’s Dilemma

Despite the setback of GRAVITAS—and the controversy surrounding the clinical relevance of genotyping—physicians understandably remain eager to find ways to minimize individual patients’ post-PCI risk.

Although GRAVITAS is important, “no one study in isolation answers every question. We’ll need a lot more and hopefully larger studies to really nail down these issues,” he concluded.

One area that Dr. Mahmud believes deserves particular attention is the influence of angiographic complexity on antiplatelet response. “Because we’re treating more and more complex lesions, it will be interesting to see how the degree of platelet inhibition [is affected by different levels of complexity] and how that [impacts] outcomes,” he said. “Arguably, if a patient has a simple focal lesion, even if he presents with ACS, you may not need very high inhibition of reactivity. And vice versa, you could have an elective patient with a very complicated lesion where you would need high platelet inhibition.”

Dr. Kleiman called for similar research. “I would like to see high reactivity defined for patients in the highest stratum of risk—those with multiple long stents, ACS, or acute MI,” he said. “Those are the folks about whom we have the most questions.”

Meanwhile, Dr. Angiolillo stressed that practitioners should continue to be guided by consensus statements, the therapeutic indications that have been validated in large clinical trials, and above all by good clinical judgment.



Sources:
1. Price MJ. Standard versus high-dose clopidogrel according to platelet function testing after PCI: Results of the GRAVITAS trial. Presented at: American Heart Association Scientific Sessions; November 16, 2010; Chicago, IL.

2. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention. JAMA. 2011;11:1097-1105.

3. Gurbel PA, Tantry US. An initial experiment with personalized antiplatelet therapy. JAMA. 2011;11:1136-1137.

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Apixaban Increases Major Bleeding in High-Risk ACS Patients

Key Points:
Novel anticoagulant apixaban increased TIMI major bleeding vs. placebo in ACS patients on antiplatelet therapy
Bleeding increase led to trial’s early stoppage
Apixaban also failed to decrease ischemic events
By Jason Kahn
Monday, July 25, 2011

The oral, direct factor Xa inhibitor apixaban increases major bleeding more than twofold when added to antiplatelet therapy in high-risk patients who have suffered an acute coronary syndrome (ACS). It was on the basis of these results, published online July 24, 2011, ahead of print in the New England Journal of Medicine, that the phase 3 APPRAISE-2 trial was halted early in November 2010.

The findings also were presented simultaneously this week at the International Society on Thrombosis and Haemostasis Congress in Kyoto, Japan.

For the APPRAISE-2 (APixaban for PRevention of Acute Ischemic and Safety Events-2) trial, researchers led by John H. Alexander, MD, of Duke University Medical Center (Durham, NC), randomized 7,392 out of a planned 10,800 high-risk patients with recent ACS and at least 2 risk factors for recurrent ischemic events to apixaban (5 mg twice daily) or placebo in addition to standard antiplatelet therapy. Roughly 81% of patients were on dual antiplatelet therapy with the remainder on aspirin alone. In addition, 44% had received PCI and 55% medical management alone. About 40% of the patients presented with STEMI.

After an interim analysis (median follow-up of 241 days), the primary efficacy endpoint of CV death, MI, or ischemic stroke was similar in the apixaban and placebo groups while the primary safety endpoint of TIMI major bleeding was more than twice as high in the apixaban group (HR 2.59; 95% CI 1.50-4.46).

Other efficacy outcomes including death, CV death, MI, and stent thrombosis were similar between groups.

It was the increase in TIMI major bleeding that caused the early trial stoppage, which was announced by the sponsors in late 2010. Other endpoints including intracranial bleeding (0.6% vs. 0.2%; P = 0.03) and fatal bleeding (0.3% vs. 0; P = NS) were also more common in apixaban patients, though there were so few fatal bleeding events that the difference was not statistically significant.

The primary efficacy and safety endpoints were consistent across multiple subgroups including those who did or did not receive PCI and those on dual antiplatelet therapy or aspirin monotherapy.

APPRAISE-2 was conducted despite increased bleeding rates in the earlier phase 2 APPRAISE trial. In that study, which assessed 4 different apixaban doses, the 2 highest (10 mg twice daily and 20 mg once daily) led to bleeding, causing those arms to be halted early. The 2 lower doses (2.5 mg twice daily and 10 mg once daily) were associated with nonsignificant trends for increased major or clinically relevant nonmajor bleeding but also decreased ischemic events.

Not a Fair Trade-Off

“We knew that adding an anticoagulant to dual antiplatelet therapy increases bleeding,” explained Dr. Alexander in a telephone interview with TCTMD. “What we were uncertain about was whether there was efficacy. So we enrolled a high-risk population and used a dose of apixaban that we thought would have the best chance of having a favorable trade-off between efficacy and bleeding. What we now know is it doesn’t reduce ischemic events, so there’s no signal here that would outweigh the increase in bleeding.”

However, the results should not automatically rule out this class of new anticoagulants in all ACS patients. Rather, the APPRAISE-2 data should be viewed as relevant only “for this drug in this dose with this population,” Dr. Alexander said. He added that another large randomized trial, ATLAS-ACS 2 TIMI 51, is testing a similar factor Xa inhibitor, rivaroxaban, in lower-risk ACS patients.

Hitinder S. Gurm, MD, of the University of Michigan Medical School (Ann Arbor, MI), was less optimistic. “We’ve not seen a signal from any of these trials that point to a reduction in major ischemic events. And if anything, there’s a considerable increase in bleeding,” he told TCTMD in a telephone interview. “Beyond [APPRAISE-2], these data should call into question the other similar trials that are being conducted.”

Hypothesis Called into Question

According to Dr. Gurm, the whole concept of adding an anticoagulant to long-term antiplatelet therapy for ACS patients should be shelved. “We think of ACS as being a thrombotic event secondary to plaque instability and by blocking thrombosis totally we could I guess reduce that, but that will come at the cost of increased bleeding,” he said. “So there is a balance point, and I think we’ve reached that balance point with good dual agent therapy. I don’t see a role for triple therapy for ACS.”

The prospect becomes even more doubtful when considering the more powerful antiplatelet agents—prasugrel and ticagrelor—that have recently been approved. “It’s another question that has to be studied, but I would think you’re less likely to see an additional benefit adding an anticoagulant to prasugrel or ticagrelor,” Dr. Alexander said.

Still, during a different phase of treatment, drugs like apixaban might make sense, Dr. Gurm amended. “Perhaps in the early phase,” he said. “Maybe we could come to a paradigm where instead of patients being started on heparin or enoxaparin, we would give them an oral factor Xa inhibitor, aspirin, and clopidogrel, then take them to the cath lab. Or especially if you’re waiting to take them to the cath lab, early therapy with oral drugs might make sense instead of using heparin. That could be where these drugs find a role, but I remain skeptical about long term therapy.”

Different Story in A-fib

The situation is altogether different in patients with venous thromboembolism (VTE) and atrial fibrillation (A-fib), where factor Xa inhibitors have proven effective, with rivaroxaban approved for deep vein thrombosis prevention and dabigatran approved for stroke prevention.

“I think APPRAISE-2 says much more about the population than the drug,” Dr. Alexander said. “Anticoagulants have very different effects in A-fib. We know warfarin is effective in A-fib, so it’s not too surprising that these novel anticoagulants are more likely to be effective, whereas in ACS, we don’t even know that warfarin is effective.”

“The way I see it, the factor Xa inhibitors have a bright future in the treatment of venous disease and patients with atrial fibrillation,” Dr. Gurm agreed. “I think that’s a great leap forward that we finally have therapies we can use in these patients.”

But not as long-term therapy in ACS patients, Dr. Alexander cautioned. “This doesn’t totally put the nail in the coffin for adding anticoagulants to antiplatelet therapy, but at least in this population at this dose with this background therapy, it doesn’t work,” he said. “And we can wait for ATLAS 2, but I’m not too optimistic.”

Source:
Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011.Epub ahead of print.

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Ticagrelor Gains FDA Approval for Use in ACS

Key Points:
Ticagrelor approved by FDA after solid outcomes in PLATO outweigh concerns about use with high-dose aspirin
Approval comes with warnings about aspirin dosing, bleeding risk
Experts predict ticagrelor will be popular due to its mortality benefit, reversibility
By Caitlin E. Cox
Friday, July 22, 2011

After a series of delays over the past several years, the US Food and Drug Administration (FDA) officially approved ticagrelor, a direct-acting reversible P2Y12 receptor inhibitor, on July 20, 2011, for reducing the rate of thrombotic cardiovascular events in patients with acute coronary syndromes (ACS).

Physicians interviewed by TCTMD expressed excitement about the new contender joining the crowded field of antiplatelet therapies.

Ticagrelor, which will be marketed as Brilinta (AstraZeneca; Wilmington, DE), may not be available in the immediate future, a company press release hints, but only after a 12-month roll-out period.

Ticagrelor’s FDA approval hinged on results from the PLATO (PLATelet inhibition and patient Outcomes) trial.

Published in the New England Journal of Medicine in September 2009, PLATO randomized more than 18,000 ACS patients in 43 countries worldwide to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). All patients also received aspirin.

At 12 months, the primary endpoint (CV death, MI, or stroke) was observed in 9.8% of ticagrelor patients compared with 11.7% of clopidogrel patients (HR 0.84; 95% CI 0.77-0.92; P < 0.001). But results from a prespecified subanalysis also revealed that ticagrelor had less effect in North American patients, who tended to receive higher aspirin doses than subjects enrolled elsewhere. Concerns about this disparity appeared to be at the heart of the debate over FDA approval.

In July 2010, an FDA advisory committee voted 7 to 1 in favor of ticagrelor’s approval, but the agency remained unconvinced and 5 months later asked for further analyses of the PLATO data.

With the FDA’s approval comes a “black box” warning highlighting 2 key areas: bleeding risk and the relationship between aspirin dose and efficacy.

In terms of bleeding, the label cautions that ticagrelor should not be used in patients with active pathological bleeding or a history of intracranial hemorrhage. It also is recommended that the drug not be started in those slated for CABG and ideally should be stopped at least 5 days prior to surgery. Clinicians should look for bleeding in patients who are hypotensive and have recently undergone angiography, PCI, CABG, or other surgical procedures. When possible, bleeding should be managed without discontinuing ticagrelor, in order to limit the risk of cardiovascular events.

With regard to aspirin, the label advises that maintenance doses above 100 mg reduce ticagrelor’s effectiveness and thus should be avoided. After any initial dose, 75 to 100 mg aspirin daily is appropriate.

New Option Greeted with Optimism

TCTMD gathered feedback from numerous physicians about ticagrelor’s long-awaited debut.

In an e-mail communication, Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), said the news was very exciting, in that now clinicians have another potential agent to treat ACS patients.

“Several unique attributes about the agent as well as the PLATO study design will render this drug more translatable to clinical practice, in my mind, than prasugrel,” he commented. “First, the fact that both clopidogrel and ticagrelor were given prior to angiography in the study makes PLATO more consistent with conventional clinical practice in ACS patients. Second, the more rapid offset of this agent will likely influence clinicians to feel more comfortable in giving this agent to a broader number of patients, even those who may have to undergo CABG.”

Neal S. Kleiman, MD, of Methodist DeBakey Heart and Vascular Center (Houston, TX), similarly pointed out that that the pivotal trial for prasugrel, TRITON-TIMI 38, studied patients whose anatomy had already been deemed suitable for PCI. “So ticagrelor was studied in a broader patient group,” he noted in telephone interview.

Paul A. Gurbel, MD, of the Sinai Center for Thrombosis Research (Baltimore, MD), whose research group has designed and led 2 pharmacodynamic investigations of ticagrelor vs. clopidogrel—the ONSET-OFFSET and RESPOND studies—also was positive about the recent approval.

ONSET-OFFSET demonstrated that ticagrelor shows more rapid onset than 600 mg clopidogrel, offers greater platelet inhibition during maintenance, and has faster offset, he told TCTMD in an e-mail communication. “These effects provided a clear-cut mechanism to explain the superior outcomes observed with ticagrelor in PLATO,” Dr. Gurbel said, while RESPOND found that ticagrelor overcame clopidogrel non-responsiveness. And an analysis that pooled patients from both studies found no evidence of high on-treatment platelet reactivity during ticagrelor therapy, he added.

“Taken together, we believe that these pharmacodynamic effects in conjunction with the PLATO results should strongly influence the choice for ticagrelor in the ACS patient. The robust effect of ticagrelor across all groups should favor widespread implementation,” he concluded, adding that the decision is further backed by the drug’s mortality benefit.

In an e-mail communication, Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), predicted that ticagrelor would be widely adopted in both STEMI and NSTEMI patients.

Asked how ticagrelor would compete with prasugrel, Dr. Stone outlined why 1 drug would be chosen over the other in different situations. Ticagrelor stands out for its effect on mortality in PLATO, he said, but ticagrelor and prasugrel work through different mechanisms that make them suitable for certain patient subgroups.

Ticagrelor can cause side effects such as dyspnea, “which while not physiologically important can be clinically worrisome,” he noted, and can cause ventricular pauses, so “must be used carefully, if at all, in patients with conduction system disease.” Prasugrel potentially comes out ahead by virtue of being given once rather than twice daily like ticagrelor, and it “has been particularly effective in suppressing stent thrombosis.”

But differences between TRITON-TIMI 38 and PLATO make it difficult to compare outcomes across trials, and much has been learned in the years since TRITON, Dr. Stone said, emphasizing that, “clearly there needs to be a head-to-head trial of these 2 agents so the appropriate therapeutic decisions can be made.”

Few Reservations

For his part, Dr. Gurbel said, “I have no reservations whatsoever about the approval of ticagrelor. It should have happened earlier.”

Dr. Kirtane, meanwhile, cautioned that it remains to be seen how possible side effects and the need for twice daily dosing with ticagrelor will play out in clinical practice. “Despite some wariness regarding the prolonged time to FDA approval and aspirin dosing issues, I would expect most clinicians to be quite pleased to have another option for their patients,” he concluded.

The key question, added Dr. Kleiman, is whether there will be less enthusiasm for ticagrelor if stent thrombosis rates, having decreased in the past few years, continue to drop.

“There’s going to be a lot more talk about clopidogrel resistance, which is a real thing, but how critical this is when we’re talking about stent thrombosis rates that are 0.4%, I’m not sure,” he noted.

In general, as new drugs become available, “[t]hey all come with a lot of promotion that gets people’s attention, but I really think people need to look at the data themselves and understand who they do and don’t want to be using the drug in,” Dr. Kleiman stressed. “When you talk about antithrombotic drugs, if you’re going to use them you’re obligated to know something about them. You need to be aggressive about getting information.”

Source:
FDA approves new medicine Brilinta (ticagrelor) for use in the US [press release]. Wilmington, DE; AstraZeneca; June 20, 2011. [Ссылки могут видеть только зарегистрированные и активированные пользователи] Published July 20, 2011. Accessed July 22, 2011.

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Coronary multidetector computed tomographic angiography to evaluate coronary artery disease in liver transplant candidates: methods, feasibility and initial experience
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Success in Implementing a Hospital-wide Evidence-based Clinical Pathways System for the Management of Cardiac Patients: The ACAP Program Experience
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At the Heart of the Fever: Kawasaki Disease
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High, low BMI resulted in significant risk for deep intracerebral hemorrhage

Biffi A. Stroke. 2011;doi:10.1161/strokeaha.111.617225.

Patients with low or high extremes of BMI were at increased risk for having a deep intracerebral hemorrhage. No association was reported on lobar intracerebral hemorrhage, however.

The single-center, prospective study involved 384 consecutive patients with intracerebral hemorrhage (ICH) — 196 with deep and 188 with lobar ICH — and 388 controls enrolled during a 6-year period. Researchers used CT to determine ICH characterization and patients’ height and weight to calculate BMI. Low BMI was defined as less than 18.5 kg/m² and high BMI was more than 30 kg/m².

Overall, patients with either low (OR=1.76; P=.011) or high BMI (OR=1.75; P=.013) were at increased risk for deep ICH, with the following characteristics associated with risk in univariate analysis: age, sex, hypertension, CAD, diabetes, hyperlipidemia and alcohol consumption of more than 3 oz per day. Neither univariate nor multivariate analysis revealed either BMI extremes to be linked with lobar ICH. The association with ICH was particularly prominent in men who had an OR of 2.85 (P=.041) vs. women who did not have an association (OR=0.89; P=.54).

“Our results suggest that BMI differentially influences risk of lobar and deep ICH, consistent with the hypothesis that BMI influences specific vascular pathologies that lead to ICH,” the researchers wrote. “In particular, these findings are most likely related to biological differences between cerebral amyloid angiopathy-related lobar ICH and hypertensive deep ICH.”
__________________________________________________ ___________________________
Intima-media thickness in carotid artery predicted CV outcomes

Polak J. N Engl J Med. 2011;365:213-221.

Intima-media thickness of the common and internal carotid artery was an independent predictor of CV events, according to an analysis of the Framingham Offspring Study.

The study also found that maximum intima-media thickness had significant, although modest, predictive power of the risk factors and also benefited risk classification.

In all, 2,965 participants (mean age, 58 years; 55% women) who had no history of CVD were included in the analysis.

During a mean follow-up of 7.2 years, 10% of the population experienced a CV event, including events related to CHD, peripheral arterial disease, stroke and HF, which was predicted by risk factors of the Framingham risk score. With every 1 standard deviation increase in intima-media thickness of the common carotid artery, the adjusted HR for CVD was 1.13 (95% CI, 1.02-1.24), whereas the HR for the maximum intima-media thickness was more pronounced (1.21; 95% CI, 1.13-1.29).

Additionally, the researchers reported that the net reclassification index rose significantly after the addition of intima-media thickness of the internal carotid artery (P<.001) but not the common carotid artery (P=.99).

“Our results show that plaque in the internal carotid artery, either measured as part of the continuous intima-media thickness or assumed to be present if the thickness exceeds a set point of 1.5 mm, offers modest incremental value to the Framingham risk score in predicting CV events,” they concluded. “We believe the intima-media thickness of the internal carotid artery should be measured in addition to the thickness of the common carotid artery for purposes of CV risk assessment.”

Polak et al continue to provide important insights into the impact of carotid intima-media thickness on CV risk. In this large cohort followed prospectively, the impact of carotid intima-media thickness was only helpful in addition to the Framingham Risk Score using internal carotid artery intima-media thickness measurements. This is interesting, as several previous publications have suggested that the common carotid artery intima-media thickness values are of equal predictive value in determining CV risk. Although the Framingham Risk Score performed well in determining future CV risk, adding increase in internal carotid artery intima-media thickness can help in further assessing future CV risk.

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FDA Panel Recommends Approval of Edwards Transcatheter Valve for Treatment of Inoperable Patients

GAITHERSBURG, MD, July 20, 2011 -- Edwards Lifesciences Corporation (NYSE: EW), the global leader in the science of heart valves and hemodynamic monitoring, announced that a U.S. Food and Drug Administration (FDA) Advisory Panel voted late today to recommend approval of the Edwards SAPIEN transcatheter heart valve for the treatment of certain inoperable patients.

Edwards submitted a PMA application in the fall of 2010 based on data from the inoperable cohort of The PARTNER Trial. This cohort compared the outcomes of 358 patients after treatment with either standard therapy or the Edwards SAPIEN valve delivered transfemorally.

"We are pleased with the panel's strong recommendation for approval, and would like to thank them for their comprehensive and thoughtful review of the data presented from The PARTNER Trial. This represents another important step on the path to what we hope will lead to FDA approval of SAPIEN," said Michael A. Mussallem, Edwards' chairman and CEO. "We would also like to thank the principal investigators and their heart teams at the PARTNER hospitals for their dedication to this clinical trial, and to their patients for participating in a study of a new therapy."

The Edwards SAPIEN valve is an investigational device in the U.S. and not yet available commercially in the U.S. It received CE Mark approval for European commercial sale in late 2007.

About Edwards Lifesciences
Edwards Lifesciences is the global leader in the science of heart valves and hemodynamic monitoring. Driven by a passion to help patients, the company partners with clinicians to develop innovative technologies in the areas of structural heart disease and critical care monitoring that enable them to save and enhance lives. Additional company information can be found at [Ссылки могут видеть только зарегистрированные и активированные пользователи]

This news release includes forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. These forward-looking statements include, but are not limited to, Mr. Mussallem's statements regarding the potential FDA approval of the Edwards SAPIEN valve. Forward-looking statements are based on estimates and assumptions made by management of the company and are believed to be reasonable, though they are inherently uncertain and difficult to predict. Our forward-looking statements speak only as of the date on which they are made and we do not undertake any obligation to update any forward-looking statement to reflect events or circumstances after the date of the statement.

Forward-looking statements involve risks and uncertainties that could cause actual results or experience to differ materially from those expressed or implied by the forward-looking statements based on a number of factors including but not limited to unexpected delays in, or changes to the outcome of, the U.S. FDA regulatory approval process or schedule. These factors are detailed in the company's filings with the Securities and Exchange Commission including its Annual Report on Form 10-K for the year ended December 31, 2010.

Edwards, Edwards Lifesciences, the stylized E logo, Edwards SAPIEN, PARTNER and SAPIEN are trademarks of Edwards Lifesciences Corporation.

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CID SpA announces the CE mark of its new Cre8TM Polymer-Free DES
Saluggia (Italy), July 19th 2011 - CID is pleased to announce that its latest Drug Eluting Stent (DES), Cre8TM, has received CE mark.
The Cre8TM polymer-free DES embodies the most advanced DES technologies to treat coronary vascular disease. Its unique distinctive features - Abluminal Reservoir Technology, Amphilimus Formulation and Bio Inducer Surface - make Cre8TM the only very effective Polymer-Free DES today available. In the NEXT study, an international prospective randomized clinical trial, it resulted being statistically superior to TAXUSTM Libertè with respect to in-stent late lumen loss (0.14 mm Cre8TM vs. 0.34 mm Taxus, p<0.0001).
The proprietary Abluminal Reservoir Technology (ART) provides a consistent drug loading onto the stent platform, thus enabling a controlled and directed elution exclusively targeted to the vessel wall.
The innovative Amphilimus™ formulation, that is Sirolimus formulated with an organic acid, is the first known use of a carrier to enhance drug bioavailability and drug distribution to the entire vessel wall.
The Bio Inducer Surface, a second generation integral pure carbon coating, demonstrates excellent results in terms of stent endothelialization and struts coverage. The use of the Bio Inducer Surface onto the Cre8TM Polymer-Free DES enables faster DES endothelialisation and reduces device thrombogenicity risk.
“We develop our stents with the objective of providing patients the best possible clinical outcome in terms of both efficacy and safety. We believe that Cre8TM represents an important achievement for the interventional cardiologist community, as it is a DES that has none of the drawbacks associated with polymers. In addition, because of the Bio Inducer Surface and Abluminal Reservoir Technology, we hope that physicians will be able to shorten the dual antiplatelet therapy period for their patients and reduce the high cost of care as well as the side effects of these drugs.” said Franco Vallana, President and C.E.O. of CID SpA.
About CID SpA
CID (Carbostent & Implantable Devices) is dedicated to contributing to human welfare by improving the quality of patient care and after-care through the development of innovative, minimally invasive implantable devices, procedures and therapies.
A strong background in the field of implantable cardiovascular devices and haemocompatible materials, expressed in a remarkable IP portfolio, and a management with an expertise gained in many years of research, development and clinical experience, allow CID to offer the investors a fair
return and its customers the necessary tools to meet new challenges.

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Top Content, June, 2011
The Most Viewed Science & Quality Content on CardioSource
Top 10 Journal Scans, June 2011
Safety of Clopidogrel Being Continued Until the Time of CABG (Eur Heart J)
Treatment and Outcomes in Patients With MI Treated With Acute Beta-Blocker Therapy (Am Heart J)
Driving Restrictions After ICD Implantation (Eur Heart J)
ICD Registry Risk Score Models for Acute Procedural Complications or Death After Implantation (Circulation)
Transcatheter Versus Surgical Aortic-Valve Replacement in High-Risk Patients (N Eng J Med)
A Randomized controlled Trial of EVAR vs OSAR for AAAs in Moderate- to Low-Risk Patients (J Vasc Surg)
Effect of Switching Antithrombin Agents for Primary Angioplasty in AMI: The HORIZONS-SWITCH Analysis (J Am Coll Cardiol)
Effects of Rosuvastatin on Progression of Stenosis in Adult Patients With Congenital Aortic Stenosis: The PROCAS Trial (Am J Cardiol)
Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the RE-LY Trial (Circulation)
ACCF/AHA/AMA–PCPI 2011 Performance Measures for Adults With CAD and Hypertension (J Am Coll Cardiol)

Top 10 Clinical Trial Summaries, June 2011
AIM HIGH
ARISTOTLE
SHARP
ASA-STAT
PARTNER Cohort A
LIPSIA-STEMI
STICH
PARTNER Cohort B
RELY
ADDITION-Europe

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What’s New in Hypertension? A Contemporary Primer
By Gregory W. Rutecki, MD | 13 Июль 2011 г.
Dr. Rutecki is Professor of Medicine at the University of South Alabama in Mobile.

A recent commentary of mine regarding hypertension was entitled, “Are Prescribing Practices for Antihypertensives Primitive? The Truth Hurts.”1 The criticism surfaced in the Wall Street Journal.2

What’s the problem? The Journal quoted Dr. Michael Alderman, who appropriately insinuated that many of us—myself included—are in a stale time warp when it comes to antihypertensive therapy.

So if this is the case, how about some new facts to bring us up to snuff? What are “hot topics” in the contemporary world of hypertension that will rescue us from being labeled as primitive?

Defining, Diagnosing, and Treating Resistant Hypertension

The old paradigm: If a patient’s blood pressure isn’t controlled with 3 antihypertensive drugs, add more (the “damn the torpedoes, full speed ahead” older approach).

The new paradigm: If a patient’s blood pressure isn’t controlled with a 3- drug regimen (and if he or she is adherent to the regimen), stop and identify the patient as having resistant hypertension.

Consider associated disease states (eg, Obstructive Sleep Apnea [OSA] or chronic kidney disease [CKD]) and add spironolactone(Drug information on spironolactone) (25 mg/d to start) to the treatment regimen.3,4
Spironolactone’s potency in this particular situation may allow discontinuation of other antihypertensive medications.

Correctly Identify Populations That Frequently Have Resistant Hypertension

The old paradigm: Primary hypertension is all the same.

The new paradigm: Although secondary causes of hypertension may be active in individuals who have resistant hypertension (eg, primary aldosterone syndromes, pheochromocytoma, or renal artery stenosis), certain groups make up a significant portion of those with resistant, primary hypertension. OSA is one such cause.

The rest of the news is good. Patients with OSA respond well to the addition of spironolactone. This drug not only helps with blood pressure control, but may benefit those with hypopneic and apneic episodes as well.5

The epidemic of CKD has also prominently propelled this group into the resistant cohort. Data are preliminary and come from small sample sizes; however, it may be that we will one day prescribe spironolactone for this hyperkalemia-prone group as well.6 Wait for further news in this regard.

Thiazide Diuretics Are Good Drugs For High Blood Pressure, But They’re Not Perfect

The old paradigm: The first definition of resistant hypertension observed that of the 3 drugs used for control, one must be a thiazide. But what if a thiazide isn’t helping?

The new paradigm: The new classification for Chronic Renal Disease (the CKD stages 1-5) defines CKD stage 3 (the level at which patients should be referred to a nephrologist) as a glomerular filtration rate (GFR) of < 60 mL/min but ≥ 30 mL/min. Patients in this category represent another sizeable portion of the resistant group. Thiazide diuretics are not effective blood pressure medications when GFR is approximately 40 mL/min or lower. This is a treatment opportunity for furosemide, dosed twice a day because of its shorter half-life.4

Not All Hypertensive Patients Are Created Equally

The old paradigm: Every hypertensive patient should receive the same battery of blood pressure medications (thiazide diuretics + beta blockers + an ACEI or ARB + a calcium channel blocker). This is the “one size fits all philosophy.”

The new paradigm: The old paradigm is wrong (it speaks exactly to Dr. Alderman’s point about primitive prescribing practices). Did you know that studies have demonstrated that beta-blockers either do not lower—or can actually raise— blood blood pressure in African Americans?7

In the ASCOT-BPLA trial (n= approximately 20,000), when atenolol(Drug information on atenolol) was compared with amlodipine
(Drug information on amlodipine) for blood pressure
management, the trial was halted early because of a 11% lower all-cause mortality in the amlodipine limb.8

If a black person with hypertension has an alternative indication for beta-blockade (decreased ejection fraction), use carvedilol(Drug information on carvedilol) instead.

Small Doses of Two Drugs are Better than Big Doses of Only One

The old paradigm: If 10 to 20 mg of an ACEI is good, then 30 mg is better and 40 mg is best.

The new paradigm: It is not only true that 2 heads are better than one. . . the same may be said for 2 antihypertensives.

A 2003 meta-analysis demonstrated that in 42 trials of hypertension therapy involving 10,968 participants, doubling the dose of monotherapy with 1 drug had only 1/5 the blood pressure lowering efficacy of adding another drug without increasing the initial drug’s dose.9


ACEIs with ARBS Don’t Add Bang To Your Buck as an Antihypertensive Combination

The old paradigm: If ACEIs are good for blood pressure and kidney disease, adding another similar renin-angiotensin-aldosterone medication (such as an ARB) will be even better.

The new paradigm: Adding an ARB to an ACEI regimen for blood pressure control provides only modest reductions in pressure (3 mm/Hg).10,11 The modest reduction may come at the price of hyperkalemia and blocking another medicine from doing a better job.

As in the first bullet point, the medicine to add in this setting may be spironolactone. This agent lowers BP in the same “add on” situation on average 25/12 mm/hg systolic and diastolic pressures, respectively.

These new paradigms are a starting point for antihypertensive therapy’s “Brave New World.” I don’t like being called “primitive” any longer.

References:
1. Rutecki GW. Are prescribing practices for antihypertensives primitive? The truth hurts. Consultant. 2010; 50:II. [Ссылки могут видеть только зарегистрированные и активированные пользователи]
2. Naik G. Getting the right hypertension drug. Wall Street Journal. August 24, 2010. D3. [Ссылки могут видеть только зарегистрированные и активированные пользователи]
3. Nishizaka MK, Calhoun DA. The role of aldosterone antagonists in the management of resistant hypertension. Current Hypertension Reports. 2005;7:343-347.
4. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. JACC. 2008;52:1749-1757.
5. Gaddam K, Pimenta E, Thomas SJ, et al. Spironolactone reduces severity of obstructive sleep apnea in patients with resistant hypertension. J Hum Hypertens. 2010;24:532-537.
6. Heshka J, Ruzicka M, Hiremath S, McCormick BB. Spironolactone for difficult to control hypertension in chronic kidney disease: an analysis of safety and efficacy. J Am Soc Hypertens. 2010;4:295-301.
7. Brewster LM, van Montfrans GA, Kleijnen J. Systematic review: antihypertensive drug therapy in black patients. Ann Intern Med. 2004;141:614-627.
8. Collier DJ, Poulter NR, Dahlof B, et al. Impact of amlodipine-based therapy among older and younger patients in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). J Hypertens. 2011;29:583-591.
9. Wald DS, Law M, Morris JK, et al. Combination therapy versus monotherapy in reducing blood pressure: meta-Analysis on 11,000 participants from 42 trials. Am J Med. 2009;122: 290-300.
10 .Holdiness A, Monahan K, Minor D, de Shazo RD. Renin angiotensin aldosterone system blockade: little to no rationale from ACE inhibitor and ARB combinations. Am J Med. 2011;124:15-19.
11. Rutecki GW. ACE Inhibitor and ARB combination therapy: rational and fashionable, but does it work? Consultant. 2011;51:303d-304d

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Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials
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Valsartan is more effective than placebo in reducing the incidence of diabetes in people with impaired glucose tolerance and cardiovascular disease or risk factors but has no effect on cardiovascular outcomes
[Ссылки могут видеть только зарегистрированные и активированные пользователи]

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HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA)
[Ссылки могут видеть только зарегистрированные и активированные пользователи]

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Genetic link to MI stronger than to stroke
Banerjee A. Circ Cardiovasc Genet. 2011;doi:10.1161/circgenetics.110.959114.

Among participants in a population-based study in England, heritability of an MI was significantly more prominent than stroke.

In the study, researchers from the University of Oxford analyzed first-degree relatives for family history of MI, stroke and related risk factors, specifically looking to determine the extent to which parental history correlated with disease in affected siblings. In all, the study featured 906 patients (66.7% men) with acute coronary syndrome and 1,015 patients with cerebral events (47.7% men), each one with complete family history data available.

Researchers reported that parental MI had a significant effect on MI in at least one sibling, with an OR for those with one affected parent of 1.48 (95% CI, 1.04-2.10), whereas for those with two affected parents, the OR was 5.97 (95% CI, 3.23-11.03). However, no associations were observed regarding parental stroke on siblings.

Similarly, despite a comparable occurrence of MI and stroke in the study population, the incidence of two siblings with the same condition was much higher in patients with ACS compared with those with cerebral events (OR=5.43; 95% CI, 3.03-9.76).

If these findings are confirmed by additional research, the way physicians predict the odds of a healthy person experiencing an MI or stroke will need refining, study researcher Peter M. Rothwell, MD, PhD, said in a press release.

“Currently, most risk models lump a patient’s family history of stroke and heart attack together. We probably should model family history of stroke and heart attack separately in the future,” Rothwell said. – by Brian Ellis
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Two studies highlight importance of transitional care in cardiac patients

Stauffer BD. Arch Intern Med. 2011;171:1238-1243.
Voss R. Arch Intern Med. 2011;171:1232-1237.

Thirty-day readmission rates and health care costs were reduced by post-discharge intervention programs for patients with heart complications, according to results of two studies.

Communication between hospital providers, patients and receiving providers at the time of hospital discharge may yield better outcomes and reduced costs, according to findings from Voss and colleagues.

Their quasi-experimental cohort study was conducted from Jan. 1, 2009, to June 30, 2010, and involved six Rhode Island hospitals. A group of fee-for-service Medicare patients received a transition intervention.

The 30-day readmission rate among patients receiving the intervention was 12.8% compared with a 20% readmission rate among patients who did not receive the intervention (OR=0.61; 95% CI, 0.42-0.88). Those who declined to participate or who were lost to follow-up had an 18.6% readmission rate (OR=0.94; 95% CI, 0.77-1.14).

“The Care Transitions Intervention appears to be effective in this real-world implementation,” the researchers wrote. “This finding underscores the opportunity to improve health outcomes beginning at the time of discharge in open health care settings.”

Stauffer and colleagues conducted a study to determine the effect of nurse-led transitional care on readmission among patients with HF who were aged at least 65 years and were discharged from Baylor Medical Center Garland from Aug. 24, 2009, to April 30, 2010.

The intervention reduced 30-day readmission rates to Baylor Medical Center Garland by 48% during the post-intervention period, according to the results. This significant reduction was better than secular reductions seen at other participating facilities.

The intervention was also associated with an average reduction in the hospital contribution margin of $227 for each Medicare patient with HF.

“Preliminary results suggest that transitional care programs reduce 30-day readmission rates for patients with heart failure,” Stauffer and colleagues wrote. “This underscores the potential of the intervention to be effective in a real-world setting, but payment reform may be required for the intervention to be financially sustainable by hospitals.”

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Afib May Not Up Death Risk in Heart Failure

By Todd Neale, Senior Staff Writer, MedPage Today
Published: August 02, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo

Action Points
Explain that atrial fibrillation may not be an independent risk factor for death in patients optimally treated for heart failure, a finding that is in contrast to prior studies.

Point out that there was a high rate of adherence to guideline-recommended medical therapy for heart failure in these patients, as evidenced by 88.4% of patients who received ACE inhibitors, angiotensin receptor blockers, or both, and 82.8% who used beta-blockers.
Atrial fibrillation may not be an independent risk factor for death in patients optimally treated for heart failure, a Norwegian study showed.

After adjustment for several confounders, having atrial fibrillation was not associated with a greater mortality risk in patients treated at specialized heart failure clinics (HR 1.03, 95% CI 0.90 to 1.19), according to Arnljot Tveit, MD, PhD, of Baerum Hospital in Rud, Norway, and colleagues.

The finding, however, contrasts with that of a 2009 meta-analysis, the researchers reported online in Clinical Cardiology.

Half of the 12 studies included in the meta-analysis from Mamas et al. did not demonstrate that atrial fibrillation was an independent risk factor for death (Eur J Heart Fail 2009; 11: 676–683).

Tveit and colleagues noted, too, that the percentage of patients taking guideline-recommended medical therapy for heart failure was higher in the current study than in the studies included in the meta-analysis.

"This improved medical treatment of heart failure and optimized thromboprophylaxis in atrial fibrillation may have reduced the impact of atrial fibrillation on prognosis in heart failure patients," they wrote.

Although several previous studies -- including observational studies and subset analyses of randomized trials -- have shown that atrial fibrillation is associated with a greater mortality risk in patients with heart failure, a few have shown that the relationship disappears after controlling for other risk factors.

To further explore the issue, Tveit and colleagues analyzed data from patients referred to 24 Norwegian specialized heart failure clinics -- which focused on optimization of treatment and patient education -- from October 2000 to February 2008. Mortality information came from the national statistics bureau.

The analysis included 4,048 patients with heart failure; about one-third (34.4%) had atrial fibrillation.

Overall, adherence to guideline-recommended medical therapy was high -- 88.4% of patients received ACE inhibitors, angiotensin receptor blockers, or both, and 82.8% used beta-blockers. Of the patients with atrial fibrillation, 85.9% were on warfarin.

Without adjusting for any confounders, there was a higher risk of death through a median follow-up of 28 months among patients with atrial fibrillation than among those in sinus rhythm (HR 1.18, 95% CI 1.04 to 1.33, P=0.008).

However, after adjustment for confounders -- including age, heart failure severity, coronary artery disease as the main cause of heart failure, use of any loop diuretic, hemoglobin level, and serum creatinine -- the relationship was no longer significant (HR 1.03, 95% CI 0.90 to 1.19, P=0.619). Age was the strongest confounder and adjusting for that factor alone rendered the association nonsignificant.

Researchers suggested that the higher mean age of those with atrial fibrillation in this study (74 years) compared with other studies is more representative of the general atrial fibrillation population. On average, those with atrial fibrillation were six years older than those without Afib.

The findings nullifying atrial fibrillation as a predictor of death were similar in the subgroups of patients with ischemic heart disease as the main cause of heart failure and those with less severe heart failure (NYHA Class I/II).

The authors acknowledged some limitations of the analysis, including the lack of information on the rate of implantable cardioverter-defibrillator use, on use of anti-arrhythmic drugs and digoxin, and on the temporal pattern or duration of atrial fibrillation.

In addition, they wrote, the findings may not be applicable to patients treated outside of a specialized heart failure clinic.

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Mortality and cardiovascular risk associated with different insulin secretagogues compared
with metformin in type 2 diabetes, with orwithout a previous myocardial infarction:
a nationwide study
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Details on Clopidogrel Discontinuation Remain Elusive, Unclear

Key Points:
Review examines perioperative, premature clopidogrel discontinuation
Although mostly observational, studies suggest early hazard
Unclear whether any ‘safe’ window exists
By L.A. McKeown
Friday, August 05, 2011

Data on cardiovascular events associated with discontinuation of clopidogrel for surgery or other reasons are conflicting and questionable. In addition, it is unclear whether there is a time threshold for discontinuation, after which event rates are negligible, according to a review published online July 30, 2011, ahead of print in the European Heart Journal.

Michael A. Gaglia Jr, MD, MSc, and Ron Waksman, MD, of Washington Hospital Center (Washington, DC), searched the medical literature from January 2000 through March 2010 for articles reporting adverse clinical events following discontinuation of clopidogrel. The review included:
13 nonrandomized studies of perioperative cessation of clopidogrel or ticlopidine
2 randomized trials comparing different durations of clopidogrel therapy
16 nonrandomized studies of premature clopidogrel discontinuation without reference to surgery

Perioperative Cessation Appears Hazardous

For patients undergoing noncardiac surgery, the 13 studies documenting perioperative thienopyridine cessation were mostly observational, but suggest a hazard for adverse cardiac events. Overall in-hospital mortality ranged from 4.9% to 20%. Perioperative stent thrombosis rates ranged from 2.0% in a study of 481 patients to 2 in 5 patients who discontinued clopidogrel in a 56-patient case series. Similarly, MACE incidence ranged from 0 in a study of 38 patients (41% of whom were taking clopidogrel at the time) to 30.7% in 192 patients who discontinued clopidogrel and underwent surgery less than 30 days after PCI.

In the 1 study that included multivariable analysis, MACE risk was increased within 30 days of cardiac or noncardiac surgery in a cohort of 481 patients who had received BMS or DES a mean of 1.1 years earlier, but neither aspirin nor clopidogrel within 24 hours before surgery was protective for these patients.

Drs. Gaglia and Waksman said it is “readily apparent” that there are few data to guide perioperative management of patients on clopidogrel, “with only small nonrandomized case series available that are almost invariably without adequate multivariable adjustment.”

Other obstacles include inconsistent and incomplete reporting of details regarding clopidogrel/aspirin, cessation, incidence of stent thrombosis, and suggested strategies for restarting clopidogrel. The available data also do not differentiate between DES and BMS patients, Drs. Gaglia and Waksman add, nor do they help clarify whether there is a safe window for surgery and/or discontinuation of clopidogrel.

Despite the ambiguity, guidelines issued by the European Society of Cardiology in 2009 on the timing of noncardiac surgery in patients who have undergone PCI recommend a minimum of 6 weeks, but optimally 3 months for BMS patients and a minimum of 12 months for DES patients. The American College of Cardiology and American Heart Association have not issued formal guidelines about perioperative discontinuation of clopidogrel, although a science advisory was issued in 2007 cautioning against premature cessation in general.

Drs. Gaglia and Waksman say the guidelines have been issued primarily “in order to bridge the considerable gap between evidence and clinical practice.”

Ambiguity Surrounding Premature Discontinuation

The studies regarding premature discontinuation of clopidogrel without reference to surgery were primarily retrospective and statistically flawed. Like the surgery studies, these studies are not uniform in terms of the proportion of patients undergoing DES and BMS.

In an early report from 2004, the incidence of stent thrombosis was 1.1% in a population of 652 patients with sirolimus-eluting stents (SES) and over half (57%) of these were in patients who had discontinued clopidogrel. In addition, all stent thromboses occurred within 13 days of PCI. But in the DIABETES trial, published in 2007, the stent thrombosis rate was 3.8% when clopidogrel was discontinued at 1 year after SES implantation. And among the 746 patients enrolled in the BASKET-LATE trial who received BMS or DES and stopped clopidogrel at 6 months, the stent thrombosis risk was higher in the DES group (2.6% vs. 1.6%).

The few retrospective studies on clopidogrel cessation have not found any effect on stent thrombosis. In one, the study authors conclude that among 15,157 patients with SES, despite the occurrence of 126 stent thromboses, clopidogrel compliance had no effect on risk. Another study of 8,146 patients who received DES, meanwhile, found the absence of clopidogrel was not a risk factor for stent thrombosis. Furthermore, a study of 10,778 patients with SES showed that discontinuation of dual antiplatelet therapy, but not thienopyridines alone, increased risk. A landmark analysis of patients who were event-free at 6 months did not show a benefit from thienopyridine therapy beyond this time point.

Then there is the issue of how premature discontinuation of clopidogrel is defined among these various studies. According to Drs. Gaglia and Waksman, while some studies used cut points of 1 year, 6 months, 3 months, or 30 days, others reported the cessation time point as patient-dependent or simply did not provide the information.

‘Conspicuous’ Lack of Evidence

“The absence of adequate randomized studies comparing different durations of clopidogrel therapy following PCI, and especially DES, should now be conspicuous,” they write.

Some studies suggest that the hazard of clopidogrel discontinuation, although highest within the first 30 days, never disappears, Drs. Gaglia and Waksman note. But details specifically regarding the risks involved in stopping aspirin are lacking in many reports, they add, and continued therapy with aspirin is often assumed but rarely verified.

Of the 2 studies that were randomized, one found no benefit from continuing clopidogrel in patients who had gone event-free for 12 months; at a median follow-up of 19 months, the rates of MI or cardiac death were similar with or without clopidogrel (1.8% vs. 1.2%; P = 0.17). The other, which was greatly underpowered, found a lower rate of death, MI, or stroke at 6 months in patients who received 180 days of clopidogrel following BMS implantation compared with those who received the antiplatelet only for 30 days (1.7% vs. 5.0%; P = 0.01).

Drs. Gaglia and Waksman conclude that future trials following patients for longer durations on dual antiplatelet therapy may help sort out some of the ongoing ambiguities regarding discontinuation. However, the introduction of prasugrel to the antiplatelet armamentarium complicates the situation further, they say, because the only available data, which come from TRITON-TIMI 38, followed patients on prasugrel for up to 15 months but do not address the issue of optimum duration.

Ongoing Studies Somewhat Limited

In an email communication with TCTMD, Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), said the paper is an excellent review of the current literature surrounding clopidogrel discontinuation.

“The complexities of clinical decision-making make it very difficult to design prospective/randomized studies in this area, which is why so many clinicians utilize empirically based recommendations,” he said.

Although fears of ‘clopidogrel rebound’ have largely abated, Dr. Kirtane added, the optimal duration of clopidogrel therapy remains unknown, with bleeding and cost factors counterbalancing the potential anti-ischemic benefits of continued clopidogrel therapy.

“Even the current ongoing studies may be somewhat limited in their eventual impact given more recent advances in stent and pharmacologic therapy,” he added.

Source:
Gaglia MA, Waksman R. Systematic review of thienopyridine discontinuation and its impact upon clinical outcomes. Eur Heart J. 2011;Epub ahead of print.

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Degree of Stenosis Not Only Factor to Consider in Carotid Surgery

Key Points:
Analysis pools patient data from 3 randomized trials of carotid surgery vs. medical therapy alone
Patients with 70% to 99% stenosis benefit most from CEA
Age, sex, time delay to surgery also affect risk
By Jason Kahn
Thursday, August 04, 2011

Age, sex, and the time delay to surgery, in addition to the degree of stenosis, all affect the risk of stroke in patients receiving carotid endarterectomy (CEA) for symptomatic disease, according to a review of randomized trials published online July 28, 2011, ahead of print in Stroke.

The paper is also being published in the Cochrane Database of Systematic Reviews 2011, Issue 4.

Kittipan Rerkasem, MD, PhD, of Chiang Mai University (Chiang Mai, Thailand), and Peter M. Rothwell, MD, PhD, of the University of Oxford (Oxford, United Kingdom), performed a pooled analysis of 6,092 patients from 3 randomized trials comparing CEA and best medical therapy alone in patients with symptomatic carotid atherosclerosis. The trials were:
NASCET (North American Symptomatic Carotid Endarterectomy Trial)
ECST (European Carotid Surgery Trial)
VACSP (Veterans Affairs trial)

The overall 30-day rate of stroke or death across all the trials was 7.1%, with a 30-day mortality rate of 1.1%. When stratified by degree of stenosis, surgery increased the risk of ipsilateral ischemic stroke in patients with low levels of carotid stenosis, but this effect lessened as the degree of stenosis increased, until patients with 70% to 99% stenosis but not near occlusion benefited greatly (table 1).

Table 1. CEA and Effect on Risk of Ipsilateral Ischemic Stroke

Degree of Stenosis
Absolute Change in Risk
P Value

< 30% Stenosis
2.2%
0.05

30%-49% Stenosis
-3.2%
0.6

50%-69% Stenosis
-4.6%
0.04

70%-99% Stenosis Without Near Occlusion
-16%
< 0.001

Near Occlusion
1.7%
0.9

In subgroup analyses based on pooled data from ECST and NASCET, sex (P = 0.003), age (P = 0.03), and time between the last symptomatic event and surgery (P = 0.009) all modified the effectiveness of CEA. For instance, the number of patients with 50% to 99% stenosis who needed to undergo CEA to prevent 1 ipsilateral stroke within 5 years was 9 for men vs. 36 for women. In addition, the number needed to treat was 5 for patients older than 75 years vs. 18 for patients younger than age 65, and 5 for patients randomized within 2 weeks of their last ischemic event vs. 125 for patients randomized more than 12 weeks from their last event.

The overall results are generalizable only to “surgically fit patients operated on by surgeons with low complication rates,” meaning less than 7% risk of stroke and death, the authors write.

“Benefit from endarterectomy depends not only on the degree of carotid stenosis, but also on several other factors, including the delay to surgery after the presenting event,” they conclude. “In particular, in patients with only 50% to 69% stenosis, there was no evidence of benefit in women and little evidence of benefit if surgery was delayed by more than 2 weeks after the presenting event.”

Paper Reinforces Practice

According to K. Craig Kent, MD, of the University of Wisconsin School of Medicine and Public Health (Madison, WI), the analysis reinforces what is already known in standard practice. “What the authors essentially said was that if you have less than 50% stenosis in a symptomatic patient, then it either hurt the patient or provided no benefit to treat them,” he told TCTMD in a telephone interview. “Then they said if you take a 50% to 69% stenosis, there’s some benefit, but it’s not an incredibly great benefit. I think we know that. That’s the way we practice.”

And in terms of combining factors such as female sex and a 50% to 69% stenosis, which according to the report lower the effectiveness of CEA, “we’re savvy enough as clinicians to understand these things are additive,” Dr. Kent said.

Two-Week Rule Should Not Exclude Patients

Nevertheless, he cautioned that over interpreting the findings would lead to an overly rigid approach, particularly with regard to the length of time from an ischemic event to surgery, which, the paper advises, should not be longer than 2 weeks. “So if you see someone that’s female and has a 60% stenosis and had a TIA 2 months ago, doing an endarterectomy on that patient would still be considered the standard of care,” Dr. Kent said. “They’re arguing that if it’s not a 70% stenosis, and it was a long time ago and in a female, maybe you don’t need to treat that person.”

Christopher K. Zarins, MD, of the Stanford University School of Medicine (Stanford, CA), also took issue with that concept. “When someone has a TIA and a greater-than-50%-stenosis lesion, you try and get that done as quickly as you can,” he said in a telephone interview with TCTMD. “But if someone comes in 3 weeks after a TIA and has a 70% stenosis, would I say, ‘Oh, you’re past 2 weeks, so you’ll get no benefits and I’m not going to fix you?’ That’s not right.”

Dr. Zarins explained that it is not uncommon for a patient to come in 3 or 4 weeks after an event. “And you do a study and you find a 70% stenosis. You go through the risk-benefit and you recommend treatment,” he said. “And that’s correct and the literature strongly supports that.”

Near Occlusions Cause Concern

Both Drs. Kent and Zarins expressed confusion over the researchers’ use of the term ‘near occlusion,’ which was not adequately defined in the paper. “What’s the difference between a 99% occlusion and a near occlusion?” Dr. Zarins asked. “Is a near occlusion 99.5%? If they had said you shouldn’t operate on occlusions, I would agree with that, but near occlusions that are 99% with a TIA, you should operate on those. As a clinician, that would be a source of confusion about how to apply that finding to clinical practice because it’s not clear what that is.”

Dr. Kent called that part of the paper “somewhat disquieting.”

“I hope they’re not saying that if you have a high grade stenosis but a normal artery beyond, you shouldn’t treat it, because I have never seen any data from NASCET or elsewhere to suggest that those patients shouldn’t be treated,” he said.

‘Shades of Gray’

Overall, the paper performs a service in pointing out “shades of gray,” in the clinical decision making process to perform CEA, Dr. Kent said. “It’s probably worthwhile reminding all of us we ought to consider all these factors, and that it’s not just black and white that everybody greater than 50% with a TIA should have surgery,” he said. “It’s just a matter of how far you should push it. If you start taking some of that to an absolute degree, I think that would be a mistake.”

For instance, “an aggressive carotid surgeon might assimilate all these data and say that a woman who has a 60% stenosis and had a TIA 2 months ago should have endarterectomy,” Dr. Kent said. “[The authors] would assimilate the data and say that individual doesn’t need endarterectomy.”

Dr. Zarins, meanwhile, maintained that “the fundamental idea that symptomatic patients greater than 50% benefit from endarterectomy is supported here. This paper does not refute that.”
Source:
Rerkasem K, Rothwell PM. A systematic review of randomized controlled trials of carotid endarterectomy for symptomatic carotid stenosis. Stroke. 2011;Epub ahead of print.

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Excess Dyspnea with Ticagrelor Does Not Compromise Mortality Benefit

Key Points:
In ACS patients, dyspnea more common with ticagrelor vs. clopidogrel
Episodes typically mild or moderate, self-limiting
No impact seen on ticagrelor’s mortality benefit
By Kim Dalton
Wednesday, August 03, 2011

Despite a higher incidence of dyspnea among patients with acute coronary syndromes (ACS) on ticagrelor compared with clopidogrel, the side effect is usually not serious and resolves spontaneously or after stopping the newer antiplatelet. Just as important, dyspnea does not attenuate the mortality advantage of ticagrelor, according to a subanalysis of the PLATO trial published online July 30, 2011, ahead of print in the European Heart Journal.

The subanalysis’ core findings were first presented in August 2010 at the European Society of Cardiology Congress in Stockholm, Sweden.

In the main PLATO (Study of PLATelet Inhibition and Patient Outcomes) trial, 18,624 ACS patients were randomized to clopidogrel (300-600 loading dose plus 75 mg daily) or ticagrelor (10 mg loading dose and 90 mg twice a day) for up to 12 months. At 1 year, the primary endpoint of death from vascular causes, MI, or stroke had occurred in significantly fewer patients in the ticagrelor group compared with the clopidogrel group (9.8% vs. 11.7%; P < 0.001).

For the current study, investigators led by Robert F. Storey, MD, of the University of Sheffield (Sheffield, United Kingdom), characterized the dyspnea reported in the original trial and investigated its effect on clinical outcomes. A total of 18,421 (98.9%) patients received at least 1 dose of their assigned drug (n = 9,235 for ticagrelor; n = 9,186 for clopidogrel) and were considered for the analysis.

Patients with Baseline Dyspnea Included

At enrollment, about 20% of patients in both treatment arms had a history of dyspnea; nearly 14% continued to experience the condition, with heart failure the most common suspected cause, followed by COPD and asthma.

Over 1-year follow-up, 14.5% of ticagrelor-treated patients and 8.7% of clopidogrel-treated patients developed dyspnea. However, only 0.4% and 0.3% of cases, respectively, were judged by the investigators to be severe.

A greater proportion of dyspnea events in the ticagrelor group than in the clopidogrel group were considered to be of unexplained or unknown etiology (27.3% vs. 20.1%) and a smaller proportion were thought to be due to cardiac-related heart failure (23.7% vs. 30.8%).

Overall, patients with dyspnea were older and more likely to have diabetes or chronic renal disease. Not surprisingly, patients in both treatment groups who had dyspnea during follow-up were more likely to have experienced the condition prior to enrollment, often associated with heart failure, COPD, and/or asthma. However, the excess dyspnea in the ticagrelor group compared with the clopidogrel group was consistent whether patients did (20.2% vs. 14.7%) or did not (13.1% vs. 7.1%) have a history of the condition.

Another difference between the treatment arms is that ticagrelor patients were more likely than clopidogrel patients to develop dyspnea within 7 days of drug initiation. Moreover, 15% of cases in the ticagrelor group were categorized by the trial investigators as causally related to the study medication compared with 6.9% of cases in the clopidogrel group (P < 0.0001).

Among those who experienced dyspnea, 26.2% of ticagrelor patients and 22.3% of clopidogrel patients prematurely discontinued their medication (P = 0.043), with the excess in the ticagrelor group being specifically attributable to dyspnea (5.9% vs. 1.6%; P < 0.0001). The dyspnea-specific discontinuation rates represent 0.9% and 0.1% of the respective overall treatment groups.

About 30 days after discontinuation of the study medications, 5.0% of ticagrelor patients and 3.1% of clopidogrel patients had ongoing dyspnea (P < 0.0001).

Ticagrelor’s Efficacy Preserved

By 1 year, the primary endpoint occurred more often among patients with vs. without dyspnea in both the ticagrelor (11.9% vs. 9.4%; P < 0.001) and clopidogrel groups (15.7% vs. 11.2%; P = 0.008), in part due to a higher incidence of MI. However, after excluding patients whose dyspnea developed in the wake of an MI and possible heart failure, Kaplan-Meier analysis showed a trend toward reduced total mortality as well as numerically lower rates of the primary endpoint, MI, and cardiovascular death in the ticagrelor arm, in line with the overall trial results (table 1).

Table 1. One-Year Outcomes in Patients with Dyspnea

Ticagrelor
(n = 1,293)
Clopidogrel
(n = 753)
Adjusted HR (95% CI)
P Value

Primary Endpoint
8.8%
10.4%
0.91 (0.67-1.23)
0.542

MI
5.4%
5.7%
1.01 (0.68-1.52)
0.945

CV Death
3.1%
4.8%
0.72 (0.45-1.16)
0.179

Total Mortality
3.7%
6.2%
0.67 (0.44-1.02)
0.060

Moreover, a landmark analysis showed that patients who reported dyspnea within the first 30 days continued to experience substantially lower cardiovascular and total mortality rates with ticagrelor from 31 days onward.

In PLATO, Holter monitoring in a subset of patients during the first week of treatment revealed a higher incidence of ventricular pauses longer than 3 seconds in the ticagrelor compared with the clopidogrel group. In this analysis, such pauses were not more common among ticagrelor patients with vs. without dyspnea.

As a whole, the current findings “at least provide reassurance that there does not appear to be any loss of treatment effect in those ticagrelor-treated patients who develop dyspnea as a side effect,” Dr. Storey and colleagues conclude. “It is particularly encouraging that the ticagrelor-treated patients with dyspnea had similar mortality rates to those without dyspnea despite having overall higher risk characteristics including greater mean age and higher incidence of diabetes mellitus and chronic renal disease.”

The finding from the ONSET/OFFSET trial (Storey RF, et al. J Am Coll Cardiol. 2010;56:185-193) that ticagrelor-related dyspnea was not associated with increases in serum NT-pro-BNP level or changes in left ventricular systolic function was replicated in this analysis, the investigators say. “This suggests that measurement of serum NT-pro-BNP may help differentiate ticagrelor-related dyspnea from a sign of heart failure and thus avoid unnecessary prescription of loop diuretics for heart failure,” they observe.

Safe But Not Necessarily Prudent

These data support the safety of giving ticagrelor to ACS patients who have COPD or heart failure, at least in the context of a carefully monitored clinical trial, said Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), in a telephone interview with TCTMD. But, he added, “physicians will need some hands-on experience to see how this plays out in real life.”

The concern is that if patients experience dyspnea, they will discontinue the medication on their own, he noted, adding, “I wouldn’t just say to a patient, ‘It’s not a big deal,’ because if a patient feels breathless, that’s a big deal for them and they’re not necessarily going to know that this is probably just a relatively benign side effect.

“Once ticagrelor is actually available, my first use will likely not be in a patient who has baseline dyspnea,” Dr. Bhatt said. “I would want first to become familiar with [the drug] in patients who are likely to tolerate it well. That’s not because I think there’s a safety issue, but for practical reasons. In real life, if a patient is dyspneic and becomes more dyspneic, evaluating that can get tricky. It requires a thorough evaluation.”

When dyspnea is caused by ticagrelor, it appears to manifest earlier rather than later. That pattern could be useful in differentiating the etiology, Dr. Bhatt said, though he cautioned that it is “not ironclad.”

According to Dr. Bhatt, ticagrelor is a major advance in the treatment of ACS, but he stressed, “I don’t think it makes sense to push a patient with dyspnea too hard and risk him getting no antiplatelet therapy. I would switch him to clopidogrel or, if it were a stented patient with a low bleeding risk, to prasugrel.”

Despite its apparently benign nature, this side effect adds to the complexity of managing patients on antiplatelet therapy because now both doctors and patients need education not only about bleeding but also the potential for dyspnea, Dr. Bhatt said. “We have to make sure that if patients develop any new symptom like dyspnea or bleeding, they give their cardiologist a call,” he added.

Better to ‘Work Through’ Dyspnea?

In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), noted, “Perhaps the most important message of the study is that dyspnea is not a sign of abnormal response to ticagrelor but rather just a side effect.”

But unlike Dr. Bhatt, Dr. Brener said he would not hesitate to prescribe ticagrelor to patients with COPD or heart failure. “It is a lot like beta blockers for COPD. We try it and a small percentage of people don’t tolerate it so we take them off,” he said, characterizing the 0.9% discontinuation rate of ticagrelor as “nothing.”

If a patient does develop dyspnea while on ticagrelor, it is clearly important to determine whether or not the condition is due to heart failure, Dr. Brener said. “But if the patient does not have heart failure, I wouldn’t be in a hurry to take them off the drug,” he added. “I would first try to get them to work through [the dyspnea].”



Source:
Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J. 2011;Epub ahead of print.

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Study: Smoking doubles risk for AF

Chamberlain A. Heart Rhythm. 2011;doi:10.1016/j.hrthm.2011.03.038.

Among participants of the Atherosclerosis Risk in Communities study, those who smoked were twice as likely to develop atrial fibrillation as those who did not. Although at a lesser risk, former smokers were also at an increased for developing the arrhythmia.

“AF is a serious health issue that decreases quality of life and significantly increases the risk of stroke,” Alanna M. Chamberlain, PhD, study co-author from the department of health sciences research at Mayo Clinic in Rochester, Minn., said in a press release. “It is my hope that our study findings will shed more light on the impact that smoking has on CVDs, and help individuals realize they can play a role in preventing the development of AF.”

The prospective study involved individuals who were either current (n=4,005), former (n=4,950) or who had never been smokers (n=6,374). Chamberlain and colleagues examined the effect of smoking status on the risk of incident AF starting at baseline (1987-1989) and ending in December 2002.

During follow up, they reported 876 AF events among participants. Compared with those who never smoked, current (HR=2.05; 95% CI, 1.17-2.47) and former (HR=1.32; 95% CI, 1.10-1.57) smokers had an elevated risk for incident AF. Specifically, among smokers, those who smoked the heaviest, or those smoking the equivalent of one pack a day for 40 years, had the greatest risk for incident AF (HR=2.31). However, quitting smoking did moderately reduce the risk for AF vs. those who continued (HR=0.88).

These results, according to researchers, remained consistent regardless of gender or race of the participant, as well as whether the event was AF or atrial flutter.
__________________________________________________ _______________________
US lacking participants in NHLBI-backed randomized CV trials

Kim E. J Am Coll Cardiol. 2011;58:671-676.

The percentage of international participation in CV randomized controlled trials sponsored by the National Heart, Lung and Blood Institute was substantial when compared with US participation, results from a new study suggested.

Researchers used The NIH registry to search for phase III or IV CV randomized controlled trials (RCTs) funded by the NHLBI that had an outcome of MI, stroke or death and were published between 1997 and 2009. Of the 1,488 that were funded by the NHLBI, only 24 studies met the full criteria.

International participation (IP) was found in 19 trials that included 151,682 patients. The median IP was 9.5%. Across 11 coronary artery disease trials, nearly 50% of them had international enrollment. High IP was also found in high-risk trials and trials testing acute interventions.

Out of all CV RCTs, CAD trials had the most substantial rates of international enrollment. The researchers also noted that the most commonly listed international site was Canada (16 of 24 trials were conducted there), and that decreased participation of US patients in NHLBI-sponsored CV trials is a cause for concern.

In an accompanying editorial, Robert M. Califf, MD, of the Duke University School of Medicine, and Robert A. Harrington, MD, of the Duke Clinical Research Institute, both in Durham, N.C., reiterated the importance of both conducting more CV RCTs in the US and increasing participant enrollment at US-based sites.

“This report by Kim and colleagues represents a wake-up call. If we fail to heed it, we may see the US clinical research enterprise go the way of so many other American industries: lost to more efficient overseas competitors,” the authors wrote. “Such an outcome would be more than an economic disaster. It would also deprive the American public relevant, high-quality evidence essential for making appropriate decisions about health care.”
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More death certificates cite diabetes as underlying cause of death

McEwen LN. Diabetes Care. 2011;34:1529-1533.

Death certificates now list diabetes as the underlying cause of death more often than in previous years, data from the Translating Research into Action for Diabetes trial suggest.

Of 2,261 participants enrolled in the study who died from 2000 to 2007, 41% had diabetes listed on their death certificates and 13% cited the disease as the underlying cause of death. These findings indicated increased reporting of diabetes as the underlying cause of death over time, the researchers said, although the frequency of the disease’s appearance on death certificates in general remained unchanged.

In contrast, the listing of cardiovascular disease as an underlying cause of death declined significantly throughout the study period, a factor that may have played a role in the increased reporting of diabetes as an underlying cause of death, the researchers said. They attributed this trend to a decrease in the reporting of cardiac causes of death for men and cerebrovascular causes of death for women. Diabetes was more likely to be recorded anywhere on the death certificate in decedents with CVD cited as the underlying cause of death.

“Although diabetes listed as any cause of death was stable over time, we have observed a statistically significant increase in reporting of diabetes as the underlying cause of death on death certificates between 2001 and 2008 independent of age at death and duration of diabetes at death,” the researchers wrote. “If this trend is indeed occurring on a national level, it may complicate the interpretation of mortality rates ascertained from death certificates.”

Могу выложить полный текст этой статьи.

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Risk factors at middle age adversely affect brain size, function later in life

Debette S. Neurology. 2011;77:461-468.

Diabetes, high BP, smoking and being overweight during middle age may have severe consequences on brain aging and cognition a decade later, new study results suggested.

“These factors appeared to cause the brain to lose volume, to develop lesions secondary to presumed vascular injury, and also appeared to affect its ability to plan and make decisions as quickly as 10 years later. A different pattern of association was observed for each of the factors,” Charles DeCarli, MD, study researcher with the University of California at Davis in Sacramento, said in a press release.

DeCarli and researchers looked at 1,352 participants (mean age, 54 years) without dementia from the Framingham Offspring Study to determine the association between midlife vascular risk factors and change in MRI markers of brain injury and cognitive function 10 years later.

They reported that hypertension was associated with accelerated white matter hyperintensity volume (P<.001), one of the MRI markers, and a decline in executive function (P=.012), whereas diabetes correlated with a marked increase in temporal horn volume (P=.012), a marker for accelerated hippocampal atrophy. Smoking also correlated with a rise in temporal horn volume (P=.012), while additionally proving detrimental to both total brain volume (P=.025) and extensive change in white matter hyperintensity volume (P=.021).

Furthermore, obesity was a predictor of a top quartile change in executive function (P=.035), whereas increasing waist-to-hip ratio led to a decline in total brain volume (P=.021).

“Our findings provide evidence that identifying these risk factors early in people of middle age could be useful in screening people for at-risk dementia and encouraging people to make changes to their lifestyle before it’s too late,” DeCarli said.

Disclosure: Dr. DeCarli serves as a consultant for Takeda Pharmaceutical Company Limited and Avanir Pharmaceuticals; receives research support from Merck Serono and the NIH; and is the editor-in-chief of Alzheimer Disease and Associated Disorders.

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APPRAISE-2: Apixaban failed to meet primary efficacy, safety endpoints

Alexander J. N Engl J Med. 2011;doi:10.1056/NEJMoa1105819.

The oral direct factor Xa inhibitor apixaban did not significantly improve the primary efficacy endpoint of patients with an acute coronary syndrome and substantially increased the risk for major bleeding, resulting in the early termination of the APPRAISE-2 trial.

“The results of the current trial raise doubt about whether meaningful incremental efficacy can be achieved with an acceptable risk of bleeding by combining a long-term oral anticoagulant with both aspirin and a P2Y12-receptor antagonist in patients with coronary disease,” the researchers wrote.

The Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2) trial was a double blind, placebo-controlled trial in which 7,392 patients with a recent ACS and at least two additional risk factors for recurrent ischemic events were randomly assigned to twice-daily 5 mg apixaban (Bristol-Myers Squibb, Pfizer; n=3,705) or placebo (n=3,687), besides standard antiplatelet therapy.

During follow-up (median, 241 days), the primary efficacy outcome of a composite of CV death, MI or ischemic stroke was not significantly improved in the apixaban group (HR=0.95; P=.51). Further analysis indicated that the study’s primary safety endpoint of major bleeding, as stated in the Thrombolysis in Myocardial Infarction definition, occurred significantly more often among those given apixaban (HR=2.59; P=.001), with a greater number of intracranial and fatal bleeding events reported vs. placebo.

“(The findings) definitively confirm the increases in bleeding observed in the phase 2 trials of factor Xa inhibitors administered in addition to antiplatelet therapy,” the researchers concluded. “Unfortunately, the reductions in ischemic events suggested in the phase 2 trial were not observed in this larger phase 3 trial.”

The trial was funded by Bristol-Myers Squibb and Pfizer.
__________________________________________________ _________________________
Torcetrapib raised HDL, may help control diabetes

An analysis of the ILLUMINATE trial data revealed new findings: Torcetrapib, a cholesteryl ester transfer protein inhibitor, may improve HDL levels and blood glucose in those with diabetes who are also taking a statin.

Researchers discovered the beneficial effects of torcetrapib while analyzing data from the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, which was halted in 2006 because patients with diabetes assigned to torcetrapib and atorvastatin (Lipitor, Pfizer) had more cardiovascular problems and a higher mortality rate vs. patients assigned to atorvastatin and a placebo. Researchers later determined that the adverse events were related to other effects of torcetrapib, not its cholesteryl ester transfer protein (CETP) inhibition, according to a press release from the American Heart Association.

Data from ILLUMINATE showed that after 3 months of treatment, more than 6,600 patients with diabetes who were taking torcetrapib and atorvastatin had lower fasting blood glucose levels (0.34 mmol/L) and fasting insulin levels (11.7 mcU/mL) than patients taking statin and placebo. Insulin resistance also improved in the investigational combination therapy group. After 6 months, average blood glucose levels were lower in the torcetrapib and atorvastatin group (7.06%) compared with the statin and placebo group (7.29%). Additionally, HDL levels improved 66.8% after 1 year with torcetrapib and atorvastatin compared with a minimal change with statin and placebo. Researchers said it is unclear whether torcetrapib’s effect on HDL may account, in part, for the improvement in diabetes control. Torcetrapib also improved glucose and insulin measurements in study participants without diabetes, although not as much.

“The possibility that CETP inhibitor drugs may not only reduce the risk of [myocardial infarction] and stroke, but may also improve the control of blood sugar in people with diabetes, is an exciting prospect that may translate into real health benefits for people with diabetes,” Philip Barter, MBBS, PhD, director of the Heart Research Institute at University of Sydney, Australia, said in a press release.

Although torcetrapib’s effect on diabetes was not as effective as other commonly used antidiabetic therapies, “inhibition of CETP has the potential to prevent a worsening of diabetic control that often occurs in people taking statin drugs,” Barter said.

ILLUMINATE included more than 15,000 participants aged 45 to 75 years with a history of MI, stroke, chest pain, peripheral vascular disease or cardiac revascularization, and all were taking antidiabetic therapies.

Although the development of torcetrapib was halted, researchers said two other CETP inhibitors that do not cause the adverse effects — dalcetrapib and anacetrapib — are in the drug approval pipeline.

In an accompanying editorial, Stephen D. Wiviott, MD, a member of the TIMI Study Group and from the CV division at Brigham and Women’s Hospital, Harvard School of Medicine, said “this analysis may provide additional insight into the relationships between two key risk factors for CV disease, lipids (in particular, HDL) and glycemia.”

However, Wiviott said the glycemic findings from ILLUMINATE may be due to chance, as is the case in some post hoc analyses.

“With these important reductions of key surrogate markers of the risk of CV disease, including LDL, HDL, triglycerides and glycemia, this seems like a drug that should be widely prescribed to those at risk for CVD. Of course, it is not now, and will never be, prescribed to our patients for these indications. The reason for this is that, despite the observed benefits on these key surrogates, patients treated with torcetrapib in ILLUMINATE had 25% more CV events, including 58% more total deaths than those treated with placebo,” Wiviott wrote.

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Sirolimus- and probucol-eluting stent shows promise

Massberg S. Circulation. 2011;124:624-632.

A sirolimus- and probucol-eluting stent demonstrated noninferiority to a zotarolimus-eluting stent regarding a host of clinical endpoints, according to study results.

The current trial involved 3,002 patients randomly assigned to the dual-drug stent or the zotarolimus-eluting stent. The aim was to demonstrate noninferiority of the dual-drug stent by evaluating for a composite primary endpoint of the combined incidence of cardiac death, target vessel-related MI or target lesion revascularization. The overall follow-up period was 1 year, with angiography scheduled at 6 to 8 months.

The sirolimus- and probucol-eluting stent yielded a 13.1% incidence rate for the combined primary endpoint vs. 13.5% for the zotarolimus-eluting stent, which the researchers said was noninferior (HR=0.97, 95% CI, 0.78-1.19).

The dual-drug stent was linked to a 1.1% incidence rate of definite/probable stent thrombosis vs. a 1.2% rate in the zotarolimus group (HR=0.91; 95% CI, 0.45-1.84).

No differences were observed in terms of angiographic efficacy. In-segment binary angiographic restenosis was 13.3% in the dual-drug group and 13.4% in the zotarolimus group (P=.95); in-stent late luminal loss was 0.31 ± 0.58 mm in the dual-drug group and 0.29 ± 0.56 mm in the zotarolimus group (P=.46).

Researchers from sites in Germany said two stents — the polymer-free dual-drug sirolimus- and probucol-eluting stent and a new generation permanent polymer zotarolimus-eluting stent — have demonstrated encouraging results in light of adverse events associated with durable polymer coatings after drug-eluting stent implantation.
__________________________________________________ ______________________
IRS1 gene variant improved insulin control for patients on certain diets
Qi Q. Circulation. 2011;124:563-571.

A high-carbohydrate, low-fat diet may improve insulin control among patients with a specific variant in the IRS1 gene, according to recent results.

The aim of the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial was to investigate whether the rs2943641 variant in the IRS1 gene, which has recently been linked to insulin resistance and hyperinsulinemia, modifies the long-term changes in insulin resistance and body weight in response to weight-loss diets.

Researchers from several sites in the United States genotyped this variant in 738 overweight adults. Eligible participants had been randomly assigned to one of four diets varying in macronutrient contents. The diet lasted 2 years, during which progress in fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and weight loss by genotypes were assessed.

Among patients in the high-carbohydrate diet group, 6-month results indicated that participants with the risk-conferring CC genotype experienced greater decreases in insulin (P=.009), HOMA-IR (P=.015) and weight loss (P=.018) than those without this genotype. Among patients in the low-carbohydrate diet group, an opposite genotype effect on changes in insulin and HOMA-IR (P≤.05) was observed.

The other two diet groups did not experience significant differences across genotypes. “The tests for genotype by intervention interactions were all significant (P<.05),” the researchers said.

The genotype effect on changes in insulin and HOMA-IR continued to be significant at 2 years among those on the diet with the highest carbohydrate content (P<.05). The 2-year results also indicated that the high-carbohydrate diet yielded greater improvements in insulin and HOMA-IR (P for genotype-time interaction ≤.009) in participants with the CC genotype than those without this genotype.

“Individuals with the IRS1 rs2943641 CC genotype might obtain more benefits in weight loss and improvement of insulin resistance than those without this genotype by choosing a high-carbohydrate and low-fat diet,” the researchers wrote.

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Oral Xa Drug Matches Warfarin in Afib

By Crystal Phend, Senior Staff Writer, MedPage Today
August 10, 2011

This randomized controlled trial compared rivaroxaban, an oral factor Xa inhibitor, to warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation.

Rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolization in both the per-protocol and intention-to-treat analysis. Rivaroxaban was not superior to warfain in the intention-to-treat analysis.

There was no difference in major bleeding between warfarin and rivaroxaban.
Review
The oral factor Xa inhibitor rivaroxaban (Xarelto) is at least as good as warfarin for stroke prevention in atrial fibrillation, with a similar rate of major bleeding and greater ease of use.

In the per protocol analysis, stroke or systemic embolism occurred at a rate of 1.7% per year with rivaroxaban compared with 2.2% per year with warfarin, Manesh R. Patel, MD, of Duke University Medical Center in Durham, N.C., and colleagues reported in the pivotal ROCKET-AF trial.

Rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolization in both the per-protocol (P<0.001) and intention-to-treat analyses (P<0.001), according to the study published online in the New England Journal of Medicine.

In the as-treated safety analysis, in which subjects must have received at least one dose of a study drug and included events which occurred while receiving the assigned drug or within two days after discontinuation, rivaroxaban was superior to warfarin (P=0.01). Rivaroxaban was not superior in the intention-to-treat analysis (P=0.12).

"For sure it's at least as good as warfarin," Patel told MedPage Today. "It's a once-a-day therapy without monitoring ... so there are some clear potential advantages here."

Safety may be another attractive point, he noted in the interview.

Although overall bleeding events didn't differ significantly for the two treatments (annual rate 14.9% rivaroxaban versus 14.5% warfarin, P=0.44), intracranial hemorrhage fell to 0.5% with rivaroxaban compared with 0.7% on warfarin (P=0.02).

Fatal bleeds also dropped to 0.2% and 0.5%, respectively (P=0.003), for a trend to fewer deaths overall in the as-treated safety population (1.9% versus 2.2% per year, P=0.07).

Bleeding from GI sites, bleeding that reduced hemoglobin levels, and bleeding that required transfusion, however, were all significantly more common with rivaroxaban, the researchers noted.

A significant increased risk of major bleeding from a gastrointestinal site occurred in the rivaroxaban arm (3.2% versus 2.2%, P<0.001).

These findings matched those reported at the American Heart Association meeting last November that led drugmaker Johnson & Johnson to apply to the FDA in January for an indication in stroke prevention in atrial fibrillation for rivaroxaban.

The drug won FDA approval last month for a separate indication -- prevention of deep vein thrombosis in patients undergoing knee or hip replacement surgery, adding to a rapidly changing landscape in anticoagulation choices.

Another new agent, the direct thrombin inhibitor dabigatran (Pradaxa) was approved for stroke prevention in atrial fibrillation last October based on the RE-LY study results showing noninferiority to warfarin at a low dose and superiority at a high dose. The higher dose, 150 mg twice daily, was approved by the FDA for use in atrial fibrillation.

Oral alternatives to warfarin for atrial fibrillation have arrived, Gregory J. del Zoppo, MD, of the University of Washington in Seattle, and Misha Eliasziw, PhD, of the University of Calgary, Alberta, announced in an editorial accompanying the NEJM paper.

"Their simplicity of use is attractive," del Zoppo and Eliasziw wrote, "and they appear to have an efficacy similar to that of warfarin, with the proviso that comparisons seem to depend on how easily the patient can be treated with warfarin."

Rivaroxaban and dabigatran don't require the blood tests, special diet, or alcohol restrictions necessary with warfarin.

Among the 14,264 ROCKET-AF patients, those randomized to warfarin were in the therapeutic INR range only 55% of the time on average, which Patel acknowledged was lower than in other anticoagulant trials.

In RE-LY, time in therapeutic range in the warfarin arm averaged 64%.

While less than optimal, the difficulty with management in ROCKET-AF "may be a reflection of what life is like in community practice," noted stroke expert Ralph Sacco, MD, of the University of Miami and AHA immediate past president.

Patel pointed to the trial's population as the oldest enrolled, with more high-risk patients, higher levels of comorbidity, and a geographic diversity across 45 countries, including some that used lower INR targets and others with poor INR management.

But, the group noted, "The efficacy of rivaroxaban, as compared with warfarin, was as favorable in centers with the best INR control as in those with poorer control."

ROCKET-AF and RE-LY both found no reduction in overall major and nonmajor clinically relevant bleeding over warfarin but lower intracranial bleeding risk.

One reason may be that both rivaroxaban and dabigatran impact a single hemostatic target whereas warfarin hits multiple targets, the editorialists suggested.

Neither trial addressed the lack of antidotes to these drugs that would be needed to reverse their anticoagulant effects in the case of life-threatening hemorrhage or surgery, del Zoppo and Eliasziw warned.

"All these issues need to be taken into account in clinical decision making," they concluded in the editorial.

Sacco agreed that physicians, patients, and professional organizations will have a job ahead of them sorting out the nuances of trial design, statistics, and pros and cons of the various anticoagulants on the horizon for stroke prevention in atrial fibrillation.

"Any new medication to help reduce stroke risk among those with atrial fibrillation would be helpful," he told MedPage Today. "What may happen, which I think would be a good thing, is there may be multiple options."

The study was funded by Johnson & Johnson and Bayer.

Patel reported having received money to his institution from Johnson & Johnson in the form of research grants and travel and trial activities, serving on an advisory board to Genzyme, and consulting for Ortho McNeil Jansen and Bayer Healthcare regarding rivaroxaban.

del Zoppo reported having no conflicts of interest to disclose.

Eliasziw reported having received funds from the National Institute of Neurological Disorders and Stroke for serving on the data safety monitoring board of the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial.

[Chevychelov]

Men, Leaner Folks Less Likely to Be Treated for High BP

By Kristina Fiore, Staff Writer, MedPage Today
Published: August 10, 2011
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Note that this report reviewed NHANES surveys to identify clinical characteristics associated with untreated hypertension, uncontrolled hypertension and apparent treatment-resistant hypertension.


Consider that this study found that in the years 2005 to 2008, more than half of uncontrolled hypertensives were untreated and unaware of their hypertension. Also note that the prevalence of apparent treatment-resistant hypertension increased significantly in the last survey and appeared to be associated with aging, obesity and diabetes.

Men and patients who are leaner and generally healthier are less likely to have their hypertension treated, researchers said.

Male sex, body mass index (BMI) below 25 kg/m2, lack of chronic kidney disease, lower heart disease risk, and making fewer visits to the doctor were associated with high blood pressure going untreated, Brent Egan, MD, of the Medical University of South Carolina in Charleston, and colleagues reported online in Circulation: Journal of the American Heart Association.

When patients were treated, those whose hypertension remained uncontrolled on one or two medications were more likely to be older and have a greater risk of heart disease, while those who were treatment-resistant (uncontrolled on three drugs or more) also had a higher risk of heart disease; but they went to the doctor more frequently, were obese, and had chronic kidney disease, too.

Defining the characteristics of these uncontrolled hypertensive patients may facilitate efforts to improve blood pressure control, the researchers said.

"Overall, physicians are doing a very good job treating and controlling hypertension," Egan said in an email to MedPage Today. "Yet there is still room for improvement."

Although the proportions of untreated and uncontrolled hypertensive patients have fallen in recent years, more than 30 million hypertensive patients remain uncontrolled in the U.S., they said.

In order to define the characteristics of both groups of patients, the researchers looked at data on 13,375 hypertensive adults from three periods of the National Health and Nutrition Examination Survey (NHANES): 1988-1994, 1999-2004, and 2005-2008.

Overall, the proportion of uncontrolled hypertensive patients fell from 73.2% in 1988-1994 to 52.5% in 2005-2008.

Clinical factors linked with untreated hypertension included male sex, infrequent healthcare visits, BMI of 25 kg/m2 or below, absence of chronic kidney disease, and 10-year Framingham heart risk below 10% (P<0.01 for all).

Egan and colleagues said that infrequent healthcare visits is a major issue in this population, with a mean of more than 40% of untreated hypertensive patients in all survey periods reporting none or just one trip to the doctor annually.

This finding suggests that increasing health care use in all settings "is critical in reducing the burden of untreated hypertension," they wrote. "Raising the perceived value of regular preventive health care services among those without clinically overt disease emerges as an important complementary educational strategy."

About a third of all uncontrolled patients reported taking one or two antihypertensive medications in all three study periods, the researchers said. These patients were older and had higher Framingham risk scores than those who were controlled on this number of medications (P<0.01). In two of the study periods, uncontrolled patients were also more likely to be male, have Hispanic ethnicity, and fewer healthcare visits.

A "logical option," Egan and colleagues wrote, would be to add an additional antihypertensive to these patients' drug regimens, as the majority "appear to be seen frequently enough to allow treatment intensification."

Said therapeutic inertia, or the failure to further treatment when patients are uncontrolled, appears to reflect a patient-provider interaction.

"In addition to provider interventions," the researchers wrote, "educating patients, especially those at higher risk, on the importance of blood pressure control may facilitate efforts to overcome therapeutic inertia."

They said the data also suggest that medication selection affects control. Those uncontrolled on one or two medications were less likely to report taking a diuretic, an ACE inhibitor, or an angiotensin receptor blocker than those who were controlled on this number of drugs -- which "aligns with the efficacy of diuretics and renin-angiotensin system blockers, especially in combination, for blood pressure control," the researchers wrote.

Apparent treatment-resistant hypertension -- disease that was uncontrolled with three or more drugs -- increased from 15.9% to 28% of treated patients between 1988 and 2008 (P<0.001).

"The rise in treatment-resistant hypertension is of real concern, and reflects a population which is aging and more obese with more diabetes and chronic kidney disease," Egan said in an email to MedPage Today.

Indeed, the clinical characteristics associated with treatment-resistant disease included obesity, chronic kidney disease, more frequent healthcare visits (four or more per year), and Framingham risk scores above 20% (P<0.01).

Infrequent use of aldosterone antagonists among this group of patients was notable, the researchers said, as several trials have shown that adding one of these agents to treatment regimens lowers systolic blood pressure by 20 to 25 mm Hg and diastolic blood pressure by 10 to 15 mm Hg in refractory patients.

Egan and colleagues added that personalized medicine -- such as hemodynamic and renin-guided therapeutics -- and genetic testing may be effective complementary approaches for treatment-resistant patients.

Though the study was limited by a relatively small sample size, self-reported data, and hypertension defined by a single measurement, the researchers concluded that national efforts to increase healthcare insurance coverage and use of primary care services may be a boon to hypertension awareness, treatment, and control.

Egan said in order to improve control among their own patients, physicians should continue to encourage health lifestyle changes and promote medication adherence. He also urged an increase in dose or number of medications when treatment goals go unmet.

For those who are still uncontrolled on three or more drugs, he said, document blood pressure outside the office to evaluate a "white-coat" effect -- though he noted that this is a "controversial area" -- to confirm resistance. Then, consider either intensifying diuretic therapy or, "while not an established part of current guidelines," hemodynamic- or renin-guided treatment changes.

[Chevychelov]

Herceptin Heart Risks Clarified for Older Patients

By Charles Bankhead, Staff Writer, MedPage Today
August 10, 2011

Explain that older breast cancer patients with heart disease or diabetes have a significantly increased risk of cardiotoxicity when treated with trastuzumab (Herceptin).

Point out that around one-quarter of the patients had a cardiac event that had a time to onset ranging from three to 132 weeks after the start of trastuzumab-based therapy, and was not always reversible.
Review
Older breast cancer patients with heart disease or diabetes have a significantly increased risk of cardiotoxicity when treated with trastuzumab (Herceptin), according to data from a single-center chart review.

More than a fourth of patients had clinically significant declines in left ventricular ejection fraction (LVEF) during treatment with the anti-HER2 antibody. Two-thirds of the episodes (8 of 12) were asymptomatic.

Of the four patients who developed symptomatic congestive heart failure (CHF), three recovered heart function over several weeks, but one patient did not regain cardiac function despite stopping trastuzumab and receiving standard CHF therapy, as reported online in Annals of Oncology.


Even though most declines in heart function were asymptomatic and all but one patient regained function, the findings point to a need for caution, the authors noted.

"The fact that the mortality rate at five years after diagnosis of CHF is approximately 50% in patients older than 65 years warrants close surveillance of early symptoms and cardiac function in the elderly breast cancer population to be treated with trastuzumab," Cesar Serrano, MD, of Vall d'Hebron University Hospital in Barcelona, and coauthors wrote in conclusion.

Cardiotoxicity was an unanticipated adverse effect of trastuzumab. As as result, initial clinical trials of the agent did not mandate monitoring of cardiac function, according to the article's background. Moreover, studies that did require monitoring employed different types and intervals of monitoring, complicating efforts to compare or combine results.

In contrast to anthracycline-related cardiotoxicity, the adverse effects of trastuzumab are neither dose related nor cumulative. The severity of trastuzumab-related cardiotoxicity varies widely but usually is reversible with discontinuation of the drug, the authors continued.

A limitation of many clinical trials in oncology is the inclusion of few older patients. With respect to trastuzumab, clinical trials in breast cancer generally limited participation to women 65 or younger and with good performance status. Therefore, extrapolation of results to older or sicker patients requires caution, the authors wrote.

Given the benefits of trastuzumab and the lack information about cardiotoxicity in older patients, Serrano and coauthors reviewed their own clinical experience with the agent.

Examination of medical records revealed 45 breast cancer patients age 70 or older treated with trastuzumab. The patients' median age at the start of trastuzumab was 75.9, and 11 patients were older than 80. About 90% of the patients had performance status 0-1, 56% received neoadjuvant or adjuvant trastuzumab, and the remaining 44% received the drug for metastatic disease.

Assessment of LVEF was performed at baseline and after a median interval of 4.5 months. The baseline LVEF averaged 64%. Median duration of trastuzumab treatment was 49 weeks.

The authors found that 12 (26.7%) patients had a cardiac event that had a time to onset ranging from three to 132 weeks after the start of trastuzumab-based therapy. Every patient had at least one risk factor for cardiac disease and eight had two or more risk factors.

The four patients who developed symptomatic CHF had stage IV breast cancer. Their baseline LVEF values ranged from 50.8% to 70%, and the time to onset of CHF was three, five, nine, and 72 weeks. Trastuzumab was discontinued in all cases, and the time to recovery in three patients was three, five, and 21 weeks.

The one patient who did not recover heart function had the latest onset of symptomatic heart failure, one risk factor for heart disease, and a baseline LVEF of 63.8%.

The eight patients with asymptomatic declines in LVEF included five patients with stage IV cancer. The number of cardiac risk factors ranged from one to six, with baseline LVEF ranging from 57% to 71.8%. The time to recovery of heart function was nine weeks or less in six of the eight patients.

Comparison of patients with and without cardiotoxicity showed no differences in treatment duration, baseline LVEF, history of anthracycline therapy, or left-sided radiation therapy.

In general, patients who developed cardiotoxicity during trastuzumab therapy had more cardiac risk factors. However, only two factors remained statistically significant in a multivariate analysis: pre-existing cardiac disease or disorders (P=0.017) and diabetes (P=0.010).

Obesity was a significant factor in univariate analysis but dropped out in the multivariate analysis, and other conventional risk factors such as dyslipidemia and hypertension failed to make the cut in either analysis.

"The incidence of cancer increases greatly with age and about 70% of all newly diagnosed cancers are in patients older than 65 years," the authors noted in their discussion.

"Given the expected increase in the absolute number of elderly cancer patients over the coming decades, information about efficacy and safety of anticancer treatments is needed in this population, as to date, they have been frequently excluded from pivotal studies."

The authors advised caution when interpreting the data. They noted the small sample size and the "very limited power to detect small differences in multivariate analysis."

[Chevychelov]

PCI for Blocked Arteries of Lasting Benefit in Diabetes

By Todd Neale, Senior Staff Writer, August 12, 2011

Explain that three-year follow-up of diabetic patients undergoing successful PCI for chronic total occlusions found significantly lower mortality and requirement for later bypass grafting compared with those with a failed procedure.


Note that PCI success rates were equivalent for those with and without diabetes.
Review

Long-term outcomes for patients with diabetes were significantly improved following successful percutaneous coronary intervention (PCI) for chronic total occlusions, researchers found.

Through a median of three years of follow-up, the mortality rate following a successful procedure was significantly lower than an unsuccessful one (10.4% versus 13%, P<0.05), according to Roxana Mehran, MD, of the Cardiovascular Research Foundation in New York City, and colleagues.

There was also a substantial reduction in the need for CABG during follow-up after a successful PCI (2.4% versus 15.7%, P<0.01), the researchers reported online in the American Journal of Cardiology.

Patients who did not have diabetes also had a significant reduction in the need for CABG after a successful procedure (3.2% versus 12.2%, P<0.01), although there was not a significant mortality difference based on procedural success.

"The finding that patients with diabetes seem to benefit more from recanalization [in terms of mortality] could be explained by the higher event rates in this high-risk subgroup, which increases the statistical power to detect a significant difference in mortality," the authors explained.

Few data existed on the long-term outcomes of PCI for chronic total occlusions in patients with diabetes, Mehran and colleagues noted.

So to explore the issue, they evaluated data on 1,742 patients who underwent PCI for 1,802 chronic total occlusions at three centers in the U.S., South Korea, and Italy from 1998 to 2007. About a quarter (23%) had diabetes, and of those, 42% were insulin dependent.

The procedural success rate did not differ based on diabetes status -- it was 69.6% for patients with diabetes and 67.9% for those without diabetes (P=0.53).

In general, mortality during follow-up was higher in the those with diabetes, although the difference reached statistical significance in patients who had a successful procedure (13% versus 6.6%, P=0.01) but not in those who had a failed procedure (10.4% versus 5%, P=0.058).

In a multivariate model, insulin dependence was the strongest predictor of mortality in patients with diabetes, associated with a doubling of the risk of death (HR 2.25, 95% CI 1.04 to 4.87).

The vast majority of patients -- 96.4% of the diabetics and 94% of the non-diabetics -- received a stent during PCI. Most of the stents were drug-eluting.

The rate of major adverse cardiac events -- all-cause mortality, MI, and target vessel revascularization -- was significantly lower when drug-eluting stents were used in place of bare-metal stents in all patients regardless of diabetes status.

The difference was solely driven by a lower rate of target vessel revascularization in patients with diabetes (14.8% versus 54.1%) and without diabetes (17.6% versus 26.5%), which held up in multivariate analyses (P<0.01 for both).

Regardless of diabetes status, the rate of stent thrombosis was not increased when drug-eluting stents were used, "suggesting that drug-eluting stents are safe for chronic total occlusion PCI in patients with and without diabetes," according to the researchers.

"However, an adequately powered randomized trial or a well-designed very large registry is needed to confidently answer the question whether drug-eluting stents are as safe as bare-metal stents in chronic total occlusion PCI."

The authors acknowledged some limitations of the study, including the inability to distinguish between patients with diabetes treated with diet alone versus those treated with oral hypoglycemic therapy, the lack of information on periprocedural and postprocedural medications, and the lack of routine measurements of glycosylated hemoglobin during admission.

In addition, the drug-eluting stents used in the registry were predominantly first-generation sirolimus-eluting and paclitaxel-eluting stents.

[Chevychelov]

Women Have More Inappropriate Cardiac Nuc Scans

By Todd Neale, Senior Staff Writer, August 12, 2011

Explain that women are more likely than men to undergo a SPECT myocardial perfusion imaging study is classified as inappropriate by appropriate use criteria.


Note that overall, tests ordered by cardiologists were more likely to be appropriate and that most of the inappropriate studies were ordered by primary care physicians.
Review
Women are more likely than men to undergo a SPECT myocardial perfusion imaging study classified as inappropriate by appropriate use criteria, researchers found.

In a community teaching hospital, most of the appropriate scans (56%) were performed in men, whereas tests in women comprised the majority of inappropriate and uncertain studies (68% and 82%, respectively), according to Aarti Gupta, MD, of Miriam and Rhode Island Hospital in Providence, and colleagues.

With all other factors being equal, a woman had a nearly threefold greater risk of having an inappropriate test (RR 2.69, 95% CI 1.26 to 5.74), the researchers reported in the July/August issue of the Journal of Nuclear Cardiology.


In an accompanying editorial, Rupa Mehta, MD, of the University of Chicago, and Kim Allan Williams, MD, of Wayne State University in Detroit, suggested that the gender disparity could be a reflection of the greater likelihood that women with chest pain will present with atypical symptoms, such as shortness of breath and fatigue.

"With the higher rate of inappropriate testing in women, it is clear that physicians have a lower 'threshold' to order a stress test in women even when it does not fall into an appropriate ordering classification," they wrote. "This may reflect an understanding and appreciation for the atypical presentation of female cardiac patients."

In response to the rapidly growing use of myocardial perfusion imaging, several organizations, including the American College of Cardiology, American Heart Association, and American Society of Nuclear Cardiology, released appropriate use criteria in 2005.

But even with the growth of the technology, women continue to be under-tested, according to the researchers.

To see whether there was a gender disparity in the appropriateness of the scans that were ordered, Gupta and colleagues applied the criteria to 314 consecutive SPECT myocardial perfusion imaging tests performed at a single hospital; 48% were performed in women.

Overall, 84% of the scans were deemed appropriate, 11% inappropriate, and 5% uncertain.

Men had a higher rate of appropriate scans, and lower rates of inappropriate and uncertain scans compared with women (P<0.01).

To explore a possible reason for the disparity, the researchers examined appropriateness as it related to who was ordering the tests -- cardiologists or primary care physicians.

Overall, tests ordered by cardiologists were more likely to be appropriate (92% versus 79%, P=0.004). Most of the inappropriate studies (74%) were ordered by primary care physicians, as were most of the uncertain tests (94%).

"This could potentially be driven by a higher percentage of low-risk patients being tested by primary care physicians compared with cardiologists, or by cardiologists having a greater understanding of the appropriate use criteria and their application in clinical practice," Gupta and colleagues wrote.

But regardless of who ordered the test, scans performed in men were more likely to be appropriate than those performed in women.

The authors noted several studies that also found gender disparity among the inappropriate and uncertain SPECT tests, and the potential for various programs to reduce the overall number of inappropriate scans.

The study by Hendel et al. showed that the incorporation of appropriate use criteria into routine practice could reduce the number of inappropriate scans (J Am Coll Cardiol 2010; 55: 156-62). Whether women still had a higher number of inappropriate tests after the intervention was not stated in the study.

Gibbons et al. found more women had inappropriate tests, but after a formalized education effort, the overall number of inappropriate scans dropped (Circulation 2011; 123: 499- 503). The number rose again, however, two years later, which highlights the "importance of effective educational methods." The authors did not separate out results for women after the education intervention.

In their editorial, Mehta and Williams noted that a limitation of the current study by Gupta and colleagues was the lack of data on abnormalities identified on the scans, which would help to further classify the appropriateness of the tests and support or rebuff the clinical decision to perform the test.

"In an era where reimbursement is being challenged for patients that do not fall into specific criteria, we, as practitioners must fight to maintain our autonomy when ordering a test that might be deemed 'inappropriate' when based on clinical judgment," they wrote.

"We must provide evidence that certain patient cohorts, such as women, may require a higher 'inappropriate' imaging rate to diagnose disease, and that the use of these tests does indeed change long-term management and potentially save lives."

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Microvascular brain damage with aging and hypertension: pathophysiological consideration and clinical implications
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Comparison of Cardiac Risk Scores in ED Patients With Potential Acute Coronary Syndrome
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Inaccuracy of home sphygmomanometers: a perspective from clinical practice
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[Chevychelov]

Coronary CTA Findings Predict Mortality Risk, or Lack Thereof

Key Points:
Obstructive, nonobstructive disease on coronary CTA both confer higher mortality risk
Absence of CAD associated with low rate of incident death
More studies needed to understand age-, sex-related differences
By L.A. McKeown
Friday, August 12, 2011

Download this article's Factoid (PDF & PPT for Gold Subscribers)


Coronary CT angiography (CTA) may be useful in patients without known coronary artery disease (CAD) to stratify mortality risk as well as identify those in whom further additional testing and/or therapy is not warranted, according to a large international registry published in the August 16, 2011, issue of the Journal of the American College of Cardiology.

For the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) study, researchers led by James K. Min, MD, of Cedars-Sinai Medical Center (Los Angeles, CA), evaluated 24,775 consecutive patients without known CAD who underwent coronary CTA for suspected coronary disease at 12 centers between 2005 and 2009.

In the per-patient analysis, obstructive and nonobstructive CAD (50% stenosis threshold) conferred increased risk of mortality compared with patients without evident CAD. In a per-vessel analysis, incident mortality showed a dose-response relationship to the number of coronary vessels exhibiting obstructive CAD, with increasing risk observed for nonobstructive, obstructive 1-vessel, 2-vessel, or 3-vessel or left main disease (table 1).

Table 1. Per-Patient and Per-Vessel Analysis: CAD vs. Normal Arteries


Risk-Adjusted HR
95% CI
P Value

Per Patient
Nonobstructive
Obstructive

1.60
2.60

1.18-2.16
1.94-3.49

0.0023
< 0.0001

Per Vessel
Nonobstructive
1-Vessel
2-Vessel
3-Vessel or Left Main


1.62
2.00
2.92
3.70

1.20-2.19
1.43-2.82
2.00-4.25
2.58-5.29

0.0018
< 0.0001
< 0.0001
< 0.0001



Similarly, per-segment analysis found higher rates of mortality were associated with greater numbers of segments with plaque, stenosis-adjusted segments with plaque, any severe proximal stenosis, and any plaque within the left main.

Absence of CAD detection on coronary CTA was associated with a low annualized rate of incident death (0.28%).

Although risk of all-cause death rose for patients aged 65 years and older with extent and severity of CAD, younger patients (< 65 years of age), in comparison, had a marked increase in risk of death associated with 2- and 3-vessel or left main CAD compared with those who had no signs of CAD (table 2).

Table 2. All-Cause Death: CAD vs. Normal Arteries


HR
95% CI
P Value

Patients < 65 Years
2-Vessel
3-Vessel or Left Main

4.00
6.19

2.16-7.40
3.43-11.2

< 0.0001
< 0.0001

Patients ≥ 65 Years
2-Vessel
3-Vessel or Left Main

2.46
3.10

1.51-4.02
1.95-4.92

0.0003
< 0.0001



Compared with men, women had higher estimated pre-test probability of CAD, yet lower rates of both obstructive and nonobstructive CAD on coronary CTA. However, they experienced higher hazard ratios for mortality for 3-vessel or left main obstructive CAD and had similar rates of death for nonobstructive, 1-vessel, and 2-vessel disease.

Results Can Inform Guidelines, Appropriate Use Criteria

According to the study authors, CONFIRM had sufficient sample size and was adequately powered to allow differential risk stratification by age group and sex. Therefore, the data extend prior studies and are “widely generalizable,” they say, especially since the international cohort encompassed patients and clinical sites within North America, Europe, and Asia.

“That [coronary CTA] can effectively risk stratify individuals without known CAD should be invaluable for guiding the development of clinical practice guidelines and appropriate use criteria,” Dr. Min and colleagues write.

As to the differences between women and men undergoing coronary CTA, the investigators note that the generally lower prevalence of disease in women has been historically associated with lower rates of invasive coronary angiographic evaluation and often leads to exclusion of cardiac causes of symptoms in women, despite being more likely to be hospitalized for angina than men.

“It remains possible in this open-label study that the identification of nonobstructive noncardiac diagnoses for symptoms, and lack of aggressive treatment for these CAD findings resulted in heightened risk of incident death,” they write. “Future studies should carefully evaluate this potential explanation and should determine the effect of primary prevention with aggressive medical therapy in this cohort.”

The age differences may be related to younger patients with greater extent and severity of CAD having more aggressive forms of atherosclerosis than their older counterparts, thus resulting in a higher mortality risk than older patients with more insidious atherosclerosis, the study authors add.

Importantly, they point out that the low death rate in patients without CAD on coronary CTA “validates the favorable prognosis that has been uniformly observed in prior smaller registries and emphasizes a clinical value of [coronary CTA] for identification of individuals in whom no further additional testing and/or therapy is necessary or indicated.”

Importance of Linking Anatomy to Outcomes

In an editorial accompanying the study, Bernard De Bruyne, MD, PhD, and Carlos Van Mieghem, MD, PhD, of the Cardiovascular Center Aalst (Aalst, Belgium), report that the sample size of CONFIRM is almost 1 order of magnitude larger than all previous studies on coronary CTA-related outcomes and focuses on “the hardest possible endpoint.” Further strengthening the results, they conclude, is that selection bias is unlikely since more than 90% of patients had low or intermediate pre-test likelihood of CAD.

But Drs. DeBruyne and Van Mieghem caution that while the likelihood of finding some degree of atherosclerosis on coronary CTA is high, it has long been recognized that how the arterial lumen appears on angiography does not necessarily indicate function or effect on myocardial blood flow. In other words, anatomy is only one of many factors that define symptoms and prognosis.

“Nevertheless, the visual impression of the luminogram and the sacred threshold of 50% diameter stenosis remain pivotal to the very definition of the presence of coronary artery disease; for the description of its extent in 1-, 2-, or 3-vessel disease; and constitute the basis for the vast majority of individual clinical decisions regarding revascularization,” they write.

The challenge for clinicians, according to the editorialists, is to properly integrate anatomy and function in the same setting to aid in diagnosis and treatment. Another area that holds promise for doing just that is the use of noninvasive fractional flow reserve (FFR), which involves calculating FFR from patient-specific coronary CTA data using computational fluid dynamics during rest and simulated maximal coronary hyperemic conditions.

“If cardiac imaging is to affect the individual clinical decision-making process, it must reconnect us with a basic foundation of cardiology that is, in fact, physiology,” they write.

Study Details

The study cohort was primarily male (54%) and middle-aged (57 ± 13 years), with a high prevalence of cardiovascular risk factors and symptoms. The majority presented with typical or atypical angina and intermediate or high pre-test likelihood of obstructive CAD.



Sources:
1. Min JK, Dunning A, Lin FY, et al. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings. Results from the international multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol. 2011;58:849-860.

2. De Bruyne B, Van Mieghem C. Coronary computed tomography angiography: CONFIRMations and perspectives. J Am Coll Cardiol. 2011;58:861-862.

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PFO-Stroke Link Takes Another Hit

Key Points:
Recurrent cerebrovascular event rate in PFO-cryptogenic stroke patients 20.3% with medical therapy vs. 10.7% after percutaneous closure over 8.7 years
Concurrent etiologies judged likely as causative in 38% of medical group, 44% of closure group
Study casts further doubt on causal role for PFO in stroke recurrence
By Jason Kahn
Thursday, August 11, 2011

Over one-third of recurrent strokes or transient ischemic attacks (TIAs) in patients with patent foramen ovale (PFO) are more likely to arise from concurrent conditions like atrial fibrillation or large artery disease, casting doubt on the causal role of the defect, according to results appearing online August 4, 2011, ahead of print in Stroke.

Researchers led by Heinrich P. Mattle, MD, of University Hospital at the University of Bern (Bern, Switzerland), looked at 308 patients with cryptogenic stroke and PFO treated at their institution from January 1994 to August 2000. Roughly half of the patients (n = 158) received medical therapy (oral anticoagulants or antiplatelets) and half received percutaneous closure (n = 150). Dr. Mattle and colleagues followed both groups for a mean of 8.7 years to see if PFO closure had an effect on the expected rate of recurrent events and to judge whether the rate of concurrent etiologies might have caused these events.

Baseline characteristics were similar between the medical and closure groups, with the exception of previous cerebrovascular events and large right-to-left shunt, which were more common in the closure group (P < 0.03 and P < 0.001, respectively).

Many Recurrent Events Not Cryptogenic

Over a mean follow-up of 8.1 years, 32 recurrent cerebrovascular events (13 strokes, 19 TIAs) occurred in the medical group, amounting to a rate of 20.3%. Sixteen of these patients died. The frequency of recurrent stroke or TIA did not differ with respect to antiplatelet or anticoagulant treatment. In the PFO closure group, there were 16 recurrent events (8 strokes, 8 TIAs), which worked out to an event rate of 10.7% over a mean follow-up of 9.2 years, with 7 deaths.

In the PFO closure group, more than half of recurrent events were judged to be cryptogenic, while this was true for almost two-thirds of recurrent cerebrovascular events in the medical treatment group. Of the remaining events, which were deemed more likely associated with concurrent etiologies, most were related to atrial fibrillation or small or large artery disease (table 1).

Table 1. Etiologies Associated with Recurrent Cerebrovascular Events

PFO Closure
(n = 150)
Medication
(n = 158)

Cryptogenic
56%
63%

Atrial Fibrillation
13%
13%

Large Artery Disease
6%
9%

Small Artery Disease
19%
6%

Antiphospholipid Antibody Disease
–
6%

Cerebral Vasculitis
–
3%

Thrombophilic Disorder
6%
–



Patients with recurrent cerebrovascular events showed similar levels of concurrent etiology between the medical treatment group and the PFO closure group (38% vs. 44%; P = 0.68). But the rate of concurrent etiologies in the medical therapy group may, in fact, have been underestimated since half of the patients with a recurrent event did not have a complete etiologic work-up.

Among patients with recurrent stroke or TIA, concurrent etiologies were more frequent in those older than age 55 at the time of the index event than in younger patients (P = 0.018). Other factors, such as atrial septal aneurysm and large right-to-left shunt showed no interaction with concurrent conditions. In the PFO closure group, patients with recurrent events more frequently had hypercholesterolemia if they also had concurrent etiologies than if they did not (100% vs. 56%; P = 0.042).

“Concurrent etiologies are identified for a considerable proportion of recurrent ischemic events [, casting] doubt on the sole causal role of PFO in the case of stroke recurrence, and indicat[ing] that secondary prevention in patients with cryptogenic stroke and PFO should not be focused on PFO closure alone,” the authors conclude. In particular, they note, “given that concurrent stroke etiologies are not prevented by percutaneous device closure of the PFO, we would not discontinue antithrombotic treatment in patients who undergo PFO closure.”

CLOSURE Confirmation

In a telephone interview with TCTMD, Anthony J. Furlan, MD, of the Case Western Reserve University School of Medicine (Cleveland, OH), agreed with the findings, but went even further. “I think it’s often not clear that even the initial stroke is due to the PFO,” he said.

In general, Dr. Furlan said the results of the current study reinforce those of the CLOSURE I trial, the only randomized, controlled study to have looked at the issue of PFO closure and cryptogenic stroke. Presented in November 2010 at the annual American Heart Association Scientific Sessions, the results provided strong evidence that percutaneous device closure lacks superiority over medical therapy alone in preventing recurrent stroke and mortality in patients with PFO.

“CLOSURE I followed patients for only 2 years, but even with that, we found an alternative reason for recurrent events in 80% of patients,” said Dr. Furlan, the trial’s principal investigator. “It’s actually reassuring that we found in a randomized trial what people are finding in their individual experiences.”

According to Dr. Furlan, there are multiple problems inherent in determining the cause of cryptogenic stroke. “The core problems are cryptogenic stroke, which is a mixed group of etiologies, vs. how do you prove something is truly due to paradoxical embolism?” he said. “And then it’s another matter to say closing the hole is any better than antithrombotic therapy. Or it’s also possible, as the authors of this paper point out, that maybe they’ve got 2 problems. Maybe they do have paradoxical embolism, but 6 years later, things change and they’ve got something different.”

Performing the Right Tests

A key for clinicians is to perform the right tests up front, which seldom happens, Dr. Furlan noted. “For example,” he said, “one of the most grossly underdiagnosed conditions in this cryptogenic stroke population is probably occult atrial fibrillation. If you only do a 24-hour Holter monitor, you’re not going to find it, but nobody does a routine 30-day event monitor. Probably the causes of cryptogenic stroke are not that many, it just depends on how hard you look.”

None of this is to say that PFOs should never be closed for cryptogenic stroke, Dr. Furlan stressed. “In CLOSURE I, [we did not conclude] that paradoxical embolism wasn’t real, or that there are no patients that should undergo endovascular closure,” he said. “All we had was anecdotal criteria and no hard data. Now, my impression is that everyone seems to agree that we were probably closing too many of these.”

In the future, Dr. Furlan expressed hope that results of CLOSURE I will be combined with those of other ongoing trials investigating PFO closure and cryptogenic stroke. “If we start putting all these trials together, we’ll be able to refine our selection criteria, and not close all these holes, willy-nilly” he said. “That’s what I’m starting to see. I think clinicians in general are being more conservative.”

Source:
Mono M-L, Geister L, Galimanis A, et al. Patent foramen ovale may be causal for the first stroke but unrelated to subsequent ischemic events. Stroke. 2011;Epub ahead of print.

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Top Content, July, 2011
The Most Viewed Science & Quality Content on CardioSource
Print
Top 10 Journal Scans, July 2011
Impact of National Clinical Guideline Recommendations for Revascularization (Arch Intern Med)
Appropriatenessof Percutaneous Coronary Intervention (JAMA)
Real-Life Observations of Clinical Outcomes With Rhythm and Rate Control (J Am Coll Cardiol)
Measuring Blood Pressure for Decision Making and Quality Reporting: Where and How Many Measures? (Ann Intern Med)
A New Risk Scheme to Predict Warfarin-Associated Hemorrhage (J Am Coll Cardiol)
Effect of Upstream Clopidogrel Treatment in Patients With STEMI Undergoing Primary PCI (Eur Heart J)
Cardiac Resynchronisation Therapy in Patients With Heart Failure and a Normal QRS Duration (Heart)
Cardiovascular Screening With Electrocardiography and Echocardiography in Collegiate Athletes (Am J Med)
Utility of Absolute and Relative Changes in Cardiac Troponin Concentrations in the Early Diagnosis of AMI (Circulation)
Development and Validation of a Risk Calculator for Prediction of Cardiac Risk After Surgery (Circulation)

Top 10 Clinical Trial Summaries, July 2011
PALLAS
APPRAISE 2
PARTNER Cohort A
AIM-HIGH
ARISTOTLE
ADDITION Europe
Rheos Pivotal Trial
OAT
SHARP
ASCEND HF

[Ссылки могут видеть только зарегистрированные и активированные пользователи]

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Potential reason for improved outcome found with GWTG-Stroke program

Reeves MJ. Circ Cardiovasc Qual Outcomes. 2011;doi:10.1161/circoutcomes.111.961755.

An increase in eligible patients receiving care based on the Get with the Guidelines-Stroke program was cited as the major reason for the performance improvement found among hospitals examined in a recent study.

Specifically, hospital participation with the program substantially improved the quality of care of patients with ischemic stroke during a 7-year period.

In the study, researchers analyzed data on patients (n=569,883; median age, 73 years) admitted with ischemic stroke to Get with the Guidelines (GWTG)-Stroke hospitals (n=1,028) from April 2003 to September 2009. Performance measures that were deemed relevant for patients with acute ischemic stroke included early and discharge antithrombotics, deep vein thrombosis prophylaxis, anticoagulants for atrial fibrillation/flutter, lipid therapy, smoking cessation and IV recombinant tissue plasminogen activator therapy.

Although noting minimal changes to the size of the target population in six of the measures, the researchers found that deep vein thrombosis prophylaxis population reduced from 52.5% to 46.8%. This, they said, was due to change in the data collection tool, particularly a format change in the 2008 form that decreased the number of patients identified as nonambulatory by day 2.

Additionally, across the study period, all measures had significant increases in eligible patients, most of which occurred without major shifts in contraindications or missing data, the researchers wrote.

“The results of the present study have important implications for other CV quality improvement programs that measure and track the quality of care through process-based performance measures,” they said. “Our results strongly suggest that the GWTG-Stroke quality improvement program increased the number of eligible patients who received guideline-based care during this period, which to the extent that these care processes are clinically effective should result in meaningful improvements in stroke outcomes.”
__________________________________________________ _______________________
Studies raise doubt on validity of animal models in CV research

Fedorov V. J Mol Cell Cardiol. 2011;51:215-225.
Glukhov A. J Mol Cell Cardiol. 2010;48:152-160.

Investigators of two studies published in the Journal of Molecular and Cellular Cardiology have found conflicting results of two adenosine triphosphate-regulated potassium channel openers when observed in mice vs. human hearts.

“In human hearts … the sulfonylurea receptor type 1 (SUR1) drug (pinacidil) doesn’t work in the atria at all, but it does affect the ventricles; it is the opposite of what happens in the mouse. The SUR2 drug (diazoxide) affected both the atria and the ventricles, and shortened the action potentials in the ventricles so much that it would cause fatal arrhythmias in people,” Igor R. Efimov, PhD, a biomedical engineer at Washington University, St. Louis, and researcher on both the mice and human studies, said in a press release.

The first study, which was published in early 2010, involved intact hearts from six wild-type mice, six SUR1(-/-) mice and five Kir 6.2(-/-) mice. Efimov and colleagues observed that 300 mcM diazoxide decreased action potential duration (ADP) in the atria (P<.001) but not the ventricles among wild-type mice hearts, whereas the same dose of pinacidil lowered ventricular ADP in both wild-type and SUR1(-/-) hearts (P<.001 for both) but not atrial ADP.

In the second study, which was recently published by the journal, the investigators used hearts from patients who had congestive HF and underwent transplant (n=8) or hearts unsuitable for transplant that were donated to research either with (INF; n=2) or without (NF; n=3) infarction.

They reported that diazoxide decreased ADP in chronic HF and INF hearts in atria and ventricles (P<.01 for both) but not in NF atria. However, pinacidil lowered ADPs in the atria and ventricles of all hearts.

As a possible mechanism for the discrepancy, Efimov said a mouse heart beats on average 600 times/minute, whereas a human heart beats on average 72 times/minute, and the difference in gene expression between mice and human hearts is very large.

“You can mutate in mice the gene thought to cause HF in humans and you don’t get the same disease because the mouse is so different. So, unfortunately, even with the help of transgenic mice, very few results made it from the animal model to the clinic,” he said.
__________________________________________________ ______________________
AACE: Obesity is a disease state

The American Association of Clinical Endocrinologists has declared that there is sufficient clinical evidence to declare obesity a disease state.

The declaration of obesity as a disease state, rather than a consequence of poor lifestyle choices, will help pave the way for more effective therapies and treatments for the growing number of obese Americans, according to a press release issued by the association. Currently, the armamentarium is bare for obesity therapies.

“Sufficient evidence has accumulated to implicate a number of heterogeneous hormonal and regulatory disorders in the pathogenesis and progression of the disease state,” Alan J. Garber, MD, PhD, AACE vice president and a member of the CHD and Prevention section of the Cardiology Today Editorial Board, stated in the release. “Thus, multiple therapeutic interventions may be necessary lifelong to delay or reverse obesity in patients. Currently, certain efforts have not prevented the proliferation of obesity in the US population as well as elsewhere. Additional interventions and alternative approaches are clearly necessary.”

On July 23, the AACE board of directors voted unanimously to declare obesity a disease state. The vote was the result of an AACE Task Force on Obesity report that concluded, based on available clinical data, insufficient data exist to suggest that obesity is not just a condition.

Having declared obesity a disease state, AACE leaders now plan to develop resources for the various modalities of obesity management, including behavior, nutrition, pharmacology and surgery. The efforts will be part of a comprehensive nutrition plan that will include sociopolitical, public and educational outreach. The association will collaborate with other professional medical societies and the FDA regarding obesity research and the consideration of anti-obesity drugs and their approval pathways, according to the release.

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Needle Before Door Safe for STEMI Patients

By Chris Kaiser, Cardiology Editor, August 16, 2011

Note that this report summarizes a survey of programs worldwide that have successfully used pre-hospital fibrinolysis as a reperfusion strategy and suggests that this stategy is safe and can improve survival compared with in-hospital administration.

Note that whether a pre-hospital fibrinolytic strategy would be appropriate in the United States is unclear. Point out that the editorialist suggests that the major challenge to successful implementation of such a strategy is the regional variations in EMS resources in the United States.
Review
It's widely recognized that shortening "door-to-needle" time improves outcomes for STEMI patients, but starting lysis before the patient reaches the hospital may give an added edge.

An analysis of seven pre-hospital fibrinolysis programs confirmed a low reinfarction rate -- ranging from 2.4% (France) to 5.8% (England/Wales) -- reported Thao Huynh, MD, MSc, from McGill Health University Center in Montreal, Quebec, and colleagues.

Rates of in-hospital stroke also were low -- less than 2% of pre-hospital fibrinolysis patients (≤0.6% in most programs), according to the study in the August JACC: Cardiovascular Interventions.

But despite those benefits, pre-hospital fibrinolysis is the exception rather than the rule in the United States.

"The major challenge to successful implementation of a pre-hospital fibrinolytic strategy is the regional variations in EMS resources. The EMS system in the United States is particularly fractionated with a wide range of both funding and available services," wrote Timothy D. Henry, MD, from the Minneapolis Heart Institute Foundation, and Bernard J. Gersh, MB, CHB, DPhil, from the Mayo Clinic College of Medicine, Rochester, Minn., in an accompanying editorial.

The Minneapolis Heart Institute's regional STEMI system, for example, includes 33 hospitals and 10 clinics throughout Minnesota and Wisconsin and "requires integration with nearly 50 different EMS agencies and a wide spectrum of resource availability."

While it may be more difficult to enact STEMI programs (with fibrinolysis) in the U.S., "the most important insight from the survey is that fibrinolytic and PCI reperfusion strategies should no longer be considered mutually exclusive," Henry and Gersh wrote.

In the current study, researchers examined STEMI programs that included pre-hospital fibrinolysis in Sweden; France; England/Wales; Vienna, Austria; Edmonton in Alberta, Canada; Houston; and Nova Scotia.

Pre-hospital fibrinolysis is recommended by the European Society of Cardiology and has been in use in Europe for more than two decades, the researchers wrote.

While pre-hospital fibrinolysis is not as widespread in the U.S. or (Canada), pre-hospital ECGs are endorsed by the American Heart Association and the American College of Cardiology. Pre-hospital ECG is a crucial step for early lysis.

In the study, most ambulance personnel were trained to interpret ECGs, and only two programs – Vienna and France -- staffed their ambulances with physicians (95% and 100%, respectively).

In Vienna and Sweden, all STEMI patients were transported directly to a PCI hospital for primary PCI. In the other programs, direct transport varied.

In England/Wales, paramedics could initiate fibrinolysis. In the other programs, paramedics had to send the ECG to the hospital and wait for authorization from a physician.

Pre-hospital fibrinolysis was administered by paramedics in Houston, Nova Scotia and Edmonton; by nurses in Sweden; and by physicians in France and Vienna.

The mortality rate was generally low for those receiving pre-hospital fibrinolysis.

France had the lowest mortality at 2.7% in-hospital and 4.5% at one year, whereas Sweden had the highest in-hospital mortality at 6.5% and 10.7% at 1 year.

Pre-hospital fibrinolysis should be seen as a complement to PCI, said Huynh and colleagues. Ideally, these programs should have formal protocols that help to identify patients that would benefit from either direct transport to a PCI hospital or pre-hospital lysis.

The authors acknowledge that the study was limited by the lack of a comparison of morbidity and mortality data across programs. Also, the program descriptions relied on self-administered surveys. Finally, there were no economic or quality assurance data.

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U.S. HF Patients May Gain Less from Beta-Blockers

By Todd Neale, Senior Staff Writer, Published: August 16, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Explain that Americans with heart failure may not respond to beta-blockers as well as their counterparts from other countries.

Point out that U.S. patients did not have a significant reduction in mortality in any of the three trials that included both U.S. patients and those from other countries and that the reasons for this difference are not known.

Americans with heart failure may not respond to beta-blockers as well as their counterparts from other countries, researchers found.

In pooled results of four major heart failure trials, beta-blockers reduced the mortality risk by 23% overall compared with placebo (RR 0.77, 95% CI 0.71 to 0.84), according to Christopher O'Connor, MD, of Duke University, and colleagues.

In two of the three trials that included U.S. patients, however, beta-blockers did not reduce mortality in the U.S. patients but did reduce mortality in patients from other countries, the researchers reported in the Aug. 23 issue of the Journal of the American College of Cardiology.

In the BEST trial, which included mostly U.S. patients, there was no mortality benefit overall, in U.S. patients, or in patients from other countries.

"This geographic difference in treatment response may be a reflection of population differences, genetics, cultural or social differences in disease management, or low power and statistical chance," O'Connor and colleagues wrote.

Although the inclusion of patients from around the world has made it easier to reach recruitment goals for very large trials, the practice has introduced challenges that come along with a geographically diverse patient populations.

To explore a possible difference by geography in major heart failure trials involving beta-blockers, the researchers examined data from four trials -- MERIT-HF (Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure), COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival trial), BEST (Beta-Blocker Evaluation of Survival Trial), and CIBIS-II (Cardiac Insufficiency Bisoprolol Study).

CIBIS-II did not include any U.S. patients, but it was included in the overall analysis.

The three trials that included patients from the U.S. and other countries involved 8,988 patients -- 46.7% came from the U.S.

In a meta-analysis of all four trials, there was a significant reduction in mortality with beta-blocker treatment, but it was significant in the patients from the rest of the world (RR 0.64) and not in the U.S. patients (RR 0.92, 95% CI 0.82 to 1.02).

Those results were consistent in the MERIT-HF and COPERNICUS trials. In the BEST trial, treatment with the investigational beta-blocker bucindolol did not reduce mortality in any patient subgroup, which was consistent with the primary results.

O'Connor and colleagues pointed to several possibilities to explain why U.S. patients with heart failure might have a lower response to beta-blockers, including differences in baseline characteristics between the studies and a slightly higher mortality rate in the placebo group among the U.S. patients.

Race could also play a role, they noted. Black patients in BEST did not have a mortality reduction with beta-blocker therapy, but non-black patients did.

That could reflect genetic differences, as previous studies have shown that genotypes associated with a poor response to beta-blockers are more prevalent in people of African descent.

In the current analysis, U.S. centers were more likely to enroll black patients than those in other countries.

Other possibilities to explain the geographical difference in response included differences in standards of care and use of evidence-based therapies, inadequate statistical power, or chance.

The authors noted, however, that "the consistency of the observation in the U.S. cohort across the MERIT-HF, COPERNICUS, and BEST trials is a potential cause for concern, and although it is possible that chance is responsible for the observation in all three instances, the consistency of the finding justifies further examination."

In an accompanying editorial, Barry Massie, MD, of the San Francisco VA Medical Center, said that "the analyses ... are provocative and possibly hypothesis generating, but they should not be interpreted as demonstrating a lesser beta-blocker benefit in North American patients, given the wide confidence intervals, particularly in COPERNICUS and MERIT-HF."

He continued, "Subsequent experience has solidified the powerful role that beta-blockers can play in preventing and even reversing myocardial systolic dysfunction in heart failure patients. Based on the totality of data with beta-blockers and their experience, few heart failure physicians would withhold carvedilol or metoprolol from their patients."

O'Connor and colleagues acknowledged that the analysis was limited in that it was performed post hoc with a small number of trials and did not account for baseline differences in the patient populations. In addition, the beta-blockers evaluated in the trials have distinct mechanisms of action.

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10 Mistakes Accountable Care Organizations Still Make
Successful ACOs require new health information exchanges, better EHR functionality, and the ability to measure true outcomes. Two experts say we're not there yet.

By Ken Terry InformationWeek
August 12, 2011 12:40 PM

When the Centers for Medicare and Medicaid Services (CMS) announced its proposed regulations for accountable care organizations (ACOs) last spring, CMS administrator Donald Berwick said "information management--making sure patients and all health care providers have the right information at the point of care--will be a core competency of ACOs."

In a new article about ACOs in the Journal of the American Medical Association, two other health policy experts reaffirm the importance of health IT, including electronic health records (EHRs), in building these organizations. At the same time, they point out that the technology is not yet up to the task.

There are major differences in user experience among some of the top tablets. We take a deeper look at some of the strengths and weaknesses of Apple's iOS, Android/Honeycomb and RIM's QNX operating systems.

In the paper, Stephen Shortell, dean of the school of public health at the University of California, Berkeley, and Sara Singer, of Harvard's school of public health, offer a list of 10 mistakes that ACOs may make. They are:

1. Overestimation of ability to manage risk.
2. Overestimation of ability to use electronic health records.
3. Overestimation of ability to report performance measures.
4. Overestimation of ability to implement standardized care management protocols.
5. Failure to balance the interests of hospitals, primary care physicians, and specialists in creating governance and management processes to adjudicate differences.
6. Failure to sufficiently engage patients in self-care management and self-determination.
7. Failure to make contractual relationships with the most cost-effective specialists.
8. Failure to navigate the new regulatory and legal environment.
9. Failure to integrate beyond the structural level.
10. Failure to recognize the interdependencies and therefore the potential cumulative "race to the bottom" of the above mistakes.

IT must operate as a business within a business - providing resources to the company - in order to get dollars they need.
Review seven steps to aligning IT with the business.

The ability to use EHRs effectively in ACOs, the authors write, can be hampered by: inadequate training and support from clinicians; disruption of practices during the early phase of implementation; and incompatibility of hospital and ambulatory-care systems.

The experience of pay-for-performance programs shows the difficulty of collecting, reporting, and analyzing performance data, Shortell and Singer noted. They predict that this reporting capability will gradually evolve over time.

In an interview with InformationWeek Healthcare, Shortell said that healthcare organizations' ability to collect and report quality data as part of Meaningful Use varies greatly across the country. "We've seen some medical groups that have EHRs that incorporate a lot of those measures, and they can capture the data and report it. But a lot simply can't. They don't have the functionality yet [in their EHRs]."

Most ACOs will also require health information exchanges to improve the continuity of care, he said. "Even those that have very sophisticated systems within silos have a problem linking them up when patients go to other doctors, are referred to hospitalists, or are hospitalized. For that, you either need a closed system like Kaiser or information exchanges that will be able to capture and aggregate that data."

One identified potential flaw in ACOs is the "failure to sufficiently engage patients in self-care management and self-determination." While few of the fledgling ACOs have experience in this kind of activity, Shortell said that health IT can play in important role in patient engagement.

"Email and other forms of online communication are a powerful means of engaging people," he pointed out. "Another part of it will be continued advances in home monitoring technologies for diabetes, asthma, and other chronic diseases. As those technologies become more cost competitive and more prevalent in people's homes, they will help engage people in their own care by monitoring blood pressure, glucose levels and so on."

The JAMA article also noted that the failure to achieve clinical integration could sink some ACOs. Again, Shortell said, health IT will be needed to map out processes of care and generate feedback on how the changes in care delivery are working. "That's where the electronic health record can pay off."

In the long run, the paper points out, ACOs will have to develop "a mature performance measurement system to provide rapid feedback about what works in different local environments." According to Shortell, this means "the ability to have accurate measures across the continuum of care on the key metrics you'll need to manage the population--particularly the high cost [of] chronic disease patients. A mature measurement system would be able to capture the total cost of care for that episode of illness. We can't do that currently."

In addition, he said, such a system would incorporate two other key outcomes measures: functional status and patient experience. "Almost no one in the country that has that level of performance maturity," he said. "Kaiser might approach it."

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New Tool Predicts VTE Risk

By Todd Neale, Senior Staff Writer, MedPage Today
August 17, 2011

Explain that a risk prediction model for venous thromboembolism (VTE) predicted events at one and five years in both prediction and validation cohorts.

The risk prediction model included information readily available from patients or general practice records.
Review
A new risk prediction model may help to estimate an individual patient's risk of venous thromboembolism up to five years out, researchers found.

The model, which includes 11 variables for men and 14 variables for women, yielded an area under the receiver operating characteristic curve (AUC) of 0.75, according to Julia Hippisley-Cox, MD, and Carol Coupland, PhD, of the University of Nottingham.

And comparing the predicted versus the observed risks at one and five years indicated that the algorithm was well calibrated, they reported online in BMJ.

"The algorithm is based on simple clinical variables which the patient is likely to know or which are routinely recorded in general practice records," they wrote.

"The algorithm could be integrated into general practice clinical computer systems and used to risk assess patients before hospital admission or starting medication which might increase the risk of venous thromboembolism," including oral contraceptives, antipsychotics, and hormone replacement therapy, they wrote.

The researchers added that the tool, which is called Qthrombosis and is available online, is not meant to assess the current risk of venous thromboembolism in symptomatic patients.

Hippisley-Cox and Coupland developed the model by examining data from patients treated at 564 general practices in England and Wales that participated in the QResearch database. None of the patients had been pregnant in the preceding 12 months, had a previous deep vein thrombosis or pulmonary embolism, or were taking oral anticoagulants at baseline.

The cohort used to derive the risk prediction model included about 2.3 million patients. During the study, there were 14,756 incident cases of venous thromboembolism -- a rate of 14.6 per 10,000 person-years.

The validation cohort included about 1.2 million people. In this group, there were 6,913 incident cases -- a rate of 14.9 per 10,000 person-years.

For both sexes, independent predictors of venous thromboembolism that were included in the risk prediction model were age, body mass index, smoking status, varicose veins, congestive heart failure, chronic renal disease, cancer, chronic obstructive pulmonary disease, inflammatory bowel disease, hospital admission in the past six months, and current prescriptions for antipsychotic drugs.

For women, additional factors were use of oral contraceptives, tamoxifen, and hormone replacement therapy.

In the validation cohort, the risk prediction equation explained 33% and 34% of the variation in the time to venous thromboembolism in women and men, respectively.

The D statistic was 1.43 for women and 1.45 for men at five years, with an AUC of 0.75 for both sexes.

Good calibration of the model was confirmed by comparing the mean predicted risks at one and five years with the observed risks. For example, for women in the top 10% of predicted risk, the mean predicted five-year risk was 2.78% and the observed risk was 2.7%. For men, the corresponding values were 2.46% and 2.35%.

The authors acknowledged some limitations of their analysis, including the lack of formally adjudicated outcomes, a reliance on information provided by the primary care physicians, a lack of genetic data, the potential for missing information, and residual confounding.

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Coronary Calcium Better than CRP to Stratify Risk
By Todd Neale, Senior Staff Writer,
Published: August 18, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

Among asymptomatic individuals with normal LDL cholesterol levels and elevated high-sensitivity C-reactive protein (hsCRP), measuring the burden of calcium in the coronary arteries with cardiac CT appears to stratify the risk of cardiovascular disease, researchers found.

The estimated rate of cardiovascular disease events through a median of 5.8 years was 2.12% for those with a coronary artery calcium (CAC) score of 0, 4.86% for those with a score of 1 to 100, and 13.65% for those with a score greater than 100, Michael Blaha, MD, of Johns Hopkins University in Baltimore, and colleagues reported in the Aug. 20 issue of The Lancet.

Looking further at patients with both low and high levels of hsCRP, the researchers found that CAC score -- but not hsCRP -- was associated with the risk of coronary heart disease events and overall Action Points
Explain that among asymptomatic individuals with normal LDL cholesterol levels and elevated high-sensitivity C-reactive protein (hsCRP), measuring the burden of calcium in the coronary arteries with cardiac CT appears to stratify the risk of cardiovascular disease.

Point out that in patients with both low and high levels of hsCRP, the researchers found that CAC score -- but not hsCRP -- was associated with the risk of coronary heart disease events and overall cardiovascular events.
cardiovascular events.

Action Points
Explain that among asymptomatic individuals with normal LDL cholesterol levels and elevated high-sensitivity C-reactive protein (hsCRP), measuring the burden of calcium in the coronary arteries with cardiac CT appears to stratify the risk of cardiovascular disease.

Point out that in patients with both low and high levels of hsCRP, the researchers found that CAC score -- but not hsCRP -- was associated with the risk of coronary heart disease events and overall cardiovascular events.

CAC score "could be used to target subgroups of patients who are expected to derive the most, and the least, absolute benefit from statin treatment," Blaha and colleagues wrote. "Focusing of treatment on the subset of individuals with low LDL cholesterol with measurable atherosclerosis might represent a more appropriate allocation of resources, reduce overall healthcare cost, and prevent the occurrence of a similar number of events."

But evidence from randomized trials that such an approach -- which remains controversial -- would actually reduce cardiovascular events in asymptomatic individuals is lacking.

Steven Nissen, MD, of the Cleveland Clinic, pointed out in an email to ABC News and MedPage Today that calcium scanning has never been shown to reduce the risk of MI or death. He called the practice "one of the worst examples of 'medicine gone wild,'" pointing to unacceptable radiation doses and the greater use of unnecessary catheterization and stenting following a scan.

Other physicians contacted, however, supported the use of CAC scoring.

"Use of CAC is helpful in saying if the process of atherosclerosis has started, and is helpful in choosing between lifestyle intervention versus lifestyle intervention plus statin therapy," wrote Christopher Cannon, MD, of Brigham and Women's Hospital in Boston.

The basis of the current analysis was the JUPITER trial, which showed that treatment with rosuvastatin (Crestor) reduced MI, stroke, and cardiovascular death in patients with normal LDL cholesterol levels but elevated hsCRP.

Blaha and colleagues identified a JUPITER-like cohort in the Multi-Ethnic Study of Atherosclerosis (MESA) to determine whether measuring CAC would stratify patients according to cardiovascular risk and potentially identify a subgroup of patients who would most benefit from statin therapy.

The analysis included 950 MESA participants who had normal LDL cholesterol levels (less than 130 mg/dL) and elevated hsCRP (2 mg/L or more). All underwent two noncontrast CT scans to measure the calcium.

The authors noted that the average measured dose of radiation in a CAC scan was 0.89 mSv in MESA, while the average dose overall with modern technology ranges from 0.5 to 1.5 mSv.

Nearly half of the patients (47%) did not have any coronary calcium (a score of 0). Another 28% had scores of 1 to 100 and 25% had scores greater than 100.

Per 1,000 person-years, rates of coronary heart disease events increased from 0.8 for patients with a CAC score of 0 to 20.2 for patients with a score greater than 100. The patterns were similar for all cardiovascular events.

Through a median follow-up of 5.8 years, 74% of all coronary heart disease events and 60% of all cardiovascular events occurred in the patients with a CAC score greater than 100.

Applying the risk reduction accompanying rosuvastatin treatment observed in JUPITER (a 44% relative reduction in the risk of MI, stroke, and cardiovascular death), Blaha and colleagues calculated that the five-year number needed to treat (NNT) to prevent one coronary heart disease event was 549 for patients with a CAC score of 0, 94 for those with intermediate CAC scores, and 24 for those with scores greater than 1oo.

The NNTs for all cardiovascular events were 124, 54, and 19, respectively.

"These results have important implications for future guidelines and public health discussions aimed at improving the efficiency of statin use in primary prevention," according to the authors, who noted that studies have suggested that asymptomatic patients with a CAC score of 0 can be treated less aggressively with an emphasis on low-cost lifestyle interventions.

Blaha and colleagues acknowledged that a cost-benefit analysis is needed in patients with both low and high hsCRP to determine whether using CAC scores to guide statin treatment improves outcomes. They also acknowledged that CAC scoring has both advantages and disadvantages compared with hsCRP.

Advantages of CAC scoring include the fact that it is a direct measure of the burden of atherosclerosis, it has small variability on repeated testing, and it has consistent thresholds of risk in different populations. Thresholds for hsCRP vary by sex and ethnic origin.

Disadvantages include radiation exposure, a risk of incidental findings leading to further imaging, and a higher cost compared with hsCRP.

Still, CAC scanning can be performed for less than $100 in many centers, the researchers noted.

"Now that CAC scoring is so inexpensive, one can make the case of testing this in most patients at intermediate risk," commented Carl Lavie, MD, of the Ochsner Heart and Vascular Institute in New Orleans, in an email.

One obstacle to the wider adoption of CAC scoring for risk stratification "is that use of preventive measures such as statins, blood pressure control, and weight loss do not reduce the coronary calcium, and this is unsettling for many physicians and patients," said Howard Weintraub, MD, clinical director of the NYU Center for the Prevention of Cardiovascular Disease, in an email.

Some physicians want to see the value of the test proven in a randomized trial as well, although that has not stopped all physicians from incorporating it into their practices.

"Although definitive proof of treatment effects is scarce, CAC identifies high cardiovascular risk, and statin therapy is most effective in high-risk patients," Axel Schmermund, MD, and Thomas Voigtländer, MD, of Cardioangiologisches Centrum Bethanien in Frankfurt, wrote in an accompanying editorial.

"In our practice, we therefore focus on CAC ... for expanded risk stratification in asymptomatic patients."

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Nocturnal ACS Linked to Belly Fat, Disordered Sleep

By Charles Bankhead, August 19, 2011

Explain that a Japanese study found that patients with nighttime-occurrence ACS were more likely to have excess visceral fat and sleep-disordered breathing than those with ACS occurring in the daytime.

Note that onset of ACS at night is an uncommon occurrence.
Review
Nighttime acute coronary syndrome (ACS) occurred significantly more often in patients with visceral fat accumulation and sleep-disordered breathing, investigators reported.

Among 25 patients with nighttime onset of ACS, two-thirds of those with ≥100 cm2 of visceral fat accumulation also had sleep-disordered breathing as compared with a fourth of patients with less visceral fat.

In contrast, sleep-disordered breathing occurred in a similar proportion of patients with and without visceral fat and daytime-onset ACS.

Patients with sleep-disordered breathing, visceral fat accumulation, and nighttime-onset ACS also had hypoadiponectinemia and nocturnal dysregulation of circulating adiponectin levels, as reported online in the American Journal of Cardiology.

"These results suggest that an association of sleep-disordered breathing and excess visceral fat with nocturnal dysregulation of adiponectin may play some role in the development of nighttime-onset ACS," Ken Kishida, MD, PhD, of Osaka University in Japan, and co-authors wrote in summation.

"Sleep-disordered breathing and excess visceral fat are treatable risk factors," they added. "Decrease of excess visceral fat and treatment of sleep-disordered breathing could be beneficial in preventing nocturnal cardiac events."

ACS during sleep occurs infrequently, and predisposing factors remain unclear but could include disordered sleep and obstructive sleep apnea (OSA). Patients with OSA have an increased risk of sudden cardiac death with nighttime onset, the authors noted in their introduction.

Kishida and colleagues recently reported dysregulation of adipocytokines during sleep in obese patients with OSA (Am J Physiol Endocrinol Metab 2008; 294: E778-E784, J Atheroscler Thromb 2011; 18: 240-247).

They hypothesized that the combination of sleep-disordered breathing, visceral fat accumulation, and nocturnal dysregulation of adipocytokines might play a role in the occurrence of ACS during sleep.

To test the hypothesis, the authors studied 109 consecutive Japanese patients from a single center who had revascularization procedures for ACS and overnight cardiorespiratory monitoring before discharge. The study population consisted of 66 patients with ST-segment elevation myocardial infarction, 27 with non-ST elevation MI, and 16 with high-risk angina.

The patients had a mean age of 66, mean body mass index of 23.8, total fat area of 239 cm2, visceral fat area of 127 cm2, and an apnea-hypopnea index that averaged 11 events per hour.

Investigators defined excess visceral fat as ≥100 cm2, apnea as cessation of airflow >10 seconds, hypopnea as a decrease in the airflow signal to <70 of the preceding level associated with >4% desaturation, and sleep-disordered breathing as an apnea-hypopnea index ≥5.

Adiponectin levels were measured shortly before sleep onset and after waking. Onset of chest pain from midnight to 7 a.m. was considered nighttime ACS, and onset any other time was considered daytime ACS.

ACS had a nighttime onset in 25 patients and daytime onset in 84. Sleep monitoring results showed that 63 (58%) of the patients had sleep-disordered breathing, and 64 (59%) had visceral fat accumulation ≥100 cm2.

Among patients with nighttime onset of ACS, 12 of 17 with excess visceral fat also had sleep-disordered breathing as compared with two of eight patients who had visceral fat accumulation <100 cm2 (P<0.05).

In patients with daytime ACS, the prevalence of sleep-disordered breathing did not differ between patients with (26 of 47) and without (22 of 37) excess visceral fat.

Circulating adiponectin levels were significantly lower before and after sleep among patients with excess visceral fat, regardless of the time of ACS onset.

Patients with nighttime-onset ACS and excess visceral fat had mean adiponectin levels 6.3 and 6.2 µg/mL, respectively, before and after sleep versus 16.9 and 18.0 µg/mL in patients with visceral fat <100 cm2 (P<0.05, P<0.01).

Among patients with daytime ACS, those with excess visceral fat had mean adiponectin levels of 6.8 and 6.7 µg/mL before and after sleep versus 11.6 and 11.7 µg/mL for patients with <100 cm2 visceral fat accumulation (P<0.01 for both).

Excess visceral fat was associated with a significantly higher apnea-hypopnea index in patients with nighttime ACS (14 versus three events per hour, P<0.05), but not in the group with daytime ACS.

Patients with nighttime ACS and excess visceral fat also had higher levels of plasminogen activator inhibitor-1 and CD40 ligand.

Calling polysomnography the gold standard for diagnosing OSA, the authors acknowledged that they had used other methods for monitoring sleep, noting that polysomnography might not be cost-effective or convenient for identifying sleep-disordered breathing in patients with ACS.

The study was also limited because there were no controls without ACS, the potential bias inherent in a single-center study, and the potential for medical therapy to affect laboratory parameters, which were taken a week after onset of ACS.

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Why the FDA Approved Dabigatran 150 mg and Not 110 mg
Samuel Z. Goldhaber, M.D., F.A.C.C. (Disclosure)
July 22, 2011

Stroke is the third most common illness in the United States, after myocardial infarction and cancer. In quality of life surveys, many respond that they prefer death to a permanently disabling stroke. Hypertension is a major risk factor for stroke. But the majority of strokes are considered “cryptogenic” because no definitive cause can be assigned.

Nonvalvular atrial fibrillation (AF) causes about 1 in every 5 to 6 strokes in the United States. These are not ministrokes or transient ischemic attacks. They are anatomically large strokes often causing permanent neurological disability and occasionally death. Embolic strokes due to AF have worse outcomes than other types of strokes. These strokes occur mostly in those over 65 years of age and especially those older than 75 years. They can terminate a lifestyle of independent living and force victims to be placed in settings where they receive round the clock skilled nursing care. These strokes disrupt, decimate, and devastate the social fabric that families have weaved over a lifetime, and they suck away the carefully sequestered savings for a planned retirement of hobbies, volunteer work, and visiting grandchildren.

Only two decades ago did we learn that we can reduce the stroke rate from nonvalvular AF by about 25% with aspirin. And for only slightly longer than one decade have we realized that we can reduce the stroke rate in nonvalvular AF by about another 40% with warfarin rather than aspirin.(1) But warfarin is cumbersome and labor intensive to use properly. The requirement of adjusting the dose according to the International Normalized Ratio (INR) to target a range of 2.0 to 3.0 requires a detailed strategic plan that coordinates laboratory testing in a frequency that varies from twice weekly to once monthly, communicates INR results to the clinician who doses the warfarin, and then informs the patient of whether the dose of warfarin requires adjustment because of new INR results that are unacceptably above or below the targeted range. In addition, warfarin is affected by hundreds of interactions with other medications and with foods. However, despite this myriad of limitations, warfarin remains remarkably effective. Well-dosed warfarin cuts the stroke rate in at risk patients to about 1-2% per year. It has also been marketed in the United States since 1954. So there are no hidden surprises about possible adverse effects.

The monopoly of warfarin (and the family of vitamin K antagonists) as the sole oral anticoagulant has been shattered. A pipeline of novel oral anticoagulants is being developed. The major anticipated advance has been increased convenience to patients and clinicians. The new drugs, whether they are anti-factor Xa or antithrombin agents, are administered in fixed doses, without any laboratory coagulation monitoring. The new anticoagulants have minimal drug-drug and drug-food interactions. It was anticipated that they would be noninferior to warfarin for stroke prevention, and that their rate of bleeding complications would not exceed that of warfarin.

In October 2010, the Food and Drug Administration (FDA) approved the novel antithrombin agent, dabigatran, in a dose of 150 mg twice daily for stroke prevention in nonvalvular AF. The pivotal clinical trial was RE-LY, a megatrial of more than 18,000 patients randomized to dabigatran 150 mg (6,076 patients), dabigatran 110 mg (6,015 patients), or warfarin (6,022 patients). The dose of dabigatran was double-blinded, but the administration of warfarin was open label. Dabigatran 150 mg twice daily surprised virtually everyone involved because it was superior to warfarin and cut the stroke rate by 34% compared with warfarin. In most circumstances, when an anticoagulant is superior in efficacy, it is less safe than the comparator drug. However, in RE-LY, the major bleeding rate was 3.3% with dabigatran 150 mg and 3.6% with warfarin. With regard to life-threatening bleeding, the frequency was 1.5% with dabigatran 150 mg versus 1.9% with warfarin. The intracranial bleeding rate was 60% lower with dabigatran 150 mg than with warfarin.(2)

Dabigatran 110 mg was noninferior to warfarin for stroke prevention. However, dabigatran 110 mg was superior to warfarin for safety, with a major bleeding rate of 2.9% compared with 3.6% for warfarin. There was a significant treatment-by-age interaction, such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients aged <75 years (1.9% versus 3.0%) and a similar risk in those aged >75 years (4.4% versus 4.4%). In contrast, dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those aged <75 years (2.1% versus 3.0%) and a higher risk of major bleeding (primarily gastrointestinal bleeding) in those aged >75 years (5.1% versus 4.4%).(3) Regardless of age, gastrointestinal bleeding occurred more often in the 150 mg than in the 110 mg group.

The FDA had to decide whether to approve dabigatran 110 mg in addition to dabigatran 150 mg. At first glance, this might seem like an easy decision. Approve dabigatran 150 mg for superior stroke prevention compared with warfarin, and target its use for patients unlikely to suffer major bleeding. And approve dabigatran 110 mg for noninferior stroke prevention compared with warfarin, and target its use for patients at high risk of gastrointestinal bleeding. If one were to choose this strategy, which was put into place in Canada, it would be important to identify subgroups in which use of the 110 mg dose would be advantageous. Among those 75 years of age or older, was it worth trading a lower stroke rate with 150 mg compared with 110 mg of dabigatran (1.4 versus 1.9 per 100 patient-years) for a higher rate of major, mostly extracranial, gastrointestinal bleeding (5.1 versus 4.4 per 100 patient-years)? The FDA didn’t think so, and neither do I.

How about dosing among patients with moderately severe chronic kidney disease, with a creatinine clearance between 30-50 ml per minute? This group is of special interest because dabigatran is metabolized primarily by the kidneys. Surprisingly, dabigatran 150 mg was especially effective in this population compared with dabigatran 110 mg, with stroke rates of 1.3 versus 2.4 per 100 patient-years, respectively. And the major bleeding rate was no greater with dabigatran 150 mg. Even patients who had major bleeding during the trial and who resumed the same dose of dabigatran did not have more major bleeding in the 150 mg group compared with dabigatran 110 mg.(4)

In a detailed investigation of major bleeding comparing dabigatran 150 mg versus 110 mg, multiple key subgroups were analyzed. These included age, gender, weight, renal function, and use of aspirin, amiodarone, or a proton pump inhibitor. The only subgroup in which dabigatran 150 mg had more bleeding than dabigatran 110 mg was among patients weighing more than 100 kg. I believe this is a biologically implausible finding and attribute it to the play of chance when multiple subgroups are undergoing exploratory analysis.(3)

The FDA does not adjudicate cost-effectiveness. This specialized area utilizes the expertise of those who study pharmacoepidemiology and pharmacoeconomics.(5) It is clear that dabigatran 150 mg is far more cost-effective than dabigatran 110 mg.(6)

Finally, we clinicians are by nature conservative. We are taught that our primary duty is to do no harm. Whereas the harm from gastrointestinal bleeding is obvious, the benefit from a stroke that is prevented and that never occurs is easily overlooked.

My initial reflexive reaction to the FDA’s not approving the dabigatran 110 mg dose was to bemoan the lack of incremental decision-making flexibility that I would have been afforded. Having the 110 mg dose would have allowed subtle texturing and molding of my day-to-day clinical practice. Would I have been tempted to opt for less gastrointestinal bleeding in some elderly patients with chronic kidney disease at the steep price of less stroke prevention? Certainly yes. Canadian physicians confront this dilemma every day. It will be interesting to track the proportion of dabigatran prescriptions in Canada that designate the noninferior 110 mg dose versus the superior 150 mg dose. Widespread use of dabigatran 150 mg holds the promise of altering the fundamental epidemiology of stroke and reducing stroke incidence in patients with nonvalvular AF. Prospective cohort studies should be undertaken in the U.S. and in Canada to track future trends over time.

Finally, let’s put the dabigatran dosing issue in perspective. The major problem with stroke prevention in AF is not whether dabigatran 150 mg should be used in preference to 110 mg. The key problem is that too many AF patients who should be treated with anticoagulants are treated with antiplatelet therapy or remain untreated. In an overview of studies since 2000, a median of 52% of AF patients received anticoagulants, 30% received antiplatelet therapy, and 18% were untreated.(7) Intensive educational updates, peer review, and patient advocacy will improve these metrics and should lead to a decrease in stroke incidence.

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What Is the Optimal Approach to Anticoagulation for Primary PCI in STEMI?
Davide Capodanno, M.D. (Disclosure)
George D. Dangas, M.D., Ph.D., F.A.C.C. (Disclosure)
August 08, 2011

Primary percutaneous coronary intervention (PCI) is the standard of care for patients with ST-segment elevation myocardial infarction (STEMI).(1) Thrombin plays a central role in arterial thrombogenesis by converting fibrinogen to fibrin, activating platelets, and promoting a procoagulant and proinflammatory enviroment. Therefore, inhibiting either thrombin generation or activity is crucial in the context of acute coronary syndromes, as well as during primary PCI, due to the risk of thrombus formation related to arterial injury or esposure of thrombogenic material from disrupted plaques to intraluminal blood.

Current ACCF/AHA guidelines provide a Class I indication for the use of an anticoagulant as soon as the diagnosis of STEMI is made.(1) Parenteral anticoagulants include indirect thrombin inhibitors, such as unfractionated heparin (UFH) and enoxaparin, and direct thrombin inhibitors, such as bivalirudin. The early initiation of UFH is common practice in many emergency departments ambulances, hospital wards or clinics, due to its universal availability, low price and ease of use as a bolus. Intravenous enoxaparin may be a viable alternative to UFH in patients with STEMI undergoing primary PCI, and sheath removal considerations should account for its long half-life.(2) Evidence supporting a prominent role of bivalirudin as the preferred anticoagulation strategy in the STEMI setting, stems from the large HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial. From 30-day, and up to 3-year follow-up, bivalirudin monotherapy (with 7% GPIIb/IIIa inhibitor infusion for thrombotic bailout) resulted in significantly lower of major bleeding, all-cause mortality and cardiac mortality compared with the combination of UFH plus routine GP IIb/IIIa blocker administration.(3) The bivalirudin arm was also associated with a reduction in reinfarction and overall similar stent thrombosis at 3 years (despite a statistically significant ~1% increase within the first 24 hours).


But how to reconcile the established benefit of bivalirudin observed in the HORIZONS-AMI trial with the widespread use and availability of heparin in clinical practice? It is certainly reasonable and abides by all the treatment guidelines to administer the most available aspirin and UFH bolus at the time of first medical contact with a STEMI patient. Upon further evaluation and hospital admission with transfer to the interventional cardiology suite for primary PCI, further consideration can be given to optimal pharmacological therapy. In the HORIZONS-SWITCH substudy, patients treated with UFH before enrollment in the HORIZONS-AMI trial were analyzed according to their subsequent randomization to bivalirudin or UFH plus a GP IIb/IIIa inhibitor. Switching to bivalirudin before primary PCI resulted in significantly reduced 30-day and 2-year major bleeding (Figure 1).(4) Consistent with the overall trial, the switching strategy also yielded significant reductions in cardiac mortality and reinfarction. These results were not related to the pre-procedure activated clotting time (ACT) value. These data support the study protocol for switching patients on UFH to bivalirudin, i.e., wait 30 minutes after discontinuing UFH, or begin bivalirudin administration in all cases before PCI, regardless of ACT. The early use of UFH before bivalirudin should not be discouraged, as pre-randomization UFH was found to be an independent predictor of reduced acute and subacute stent thrombosis.(5) Bivalirudin can be discontinued at the completion of the index procedure, or continued for 2 to 6 hours after PCI at low dose if clinically indicated (ie. residual dissection, TIMI flow grade under 3, reduced blush grade, residual coronary microthrombi, ulcerated or aneurismal lesions). It is clinically reasonable to extend the infusion when the interventional result is somewhat imperfect, especially in the presence of a slowly absorbed oral thienopyridine agent.

In addition, this optimal anticoagulant approach should be pursued on a background of optimal antiplatelet pharmacotherapy including aspirin and an adenosine diphosphate (ADP) receptor (P2Y12 receptor) antagonist. The finding of a significant greater incidence of acute stent thrombosis with bivalirudin in STEMI provides the opportunity for strategies that enhance periprocedural platelet inhibition. In the HORIZONS-AMI trial, a 600-mg loading dose of clopidogrel had no effect on acute stent thrombosis but was associated with a significant decrease in subacute stent thrombosis compared with a 300-mg loading dose.(5) This finding is consistent with the fact that a 300-mg loading dose of clopidogrel leads to lower and slower platelet inhibition than 600 mg, perhaps even more so in the STEMI setting with reduced drug absorption and metabolism in relation to hemodynamic instability. In this regard, more rapidly acting and potent ADP receptor antagonists than clopidogrel, such as prasugrel or ticagrelor, have the potential to provide incremental benefits; e.g. full antiplatelet activity can be achieved within 30-60min and with less dependence on absorption and hepatic metabolism. Patients who received bivalirudin in the TRITON-TIMI 38 (Trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel—Thrombolysis in Myocardial Infarction 38) and PLATO (Platelet Inhibition and Patient Outcomes) trials, however, were substantially under-represented, hampering any attempt to draw meaningful considerations in the setting of STEMI (Figure 2).(6,7) Given the lower stent thrombosis rates associated with use of these new potent agents compared to clopidogrel in STEMI, one may select them in anticipation of improved outcomes. Nonetheless, clinical trials with these new agents in combination with bivalirudin in STEMI are currently under way in order to investigate whether preloading with a potent ADP antagonist may further reduce early stent thrombosis and improve the prognosis in patients treated with bivalirudin.
References

1. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54:2005-41.

2. Montalescot G, Cohen M, Goldstein P et al. ATOLL: an international randomized study comparing IV enoxaparin to IV UFH in primary PCI. Presented at European Society of Cardiology Congress, Stockholm, August 30, 2010.

3. Stone GW, Witzenbichler B, Guagliumi G, et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomized controlled trial. Lancet. 2011;377:2193-204.

4. Dangas GD, Mehran R, Nikolsky E, et al. Effect of switching antithrombin agents for primary angioplasty in acute myocardial infarction. The HORIZONS-SWITCH analysis. J Am Coll Cardiol. 2011;57:2309-16.

5. Dangas GD, Caixeta A, Mehran R, et al. Frequency and predictors of stent thrombosis after percutaneous coronary intervention in acute myocardial infarction. Circulation. 2011;123:1745-56.

6. Montalescot G, Wiviott SD, Braunwald E. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double blind, randomized controlled trial. Lancet. 2009;373:723-31.

7. Steg PG, James S, harrington RA, et al. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation. 2010;122:2131-41.

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Should All Patients With HF Get Aldosterone Blockade
Muthiah Vaduganathan (Disclosure)
Mihai Gheorghiade, M.D., F.A.C.C. (Disclosure)
August 19, 2011

Introduction

Neurohormonal mechanisms play a central role in mediating the end-organ dysfunction that occurs in heart failure (HF) syndromes. Systemic activation of the mineralocorticoid receptor triggers cellular and genomic changes that underlie the functional and structural cardiorenal deterioration.(1) Mineralocorticoid receptor antagonists (MRA) have emerged as a class of therapeutic agents that act to prevent receptor activation and modulate its deleterious downstream effects. Over the last two decades, MRAs have joined the current drug armamentarium of lifesaving therapies available in HF (β-blockers, ACE-inhibitors). The recent American College of Cardiology Foundation (ACCF) / American Heart Association (AHA) management guideline update has reinforced the utility of MRAs (class I indication, “is recommended”) for patients with chronic HF.(2) Despite these recommendations, a large quality improvement program found that less than one-third of eligible patients admitted with HF received aldosterone antagonist therapy at discharge.(3) In an analysis of U.S. pharmacy/medical claims of almost 400,000 patients with presumable diagnosis of HF, less than 1% received eplerenone and only 15.5% received any aldosterone blocker.(4) Similar disappointing rates of MRA discharge prescription were noted in various regions of the world and were substantially lower than other lifesaving therapies, particularly in North America.(5)

Relatively low doses of MRAs are known to improve clinical outcomes in a broad spectrum of patients with HF. However, they may be associated with an increased risk for hyperkalemia, particularly in patients with renal insufficiency, diabetes and/or in those concurrently taking other RAAS inhibitors. The potential risk of hyperkalemia does not explain the reduced uptake of this therapy in North America.(3,4)

Matching this therapeutic intervention with the right patient is of paramount importance. We attempt to characterize the patient profiles that are best suited for a therapeutic trial with MRAs in the outpatient setting or in the hospital, hoping that higher and more appropriate utilization of this life-saving therapy can be achieved.

Chronic Heart Failure

Three large trials, RALES (Randomized Aldactone Evaluation Study)(6), EPHESUS (Eplerenone Heart Failure Efficacy and Survival Study)(7), and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure)(8) have helped us define the therapeutic boundaries of aldosterone blockade in patients with chronic HF.

The RALES trial(6) enrolled patients with moderate-to-severe symptomatic HF including patients with New York Heart Association (NYHA) class III or IV and reduced EF (mean of 25.6%). After a mean follow-up of 24 months, there was a 30% risk reduction in all-cause mortality, a 35% reduction in rates of rehospitalization and a 36% reduction in progressive HF in the spironolactone arm compared to placebo. Concomitant treatment with β-blockers was low in this trial (11%). The EPHESUS trial(7) included patients 3-14 days post-AMI with either HF with reduced EF or diabetes. Notably, mean EF in this study sample was higher (33%) and included patients with less severe symptoms (NYHA classes II-IV). Eplerenone, a selective MRA, achieved similar reductions in mortality and rehospitalization compared to placebo after a mean follow-up of 16 months. It is known that heightened neurohormonal activation may contribute to fatal ventricular arrhythmias in the background of a failing myocardium.(9) Moreover, eplerenone reduced the risk of early post-MI sudden cardiac death (SCD) just thirty days after randomization by 37%(10), an effect that was more pronounced in patients with EFs less than 30%.(11) Since implantable cardioverter-defibrillators in patients hospitalized with worsening HF are associated with poor post-discharge outcomes(12), MRAs may be a critical intervention in the post-MI patient. Most recently, the EMPHASIS-HF study evaluated the effects of eplerenone in 2,737 patients with chronic HF with mild symptoms (NYHA class II). The “typical” patient represented in this trial was an older, obese Caucasian male with a mean EF of 26%. After a median follow-up of 21 months, composite cardiac death and hospitalization occurred in 18.3% of patients receiving eplerenone and 25.9% of patients in the placebo arm.(8) Interestingly, these favorable endpoints were primarily driven by reductions in early hospitalization, rather than cardiac mortality. This is surprising given that rehospitalization is integrally related to congestion, remodeling and adverse outcomes.(13) Event rates were especially high in this trial, primarily because patients were randomized after hospitalization for HF.

The primary concern related to the use of these agents is the rates of life-threatening hyperkalemia and renal dysfunction, especially when co-administered with ACE-inhibitors. In RALES, serious hyperkalemia occurred infrequently with rates of only 2% (14/822) in the spironolactone arm. Overall, the rates of any adverse effect requiring discontinuation during the trial period were also minimal (8% in the spironolactone group vs. 5% in placebo).(6) Despite these low reported trial rates, a population-based study from Canada has demonstrated that increased rates of prescription of spironolactone after publication of the RALES trial correlated with the higher rates of hyperkalemia-related hospitalizations.(14) More recently, in EMPHASIS-HF, the incidence of hyperkalemia (>5.5 mmol/L) was higher in the eplerenone-treated group compared to the placebo group (11.8% vs. 7.2%).(8) We must keep in mind that in all three trials, there was no mortality directly related to hyperkalemia. Other less-serious side effects experienced by patients taking spironolactone included gynecomastia, menstrual irregularities and impotence. These sexual side effects are minimized by the use of the more selective MRA, eplerenone.

Based on our existing knowledge in chronic HF, MRAs have clinical utility in several important subsets. All patients with mild, moderate or severe chronic HF with evidence of LV systolic dysfunction and patients after AMI with clinical HF symptomatology should be considered for MRA therapy. Theoretically, use of these agents with non-potassium-sparing diuretics may be beneficial to help correct renal electrolyte imbalances. Notably, the risk of hypokalemia (<4.0 mmol/L) in EMPHASIS-HF was significantly reduced in the eplerenone group. Certainly, we must limit use of MRAs in the patients who were excluded from these trials including those with serum creatinine >2.5 mg/dL and serum potassium >5.0 mmol/L. Furthermore, it is essential that judicious use of these agents be exercised in patients with established comorbid conditions that increase risk for developing hyperkalemia including diabetes and renal dysfunction. In all three trials, MRAs reduced the rates of the primary outcome in all pre-specified groups including patients with baseline renal dysfunction. Additionally, with ever-growing drug cocktails in HF, it is important for clinicians to be mindful of drug interactions that can result in metabolic abnormalities. Interestingly, despite the increased risk of hyperkalemia with concomitant use of ACE-inhibitors, the mortality benefits of MRAs were uniformly superior in patients already on ACE-inhibitors and B-blockers at the time of trial enrollment.(7,8) The incremental benefits of MRAs were also particularly evident in patients receiving digoxin. This is important since digoxin use has decreased substantially in the last decade, despite being approved by the FDA.(15)
Acute Heart Failure Syndromes

Excess sympathetic drive and compensatory activation may have similar detrimental consequences in patients with acute heart failure syndromes (AHFS) as they do in chronic HF.(16) In addition, patients presenting with right-sided HF and hepatic congestion may have impaired clearance of aldosterone and elevated circulating neurohormonal factors.(17) Although we lack definitive clinical evidence, MRAs may have a dual effect in AHFS: preventing progression of HF and as a safe and effective diuretic, possibly preventing the potential negative effects of non-potassium diuretics on end outcomes. Indeed, insight from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial revealed that elevated serum levels of aldosterone and lack of provision of MRAs at discharge were independently associated with adverse outcomes in this population.(18) Moreover, the mortality benefit observed in our chronic HF trials utilized non-natriuretic doses of MRAs. Carefully up-titrating to maximally tolerated dosage may help relieve congestion and improve HF symptomatology in acutely decompensating patients.(19) Furthermore, patients with acutely decompensated HF treated with long-term loop diuretics may be predisposed to developing diuretic resistance and its attendant adverse events. MRAs have been shown to ameliorate receptor-level responsiveness and augment natriuresis in AHFS.(20-22) In these small studies, the rates of hyperkalemia and renal dysfunction were minimal and normalized shortly after MRA discontinuation.

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Table: Study design, clinical characteristics, major outcomes and rates of hyperkalemia in RALES, EPHESUS and EMPHASIS-HF
RALES6 EPHESUS7 EMPHASIS-HF8
No. of patients 1663 6632 2737
NYHA Class III, IV II-IV, post-MI II
MRA Spironolactone Eplerenone Eplerenone
Mean Dose (mg daily) 26 43 39
Follow-up (months) 24 16 21
Mean Age (years) 65 64 69
Male (%) 73 72 77
Mean EF (%) 26 33 26
All-cause mortality (ARR %) 11.3 2.3 3.0
Cardiac mortality (ARR %) 9.8 2.3 2.7
All-cause hospitalization (ARR%) 8.3 1.1 5.9
Hyperkalemia Definition ≥6 mmol/L ≥6 mmol/L ≥5.5 mmol/L
Hyperkalemia (Risk excess %) 0.5 1.6 4.6
NYHA = New York Heart Association; MRA = mineralocorticoid receptor antagonists; EF = ejection fraction; ARR = absolute risk reduction

Clinicians are hesitant to initiate MRA therapy during hospitalization, as evidenced by the poor rates of discharge prescription. We speculate that this may be primary related to concerns of hyperkalemia and adverse side effect profiles of these agents in the acute setting since a significant number of patients have a hospital course complicated by worsening renal function, many have diabetes (~40%) and the majority are concomitantly taking an ACE-inhibitor or ARB. However, patients may be particularly amenable to change during hospitalization and adding underutilized, but efficacious, agents to their existing regimen may be beneficial. The hospitalization provides a unique opportunity for clinicians to optimize medical therapy and provide assistance extending beyond mere symptomatic relief.(23,24) If MRAs are administered as indicated with close monitoring and surveillance, especially immediately after initiation and at higher therapeutic doses, metabolic derangements can be identified early and successfully managed. There is an enormous unmet need in AHFS with alarmingly high mortality and rehospitalization rates seen within the first 90 days of discharge.(25) The minor risk of metabolic fluctuations may be a small price to pay for these dismal event rates.
Matching the Right Drug with the Right Patient

MRAs have successfully linked our basic science understanding of HF pathophysiology to its direct clinical management. Although MRAs are well-established and provide a consistent mortality benefit (albeit through an unknown mechanism), they remain an underutilized class of agents in the setting of HF. Currently, we are only offering this potentially life-saving therapy to a minority of eligible patients. Treatment should not be provided based solely on structured algorithms, clinical care teams involving physicians, nurses, pharmacists, patients and their families must work together to determine appropriateness of MRA initiation.

It is also important to appropriately adjust and up-titrate dosage to achieve maximal natriuretic and mortality benefit. Initial studies suggest that MRAs may have two distinct beneficial effects in HF. At lower doses (25-50 mg/day), the drug has minimal cardiac penetration, but has a documented mortality benefit. Mean doses utilized in RALES, EPHESUS and EMPHASIS-HF were 26 mg, 43 mg and 39 mg daily, respectively. At higher drug levels (50-75 mg/day), similar to dosing employed by our hepatology colleagues, natriuretic effects are achieved and help to modulate intravascular volume and congestion. At these dosing ranges in the RALES trial, spironolactone significantly decreased sodium retention within days of drug initiation.(6) Starting at trial doses and up-titrating if necessary (and tolerated) to attain diuretic effect may be a plausible treatment strategy.

As our clinical experience and familiarity with this class of agents continue to grow, we will hopefully be able to close this apparent gap between evidence-based guidelines and clinical practice in the setting of HF. As with most agents available for use in the setting of HF, one size certainly does not fit all. Careful selection of patients and vigilant follow-up after initiation of MRAs are imperative for therapeutic success. Despite initial concerns that a treatment-patient mismatch existed for MRAs, contemporary appropriateness guidelines have shown that use of these agents in patients with documented contraindications was only 0.5%.(3)

Further research will be necessary to shed light on whether we can extend the clinical usefulness of MRAs to other important patient populations with HF. Unfortunately, we currently lack substantial clinical evidence regarding the efficacy of aldosterone blockade in the setting of HF with preserved EF and in AHFS. In the near future, hopefully we will be able to better ascertain drug appropriateness in these special populations. We also eagerly await the development of novel MRAs that confer higher receptor specificity that may lessen the metabolic fluctuations and adverse risk profiles associated with current therapies. In this era of heart failure management, clinical trials tend to define the limits of our therapeutic boundaries. However, we must also be mindful of our lack of understanding of MRA effectiveness in “real world”, unselected patients. Tailoring and individualizing therapy to fully balance the benefits and risks of aldosterone antagonism will be necessary for the treatment of each and every patient.

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References

1. Francis GS, Goldsmith SR, Levine TB, Olivari MT, Cohn JN. The neurohumoral axis in congestive heart failure. Ann Intern Med 1984;101:370-7.

2. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009;53:e1-e90.

3. Albert NM, Yancy CW, Liang L, et al. Use of aldosterone antagonists in heart failure. JAMA 2009;302:1658-65.

4. Margolis J, Gerber RA, Roberts C, Gheorghiade M. Adherence to aldosterone-blocking agents in patients with heart failure. Am J Ther 2010;17:446-54.

5. Blair JE, Zannad F, Konstam MA, et al. Continental differences in clinical characteristics, management, and outcomes in patients hospitalized with worsening heart failure results from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) program. J Am Coll Cardiol 2008;52:1640-8.

6. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.

7. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21.

8. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21.

9. Aronson D, Burger AJ. Neurohormonal prediction of mortality following admission for decompensated heart failure. Am J Cardiol 2003;91:245-8.

10. Pitt B, White H, Nicolau J, et al. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol 2005;46:425-31.

11. Pitt B, Gheorghiade M, Zannad F, et al. Evaluation of eplerenone in the subgroup of EPHESUS patients with baseline left ventricular ejection fraction <30%. Eur J Heart Fail 2006;8:295-301.

12. Wang NC, Piccini JP, Konstam MA, et al. Implantable cardioverter-defibrillators in patients hospitalized for heart failure with chronically reduced left ventricular ejection fraction. Am J Ther 2010;17:e78-87.

13. Blair JE, Khan S, Konstam MA, et al. Weight changes after hospitalization for worsening heart failure and subsequent re-hospitalization and mortality in the EVEREST trial. Eur Heart J 2009;30:1666-73.

14.Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-51.

15. Gheorghiade M, Braunwald E. Reconsidering the role for digoxin in the management of acute heart failure syndromes. JAMA 2009;302:2146-7.

16. Albaghdadi M, Gheorghiade M, Pitt B. Mineralocorticoid receptor antagonism: therapeutic potential in acute heart failure syndromes. Eur Heart J 2011.

17. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;53:557-73.

18. O'Connor CM, Miller AB, Blair JE, et al. Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program. Am Heart J 2010;159:841-9 e1.

19. Schrier RW, Gheorghiade M. Challenge of rehospitalizations for heart failure: potential of natriuretic doses of mineralocorticoid receptor antagonists. Am Heart J 2011;161:221-3.

20. Ceremuzynski L, Budaj A, Michorowski B. Single-dose i.v. Aldactone for congestive heart failure: a preliminary observation. Int J Clin Pharmacol Ther Toxicol 1983;21:417-21.

21. Hensen J, Abraham WT, Durr JA, Schrier RW. Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention. Am J Nephrol 1991;11:441-6.

22. van Vliet AA, Donker AJ, Nauta JJ, Verheugt FW. Spironolactone in congestive heart failure refractory to high-dose loop diuretic and low-dose angiotensin-converting enzyme inhibitor. Am J Cardiol 1993;71:21A-8A.

23. Gheorghiade M, Peterson ED. Improving postdischarge outcomes in patients hospitalized for acute heart failure syndromes. JAMA 2011;305:2456-7.

24. Metra M, Gheorghiade M, Bonow RO, Dei Cas L. Postdischarge assessment after a heart failure hospitalization: the next step forward. Circulation 2010;122:1782-5.

25. Gheorghiade M, Abraham WT, Albert NM, et al. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA 2006;296:2217-26.

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Speedy Treatment for Heart Attacks Called 'Finest Moment'

By Chris Kaiser, Cardiology Editor, August 22, 2011

Note that current guidelines recommend that for patients with ST-segment–elevation myocardial infarction who receive primary percutaneous coronary intervention that the time from hospital arrival to mechanical reperfusion, should not exceed 90 minutes.

Point out that nationally within the last five years the door-to-balloon time has declined markedly with corresponding increases in the percentage of patients who had times <90 minutes.
Review
Over a span of five years, the initiative to improve door-to-balloon time for people experiencing out-of-hospital myocardial infarction has resulted in significantly lower transport and treatment times, a nationwide analysis showed.

From 2005 to 2010, door-to-balloon time declined from a median of 96 minutes to 64 minutes, reported Harlan R. Krumholz, MD, from Yale University School of Medicine, and colleagues.

Moreover, there were corresponding increases in the percentage of patients who had times under 90 minutes (44.2% to 91.4%), as well as under 75 minutes (27.3% to 70.4%), according to the study published online in Circulation: Journal of the American Heart Association.

"These results show the profession at one of its finest moments," Krumholz told MedPage Today in an interview. "The research isn't top-down research. It's about trying to ferret out the secrets of success from those doing the best."

There were no financial incentives for the door-to-balloon initiative to go forward. It is about disseminating best patient practices, Krumholz noted.

"Over this five-year period, we've had this extraordinary change in practice. And now any American who has a heart attack that requires angioplasty can feel confident that he or she will be treated very quickly," he said.

A study in 2006 showed that only a third of patients received primary PCI within 90 minutes, and a third waited longer than two hours after arriving at the hospital (J Am Coll Cardiol 2006; 47: 45–51), but that same year Krumholz and colleagues reported that a handful of simple measures could substantially shorten that time interval.

This latest publication represents a culmination of those efforts, Krumholz said in an email.

First, the Centers for Medicare and Medicaid Services (CMS) began to publicly report the percent of patients treated within recommended times. Then, the American College of Cardiology and others launched the D2B Alliance, which advocated the "adoption of key strategies that had been shown to reduce delays based on a study funded by the National Heart, Lung, and Blood Institute." Finally, the American Heart Association launched Mission: Lifeline, another national initiative created to speed the care of STEMI patients.

Studies charting the success of D2B times following these initiatives were generally from registries, which represent a "selected sample" of U.S. hospitals, Krumholz and colleagues wrote.

"There has been no national assessment of the trends in D2B times, nor do we know whether improvements in D2B times were shared equally among patient and hospital groups," they said.

To fill in those gaps, they analyzed data reported by hospitals to CMS for inclusion in the time to PCI inpatient measure. During the study period, the number of patients was fairly constant, ranging between 48,977 and 53,682.

At baseline, slightly more than half of all patients were between the ages of 46 and 65, three-quarters were men, and 80% were white. These numbers did not vary significantly during the study period.

In 2005, 44.2% and 27.3% of patients had D2B times in under 90 and 75 minutes, respectively. In 2010, those numbers were 91.4% and 70.4%.

The investigators found a median drop in D2B time of 32 minutes during the time span (96 to 64 minutes), which represents a greater than 30% relative decline.

"This improvement, experienced across the country and across different types of hospitals, represents a remarkable elevation in practice that was achieved over a relatively short period of time and in the absence of financial incentive," researchers wrote.

They also said that these improvements were likely due to multiple factors, rather than one single overriding action, including:
Published articles that identified strategies for improving door-to-balloon time
National initiatives by various organizations
Identifying "exceptional" performers and analyzing their methods
CMS' emphasis on quality improvement in this area


Krumholz noted that each hospital had to find places to "shave minutes" off their D2B times. There generally wasn't one single area that could decrease D2B time by significant amounts of time.

He compared it to racing pit crews, who work tirelessly to cut mere seconds from every action during a pit stop.

Christopher White, president of the Society for Cardiovascular Angiography and Interventions (SCAI), told MedPage Today that these improvements could not have happened if the medical professions involved were practicing in silos.

"One of the major changes in practice was for cardiologists to allow EMTs or ED physicians to activate the cath lab before the cardiologist determined or confirmed the patient had an MI," White said. "That was a huge shift and very necessary for reducing door-to-balloon time."

While seconds can still be cut from existing D2B protocols, there is one area on which stakeholders will focus more attention going forward: transfer times for patients who must be transported to a PCI-capable hospital.

CMS is considering publicly reporting transfer times, Krumholz and colleagues said. "More importantly, current research shows that these times can be reduced through greater coordination between hospitals."

Limitations to the study included modifications to the CMS reporting process over the time period, which could have affected results.

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CVD Risk Prediction Improved by Homocysteine

By Charles Bankhead, Staff Writer,
Published: August 22, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Explain that an analysis of two large databases found that adding homocysteine determination to the Framingham Risk Score significantly improved prediction of cardiovascular disease events.

Note that adding homocysteine reclassified risk for approximately 20% of patients in the intermediate cardiovascular disease risk category.

Risk stratification for cardiovascular disease (CVD) improved significantly with the addition of homocysteine level to the Framingham Risk Score, investigators reported.

A homocysteine level >15 µmol/L predicted as much as a 172% increased risk of CVD across two disparate cohorts. In particular, the addition of homocysteine to traditional risk factors led to reclassification of about 20% of patients in the intermediate-risk category, as reported in the Journal of the American College of Cardiology.

"Our results lend support to previously published data exploring the association between homocysteine and cardiovascular disease and coronary heart disease (CHD) events," Luis Afonso, MD, of Wayne State University in Detroit, and coauthors wrote in conclusion.

"Of note, unlike any previous study, our analyses were adjusted for C-reactive protein (CRP), an independent predictor of future CVD events."

Traditional risk factors account for a majority of CVD risk, but a substantial minority of events remains incompletely explained. In an effort to hone risk prediction, investigators have examined numerous nontraditional factors, especially biomarkers, such as CRP, coronary artery calcium, and homocysteine level.

Studies of homocysteine as a CVD risk factor have yielded inconsistent results. Moreover, previous studies have focused largely on Caucasian populations and patients with pre-existing CVD.

"To date, no study has systematically explored the predictive value of homocysteine beyond existing risk predicted by the Framingham Risk Score (particularly in individuals without overt CVD) or assessed whether homocysteine level contributes to reclassification of individuals in the intermediate-risk Framingham Risk Score category," the authors wrote.

To address limitations of previous studies, Afonso and colleagues examined the risk-prediction value of homocysteine in two data sets: the Multi-Ethnic Study of Atherosclerosis (MESA), a community-based, ethnically diverse cohort of healthy adults; and the Third National Health and Nutrition Examination Survey (NHANES III), a representative sample of the general population.

The authors investigated potential associations of homocysteine with composite CVD and hard CHD events in MESA and with CVD and CHD mortality in NHANES III.

Composite CVD comprised myocardial infarction, resuscitated cardiac arrest, definite angina, probable angina, stroke, stroke death, CHD death, other atherosclerotic death, and other CVD death. A hard CHD event was defined as MI, resuscitated cardiac arrest, or CHD death.

Risk estimates for MESA were based on six years of follow-up. Framingham Risk Score (based on 10-year risk) was adjusted to obtain six-year estimated risk. Patients were assigned to four risk categories: very low, <3%; low, 3% to <6%; intermediate, 6% to 12%; and high, >12%.

The NHANES data set had 15 years of follow-up and was adjusted to obtain 10-year risk estimates: very low, <5%; low, 5% to <10%; intermediate, 10% to <20%; and high, >20%.

The final analyses comprised 6,450 study participants from MESA and 6,797 NHANES III participants.

After adjustment for traditional risk factors and CRP, a homocysteine level >15 µmol/L was associated with a hazard ratio of:
1.79 for composite CVD (P=0.006)
2.22 for CHD events (P=0.01)
2.72 for CVD mortality (P<0.001)
2.61 for CHD mortality (P<0.001)


When added to the Framingham Risk Score, homocysteine led to reclassification of 12.9% and 18.3% of the MESA and NHANES III cohorts overall and to reclassification of 21.2% and 19.2% of the intermediate-risk patients in the MESA and NHANES III cohorts, respectively.

Investigators also analyzed the data sets by means of the net reclassification improvement (NRI) index, using Framingham Risk Score with and without homocysteine. The addition of homocysteine resulted in significant reclassification in the MESA (NRI 0.35, P<0.001) and NHANES III cohorts (NRI 0.57, P<0.001).

The analyses showed increases in the area under the receiver operating characteristic curve of 0.025, indicating a 2.5% increase in probability of an event, indicating a 2.5% improvement, authors of an editorial noted.

"This small increase is typical of models that already contain at least a handful of strong predictors," Arduino A. Mangoni, MD, of the University of Aberdeen in Scotland, and Richard J. Woodman, PhD, of Flinders University in Adelaide, Australia, wrote.

"It is often hard to be convinced that such small changes will translate into meaningful differences in patient management, even if from a public health perspective, changes of this magnitude might be meaningful."

Nonetheless, the study "provides a sound rationale for adding homocysteine in CVD risk assessment," Mangoni and Woodman added. However, they offered several reasons for cautious interpretation of the results:
Framingham Risk Score is not universally accepted for risk assessment
The Framingham model's applicability outside the U.S. has yet to be proven
Use of the Framingham model in the NHANES cohort might have been inappropriate because several participants had a history of MI or cerebrovascular disease
The NRI by itself does not indicate whether reclassification occurred

Afonso and colleagues also acknowledged the study was limited by having a single baseline homocysteine measurement, which could vary based on a number of factors including food intake, position when blood drawn, time of day, as well as cobalamin and folate levels.

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Metabolic Syndrome Linked to Kidney Disease

By Nancy Walsh, Staff Writer, August 22, 2011

Explain that a systematic review and meta-analysis found an association between components of the metabolic syndrome and the development of chronic kidney disease as measured by an estimated glomerular filtration rate <60 mL/min per 1.73 m2.

Note that risk was associated with each component and increased when multiple components were present, indicating a significant trend.
Review

Metabolic syndrome and its individual components -- hypertension, high triglycerides, low HDL cholesterol, central obesity, and impaired fasting glucose -- are all associated with the development of chronic kidney disease (CKD), a meta-analysis determined.

In a pooled analysis, the odds ratio for developing CKD, defined as an estimated glomerular filtration rate below 60 mL/min per 1.73 m2, was 1.55 (95% CI 1.34 to 1.80) in patients with the metabolic syndrome, according to Sankar D. Navaneethan, MD, of the Cleveland Clinic, and colleagues.

And although the risk of CKD did not increase for patients with only one component of the syndrome, the odds ratio rose to 1.96 (95% CI 1.71 to 2.24, P<0.01) when all five syndrome components were present, the researchers reported online in the Clinical Journal of the American Society of Nephrology.

"The public health relevance of these results is underscored by the fact that the prevalence of [metabolic syndrome] and its components is increasing over time, and findings suggest that the CKD burden might rise commensurately," they stated.

Because previous studies exploring the association of the metabolic syndrome and CKD have had conflicting results, Navaneethan and colleagues conducted a systematic review and meta-analysis that included 11 prospective studies and more than 30,000 patients.

The outcome measures of interest were estimated glomerular filtration rate, microalbuminuria, and proteinuria.

Three of the studies included European or American patients, while participants in the other eight were Asian.

The number of patients in the studies ranged from a low of 175 to more than 17,000, and duration of follow-up was 3.5 to 12 years.

The odds ratios for the development of chronic kidney disease for the individual components of the metabolic syndrome were:
Hypertension, OR 1.61 (95% CI 1.29 to 2.01)
Hypertriglyceridemia, OR 1.27 (95% CI 1.11 to 1.46)
Low HDL, OR 1.23 (95% CI 1.12 to 1.36)
Abdominal obesity, OR 1.19 (95% CI 1.05 to 1.34)
Impaired fasting glucose, OR 1.14 (95% CI 1.03 to 1.26)


The association was statistically significant for all five (P<0.01) and became stronger with a higher number of components of the metabolic syndrome (P for trend 0.02).

Three studies found increased risks for developing proteinuria among patients with metabolic syndrome, but a pooled analysis could not be done because of small numbers and differences in the studies.

Significant statistical heterogeneity was seen among the studies, but on univariate meta-regression no differences in risk were identified according to CKD criteria and definitions, duration of follow-up, or study location.

The researchers noted that previous reports have linked elevated triglycerides and low HDL with the development of chronic kidney disease, but "these factors are often overlooked in clinical practice."

They also emphasized the importance of the 19% increased risk for CKD in patients with abdominal adiposity.

"With the increasing problem of obesity across the globe, the burden of [metabolic syndrome] is expected to rise rapidly, further underscoring the relevance of our findings," they observed.

Potential weaknesses of their analysis were the observational nature of the studies, their heterogeneity, and the possibility of attrition or selection bias.

"Our results emphasize the need to identify individuals with the constellation of these metabolic risk factors earlier and consider multidisciplinary interventions, particularly lifestyle modifications, to retard the development of CKD," concluded Navaneethan and colleagues.

Three of the authors have received support from the National Institutes of Health.

All authors reported no conflicts of interest.
Primary source: Clinical Journal of the American Society of Nephrology
Source reference:
Thomas G, et al "Metabolic syndrome and kidney disease: a systematic review and meta-analysis" Clin J Am Soc Nephrol 2011; DOI:10.2215/CJN.02180311.

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Stents Work for Some Very Young Patients

By Todd Neale, Senior Staff Writer, Published: August 22, 2011
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Note that percutaneous coronary intervention with stent implantation is uncommon in children and extremely rare in infants due to perceived risk as well as technical difficulty.

Note that this study reports a small experience with children and infants who successfully underwent percutaneous coronary intervention with stent implantation suggesting that the procedure is feasible and relatively safe as a palliative and temporary solution.

A percutaneous coronary intervention (PCI) involving a stent implantation appears to be a viable option for infants and young children with coronary stenosis, a small case series suggested.

Stenting was performed successfully in four children younger than 15 months, with no procedural complications, András Bratincsák, MD, PhD, of Rady Children's Hospital in San Diego, and colleagues reported online in Catheterization and Cardiovascular Interventions.

The average amount of time free from additional interventions was 434 days, although one patient died after developing stent thrombosis and undergoing surgery to repair the problem.

"Our experience suggests that coronary artery stent implantation is a feasible and relatively safe palliative option in infants and toddlers with coronary stenosis," Bratincsák and colleagues wrote.

They added, however, that stenting is not meant to be a permanent fix in young children because the stents cannot be dilated to diameters large enough for adults.

"It is a viable strategy for bridging patients with acute ischemia or poor ventricular function to elective surgical revascularization or transplantation," they wrote.

Although PCI is rarely performed in infants and children because of the risks and difficulty of the procedure, Bratincsák and colleagues wanted to review the feasibility of the approach in young patients.

They performed a retrospective review of children who underwent PCI at Rady Children's Hospital over a four-year period, identifying seven patients younger than 18 who received stents in the proximal portion of the left or right coronary artery.

The described case series focused on the four patients younger than 15 months, who ranged in age from 7 to 14 months.

In those patients, the indications for PCI included congenital ostial stenosis of the left or right coronary arteries in two patients, a worsening of acute coronary syndrome symptoms after surgical repair of anomalous left coronary artery arising from the pulmonary artery in one, and acute left ventricular dysfunction and ventricular fibrillation secondary to external compression of the left main coronary artery after the dilation of a right pulmonary artery stent in one.

Before the intervention, the mean coronary artery diameter was 0.65. Balloon angioplasty failed to effectively open the blocked arteries, resulting in the implantation of bare-metal stents in all four patients. The stents were dilated to a mean internal diameter of 2.5 millimeters.

There were no procedural complications, and "excellent" revascularization was achieved in all four patients.

All of the patients received aspirin, and three of the four also received clopidogrel (Plavix).

Two of the patients, both of whom received dual antiplatelet therapy and had an implanted stent diameter greater than 2.5 mm, did not experience in-stent restenosis or stent thrombosis. One -- a male with Crouzon syndrome -- eventually underwent heart transplantation and the other -- a female with William's syndrome -- had a patent stent three years after PCI.

One of the other patients -- a female diagnosed with anomalous left coronary artery from the pulmonary artery -- developed mild in-stent restenosis 302 days after PCI and eventually underwent elective surgical repair of the proximal left main coronary artery, which included stent removal.

The final patient -- a male with a history of ventricular septal defect -- did not fare as well.

He did not receive clopidogrel post-PCI and experienced stent thrombosis four days after implantation despite adequate heparinization. He required extracorporeal membrane oxygenation support, and after physicians unsuccessfully attempted to reopen the blocked stent, he underwent surgical repair of the left main coronary artery. He died three days after the surgery due to intracranial hemorrhage.

"Our case mix illustrates the variety of possible causes of acute coronary syndrome in children," researchers wrote.

Furthermore, as a temporary solution, stenting has similar immediate and mid-term efficacy as surgical repair, but "substantially lower" relative risk. However, these young patients must maintain dual antiplatelet therapy for at least 12 months, unless contraindicated, the authors emphasized.

[Chevychelov]

Coronary CTA identified CAD mortality risk in patients

Min J. J Am Coll Cardiol. 2011;58:849-860.
By

Coronary CTA successfully identified those at heightened risk for all-cause mortality, providing worsened prognosis for patients with obstructive or nonobstructive coronary artery disease, according to a study.

The researchers evaluated 24,775 patients aged at least 18 years from 12 centers using Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry (CONFIRM) data gathered between 2005 and 2009 who underwent at least 64-detector row coronary CTA for suspected CAD. CAD severity was judged on a per-patient, per-vessel and per-segment basis, and the severity was defined as either none (0% stenosis), mild (1%-49% stenosis), moderate (50%-69% stenosis) or severe (≥70% stenosis). Patients with known CAD or a history of MI, coronary revascularizations and cardiac transplant were excluded from the study.

The coronary CTA scans were performed on a variety of different scanner platforms, and then analyzed by level 3-equivalent cardiologists who had experience interpreting several thousand coronary CTA scans. Any uninterpretable coronary artery segment that was scanned was scored similarly to the most proximal segment that was evaluable, according to researchers. Time to mortality was then estimated using multivariable Cox proportional hazards models.

A follow-up was obtained for 96.3% of patients. Researchers recorded 404 deaths in the follow-up, and an increasing severity of CAD in men, patients with diabetes, hypertension, dyslipidemia, family history of CAD, who currently smoke, typical angina, and high pre-test likelihood of CAD. Patients who had died before follow-up “had significantly more severe coronary artery stenosis in the majority of coronary segments” compared with patients who were alive at follow-up. Only 0.65% of deaths occurred in patients without evident CAD.

“The study cohort was middle-aged with a high prevalence of CV risk factors and symptoms,” researchers wrote. “They presented with typical or atypical angina in the majority of cases, with the majority of individuals having intermediate or high pre-test likelihood of obstructive CAD.”

Overall, both obstructive and nonobstructive CAD presented increased risk for mortality compared with patients without evident CAD, according to researchers. Patients with nonobstructive, obstructive one-vessel, two-vessel, or three-vessel or left main CAD had an increased risk of mortality, with two-vessel and three-vessel showing higher hazards for death in younger patients, and three-vessel CAD showing higher hazards for women compared with men.

“These results of the CONFIRM registry represent the first prospective international multicenter data to relate [coronary] CTA-determined extent and severity of CAD to all-cause mortality and demonstrate the independent prognostic value of both obstructive as well as nonobstructive CAD by [coronary]CTA,” the researchers wrote.
__________________________________________________ ______________________

New FDA guidelines aim to clarify benefit-risk determinations for medical devices
By

FDA has approved draft guidance clarifying how benefit-risk determinations are made during premarket review of certain medical devices, according to a press release.

“Clinical data is the foundation for determining the safety and effectiveness of medical devices requiring FDA premarket approval,” FDA Center for Devices and Radiological Health director Jeffrey Shuren, MD, stated in the news release. “As medical devices grow increasingly complex, many factors impact our benefit-risk determinations, especially for PMA devices. This guidance aims to provide more clarity to manufacturers about what factors we consider when making an approval decision.”

The guidance focuses on the regulatory pathway for high-risk medical devices: premarket approval applications (PMAs). Recommendations within the guidance are intended to improve predictability, consistency and transparency of the premarket review process for applicable devices, and could help manufacturers navigate the approval process more easily, the release noted.

Safety and effectiveness data make up the FDA’s review of PMAs, with safety data addressing risk and the device manufacturer’s ability to mitigate such risk. Effectiveness data considers benefits and other information in determining whether the benefits of using the device outweigh the risks.

According to the release, however, safety and effectiveness data alone may not provide a complete picture of the benefits and risks involved. For this reason, FDA medical device reviewers examine factors like the severity of the disease the product diagnoses or treats — as well as whether or not alternative tests or treatments may be available. Reviewers also might take into account whether a device should be considered new or first-of-its-kind, especially if it treats a disease with no other treatment.

The guidance also proposes medical device reviewers use a worksheet to document how they make benefit-risk determinations, the release noted, adding that in certain cases such a document could be made public post-approval — enhancing the transparency of the FDA’s decision-making process.
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Patient survival with beta-blockers varies in US vs. rest of the world

O’Connor C. J Am Coll Cardiol. 2011;58:915-922.
By

A meta-analysis of randomized trials evaluating beta-blockers in patients with HF has reported that among those in the United States, beta-blockade correlated with a lower survival benefit compared with those in the rest of the world.

The analysis included 8,988 patients with HF (46.7% from the US) enrolled in the COPERNICUS, MERIT-HF and BEST randomized, double blind, placebo-controlled trials.

According to results, the reduction in RR for each beta-blocker among those in the US cohort was minimal and no longer significant when compared with the overall cohort, whereas those in the rest of the world experienced a mortality benefit with beta-blockade.

In a pooled analysis that also included patients from the CIBIS-II trial (n=11,635), patients taking beta-blockers had an overall RR of death of 0.77 (95% CI, 0.71-0.84) vs. placebo. Only those in the rest of the world cohort, however, had a statistically significant survival benefit with beta-blockers (RR=0.64; 95% CI, 0.56-0.72).

Postulating on the reasons behind this discrepancy, the researchers said geographic difference in treatment response may be due to differences in populations, genetic factors, cultural or social differences in disease management, or low power and statistical chance.

“Whatever the cause, geographic differences are reported frequently in the literature, and these findings support the need to re-evaluate the conduct, methodology and analysis procedures of international trials to ensure that the generalizability of study findings can accurately be determined,” they said.

[Chevychelov]

Cholesterol-Lowering Foods Beat Low-Saturated Fat Diet

By Kristina Fiore, Staff Writer, August 23, 2011

Explain that a dietary intervention study of cholesterol-lowering foods with either two or seven counseling sessions significantly lowered LDL cholesterol compared with a control diet emphasizing reduced saturated fat consumption.

Note that the results between the groups receiving two versus seven counseling sessions were not significantly different.
Review
Eating a predominantly vegetarian diet focused on lowering cholesterol -- and getting advice on how to do so effectively -- can drop LDL levels more than a diet focused only on reducing saturated fat, researchers found.

A diet rich in cholesterol-lowering foods dropped LDL by 13% to 14% over six months, depending on the level of accompanying counseling, compared with a drop of just 3% for patients on a control diet, David Jenkins, MD, of St. Michael's Hospital in Toronto, and colleagues reported in the August 24/31 issue of the Journal of the American Medical Association.

"Our data demonstrate the cholesterol-lowering potential of a dietary portfolio intervention that counsels participants to increase consumption of cholesterol-lowering foods denoted by the FDA to have a heart-health benefit," they wrote.

Foods with known cholesterol-lowering properties -- such as nuts, soy, and barley -- have been shown to be effective in lowering serum cholesterol in metabolically controlled conditions, the researchers said.

So they assessed whether eating a diet consisting of these foods decreased LDL cholesterol compared with a control diet that emphasized eating fiber and whole grains.

They enrolled 351 patients with hyperlipidemia at four centers across Canada, who were given one of three diet plans: a "dietary portfolio" that emphasized plant sterols, soy protein, viscous fibers, and nuts with either two counseling sessions or seven sessions over six months, or a control diet focused on lowering saturated fats without counseling. Control patients were not allowed to eat foods in the intervention portfolio, the researchers said.

The 51 patients who were taking statins before the study had discontinued them at least two weeks prior.

Mean LDL cholesterol at baseline was 171 mg/dL.

In the modified intention-to-treat analysis of 345 patients, the researchers saw significant reductions in LDL cholesterol only for patients in both arms of the portfolio diet: a 13.8% reduction for those who had intensive counseling and a 13.1% drop for those with "routine" counseling (P<0.001 for both) compared with a nonsignificant 3% drop for those on the control diet.

Jenkins and colleagues said the LDL reductions were "approximately half those observed with early statin trials, that were associated with 20% reductions in coronary heart disease mortality."

"Further study is needed to determine whether cholesterol reduction using these portfolio components is associated with lower rates of coronary heart disease events," they wrote.

They also noted that more frequent visits to the clinic appear to be unnecessary in achieving significant reductions in LDL. "The near maximal effectiveness of only two clinic visits enhances the suitability of this dietary approach for clinical application," they added.

The portfolio diet also improved the ratio of total cholesterol to HDL cholesterol, dropping 8.2% for the routine counseling and 6.6% for the intensive counseling (P<0.001 for both). Those reductions were significantly greater than those for the control diet, but weren't significantly different from each other, the researchers said.

The cholesterol-lowering diet also reduced the calculated 10-year heart risk by 10.8% for those on routine counseling and by 11.3% for those on intense counseling, which was significantly greater than the nonsignificant 0.5% drop in risk for those on the control diet.

The researchers noted that reductions in LDL were associated with dietary adherence for those on the cholesterol-lowering diet (P<0.001).

"Convincing people to change dietary patterns is difficult, much less convincing them to become vegetarians," Jana Klauer, MD, a primary care physician in New York, said in an email to MedPage Today and ABC News. "But it can be done -- just look at Bill Clinton," noting the former president and heart disease patient who recently became a vegan in order to glean its benefits to lower his cardiovascular risk.

But Merle Myerson, MD, EdD, of St. Luke's and Roosevelt Hospitals in New York, said the counseling component is perhaps the trickiest part.

"Medicare and most insurances do not reimburse for one session of nutrition counseling, unless you have diabetes or end-stage renal disease, much less the kind of patients in this study," she said, adding that she doubts patient adherence would be sufficient in the long run.

The study was limited because the intervention was complex and lipid-lowering effects couldn't be pegged to specific components. Also, they cautioned about its high overall dropout rate of 22.6%, though they noted this is "an attrition rate common to dietary studies at these levels of intensity."

As well, the study may lack generalizability because its population was predominantly white, with low-to-intermediate risk of cardiovascular disease, and may not translate to those with a higher risk of disease.

Still, they concluded that "a meaningful 13% LDL reduction can be obtained after only two clinic visits of approximately 60- and 40-minute sessions."

[Chevychelov]

LV Filling Problems Signal HF Risk

By Crystal Phend, Senior Staff Writer, August 23, 2011

Explain that a longitudinal population-based study found that diastolic dysfunction increased with age and over time and was associated with the development of heart failure.

Note that progression of diastolic dysfunction to a more severe degree was associated with a higher incidence of heart failure.
Review
Worsening left ventricular diastolic function may contribute to heart failure onset, according to a longitudinal population-based study.

Diastolic dysfunction predicted an 81% elevated risk of developing heart failure over four years even after adjustment for the traditional risk factors (HR 1.81, 95% CI 1.01 to 3.48), Richard J. Rodeheffer, MD, of the Mayo Clinic in Rochester, Minn., and colleagues found.

One in four persons with moderate to severe diastolic dysfunction developed heart failure during further long-term follow-up, they reported in the Aug. 24/31 issue of the Journal of the American Medical Association.

Persistence of or progression to more severe problems with left ventricular filling was associated with higher heart failure incidence (P<0.001).

"Although confirmation in other studies would be helpful, our data suggest that persistence or progression to diastolic dysfunction is a risk factor for heart failure in elderly persons," the group wrote in the paper.

They analyzed diastolic findings among 2,042 individuals ages 45 and older (mean 61) examined in the Olmsted County (Minnesota) Heart Function Study.

In a previous study, body fat was linked to left ventricular diastolic dysfunction. In the current study, the mean body mass index at baseline for the 1,402 participants who later had a repeat examination four years later was 28.3, and only one-quarter of them had a BMI less than 25. These numbers did not change at the repeat exam.

However, BMI did not predict LV diastolic dysfunction from exam one to exam two in this cohort. The mean BMI for those who developed LV dysfunction and those who did not was 28.1 kg/m2. The unadjusted odds ratio (OR) was 0.99 (95% CI 0.99 to 1.01), while the OR adjusted for age and sex was 1.0 (95% CI 0.99 to 1.01).

At the repeat examination, researchers found an overall increase in diastolic dysfunction prevalence from 23.8% to 39.2% and in prevalence of moderate to severe cases from 6.4% to 16.0% (both P<0.001).

Further follow-up over 6.3 years linked heart failure onset to worse diastolic function (P<0.001 for trend). The heart failure incidence rates were:
2.6% in those whose diastolic function remained normal or normalized
7.8% in those whose left ventricular diastole became or remained mildly dysfunctional
12.2% in those who progressed to or continued to have moderate to severe diastolic dysfunction


While left ventricular diastolic dysfunction was associated with advancing age, especially once individuals reached 65 (OR 2.85, 95% CI 1.77 to 4.72), diastolic dysfunction wasn't clearly linked to change in systolic function.

Nor were only those with risk factors affected.

Among apparently healthy participants without hypertension, diabetes, coronary artery disease, heart failure, or cardiovascular drug use, prevalence of diastolic dysfunction rose from 11.3% to 29.8% over four years (P<0.001) and 19.9% showed worsening diastolic function over time.

"That diastolic dysfunction worsened even in healthy persons supports the concept that aging may be accompanied by progressive deterioration in diastolic function," Rodeheffer's group wrote in the paper.

"This age-related progression of diastolic dysfunction in the population contributes to the pathophysiologic substrate from which overt heart failure emerges," they added.

The investigators cautioned, though, that their findings may have underestimated the effect of worsening diastolic dysfunction because participants lost to follow-up between examinations were sicker, with worse diastolic dysfunction, and higher mortality rates yielding survival and participation bias.

Generalizability of these findings from a largely white population to other races and ethnicities is not clear, the group added.

[Chevychelov]

FDA Warns Against High-Dose Citalopram

By John Gever, Senior Editor, Reviewed by
August 24, 2011

Review

Citing increased risk of cardiac arrhythmias and a lack of therapeutic benefit associated with high doses of the selective serotonin reuptake inhibitor (SSRI) citalopram hydrobromide (Celexa), the FDA has reduced the recommended maximum to 40 mg/day.

Previously, the agency had approved a 60-mg/day dose of the antidepressant for certain patients.

The new dosing instruction was prompted by postmarketing surveillance reports and a prospective trial linking the 60-mg dose to unacceptable QT interval prolongations and Torsade de Pointes.

The trial -- a randomized, placebo-controlled, crossover study in 119 adults -- examined citalopram's effects on QT intervals at doses of 20 mg and 60 mg, the FDA said.

Relative to the placebo phase, the 20-mg dose produced mean QT prolongation of 8.5 msec (90% CI 6.2 to 10.8). At 60 mg, QT intervals were extended by an average of 18.5 msec (90% CI 16.0 to 21.0).

By interpolating these results, the FDA estimated that a 40-mg dose would prolong QT intervals by an average of 12.6 msec (90% CI 10.9 to 14.3), which it deemed marginally acceptable.

"As a result of this thorough QT study, FDA has determined that citalopram causes dose-dependent QT interval prolongation and should no longer be used at doses above 40 mg per day," the agency said in a drug safety communication.

Congestive heart failure, bradyarrhythmias, and predispositions to potassium or magnesium deficiencies are risk factors for Torsade de Pointes, the FDA noted.

Consequently, the agency recommended that patients with these conditions should undergo regular electrocardiography if given citalopram, and hypokalemia and hypomagnesemia should be corrected before starting patients on the drug.

Patients currently taking citalopram at doses higher than 40 mg/day should not stop the drug abruptly, but should talk to their doctors about lowering the dose, and should seek treatment immediately for irregular heartbeats, shortness of breath, fainting, or dizziness.

Package inserts for citalopram, which is also available in generic forms, will be rewritten to include the new information, the agency said.

The FDA did not indicate that the cardiac effects were an issue with escitalopram (Lexapro), which is the S-enantiomer of citalopram -- suggesting that the arrhythmias stem from the latter's R-enantiomer.

[Chevychelov]

Anticoagulation therapy: New score for hemorrhage risk

Gregory B. Lim
Abstract

A new scoring scheme to predict the risk of warfarin-associated hemorrhage in patients with atrial fibrillation (AF) has been published by researchers from the ATRIA (Anticoagulation and Risk Factors in AF) study group based at Kaiser Permanente in the US. Warfarin is commonly prescribed to patients with AF to reduce the risk of thrombosis, but according to Dr Margaret Fang, lead author of the report, “anticoagulants can significantly reduce a person's risk of AF-related stroke; however, anticoagulants also [confer] significant risks—in particular, an increased risk of bleeding.
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[Chevychelov]

Antithrombotic drug and stent choices in primary PCI
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Кого интересует,то что ниже, быстрее забирайте. Пишут, что доступ временный.

Dietary factors associated with hypertension
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Managing kidney disease with blood-pressure control
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A comprehensive review of the clinical aspects of primary aldosteronism
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Prenatal programming—effects on blood pressure and renal function
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Blood pressure lowering in patients with diabetes—one level might not fit all
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Epidemiology of hypertensive kidney disease
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The relationship between blood pressure and cognitive function
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The role of Rho protein signaling in hypertension
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Novel therapeutic targets for hypertension
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Assessment and management of hypertension in children and adolescents
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Aldosterone and arterial hypertension
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[Chevychelov]

2011 Safety Alerts for Human Medical Products

Drugs and Therapeutic Biological Products
Product Name Date Issued/Updated
5-alpha reductase inhibitors (5-ARIs): Label Change - Increased Risk of Prostate Cancer 06/09/2011
Abacavir - Ongoing Safety Review: Possible Increased Risk of Heart Attack 03/01/2011
Acetadote (acetylcysteine) Injection: Recall - Particulate Matter Found in a Small Number of Vials 01/01/2011
Acetaminophen Prescription Products Limited to 325 mg Per Dosage Unit: Drug Safety Communication 01/13/2011
Aidapak Services Repackaged Pharmaceuticals: Recall - Potential Cross Contamination with Beta Lactam Products 06/03/2011
Albuterol Sulfate Inhalation Solution 0.083%, 3 mL Unit Dose Vials: Recall - Mislabeled Unit Dose Vials 01/03/2011
American Regent Injectable Products: Recall - Visible Particulates in Products 07/20/2011
Angiotensin Receptor Blockers (ARBs): Drug Safety Communication - Drug Safety Review Completed 06/02/2011
Antipsychotic drugs: Class Labeling Change - Treatment During Pregnancy and Potential Risk to Newborns 02/22/2011
Avandia (rosiglitazone): REMS - Risk of Cardiovascular Events 05/18/2011
Benzocaine Topical Products: Sprays, Gels and Liquids - Risk of Methemoglobinemia 04/07/2011
Birth Control Pills Containing Drospirenone: Possible Increased Risk of Blood Clots 05/31/2011
Butalbital, Acetaminophen, and Caffeine Tablets (USP 50mg, 325mg, 40mg) and Hydrocodone Bitartrate and Acetaminophen Tablets (USP 7.5mg, 500mg): Recall - Bottle Mislabeled 06/27/2011
CardioGen-82 PET Scan: Drug Safety Communication - Increased Radiation Exposure 07/26/2011
Celexa (citalopram hydrobromide): Drug Safety Communication - Abnormal Heart Rhythms Associated With High Doses 08/24/2011
Chantix (varenicline): Label Change - Risk of Certain Cardiovascular Adverse Events 07/22/2011
Citalopram And Finasteride by Greenstone: Recall - Possible Mislabeling 03/28/2011
Coumadin (warfarin sodium) Crystalline 5 mg Tablets: Recall - Tablets May Have Higher than Expected Potency 05/03/2011
Diflucan (fluconazole): Drug Safety Communication – Long-term, High-dose Use During Pregnancy May Be Associated With Birth Defects 08/03/2011
Endocet (Oxycodone / Acetaminophen) Tablets, ( 10mg, 325mg ) : Recall - Some Bottles Contain Different Strength Tablets 06/27/2011
Erythropoiesis-Stimulating Agents (ESAs) In Chronic Kidney Disease: Drug Safety Communication - Modified Dosing Recommendations 06/24/2011
H & P Industries Povidone Iodine Prep Pads: Recall - Potential Microbial Contamination 03/18/2011
Hydrocodone Bitartrate And Acetaminophen Tablets, Phenobarbital Tablets by Qualitest: Recall - Incorrect Package Labeling 02/07/2011
Indomethacin for Injection: Recall of One Lot - Particulate Matter 06/15/2011
Irinotecan Hydrochloride Injection: Recall - Fungal Microbial Contaminant 03/28/2011
Kaletra (lopinavir/ritonavir): Label Change - Serious Health Problems in Premature Babies 03/08/2011
Lansoprazole Delayed-Release Orally Disintegrating Tablets by Teva Pharmaceuticals: Letter to Healthcare Professionals - Clogged, Blocked Oral Syringes and Feeding Tubes 04/15/2011
Long-Acting Beta-Agonists (LABAs): New Safe Use Requirements 04/15/2011
Meds IV Pharmacy, IV Compounded Products Recall: Outbreak of Serratia Marcescens Bacteremia in Alabama Hospitals 03/30/2011
Methylene Blue: Drug Safety Communication - Serious CNS Reactions Possible When Given to Patients Taking Certain Psychiatric Medications 07/26/2011
Metronidazole Tablets, 250mg: Recall - Underweight Tablets 01/06/2011
Morphine Sulfate Oral Solution 100 mg per 5 mL (20 mg/mL): Medication Use Error - Reports of Accidental Overdose 01/10/2011
Multaq (dronedarone): Drug Safety Communication - Increased Risk of Death or Serious Cardiovascular Events 07/21/2011
Multaq (dronedarone) - Drug Safety Communication: Risk of Severe Liver Injury 01/14/2011
Nature Relief Instant Wart and Mole Remover: Recall - Risk of Severe Skin Burns 06/27/2011
Needleless Pre-filled Glass Syringes: Stakeholder Advisory - Compatibility Problems with Needleless Intravenous Access Systems 05/06/2011
Nulojix (belatacept): Risk Evaluation and Mitigation Strategy (REMS) 07/07/2011
Oral Osteoporosis Drugs (bisphosphonates): Drug Safety Communication - Potential Increased Risk of Esophageal Cancer 07/21/2011
Pradaxa (dabigatran etexilate mesylate) Capsules: Special Storage and Handling Requirements 03/30/2011
Proton Pump Inhibitor drugs (PPIs): Drug Safety Communication - Low Magnesium Levels Can Be Associated With Long-Term Use 03/02/2011
Revlimid (lenalidomide): Ongoing Safety Review - Increased Risk of Developing New Malignancies 04/08/2011
Risperdal (risperidone) and Risperidone: Recall - Uncharacteristic Odor 06/20/2011
Risperidone (Risperdal) and Ropinirole (Requip): Medication Errors - Name Confusion 06/13/2011
Tamiflu (oseltamivir phosphate) for Oral Suspension: Label Change-New Concentration (6 mg/mL) 07/11/2011
Terbutaline: Label Change - Warnings Against Use for Treatment of Preterm Labor 02/17/2011
Topamax (topiramate): Recall - Musty Odor 04/15/2011
Topamax (topiramate): Label Change - Risk For Development of Cleft Lip and/or Cleft Palate in Newborns 03/04/2011
Triad Alcohol Prep Pads, Alcohol Swabs, and Alcohol Swabsticks: Recall Due to Potential Microbial Contamination 06/08/2011
Tumor Necrosis Factor (TNF) blockers, Azathioprine and/or Mercaptopurine: Update on Reports of Hepatosplenic T-Cell Lymphoma in Adolescents and Young Adults 04/14/2011
Tylenol Extra Strength Caplets, 225 count bottles: Recall - Uncharacteristic Odor 06/29/2011
Tysabri (natalizumab): Update of Healthcare Professional Information 04/22/2011
Unapproved Cough, Cold, Allergy Products: FDA Prompts Removal From Market 03/02/2011
Warfarin Sodium Tablets (Jantoven), 3mg: Recall - Mislabeled Bottles Containing Higher Dosage 02/21/2011
Yervoy (ipilimumab): Risk Evaluation and Mitigation Strategy (REMS) - Severe Immune-Mediated Adverse Reactions 04/06/2011
Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy) 06/30/2011
Vasopressin Injection USP, Multiple Dose Vials: Recall - Sub-Potency 08/04/2011
Victoza (liraglutide [rDNA origin]) Injection: REMS - Risk of Thyroid C-cell Tumors, Acute Pancreatitis 06/13/2011
Zocor (simvastatin): Label Change - New Restrictions, Contraindications, and Dose Limitations 06/08/2011
Zyvox (linezolid): Drug Safety Communication - Serious CNS Reactions Possible When Given to Patients Taking Certain Psychiatric Medications 07/26/2011

Special Nutritional and Cosmetic Products
Product Name Date Issued/Updated
SimplyThick: Public Health Notification - Risk of Life-Threatening Bowel Condition 06/05/2011
Multi-Mex Distributor Inc. Dietary Supplements: Recall - Product Packaging Mimics OTC Antibiotics 05/10/2011
Pentrexyl Forte Natural: Recall - Misleading Packaging 05/23/2011
Soladek Vitamin Solution: Unapproved Product May Contain Dangerously High Levels of Vitamins A and D 03/29/2011

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[Chevychelov]

24-Hour Monitoring Best to Diagnose Hypertension

By Crystal Phend, Senior Staff Writer, August 24, 2011

Action Points
Explain that this study found that ambulatory blood pressure monitoring is the most cost-effective way to confirm a hypertension diagnosis before starting treatment.


Point out that the American Heart Association recommends home monitoring for newly diagnosed or suspected hypertension with ambulatory monitoring reserved for equivocal cases to help establish the diagnosis.
Review
Ambulatory blood pressure monitoring is the most cost-effective way to confirm a hypertension diagnosis before starting treatment, researchers found.

The cost-savings from avoiding misdiagnosis was greater with ambulatory monitoring than with further blood pressure measurements in the office or at home, Richard J. McManus, MSc, MBBS, of the University of Birmingham, England, and colleagues reported.

Ambulatory confirmation saved from $92 (£56) to $533 (£323) across groups in the modeling study released online in The Lancet.


Moreover, ambulatory monitoring slightly boosted quality-adjusted life years among patients older than 50.

"Ambulatory monitoring for most people before the start of antihypertensive treatment should be seriously considered," McManus' group argued in the paper.

In response, the British regulatory agency that helped fund the study is altering its guidelines to recommend ambulatory monitoring as a best practice.

The National Institute for Health and Clinical Excellence (NICE) announced the change at a press briefing held in London the same day as the Lancet paper was published.

The American Heart Association recommends home monitoring for newly diagnosed or suspected hypertension with ambulatory monitoring reserved for equivocal cases to help establish the diagnosis.

The traditional approach has been two repeat visits for in-office measurement after an initial finding of elevated blood pressure, Thomas A. Gaziano, MD, of Brigham and Women's Hospital in Boston, noted in a commentary accompanying the Lancet study.

That ambulatory monitoring is cost-saving isn't surprising because it addresses the problem of white-coat hypertension, he pointed out.

"Improved diagnosis by both home and ambulatory monitoring results in reduction of morbid or fatal, as well as expensive, events attributable to cardiovascular disease, and minimizes treatment of people who otherwise would be incorrectly labelled hypertensive," Gaziano wrote in the commentary.

The financial savings with ambulatory monitoring compared with home monitoring was likely because the automated ambulatory monitoring device has greater accuracy, suggested Joseph Diamond, MD, director of nuclear cardiology at Long Island Jewish Medical Center in Hyde Park, N.Y.

Whether serially-obtained automated blood pressure measurements could be just as accurate and cost-effective if taken in the office isn't clear, he noted in a statement sent to reporters.

McManus' group modeled cost-effectiveness on a hypothetical primary-care population age 40 and older that screened positive for a blood pressure over 140/90 mm Hg and had hypertension risk factor prevalence similar to the general population.

After accounting for costs associated with equipment, consumables, maintenance, and staff time as well as costs of treatment for hypertension and cardiovascular events, ambulatory monitoring for 24 hours to confirm hypertension diagnosis was less expensive in all gender and age groups than several repeat office visits or home measurements over a week's time.

These savings "were primarily because of the costs of hypertensive treatment that were avoided because of the higher specificity of ambulatory monitoring," the researchers noted.

They pointed to the example of 60-year-old men for whom ambulatory monitoring cost $69 (£42) more per diagnosis but saved $237 (£144) in treatment costs compared with clinic monitoring, while costs for subsequent cardiovascular events and follow-up were similar between groups.

Home monitoring had similar results as office visits for both quality of life and costs across age and gender groups.

Even in the younger age groups for whom ambulatory monitoring was associated with a small reduction in quality-adjusted life years and cost-effectiveness ratios greater than $82,470 (£50,000) per QALY, it remained most cost effective.

The only assumptions that changed the ranking of the three methods were if home monitoring was as accurate as ambulatory testing and if treating people who did not have true hypertension actually reduced their cardiovascular risk.

If repeat screening was done on a yearly rather than every-five-year basis for those who screened negative for hypertension, home monitoring became more cost-effective for younger age groups, although "unrealistic in clinical practice where annual ambulatory monitoring would be judged excessive for most people."

The researchers noted that if they had included small negative effects of treatment side effects in their analysis, the cost-effectiveness of ambulatory monitoring would have looked even better.

The results are likely widely generalizable to primary care, they added, pointing to prior studies from the U.S., Australia, and Italy that found cost savings with ambulatory rather than further in-office monitoring.

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Heart Failure Deaths Down in U.S.

By Kristina Fiore, Staff Writer, Reviewed by
August 26, 2011

Review

Death rates in patients hospitalized for congestive heart failure have fallen over the last decade, particularly among the oldest patients, government researchers found.

Between 2000 and 2007, overall mortality rates were cut nearly in half, from 55 to 28 per 1,000 admissions, according to a News and Numbers data brief from the Agency for Healthcare Research and Quality.

Patients 85 and older saw the greatest drop, from 87 to 48 deaths per 1,000 admissions, the researchers found.

"We see [the decline] cutting across all age groups," Ernest Moy, MD, MPH, medical officer for the AHRQ and an author on the report, told MedPage Today. "Older patients still have the highest death rates, but it's also falling."

Mortality rates among patients 65 and up fell from 64 to 34 deaths per 1,000 admissions during the period, and rates among patients ages 45 to 64 fell from 28 to 15 deaths per 1,000 admissions.

For those ages 18 to 44, the decline was from 19 to 12 deaths per 1,000 hospital admissions, the researchers found.

Moy said the declines are statistically significant: "We believe they are real, that hospitals are taking better care of patients," he said.

Yet he noted that disparities appear to exist between urban and rural hospitals, with greater declines in mortality rates for patients seen in metropolitan facilities than for those in smaller cities.

"It's a little disconcerting," Moy said. "Over time, it's been falling, but it's still an area of concern."

The researchers also saw that rates fell slightly more for patients with Medicare rather than private insurance, and rates for private insurance were still higher than those for Medicare patients in 2007 (35.6% versus 26.9%).

Moy said that patients who develop heart failure before they're eligible for Medicare may indicate that they have a more serious form of the condition, which may explain why death rates for those with private insurance are higher.

The findings are part of the 2010 National Healthcare Disparities Report, which assesses disparities in access to and quality of healthcare in the U.S.

From the American Heart Association:
Updates in HF and CAD
Heart Disease and Stroke 2011 Statistical Update

Primary source: Agency for Healthcare Research and Quality
Source reference:
2010 National Healthcare Quality & Disparities Report

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Early Preeclampsia Triples Risk of Hypertension

By Charles Bankhead, Staff Writer,
Published: August 26, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Explain that a study of cardiovascular risk factors 10 years after pregnancy showed that women who had preeclampsia before 32 weeks gestation had more than triple the risk of hypertension compared with controls who had a pregnancy without preeclampsia.


Note that meeting criteria for metabolic syndrome and waist circumference were also increased in those with a history of preeclampsia.
Preeclampsia before 32 weeks of gestation more than tripled a woman's odds of hypertension before age 40, a study of cardiovascular risk after preeclampsia showed.

Women who had developed preeclampsia had significantly higher mean systolic and diastolic blood pressure 10 years later than a matched control group of women who did not have preeclampsia, according to an article published online in the European Journal of Cardiovascular Prevention & Rehabilitation.

Women with a history of preeclampsia also had a twofold greater prevalence of metabolic syndrome. Waist circumference, too, was significantly greater in the preeclampsia group, which had a numerically greater body mass index (BMI).

Lipids, glucose, and C-reactive protein levels did not differ between women who had a history of preeclampsia and those who did not.

"The etiology of preeclampsia is as yet unresolved," Jose T. Drost, MD, of Isala Clinics in Zwolle, the Netherlands, and co-authors wrote in conclusion.

"Research on genetics and metabolic biomarkers is needed for a better understanding of its pathogenesis. Additional research should focus on the cost-effectiveness of cardiovascular screening programs and the timing of treatment of cardiovascular risk factors in women with previous preeclampsia."

Several studies have demonstrated associations between preeclampsia and future cardiovascular disease (CVD), and the magnitude of the association appears related to the severity of metabolic disturbances caused by preeclampsia.

Although the etiology of preeclampsia remains largely undetermined, early-onset preeclampsia (before 32 weeks of gestation) has a different pathophysiology than preeclampsia later in pregnancy, the authors wrote in their introduction.

Early preeclampsia induces an inflammatory response in the maternal circulation, leading to vasoconstriction and activation of the thrombotic cascade in the mother. Placental lesions associated with preeclampsia resemble early atherosclerosis, the authors continued.

In most cases, preeclampsia symptoms dissipate within a few weeks. However, decades later, women with a history of preeclampsia have at least a twofold greater risk of CVD.

Data from intermediate follow-up of women with a history of preeclampsia are scant, resulting in an uncertain time frame during which CVD risk factors develop. The lack of data is especially pertinent to the subgroup of women who develop the condition early in pregnancy, who might be targeted for early prevention.

Drost and colleagues sought to examine the emergence of CVD risk factors in women 10 years after an episode of early preeclampsia, defined as diastolic blood pressure ≥90 mmHg accompanied by proteinuria ≥0.3 g/24 h occurring before 32 weeks of gestation.

The study population consisted of women who responded to a mailed questionnaire and invitation to participate in a cardiovascular screening program. The investigators subsequently recruited 339 women with a history of early preeclampsia and 332 age-matched women with uncomplicated pregnancies.

Baseline characteristics included a mean age of 39 and mean interval of nine to 10 years since childbirth. Offspring of the preeclampsia group had a significantly lower mean birth weight (about 3.2 lbs versus 7.5 lbs, P<0.05), and the preeclampsia group had a significantly higher rate of stillbirth (14.8% versus 3.9%, P<0.05).

As compared with the control group, women with a history of early preeclampsia had significantly higher mean blood pressure (127/86 versus 119/79 mmHg, P<0.001 for systolic and diastolic pressure) and waist circumference (86.5 versus 83.2 cm, P=0.001) and a trend toward higher BMI (26.9 versus 26.2, P=0.066).

The authors reported that 43.1% of the preeclampsia group had hypertension (≥140/90 mmHg) as compared with 17.2% of the control group. The difference translated into an odds ratio of 3.5 for the preeclampsia group (P<0.001).

Fewer than half of the hypertensive women received adequate antihypertensive therapy (20.6% in the preeclampsia group versus 2.1% in the control group, P<0.05).

Twice as many women with a history of preeclampsia met diagnostic criteria for metabolic syndrome (18% versus 9%), resulting in an odds ratio of 2.18 (P=0.002).

No other clinical or metabolic parameters differed significantly between groups.

The authors cautioned that their findings cannot be extrapolated to women after 32 weeks of gestation with preeclampsia. There also may have been some bias as the women with preeclampsia were more motivated to participate than the controls, researchers said.

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ESC: Anticoagulants Top Meeting Agenda

By Todd Neale, Senior Staff Writer,
Published: August 26, 2011

PARIS -- The ARISTOTLE trial pitting the novel anticoagulant apixaban against warfarin for preventing stroke in patients with atrial fibrillation looks like it will be the stand-out of this year's meeting of the European Society of Cardiology here.

The top-line results -- which were reported by Bristol-Myers Squibb and Pfizer in June -- showed that apixaban, a direct factor Xa inhibitor, was as effective as warfarin at preventing stroke and systemic embolism in patients with arrhythmia.

"We got a hint that this is a positive trial and we're really looking forward to this because the new anticoagulants are the next wave of therapy in afib," according to Christopher Cannon, MD, a cardiologist at Brigham and Women's Hospital in Boston and Editor-in-Chief of CardioSource.

Cannon previewed some of the trials via webcam in an exclusive interview with MedPage Today.

Some of the other highlights include a subanalysis of the ROCKET-AF trial looking at the use of rivaroxaban to prevent stroke in patients with atrial fibrillation and renal dysfunction and another of the RE-LY trial examining the use of dual antiplatelet therapy in patients taking dabigatran (Pradaxa) or warfarin.

Attendees will also hear results from the PRODIGY trial, which compared six months versus 24 months of dual antiplatelet therapy following PCI, and the dal-VESSEL trial, which evaluated the safety and efficacy of the novel CETP inhibitor dalcetrapib.

Overall, there are 27 presentations scheduled for three Hot Line sessions and two Clinical Trial Update sessions.

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Calcium Scans Pick Up Controversy in Cardiology

By Crystal Phend, Senior Staff Writer,
Published: August 26, 2011
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Note that the state of Texas has enacted legislation which mandates insurance coverage for imaging tests, such as noncontrast CT scans, for CVD screening in men between 45 and 75 years and women ages 55 to 75 years with intermediate risk or greater.

Point out that over 2 million people in Texas would be eligible for screening with a projected one time cost of almost $500 million. Also point out that there are no randomized clinical trials demonstrating improved outcomes from imaging screening and that CT studies carry a potential risk from radiation-induced cancer.

Coronary artery calcium scans might be the best thing since sliced risk scores or the worst example of "medicine gone wild," garnering strong and divisive opinions in cardiology.

The noncontrast CT screening test is vying for a role in determining which otherwise low- to moderate-risk patients may need more aggressive cardiovascular prevention.

When news broke last week of a study in The Lancet suggesting that calcium scans predicted risk of cardiovascular events better than high-sensitivity C-reactive protein (CRP) in a relatively healthy population like that in the JUPITER trial, major networks carried breathless statements about the technology:
"Before you go on a cholesterol medication, I want you to ask your doctor about this: A coronary artery calcium test." -- Dr. Richard Besser on ABC
"Unless you do the imaging, you are really playing Russian roulette with your life." -- Dr. Arthur Agatston in a CNN report

While these reports were criticized in Forbes and the healthcare media watchdog Health News Review, some leading cardiologists find themselves just as impressed by coronary artery calcium screening.

"There are so many different agendas we can view this with; there's no surprise this is not something that has uniform vision from all the individuals involved," he explained in an interview with MedPage Today.

Calcium Scores for Risk Reclassification

Statin therapy guided by traditional risk factors enumerated in the Framingham risk score, which uses age, gender, cholesterol, smoking status, and blood pressure, can provide an important first step in prediction but leaves much to be desired. The estimated risk is based on population data.

The high-risk population by traditional factors clearly needs lifestyle intervention and consideration of a statin medication, and calcium score won't change that decision making.

But persistent rates of heart attack and other events in the intermediate- and low-risk groups suggest that traditional factors are missing important clues of impending danger.

Calcium scanning has looked good in studies reclassifying risk.

In one large cohort study published in the Journal of the American College of Cardiology earlier this year, calcium score independently predicted 25% elevated risk of coronary events and 12% elevated risk of death from any cause.

It improved prediction by 23.8% over what Framingham score, body mass index, and known cardiovascular disease could do compared with a 10.5% improvement by high-sensitivity CRP.

Based on results like these, the American Heart Association updated its guidelines in 2010 to call calcium scans "reasonable" in intermediate-risk patients, putting it on par with echo screening of carotid intima-medial thickness (IMT).

The Society for Heart Attack Prevention and Eradication now recommends calcium and carotid IMT scans for all intermediate-risk people ages 45 to 80 and for men 35 and older who are diabetic or have a family history of premature coronary disease.

Another advantage of coronary scans, according to some reports, is their power for patient motivation.

Calcium scores moved patients to get to work on their heart disease risk factors -- reducing blood pressure, LDL cholesterol, and waist circumference compared with patients who didn't get the scan, another JACC study reported in March.

A meta-analysis in the Archives of Internal Medicine suggested that noninvasive imaging may not be very motivating for physicians to change prescribing.

But "you'd be surprised how if you tell a 55-year-old that his cholesterol is 260, he's going to look at you and go 'Okay, yeah, I know that's high,'" Weintraub said. "However, if you tell a 55-year-old he has the arteries of a 75-year-old, that tends to get his attention."

Not Just a Simple Test

Calcium scanning got all the wrong kind of attention initially from many physicians.

"There has been a lot of controversy around calcium scoring because most of the early proponents owned their equipment and had a huge conflict of interest," William W. O'Neill, MD, chief medical officer of the University of Miami Health System, noted in an email to MedPage Today and ABC News.

High-sensitivity CRP has faced the same concern, with the pivotal JUPITER trial of statins in lower-risk, high-CRP patients led by a patent holder on the CRP blood test, Paul Ridker, MD, MPH, of Brigham and Women's Hospital in Boston.

Also, "many of us were initially bothered by the way calcium scanning was introduced, as a for-profit test marketed directly to the community, without good evidence to support its use," de Lemos explained in an email.

Calcium scans, generally, aren't reimbursed by insurance, with the exception of coverage mandated by a 2009 Texas state law. The average out-of-pocket cost runs about $100 elsewhere.

Recent studies have redeemed the test in many minds, but there's still no randomized trial showing that coronary artery calcium-guided therapy leads to better outcomes, de Lemos noted.

But no screening method has such large-scale clinical trial evidence, noted Amit Khera, MD, MSc, a cardiologist at UT Southwestern.

The widely used Framingham risk score hasn't been tested in a randomized trial. Even CRP, for which the randomized JUPITER trial demonstrated benefit of treating patients with high CRP as their sole risk factor, doesn't have gold standard evidence since JUPITER didn't include a low CRP arm.

"What we need from our imaging colleagues are trial data, not assumptions of what might work without formal evaluation," Ridker argued in an email to MedPage Today.

"Remember, the imaging community also assumed for years that statins would reduce coronary artery calcium scores, but when trials were finally done this turned out to be a completely wrong assumption," he noted.

The lack of change in calcium score with treatment can be troubling to some physicians and patients, Weintraub noted.

And that often leads to unnecessary catheterization and stenting, "so actual costs to the healthcare system are very high," added Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic, who called calcium scanning "one of the worst examples of 'medicine gone wild'" in an email to MedPage Today and ABC News.

Incidental findings are a well-known concern with CT imaging, including when imaging coronary arteries for calcium.

Radiation, too, is an issue.

One calcium scan confers the equivalent of 10 chest X-rays or two mammograms, which could be expected to result in cancer in nine per 100,000 persons tested, according to an analysis done by Khera at the time the Texas law passed.

Though one-third the radiation a person gets on average from the sun and environment are offset by a potential reduction in cardiovascular deaths, the cancer risk is important when talking about asymptomatic individuals, Khera noted.

"In the absence of evidence, why use a test that is associated with radiation, cost, and leads to a number of downstream consequences instead of a simple panel of blood tests along with data on age, smoking, and blood pressure?" Ridker questioned in an email.

Competition or Collaboration?

Yet it may not be an either-or situation between calcium scanning and other noninvasive screening methods.

In the JACC cohort study that showed incremental predictive power of calcium scoring, its combination with high-sensitivity CRP had better discriminatory power than either measure alone.

"I think ultimately it's going to be a combination of things," Weintraub told MedPage Today. "We've known for a long time that CRP and calcium scores don't necessarily coincide."

Calcium in the arteries points to stable plaque, while inflammatory markers like high-sensitivity CRP indicate vulnerability of plaque to rupture, he noted.

Carotid IMT images the coronary arteries with ultrasound, eliminating the radiation concerns, and may be particularly useful for risk prediction in younger people in whom the calcium score is likely to be zero.

Some evidence also suggests carotid IMT is a better predictor of stroke risk, whereas calcium score may be a better predictor of coronary events, Khera noted.

So which test or combination of tests you choose may depend to some degree on the individual patient, he suggested.

"We're in the sorting out period right now," he told MedPage Today. "The positive is these are all potential new tools that can be used, and they all have some value. It's just figuring out how to use each test and where they should be used and what to do about them."

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ESC: Hot Line Sizzles Even When Data Are Not So New

By Peggy Peck, Executive Editor, Published: August 27, 2011

PARIS -- By the numbers, the European Society of Cardiology meeting is the largest cardiology meeting in the world -- more than 30,800 registrants, representing 154 countries, who will have the opportunity to hear and see findings from 4,276 studies.

But at an opening press conference the meeting organizers all agreed that most of the interest here is focused on the results of a single study -- ARISTOTLE -- that will take center stage Sunday during a Hot Line plenary session.

The results of the trial, which compared the investigational factor Xa inhibitor, apixaban (Eliquis), against warfarin for prevention of stroke in patients with atrial fibrillation, will not surprise anyone because two months ago the two companies that developed the drug, Bristol-Myers Squibb and Pfizer, reported positive top-line data in a press release.

In the U.S., organizations like the American College of Cardiology and American Heart Association typically don't include trials that have had a pre-release of data as breaking clinical trials. For example, when results of the ENHANCE trial, a study of ezetimibe/simvastatin (Vytorin) versus simvastatin were released at a company press conference two months before the ACC's annual meeting, ENHANCE was not included in the ACC's breaking clinical trial line-up, but was instead presented during a separate plenary session.

But that early release was not viewed as a problem by the ESC because, as Michael Böhm, MD, PhD, of University Hospital of Saarland, Homburg, Germany, told MedPage Today, those top-line data did not include "important details" that will be presented during the Hot Line presentation. Since the companies presented only scant information, the ESC decided that the full results met its criteria for presentation, explained Böhm, who chairs the ESC program committee.

And in any event, Böhm, ESC President Michel Komajda, MD, of Pitié Salpetrière Hospital in Paris, and ESC's communication chairman, Kurt Huber, MD, director of cardiology at Wilhelminen Hospital in Vienna, all agreed that ARISTOTLE was a study too good to pass up for the ESC meeting.

Not that there was any paucity of material for the program committee to choose as 10,836 abstracts were submitted, Böhm said, with most of them coming from Japan. However, the country with the most accepted abstracts was Germany with 514 papers. U.S. researchers, by contrast, are reporting 201 papers here, but one of those accepted abstracts was ARISTOTLE.

Komajda said this year's meeting will also feature results from 15 registries, data that he said reflect real-world findings.

The ESC meeting continues through Wednesday.

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ESC: Guideline Issued to Treat CVD in Pregnancy

By Todd Neale, Senior Staff Writer,
Published: August 27, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

Action Points
Explain that the European Society of Cardiology has released guidelines for the management of cardiovascular disease during pregnancy, although most of the recommendations are based on small studies, retrospective data, registries, expert consensus, or a combination.

Point out that the guidelines recommend pre-pregnancy risk assessment and counseling in all women with known or suspected congenital or acquired cardiovascular and aortic disease.

PARIS -- Despite a dearth of prospective, randomized data, the European Society of Cardiology has released guidelines for the management of cardiovascular disease during pregnancy.

Because of the lack of evidence, most of the recommendations are classified as level C, meaning that they are based on small studies, retrospective data, registries, expert consensus, or a combination.

They were crafted by the ESC's task force on the management of cardiovascular diseases during pregnancy -- chaired by Vera Regitz-Zagrosek, MD, of Charité Universitaetsmedizin Berlin -- and published online in the European Heart Journal before the start of the society's annual meeting here. The guidelines will be formally introduced later in the meeting.

Even though a small fraction of pregnancies in developed countries -- 0.2% to 4% -- are complicated by cardiovascular diseases, "knowledge of the risks associated with cardiovascular disease during pregnancy and their management are of pivotal importance for advising patients before pregnancy," the authors wrote.

They added that heart disease is the leading cause of maternal death during pregnancy.

Regitz-Zagrosek and colleagues noted that the guidelines come at a time when the risk of cardiovascular disease in pregnant women is growing as a result of increasing age at first pregnancy and higher rates of diabetes, hypertension, and obesity.

Also contributing are improvements in the treatment of congenital heart disease, which allows more women to reach reproductive age. In western countries, congenital heart disease accounts for 75% to 82% of cases of cardiovascular disease during pregnancy.

There are particular considerations surrounding the treatment of cardiovascular disease in pregnant women, according to the authors, because of the physiological changes that occur during gestation.

Pregnancy leads to increased blood volume and cardiac output; reductions in systemic vascular resistance and blood pressure; and a higher risk of thromboembolic events. In addition, some changes affect the absorption, excretion, and bioavailability of medications.

The guidelines detail screening for heart disease in pregnant women, assessing risk, and counseling.

Although there are multiple methods for assessing the risk of cardiovascular events in pregnant women, the authors recommended using the World Health Organization risk classification, which takes into account all known maternal cardiovascular risk factors, including underlying heart disease and comorbidities.

According to this system, as risk increases, so does the frequency of the recommended follow-up visits during pregnancy. The guidelines state, however, that women at the highest risk should be advised against pregnancy altogether. If pregnancy occurs, termination should be discussed, but if gestation continues, the woman should be followed monthly or bimonthly, the authors wrote.

Contraindications to pregnancy in this classification include:
Pulmonary arterial hypertension of any cause
Severe systemic ventricular dysfunction
Previous peripartum cardiomyopathy with any residual impairment of left ventricular function
Severe mitral stenosis
Severe symptomatic aortic stenosis
Marfan syndrome with the aorta dilated more than 45 mm
Aortic dilatation greater than 50 mm in aortic disease associated with bicuspid aortic valve
Native severe coarctation


The guidance includes both general recommendations and more specific advice for certain groups -- those with congenital heart disease, aortic disease, valvular heart disease, coronary artery disease and acute coronary syndromes, cardiomyopathies and heart failure, arrhythmias, hypertensive disorders, or venous thromboembolism.

The class I general recommendations (all level C evidence) are as follows:
Pre-pregnancy risk assessment and counseling is indicated in all women with known or suspected congenital or acquired cardiovascular and aortic disease.
Risk assessment should be performed in all women with cardiac diseases of childbearing age and after conception.
High-risk patients should be treated in specialized centers by a multidisciplinary team.
Genetic counseling should be offered to women with congenital heart disease or congenital arrhythmias, cardiomyopathies, aortic disease, or genetic malformations associated with cardiovascular disease.
Echocardiography should be performed in any pregnant patient with unexplained or new cardiovascular signs or symptoms.
Before cardiac surgery, a full course of corticosteroids should be administered to the mother whenever possible.
The same measures used in non-pregnant patients should be used in pregnant patients for the prevention of infective endocarditis.
Vaginal delivery is recommended as the first choice in most patients.

The single class III (level C) general recommendation advises against the use of prophylactic antibiotic therapy during delivery.

The guidelines conclude with a section on the use of cardiovascular drugs during pregnancy and breastfeeding, although there are no specific recommendations regarding treatment.

"In case of emergency, drugs that are not recommended by the pharmaceutical industry during pregnancy and breastfeeding should not be withheld from the mother," the authors wrote. "The potential risk of a drug and the possible benefit of the therapy must be weighed against each other."

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Apixaban Prevents Strokes, Boosts Survival in Afib Patients

This report is part of a 12-month Clinical Context series.By Peggy Peck, Executive Editor
Published: August 28, 2011
Reviewed by Michael Mullen, MD; Clinical Instructor of Vascular Neurology, University of Pennsylvania.

PARIS -- Compared with warfarin treatment, atrial fibrillation patients treated with the investigational factor Xa inhibitor apixaban had fewer strokes or embolic events, fewer major bleeding events, and were less likely to die during an average of almost two years of treatment, researchers said.

Those results emerged from the 18,201-patient ARISTOTLE study, which was published online today by the New England Journal of Medicine.

"The primary outcome of stroke or systemic embolism occurred in 212 patients in the apixaban group (1.2% per year) as compared with 265 patients in the warfarin group (1.60% per year)," Christopher B. Granger, MD, of the Duke Clinical Research Institute at Duke Action Points
Explain that apixaban, an oral factor Xa inhibitor, was compared to dose adjusted warfarin in subjects with atrial fibrillation.


Note that in the primary outcome of hemorrhagic or ischemic stroke or systemic embolization, apixaban was superior to warfarin.


Note that apixaban had a lower rate of major bleeding and a lower rate of death from any cause than warfarin.
University Medical Center in Durham, NC, and colleagues wrote.Action Points
Explain that apixaban, an oral factor Xa inhibitor, was compared to dose adjusted warfarin in subjects with atrial fibrillation.

Note that in the primary outcome of hemorrhagic or ischemic stroke or systemic embolization, apixaban was superior to warfarin.

Note that apixaban had a lower rate of major bleeding and a lower rate of death from any cause than warfarin.

Additionally, the hazard ratio in the apixaban group was 0.79 (95% CI 0.66 to 0.95; P<0.001 for noninferiority and P=0.01 for superiority.

The benefit was largely driven by the difference in hemorrhagic stroke -- 0.24% per year for apixaban (40 strokes) versus 0.47% (78 strokes) for warfarin (HR 0.51, 95% CI 0.35-0.75, P<0.001). The rate of ischemic stroke was similar in both arms of the trial, 0.9% per year with apixaban and 1.05% per year with warfarin (P=0.42).

The authors concluded that the lower risk of hemorrhagic stroke "suggests there is a specific risk associated with warfarin, possibly related to its inhibition of multiple coagulation factors or interaction between warfarin and tissue factor VIIa complexes in the brain."

The median age of patients in ARISTOTLE was 70, and all had at least one additional risk factor for stroke. About a fourth of the patients were treated at centers in North America and 40% were treated at European centers. The rest of the clinical sites were in South America or the Asian Pacific.

Background therapies included ACE inhibitors or ARBs in about 70% of patients, as well as beta-blockers (63-64%), statins (45%), and aspirin (31%). About 41% of patients had normal creatinine clearance, and 42% had mildly impaired creatinine clearance.

The 9,120 patients in the apixaban arm received 5 mg bid (2.5 mg in selected patients) while warfarin patients were treated to target (international normalized ratio [INR], 2.0 to 3.0). Blinding was assured with sham INR testing in the apixaban arm.

On average the warfarin patients had INRs in therapeutic range 62% of the time.

In addition to publication in NEJM, the ARISTOTLE results were reported at the European Society of Cardiology meeting during a Hot Line session today.

Asked about the results, Elliott Antman, MD, professor of medicine at Harvard Medical School, and a spokesperson for the American Heart Association, called the trial results "not only a home run, but an out of the park home run."

Indeed, when compared with the other emerging oral agents -- dabigatran (Pradaxa), which is FDA approved for stroke prevention in patients with atrial fibrillation, and rivaroxaban (Xarelto), which is approved for prevention of DVT in patients undergoing joint replacement surgery -- apixaban does have some advantages.

For example, rivaroxaban, which is also a direct factor Xa inhibitor, demonstrated that it was not inferior to warfarin, but there was not proof of superiority to warfarin in ROCKET-AF. And a pivotal trial that compared dabigatran with warfarin found higher rates of myocardial infarction, gastric distress, and dyspnea among patients treated with dabigatran.

But in an NEJM editorial, Jessica L. Mega, MD, MPH, of Harvard Medical School in Boston, wrote that dabigatran (150 mg bid) is the only one of the three agents to have "significantly reduced the risk of ischemic stroke compared with warfarin."

Mega noted that a third direct factor Xa inhibitor (edoxaban) is currently being tested in the ENGAGE study, which is being conducted by her colleagues at Brigham and Woman's Hospital (including Antman, who is the principal investigator for that study).

Nonetheless, she wrote that warfarin is unlikely to be swept away by the new agents because although it does require INR monitoring and dietary restrictions -- it easily beats any of competitors on cost, estimated at $4.00 a month compared with as much as $160/month for dabigatran.

Ralph Brindis, MD, a cardiologist at Kaiser Permanente in Oakland, Calif., and immediate past president of the American College of Cardiology, said the ARISTOTLE results were "just another stake or dagger in the heart of warfarin for prevention stroke."

He said, however, that as good as the apixaban numbers were, they won't necessarily translate into a big win when -- or if -- the FDA approves the drug.

A potential downside of these new drugs is that it is not possible to monitor adherence. No need for blood tests could make the drugs very appealing to patients, but for clinicians that is not necessarily the case since "one of the strengths of warfarin is that we know the patient is adhering because we are getting the blood tests," he explained.

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SATURN Statin Trial a Dead Heat

By John Gever, Senior Editor, September 02, 2011

Review

Rosuvastatin (Crestor) failed to beat atorvastatin (Lipitor) for improving atheroma volume in a large head-to-head trial, the drug's manufacturer reported.

AstraZeneca issued a terse statement outlining the top-line results of the trial.

"The results for the primary efficacy measure, which was change from baseline in percent atheroma volume in a ≥40 mm segment of the targeted coronary artery as assessed by intravascular ultrasound (IVUS), demonstrated a numerically greater reduction in favor of Crestor versus atorvastatin but did not reach statistical significance," the statement said.

The two-year SATURN study compared 40 mg/day of rosuvastatin to 80 mg/day of atorvastatin in some 1,300 patients.

However, the company said, rosuvastatin treatment did lead to a significantly greater reduction in the trial's secondary efficacy measure, total atheroma volume within the targeted coronary artery.

AstraZeneca's statement did not give numerical results. It said the data and interpretations would be presented at the American Heart Association's scientific meeting in November.

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FDA Reviewer Slams Xarelto for Stroke Prevention in Afib

By Emily P. Walker, Washington Correspondent,
Reviewed by
September 06, 2011

Review

WASHINGTON -- Rivaroxaban (Xarelto) is not as effective as warfarin for preventing strokes in patients with atrial fibrillation and should not be approved for the new indication, according to an FDA reviewer.

That opinion was set forth in briefing documents prepared for the FDA's Cardiovascular and Renal Drugs Advisory Committee meeting Thursday. The committee will review Johnson & Johnson's application to extend marketing approval for its direct oral factor Xa inhibitor rivaroxaban to include prevention of stroke and systemic embolism in patients with nonvalvular approved atrial fibrillation.

But, in its briefing documents the company argued that the "benefits of treatment with rivaroxaban clearly outweigh the risks when compared with warfarin therapy."

Results from the company-sponsored ROCKET-AF study found that rivaroxaban (Xarelto) was at least as good as warfarin for stroke prevention in atrial fibrillation, with a similar rate of major bleeding and greater ease of use. Johnson & Johnson is seeking approval that indicates their drug works better at preventing strokes than warfarin.

But the briefing documents held no joy for J & J as one of the three FDA reviewers concluded that the company failed to prove that rivaroxaban was superior to warfarin for stroke prevention. The reviewer is recommending that the agency issue a complete response letter to the company rather than approve the new indication. Rivaroxaban is approved for prevention of DVT in patients undergoing joint replacement surgery.

The FDA reviewers pored over results from the ROCKET-AF study, which enrolled more than 14,000 adults with nonvalvular atrial fibrillation who were at a high risk for thrombotic events. Patients were evenly randomized to 20 mg of rivaroxaban daily or to warfarin. The primary endpoint was time to a composite endpoint of stroke or systemic embolism.

The time period for the primary efficacy endpoint was any thrombotic events occurring while the patient was "on treatment," which was defined as last dose plus two days. By that standard, rivaroxaban was superior to warfarin (P=0.01).

But there were more strokes and embolisms in the rivaroxaban group than in the warfarin group during the period when patients stopped taking their study drug and transitioned to warfarin or other appropriate therapy for the open-label portion of the study. Based on those "intent-to-treat" data, rivaroxaban was no longer superior to warfarin. It was, however, shown to work at least as well as warfarin.

After the ROCKET-AF study was completed, the company developed instructions detailing a treatment plan for transitioning patients from rivaroxaban to warfarin, but those instructions haven't been evaluated. A study testing how to transition patients would have to be done before rivaroxaban could be approved, according to the FDA reviewer.

The FDA requires that drugs approved for life-threatening conditions -- such as stroke -- be shown to be at least as effective as other available drugs. But as the FDA reviewer pointed out, the agency "generally prefer[s] an intention-to-treat analysis as the basis of a superiority claim."

Additionally, according to the FDA reviewer, the per-protocol analyses where rivaroxaban came out a winner is "misleading" because improper dosing of warfarin may have been to blame. The company did not show that when warfarin -- which is notoriously tricky to correctly dose -- is used "skillfully" that rivaroxaban would work any better, the reviewer said.

"Thus, the data do not convincingly demonstrate that rivaroxaban is as effective in preventing strokes and systemic emboli as warfarin when warfarin is used skillfully," the reviewer said.

Another warfarin study -- RE-LY -- found that the direct thrombin inhibitor dabigatran (Pradaxa) was more effective in preventing strokes in high-risk patients than warfarin (and that study did a better job at correctly dosing warfarin, the reviewer said). Last October, dabigatran received marketing approval for prevention of stroke in patients with nonvalvular atrial fibrillation.

The reviewer noted that there are no data available from a rivaroxaban versus dabigatran match-up, and left open the question of whether such a study was in order.

In its briefing documents, the company stressed the ease of use and management of rivaroxaban, which does not require INR monitoring, nor does it require dietary restrictions -- both of which are required with warfarin therapy.

"Additional medications such as rivaroxaban would give the physician a wider range of therapeutic options that can be tailored to the individual patient," the company said.

But the FDA reviewer didn't see approval as a benefit for patients: If rivaroxaban is approved, he wrote, "patients taking it might be at greater risk of harm from stroke and/or bleeding than if they were treated with warfarin used skillfully."

"In the opinion of this reviewer, rivaroxaban should not be approved unless the sponsor submits convincing information that it is as safe and effective for its target indication as warfarin when it is used skillfully or that it is as safe and effective as another approved agent, such as dabigatran," the reviewer said.

Despite the overwhelmingly negative tone of the FDA review, there were no new safety issues uncovered, the reviewers said.

In fact, rivaroxaban-treated patients experienced numerically fewer critical organ bleeds, intracranial hemorrhages, hemorrhagic strokes, and fatal bleeds compared with patients treated with warfarin.

The Cardiovascular and Renal Drugs Advisory Committee will vote Thursday afternoon on whether rivaroxaban should be approved, and, if so, whether its label should state it works better than warfarin at preventing strokes.

[Chevychelov]

Elevated cathepsin S serum levels linked with increased risk for death

Jobs E. JAMA. 2011;doi:10.1001/jama.2011.1246.

Higher serum cathepsin S levels are associated with an increased mortality risk among elderly patients, according to a study.

In a prospective study using two community-based cohorts — the Uppsala Longitudinal Study of Adult Men (ULSAM) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) — serum samples were used to measure cathepsin S. Both studies took place in Uppsala, Sweden. ULSAM was initiated in 1970 and had 1,009 participants. PIVUS took place between 2001 and 2004 and had 987 participants.

Anthropometrical measurements, BP, blood sampling and questionnaires regarding socioeconomic status, medical history, smoking habits, medication use and physical activity level were investigated by researchers in both studies. Serum levels of cathepsin S, inflammatory markers and cystatin C were all measured by an enzyme-linked immunosorbent assay. Both studies used Cox proportional hazard regression and three multivariable models to find associations of serum level of cathepsin S with total mortality. The ULSAM study included CV and cancer mortality.

When adjusted for age, systolic BP, diabetes, smoking status, BMI, total cholesterol, HDL, antihypertensive treatment, lipid-lowering treatment and history of CVD, Cox regression models showed that higher serum cathepsin S was associated with an increased risk for mortality. Cathepsin S was also associated with an increased mortality risk for CV and cancer mortality in the ULSAM cohort. In a follow-up, 413 participants in the ULSAM cohort died of CVD (131 deaths) and cancer (148 deaths), whereas 100 participants in the PIVUS cohort died. Incidence rate per 1 unit increase of cathepsin S was 0.44/100 person-years at risk in ULSAM, and 0.15/100 person-years at risk in PIVUS. Total mortality after adjustment for age, sex, lifestyle factors and established CV risk factors had an HR of 1.04 in ULSAM and 1.03 for PIVUS. In ULSAM, CV mortality had an HR of 1.05 and cancer mortality had an HR of 1.06.

__________________________________________________ _______________________________

Review: Single cryoballoon ablation procedure in patients with paroxysmal and persistent AF yields mixed results

Andrade J. Heart Rhythm. 2011;doi:10.1016/j.hrthm.2011.03.050.

A single cryoballoon ablation procedure results in high acute and medium-term efficacy rates for paroxysmal atrial fibrillation and lower success rates when used as stand-alone therapy for persistent atrial fibrillation, according to a systematic review.

Researchers conducted a literature search using Medline, Embase and Biosis for abstracts specifically referencing cryoballoon for AF ablation. According to researchers, the search was limited to adults aged at least 19 years and publications dated between January 2000 and January 2011, but the language was not restricted to English. Overall, 23 articles were retained for final analysis: 20 reporting cryoballoon for paroxysmal AF, one reporting cryoballoon ablation for persistent AF, and two reporting cryoballoon ablation for both paroxysmal and persistent AF.

Results show that the ablation procedure was performed exclusively with cryoballoon in nine of 23 studies. Cryoballoon was combined with focal ablation in the remaining 14 studies in up to 17.1% of patients. Of 23 studies, 91.67% to 100% of patients and 94.87% to 100% of targeted veins had acute procedural success. Complete pulmonary vein isolation resulted in 77.81% of patients who underwent ablation with the cryoballoon catheter alone (95% CI, 74.99-80.45) and 92.64% of targets veins (95% CI, 91.76-93.45). In studies with cryoballoon ablation combined with concomitant focal cryoablation, 98.85% of patients (95% CI, 97.69-99.54) and 98.24% of targeted veins (95% CI, 97.69-98.68) achieved complete pulmonary vein isolation.

In 1-year freedom from recurrent AF off antiarrhythmic drug, there was a 73% 3-month blanking period and 60% no blanking period in patients with paroxysmal AF, whereas cryoballoon-based pulmonary vein isolation alone for persistent AF resulted in a 1-year freedom from AF of 45%, according to researchers. Researchers also found evidence that catheter ablation of persistent and permanent AF may require more extensive ablation beyond pulmonary vein isolation vs. paroxysmal AF. Treating paroxysmal AF with focal point-by-point radiofrequency ablation has shown success, but complications that included cardiac perforation with pericardial tamponade, injury to esophagus, phrenic nerve and aorta, and pulmonary vein stenosis were reported in 5% to 6% of patients.

[Chevychelov]

Panel Endorses Xarelto for Stroke Prevention

ADELPHI, Md. -- An FDA advisory committee has voted 9-2, with one abstention, to recommend that the FDA approve the direct oral factor Xa inhibitor rivaroxaban (Xarelto) to prevent stroke in patients with atrial fibrillation.

The overwhelmingly positive endorsement by the FDA's Cardiovascular and Renal Drugs Advisory Committee came just two days after the release of briefing documents prepared by an FDA reviewer -- documents that assailed the efficacy and safety of the drug.

Johnson & Johnson, which partnered with Bayer to develop rivaroxaban, had already secured marketing approval for the direct oral factor Xa inhibitor to prevent deep vein thrombosis in patients undergoing joint replacement surgery. In the application reviewed by the panel Thursday the company sought to extend marketing approval to include the stroke prevention indication.

The advisory committee spent most of the day reviewing J&J's ROCKET-AF study of more than 14,000 patients with nonvalvular atrial fibrillation who were at a high risk for thrombotic events. The study found that rivaroxaban (Xarelto) was at least as good as warfarin for stroke prevention in atrial fibrillation, with a similar rate of major bleeding and greater ease of use.

If the FDA approves rivaroxaban, J&J would like to claim that their drug does work better than warfarin because ROCKET-AF showed the drug worked better than warfarin in patients when success was measured two days after the patients stopped taking rivaroxaban. (P=0.01).

However, there were more strokes and embolisms in the rivaroxaban group than in the warfarin group during the period when patients stopped taking their study drug and transitioned to warfarin or other appropriate therapy for the open-label portion of the study. Based on those "intent-to-treat" data, rivaroxaban was no longer superior to warfarin.

"Clearly it is not superior to warfarin," said panelist Sanjay Kaul, MD, a cardiologist at Cedars-Sinai Medical Center in Los Angeles

Warfarin, an inexpensive drug, is a mainstay in stroke prevention. But it's notoriously tricky to dose and requires INR testing to get it right as well as dietary restrictions to keep it right, which makes warfarin unpopular with many patients -- and many physicians.

The rivaroxaban, on the other hand, is one 20 mg pill a day, and neither INR monitoring nor dietary restrictions are required.

Panelists voiced concerns about a spike in adverse events seen when patients stopped taking rivaroxaban and were transitioned to warfarin at the end of the study.

Panelist Steven Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic, who was one of the two panel members who voted against recommending approval for rivaroxaban, said it's very common to interrupt anticoagulant treatment.

"Although warfarin is a drug we love to hate, its treatment effects are slow and it's forgiving," he said. By comparison "the first few days you stop rivaroxaban, pretty bad things happen. We haven't studied that. And it makes me concerned."

Most panelists favored requiring J&J to perform a postmarketing study to examine what is the safest way to transition patients off rivaroxaban onto a new drug. Several panelists wanted that study done before the FDA approved the drug.

But physicians who work for J&J said the adverse events observed in the study wouldn't be mirrored in the real world because patients generally don't just stop taking a blood thinner cold-turkey as they did in the study. In the "real world," patients are transitioned more seamlessly onto a different anticoagulant, the company said.

An FDA reviewer and panelists were also concerned that warfarin wasn't administered ideally in the trial, causing rivaroxaban to appear more effective than it may have been had warfarin been dosed properly. Just 56% of patients who received warfarin in the ROCKET-AF were in the ideal INF range of 2 to 3 during the study, which the panel criticized as being way too low.

"INR control in ROCKET was worse than in other recent trials, which might have biased the overall results in favor of rivaroxaban," said FDA reviewer Martin Rose, MD, who authored a highly critical review of rivaroxaban that was released several days before Thursday's meeting.

One of those recent trials is the RE-LY trial, which found that the direct thrombin inhibitor dabigatran (Pradaxa) was more effective in preventing strokes in high-risk patients than warfarin.

But panel chairman Michael Lincoff, MD, another cardiologist from the Cleveland Clinic, said the spotty warfarin dosing in ROCKET-AF was acceptable because it was similar to how warfarin is used outside of clinical trials.

Dabigatran was a constant topic of conversation at the meeting, with panelists and the FDA making comparisons between rivaroxaban and dabigatran, despite the fact that no trial has yet been conducted pitting the two anticoagulants head-to-head.

"Any current expert will say it's important to do head-to-head clinical trials," said Robert Califf, MD, director of Duke University's Translational Medicine Institute and a principal investigator in the ROCKET-AF trial.

Some panelists questioned the need for another blood thinner that was shown to be noninferior to warfarin, when dabigatran was shown to be superior to warfarin.

But others at the meeting -- including a patient representative -- said more oral anticoagulants are needed because warfarin is not always well-tolerated and dabigatran can cause gastrointestinal side effects.

"All afib patients are aware of the three drugs we need to take," said patient representative Debra McCall of California. "A drug to regulate rhythm, a drug to regulate rate, and a blood thinner. We have options for rate and rhythm, but we don't have many options for blood thinners."

Following the committee vote the American Heart Association released a statement noting it will review its guidelines for anticoagulation therapy in patients with nonvalvular atrial fibrillation if the FDA does decide to approve the drug for stroke prevention in that population.

"For the millions of patients with atrial fibrillation, stroke is a real health threat, and the emerging studies of new anticoagulant drugs like rivaroxaban have been very encouraging," said Gordon Tomaselli, MD president of the American Heart Association.

The FDA is expected to make an approval decision on rivaroxaban by Nov. 4. The agency isn't required to follow the advice of its advisory committees, but it often does.

[Chevychelov]

Statin-Hemorrhage Link Disputed

By Todd Neale, Senior Staff Writer, September 12, 2011

Explain that a new retrospective cohort study found no association between statin use and intracerebral hemorrhage in patients with an ischemic stroke in contrast to other trial results.

Note that the risk of recurrent ischemic stroke was reduced for statin users in all of the recent studies including this one.
Review

Statins do not appear to be associated with a greater risk of intracerebral hemorrhage in patients who have had an ischemic stroke, a retrospective cohort study showed.

In fact, through about four years of follow-up, the rate of intracerebral hemorrhage was slightly lower in the statin users (2.94 versus 3.71 per 1,000 patient-years), according to Daniel Hackam, MD, PhD, of the University of Western Ontario in London, and colleagues.

The difference was not significant (HR 0.87, 95% CI 0.65 to 1.17), they reported online in Archives of Neurology.

The findings contrast with a post hoc analysis of the SPARCL (Stroke Prevention by Aggressive Lowering of Cholesterol Levels) trial, which found that the significant decrease in recurrent ischemic stroke with atorvastatin (Lipitor) was accompanied by a greater risk of hemorrhagic stroke (2.3% versus 1.4%).

The Heart Protection Study also suggested a greater risk of hemorrhagic stroke with statins in patients with a history of cerebrovascular disease (1.3% versus 0.7%).

A recent meta-analysis from the Cholesterol Treatment Trialists' Collaboration, however, showed no significant association between statin use and intracerebral hemorrhage, Hackam and colleagues noted.

In an accompanying editorial, Philip Gorelick, MD, MPH, of the University of Illinois in Chicago, said the discrepancy in findings from the clinical trials and the current observational study could be the result, at least in part, of the different study designs.

"Until we have additional, high-level evidence to clarify the statin-intracerebral hemorrhage risk relationship, I recommend careful control of modifiable risks for brain hemorrhage such as blood pressure in those who are treated with a statin," Gorelick wrote.

"Other statin-associated risks for intracerebral hemorrhage such as history of intracerebral hemorrhage or use of antithrombotic therapy, and possibly the presence of cerebral microbleeds, should be carefully considered in the clinical decision-making process," he wrote.

Hackam and colleagues retrospectively examined data from 17,872 patients with a history of ischemic stroke who lived in Ontario -- half who started on statins within 120 days of discharge and half who did not. The two groups were matched using propensity scores.

Using six healthcare databases, the researchers followed the patients (mean age 78; 54% female) for a median of 4.2 years. During that time, there were 213 intracerebral hemorrhages.

Consistent with previous studies, statin use was associated with a significantly lower risk of ischemic stroke (HR 0.83, 95% CI 0.75 to 0.92).

The rate of hemorrhage, however, did not differ between statin users and nonusers either overall or in analyses looking at the doses of the cholesterol-lowering medications.

After excluding patients who were not adherent to statin treatment and control patients who started taking statins during follow-up, statin use was associated with a significantly lower risk of intracerebral hemorrhage (HR 0.65, 95% CI 0.47 to 0.91).

Statins also appeared to have a protective effect in a multivariate analysis in a larger patient population (HR 0.79, 95% CI 0.63 to 0.99).

The researchers found that statin use was not associated with bone mineral density testing, vitamin D or B12 screening, gastrointestinal endoscopy, or elective knee arthroplasty, which indicates that the results were not due to healthy user bias or differences in quality of care between statin users and nonusers.

"Physicians should continue to adhere to current treatment guidelines recommending statin therapy for most patients with a history of ischemic stroke," Hackam and colleagues concluded.

In his editorial, Gorelick noted that there remains some question about the safety of using statins in patients who have a history of intracerebral hemorrhage, as highlighted by an analysis published earlier this year.

"The clinical decision to administer a statin following intracerebral hemorrhage remains a challenging one with available evidence tilting in the direction of withholding such therapy, especially when there is a history of lobar brain hemorrhage," he wrote.

The researchers acknowledged some limitations of their study, including the lack of information on some characteristics, including blood pressure profile, lipids, leukoaraiosis on neuroimaging, and lifestyle habits, the unknown applicability of the findings to younger patients, the lack of adjudication of the clinical events, and the possible misclassification of statin use.

[Chevychelov]

Control of CV Risks Improves Male Sexual Function

By John Gever, Senior Editor, Published: September 12, 2011
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Note that avoidance of risk factors and the adoption of healthy lifestyle behaviors is associated with reduction of MI, cardiac death, and stroke but few adhere to all of the tenets of a healthy lifestyle.


Point out that these two studies describe benefits of healthy lifestyle on erectile dysfunction and may lead more individuals to adopt these changes and improve health.

Erectile dysfunction (ED) is a cardiovascular risk factor independent of others, even as interventions leading to improvements in such risk factors also appear to alleviate ED, according to two separate meta-analyses.

In one, pooled data from 12 prospective cohort studies indicated that men with ED had increased risks of 35% to 48% for outcomes including cardiovascular disease, coronary heart disease, and stroke, according to Li-Qiang Qin, MD, PhD, and colleagues at Soochow University in Suzhou, China.

The other meta-analysis, with data from six clinical trials, found that successful lifestyle modifications as well as lipid-lowering statin therapy -- intended to improve conventional cardiovascular risk factors -- led to better sexual function, reported Bhanu Gupta, MD, and colleagues at the Mayo Clinic in Rochester, Minn.

The Chinese study appeared in the Sept. 20 issue of the Journal of the American College of Cardiology, while the Mayo review was published online in Archives of Internal Medicine.

As both research groups observed, an association between ED and cardiovascular disease has been noted previously but whether it was causal -- and, if so, in which direction -- remained unclear.

The new studies do not fully resolve these questions. But Qin and colleagues indicated that their analysis points to ED as an independent risk factor for cardiovascular disease.

Gupta and colleagues, meanwhile, concluded that ED is a lifestyle condition that is amenable to the same interventions known to be effective against other lifestyle-related cardiovascular risk factors.

But neither study examined whether drug treatments or other therapies targeting ED specifically -- such as sildenafil (Viagra) and related drugs -- affect cardiovascular risk.

Qin and colleagues searched for prospective cohort studies that looked for associations between ED and risk of fatal and nonfatal cardiac events, heart failure, peripheral artery disease, stroke, sudden death, or all-cause mortality.

Outcomes including acute MI, angina, and other ischemia were lumped together as "coronary heart disease." In turn, these outcomes plus stroke, cardiac arrest, heart failure, peripheral artery disease, and sudden death were all considered "cardiovascular disease."

They found 12 studies meeting their requirements, with a total of more than 36,000 participants.

After adjusting for covariates when possible, Qin and colleagues calculated the following relative risks for adverse outcomes associated with ED, relative to study participants who did not have ED:
Cardiovascular disease, 1.48 (95% CI 1.25 to 1.74)
Coronary heart disease, 1.46 (95% CI 1.31 to 1.63)
Stroke, 1.35 (95% CI 1.19 to 1.54)
All-cause mortality, 1.19 (95% CI 1.05 to 1.34)


In two of the included studies, the reference group was men with minimal to mild ED rather than no ED at all. But excluding them from the meta-analysis did not change the associations substantially, Qin and colleagues indicated.

Other sensitivity analyses also suggested that the relative risks identified in the primary calculations were robust.

However, the researchers noted that ascertainment of ED, enrollment criteria, and other aspects of the included studies varied considerably. Those studies relying on participants' self-reporting of ED may have underestimated its prevalence "because of embarrassment," Qin and colleagues noted.

The Mayo analysis was considerably smaller. Gupta and colleagues drew on a total of six randomized trials conducted since 2004 -- four testing lifestyle modifications and two in which atorvastatin (Lipitor) therapy was the intervention -- with 740 participants, in which effects on ED were measured.

Despite the small number of participants, pooled data from these studies demonstrated that cardiovascular risk-oriented interventions significantly relieved ED.

With ED outcomes standardized to weighted mean differences in International Index of Erectile Function scores, the overall improvement was 2.66 points (95% CI 1.86 to 3.47), Gupta and colleagues reported.

Dropping the two statin studies from the analysis, which had a total of 143 participants, did not affect the result much -- pooled data from the four lifestyle intervention studies showed improvements in ED scores of 2.40 points (95% CI 1.19 to 3.61).

Interventions in those studies included a number of programs, some stressing diet and others emphasizing physical activity.

The statin studies themselves were harder to interpret. One found a significant improvement in ED scores, whereas the other did not -- but with just 12 participants total, its impact on the pooled analysis was minimal.

Gupta and colleagues said the findings could be translated immediately into clinical practice.

Noting that phosphodiesterase-5 (PDE-5) inhibitor drugs such as sildenafil "are the mainstay of therapy for ED," the researchers indicated that physicians would do well to stress diet and exercise as well.

"Adoption of lifestyle modifications and CV risk factor reduction will provide incremental benefit regardless of PDE-5 inhibitor use," they wrote.

To the extent that ED is itself a cardiovascular risk factor, such interventions could also stave off more serious outcomes.

In an invited commentary accompanying the Mayo review, two other researchers concurred.

Militza Moreno, MD, and Thomas A. Pearson, MD, MPH, PhD, of the University of Rochester, noted that acute cardiovascular events and heart failure have serious negative effects on quality of life, as does ED.

"It may be the motivation to prevent one of these other poor outcomes that tips the balance toward lifestyle change," they wrote.

"Both clinicians and public health practitioners should be reassured that the benefits of their lifestyle modification efforts are overwhelmingly positive and continue to grow," they added.

[Chevychelov]

EASD: No Microvascular Benefit With Intense BP, Glucose Control

By Kristina Fiore, Staff Writer, September 15, 2011

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that the combination of intensive blood pressure and glucose management did not protect against microvascular endpoint measures compared with standard care in a study of type 2 diabetics.


Note that the combination of intensive therapies also did not affect single markers of microvascular disease compared with either therapy alone.
Review

LISBON -- Aggressively lowering blood pressure and blood glucose together won't provide any microvascular benefits to type 2 diabetes patients, researchers said here.

In an analysis of data from the ACCORD trial, neither intense glycemic management nor intense blood pressure control reduced the risk of a composite of microvascular outcomes, Patrick O'Connor, MD, of HealthPartners Research Foundation in Minneapolis, reported during an oral session at the European Association for the Study of Diabetes meeting here.

There was no interaction between the two treatments on that outcome; nor did the combination have significant effects on a host of individual microvascular outcomes including microalbuminuria, macroalbuminuria, or renal failure.

"None of the prespecified outcomes were further significantly reduced in those intensively treated for both glycemia and blood pressure compared with either regimen alone, signifying the lack of an additional beneficial effect from combined intensive management," O'Connor said.

Some work has shown that lowering blood pressure and blood glucose individually diminish some microvascular complications of type 2 diabetes, but there are few data on the combined effects of these interventions.

O'Connor and colleagues analyzed data from the ACCORD blood pressure trial, totaling 4,733 adults with type 2 diabetes and hypertension.

Patients were randomized to either intensive blood pressure control, with a systolic target of 120 mm Hg or less, or standard control of 140 mm Hg or less. They were also separately randomized to either intense blood glucose management (HbA1c under 6%) or a standard target (HbA1c 7% to 7.9%).

Prespecified outcomes included one composite microvascular outcome measure -- dialysis or renal transplantation, high serum creatinine, and retinal photocoagulation or virectomy -- and nine single measures of kidney, eye, or peripheral nerve function.

The researchers looked at two-way interactions between glycemia and blood pressure treatment.

They found that over a mean of 4.7 years, the primary microvascular outcome occurred in 11.4% of those in the intensive blood pressure arm and 10.9% of those in the standard blood pressure arm.

Overall, neither intensive intervention had any effect on whether patients reached the primary composite outcome of microvascular disease.

Nor were there many significant effects on the nine individual markers of microvascular disease, except those on intensive blood pressure management were less likely to develop microalbuminuria (HR 0.84, P=0.02).

Moreover, those on intensive glycemic management had a reduced risk of three outcomes: macroalbuminuria (HR 0.68, P=0.002), loss of vibratory sensation (HR 0.89, P=0.02), and loss of pressure sensation (HR 0.76, P=0.001).

O'Connor and colleagues found no significant interactions between intensive blood pressure and glycemic management for any of the outcomes.

"The benefits seen on the one hand with blood pressure control, or on the other hand with glucose control, were not amplified by an interaction," he said during the session.

In regression analyses, assignment to either intensive program was not a predictor of renal failure as defined by initiation of dialysis or end-stage renal disease. The only significant predictors were serum creatinine and albuminuria at baseline.

O'Connor noted, however, that the low proportions of patients who achieved the primary endpoint could have reduced the power of the analysis.

"The short duration of the study doesn't permit for the full assessment of the impact of the interventions," he said.

[Chevychelov]

EASD: Biomarkers May Predict CAD, Death in Diabetics

By Kristina Fiore, Staff Writer, September 15, 2011

Action Points
Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that both elevated peroxiredoxin-4 and resistin were associated with cardiovascular events and death in patients with type 2 diabetes in two separate studies.


Note that the association with both new biomarkers remained significant after controlling for a number of variables, but that other markers of oxidative stress or inflammation were not measured.
Review

LISBON -- Two biomarkers may be associated with cardiovascular events and death in type 2 diabetes patients, researchers reported here.

The antioxidant peroxiredoxin-4 (Prx4) and the inflammatory protein resistin were significantly associated with both outcomes in two separate trials reported here at the European Association for the Study of Diabetes meeting.

Esther Gerrits, MD, of the University Medical Center Groningen in the Netherlands, said hyperglycemia induces oxidative stress and endothelial damage, which subsequently leads to both microvascular and macrovascular complications in patients with diabetes.

The antioxidant stress system typically protects against oxidative stress, she said, and circulating levels of Prx4 have been proposed as a novel biomarker of oxidative stress.

It is the only secretable form of the six isoforms of the antioxidant, she added, and has previously been linked with sepsis, type 1 diabetes, and myocardial infarction, as well as other inflammatory markers such as C-reactive protein and interleukin-6.

To investigate, Gerrits and colleagues looked at data from the prospective, observational ZODIAC-28 study of 1,067 Dutch primary care patients with type 2 diabetes. They assessed two cohorts, one starting in 1998 and the other in 2001.

Prx4 was assessed in baseline serum samples, and the median value was 0.86 U/L.

Over a median follow up of 9.8 years, 32.3% of patients died. Of those, 43% were attributable to cardiovascular causes, Gerrits said.

She and colleagues found that increased levels of Prx4 were associated with high rates of both cardiovascular and all-cause death, and remained significant after controlling for numerous confounders, including age, gender, body mass index (BMI), serum creatinine, smoking, diabetes duration, systolic blood pressure, cholesterol-HDL ratio, history of complications, and albuminuria.

These patients had an 80% increased risk of all-cause death (95% CI 1.53 to 2.12), which remained a significant 51% increased risk in controlled analyses (95% CI 1.24 to 1.82).

The results were similar for cardiovascular mortality, with an 83% higher risk for those with elevated Prx4 (95% CI 1.46 to 2.30), which remained a significant 52% greater risk after controlling for confounders (95% CI 1.13 to 2.04).

Gerrits noted that although antioxidants are thought to be protective of oxidative stress, it is clearly a biomarker of mortality in this study.

"We don't know the underlying mechanisms yet, but we can speculate that Prx4 has been upregulated in cases of oxidative stress," she said.

But Lise Tarnow, MD, of the Steno Diabetes Center in Gentofte, Denmark, who moderated the session, noted that the researchers did not add other makers of inflammation to their adjusted model.

In a second study, Claudia Menzaghi, PhD, of the Casa Sollievo della Sofferenza in San Giovanni Rotondo in Italy, and colleagues found that elevated levels of resistin also are tied to cardiovascular events and death in type 2 diabetes patients.

Serum resistin, a pro-inflammatory cysteine-rich protein secreted by macrophages, has been associated with an increased risk of cardiovascular events in the general population, but few studies have looked at associations specifically for type 2 diabetes patients.

So they looked at data from four studies -- two case-control studies and and two prospective trials. The case-control data came from 798 patients in the Gargano Heart Study and 1,050 patients in the Joslin Heart Study.

Prospective data came from the 350 patients in the Gargano Heart Study-Prospective and from the 1,028 patients in the Gargano Mortality Study.

Menzaghi and colleagues found that in the case-control studies, serum resistin was significantly higher in patients with coronary artery disease than in those without, and remained so even after controlling for BMI, diabetes duration, and baseline therapies.

In the prospective studies, those with higher levels had a significantly greater risk of cardiovascular events and all-cause death than those with lower levels, which remained after controlled analyses:
Gargano Heart Study-Prospective: HR 1.35, 95% CI 1.14 to 1.59, P=0.001
Gargano Mortality Study: HR 1.13, 95% CI 1.05 to 1.21, P=0.001


The researchers also found that patients in the prospective studies who had resistin levels greater than the median were significantly more likely to have a major cardiovascular event and were more likely to die (P=0.000023 and P=0.0006, respectively).

Menzaghi said resistin is an independent predictor of major cardiovascular events and all-cause death, and may be useful for "improving the predictability of cardiovascular disease in patients with type 2 diabetes."

Tarnow noted that the researchers in this study also did not control for other well-known markers of inflammation, and that correcting for these factors "is very important in the future, as we are facing more challenges with the increasing number of markers that we are measuring."

[Chevychelov]

ASBMR: Heart Failure Raises Fracture Risk
By Nancy Walsh, Staff Writer, Published: September 17, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that heart failure in older adults increases their likelihood of osteoporotic fractures by almost 30%, independent of risk factors and bone mineral density (BMD).

SAN DIEGO -- Heart failure in older adults increases their likelihood of osteoporotic fractures by almost 30%, independent of risk factors and bone mineral density (BMD), Canadian researchers reported here.

Among adults 50 and older in Manitoba who had their first BMD test between 1998 and 2007, 10% of those with heart failure developed a major fracture over a five-year period compared with only 5% of those without heart failure, according to Sumit Majumdar, MD, of the University of Alberta.

The unadjusted hazard ratio (HR) for fracture in patients with heart failure was 2.45 (95% CI 2.11 to 2.85, P<0.001), he reported.

"Both osteoporosis and heart failure are common and costly conditions that are underdiagnosed and undertreated, and they share etiologic features such as older age, smoking, and diabetes," Majumdar said at the annual meeting of the American Society for Bone and Mineral Research.

Several recent studies have suggested an association between osteoporosis and heart failure, but none of them have included measures of BMD.

To further explore the possible evidence of a connection, the researchers analyzed data from administrative sources and an osteoporosis clinical registry. They obtained information on heart failure diagnoses as well as nontraumatic fractures of the vertebrae, hip, distal radius, and humerus. Patients were followed until 2009.

The cohort included 45,509 adults, 1,841 of whom had been diagnosed with heart failure within the previous two years.

The 4% of the population who had heart failure were more often men (17% versus 7%) and older (74 versus 66 years).

In addition, they had lower total hip T scores (−1.3 versus −0.9, P<0.001) and had experienced significantly more previous osteoporotic fractures (21% versus 13%), Majumdar said.

A total of 40% of patients with heart failure had a T score at any site below −2.5, compared with 29% of those without heart failure.

And 60% of the heart failure group were taking loop diuretics, which are known to increase fracture risk, compared with only 4% of the larger population, which was a 15-fold difference, he observed.

There were 2,703 major fractures during a median follow up of five years.

"In terms of fracture-free survival, the Kaplan-Meier survival curves started to separate shortly after the first bone mineral density test and continued to diverge out to ten years. The median time to fracture was 3.6 years," Majumdar reported.

The HR for fracture in patients with heart failure after adjustment for age and sex was 1.64 (95% CI 1.45 to 1.86).

After adjustment for comorbidities, osteoporosis risk factors, and the effects of medications, the HR was 1.33 (95% CI 1.11 to 1.60, and remained elevated even after adjustment for total hip BMD (HR 1.28, 95% CI 1.06 to 1.53).

"This meant that patients with heart failure had a 28% increased fracture risk over five years regardless of risk factors or BMD scores," he said.

Limitations of the study included the absence of radiographic confirmation of fractures and a lack of measures of heart failure severity such as ejection fraction.

"Important implications of the study were that it opens up new avenues for research in terms of mechanisms of the diseases. Clinically, we need to recognize that a diagnosis of heart failure portends an increased risk of fracture, so we should be paying much more attention to bone health in patients with heart failure," Majudar concluded.

[Chevychelov]

Anti-Nausea Drug Linked to Arrhythmias
By Peggy Peck, Executive Editor, Published: September 15, 2011


WASHINGTON -- A drug used to treat nausea and vomiting caused by chemotherapy may trigger dangerous and possibly lethal changes in heart rhythms, the FDA warned Thursday.

The drug, ondansetron (Zofran), may increase the risk of "developing prolongation of the QT interval of the electrocardiogram, which can lead to an abnormal and potentially fatal heart rhythm, including Torsade de Pointes," the FDA said.

In a warning issued to clinicians, the FDA said that patients at greatest risk include those with "underlying heart conditions, such as congenital long QT syndrome, [and] those who are predisposed to low levels of potassium and magnesium in the blood" as well as patients who are taking other medications also associated with QT prolongation.

Ondansetron is a 5-HT3 serotonin receptor antagonist, commonly prescribed to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery.

The FDA said it has ordered GlaxoSmithKline, which markets Zofran, to conduct a thorough QT study to determine the degree to which the drug may cause QT interval prolongation. The agency expects the results next summer.

In the interim, the FDA has ordered that the drug's label be changed to include "a warning to avoid use in patients with congenital long QT syndrome because these patients are at particular risk for Torsade."

The label will also recommend ECG monitoring in certain patients including those with hypokalemia or hypomagnesemia, congestive heart failure, bradyarrhythmias, and in patients who are taking other medications that increase the risk of QT prolongation.

[Chevychelov]

FDA panel recommends approval for rivaroxaban
By

The FDA's Cardiovascular and Renal Drugs Advisory Committee voted 9-2, with one abstention, to approve the use of rivaroxaban for the reduction of stroke and non-CNS systemic embolism in patients with non-valvular atrial fibrillation, according to a press release.

The vote follows a review issued by the FDA which suggests withholding from approval due to a noninferior result of rivaroxaban vs. warfarin and insufficient information on rivaroxaban's safety profile.

The panel based its decision on the results of the ROCKET-AF trial. The study involved 14,264 patients across 1,178 sites in 45 countries. Patients were diagnosed with persistent or paroxysmal AF with additional risk factors for stroke, and were randomly assigned to warfarin (Coumadin, Bristol-Meyers Squibb) or rivaroxaban (Xarelto, Johnson & Johnson). Patients who were assigned to rivaroxaban received a 20mg dose once daily, and warfarin was titrated to a target range of two to three.

Overall, a decreased rate of stroke and non-CNS embolism events were associated with rivaroxaban during treatments vs. warfarin (P=.015). In the intention-to-treat analysis, rivaroxaban was noninferior to warfarin (P=.117). The rate of bleeding and adverse events was similar between the rivaroxaban and warfarin arms, but rivaroxaban was associated with less intercraniall hemorrhage and fatal bleeding.

"No one, I believe, doubts that rivaroxaban is effective in preventing stroke in patients with AF," Norman Stockbridge, MD, director of the division of cardiovascular and renal drug products at FDA , said in the opening remarks of the meeting. "Nor are there safety issues that would cause one to question that the stroke reduction benefit was on the whole worthwhile … By at least one analysis, rivaroxaban was superior to warfarin in the ROCKET AF study. Nevertheless, the clinical reviewers question whether the study can be interpreted as showing that rivaroxaban is even as good as warfarin."

When asked if rivaroxaban merits a superior claim to warfarin, 1 out of 12 voted yes and 9 voted no; a claim as an effective alternative to warfarin, 4 voted yes and 5 voted no; a claim as effective, 7 voted yes and 3 voted no; and a claim for patients failing other anticoagulant therapy, 7 voted yes and 2 voted no.

"What constitutes failure," Sanjay Kaul, MD, director of cardiovascular diseases fellowship training program at the Cedars-Sinai Heart Institute, said, "[is] if patients are, for some reason, not well anticoagulated on warfarin, if they don't want to be on warfarin because of the diet or the medications they are on, or if patients simply refuse to take warfarin because they don't want to be bothered with monitoring anticoagulation. Those will be the types of patients where, I think, rivaroxaban would be an effective alternative to warfarin and other anticoagulants that are approved. So, third line option."

Overall, 4 out of 12 committee members thought it would be beneficial to resolve issues for rivaroxaban pre-market vs. post-market.

"I would really like to see this drug tested in this AF population twice daily because it makes a lot more sense from a pharmacodynamic point of view," Steven Nissen, MD, chair of the department of cardiovascular medicine at the Cleveland Clinic Foundation, said. "And, you know, maybe this drug will have more point estimates and confidence intervals and look more like dabigatran if it's studied in a more optimal dosage regimen."

While the FDA is not required to follow the recommendations of the advisory committee, it usually does. - by Casey Murphy
__________________________________________________ ______________________
Hemodynamic response to LV pacing predictive of need for post-CRT remodeling

Duckett S. J Am Coll Cardiol. 2011;58:1128-1136.
By

Acute hemodynamic response to left ventricular pacing is useful for predicting patients who are likely to remodel after cardiac resynchronization therapy for dilated cardiomyopathy and ischemic cardiomyopathy, according to a study.

Researchers collected information for the study from patients undergoing dilated and ischemic cardiomyopathy for cardiac resynchronization therapy (CRT). Patients underwent echocardiography before CRT, implant hemodynamic evaluation during CRT, an occlusive venogram, and LV volumes were assessed before and after CRT. Optimal coronary sinus LV lead position was determined by the largest percentage rise in the maximum rate of LV pressure to dual-chamber LV pacing. Reverse remolding was determined if there was at least a 15% reduction in LV end-systolic volume, and symptomatic response was evaluated by NYHA functional class and quality-of-life questionnaire every 6 months, according to the study.

Overall, 33 patients underwent CRT; 21 undergoing dilated and 12 ischemic cardiomyopathy. “The maximum rate of LV pressure increased significantly from baseline (P<.001) with dual-chamber LV pacing or the optimal LV lead position,” researchers said.

Reverse remolding was exhibited in 56% of patients. When predicting remolding, a more than 10% improvement in maximum rate of LV pressure from baseline with dual-chamber LV pacing was more sensitive vs. echocardiographic parameters, according to the study. Reverse remolding was experienced in 61% of patients with dilated cardiomyopathy vs. 45% with ischemic cardiomyopathy.

According to the study, there was a strong relationship for acute hemodynamic response and reverse remolding for dilated cardiomyopathy (P=.01) and ischemic cardiomyopathy (P=.04). When it came to patients with dilated cardiomyopathy, reverse remolding had a statistically significant relationship between systolic dyssynchrony index (P=.004) and intraventricular ejection fraction (P=.006). Reverse remolding was only statistically significant with intraventricular ejection fraction (P=.006), when it came to patients with ischemic cardiomyopathy.

[Chevychelov]

EASD: Gliptin Tx Works Long-Term for Glycemic Control

By Ed Susman, Contributing Writer, September 19, 2011

Action Points
Note that these studies were published as abstracts and were presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that long-term treatment of type 2 diabetes with dipeptidyl peptidase-4 (DPP-4) inhibitors for two years appeared to maintain improvement in glycosylated hemoglobin A1c levels.


Note that the reduction in HbA1c was observed for add-on therapy with metformin and for metformin plus sulfonylurea.
Review
LISBON -- Long-term treatment of type 2 diabetes with dipeptidyl peptidase-4 (DPP-4) inhibitors for two years appeared to maintain improvement in glycosylated hemoglobin A1c levels, researchers reported here.

In one study, treatment with linagliptin (Tradjenta) at the end of a 24-week randomized clinical trial resulted in a mean 0.8% decline in HbA1c after 102 weeks of treatment. In addition, patients still had a 0.8% decline in HbA1c, reported David Owens MD, at the European Association for the Study of Diabetes. Owens is from the Center for Endocrinology and Diabetes Science at Cardiff University in the U.K.

In a second study, Douglas Fleming, MD, an investigator for Bristol-Myers Squibb in Princeton, N.J., said treatment with its DPP-4 inhibitor saxagliptin (Onglyza) showed a similar pattern after 52 weeks of therapy: Patients taking saxagliptin (5 mg) in addition to insulin were able to achieve a 0.37% net decline in HbA1c, regardless of whether the patients were also taking metformin.


"The results seen in these extension studies is what we would have expected to see in treating type 2 diabetes patients over the long term," commented Carolyn Deacon, PhD, senior lecturer at the Panum Institute, University of Copenhagen. Deacon moderated the session during which Owens and Fleming presented their findings.

Linagliptin: Long-Term Glycemic Control

Owens said that in his study, patients were randomized to receive linagliptin or placebo for 24 weeks in four controlled clinical trials aimed at determining the efficacy of linagliptin.

In the open-label extension study, patients initially treated with linagliptin were continued on the drug for an additional 78 weeks. Patients initially started on placebo were switched to linagliptin (5 mg) for 78 weeks. The total follow-up time was two years.

For the pooled results, 1,532 patients were included in the 102-week linagliptin study and 589 patients in the 78-week group. The patients were about 57 years of age and about 52% were men. About 57% of the total group was white; about 42% was Asian.

By the end of 102 weeks, the HbA1c had not changed, which Owens noted met the coefficient of durability of 0.14%, meaning there was no relevant increase in HbA1c from week 24 to week 102 (P<0.0001).

He demonstrated that the maintenance of HbA1c levels was similar for the following:
Patients on linagliptin monotherapy achieved a mean 0.5% decrease from a baseline value of 7.98%.
Patients who had linagliptin added onto metformin achieved a mean 0.74% reduction in HbA1c from a baseline value of 8.06%.
Patients with linagliptin added on to treatment with metformin and a sulfonylurea achieved a mean 0.7% reduction in HbA1c from a baseline value of 8.13%.
Patients with an initial combination with pioglitazone (Actos) achieved a 1.5% reduction in HbA1c from baseline levels of 8.55%.


"Linagliptin provides sustained long-term glycemic control when used as monotherapy or add-on to other glucose-lowering agents over two years," Owens said.

In addition, he said that linagliptin was well tolerated by patients during the study and that there was no clinically relevant increase in hypoglycemia or weight gain.

Sustained Results With Saxagliptin Add-On

The story was similar for patients in the saxagliptin study, Fleming illustrated in his oral presentation.

The researchers tested oral saxagliptin for 24 weeks to assess the short-term efficacy and safety of the molecule and then tested its long-term efficacy for 28 weeks. The 24-week trial results were presented at the American Diabetes Association meeting in June.

The enrollees were about 57-years-old; about 57% were women. More than three-fourths were white. The mean duration of type 2 diabetes was 12 years. The baseline HbA1c at the start of the trial was about 8.7%.

In the 52-week analysis, patients achieved a 0.75% decrease from baseline in HbA1c if they were taking saxagliptin (5 mg) added to insulin. That compared with a 0.38% reduction among the patients taking placebo (P<0.0001).

Initially, 304 patients started the study on saxagliptin and 151 patients were enrolled on placebo. About 18% of patients dropped out of the trial, so that 246 patients finished the trial on saxagliptin and 125 finished the trial on placebo.

Fleming also noted a greater increase from baseline mean daily insulin dose in patients who received placebo compared with patients who received saxagliptin.

The proportion of patients in each treatment group who experienced at least one adverse event over the 52-week treatment period was similar. The most common events included hypoglycemia, urinary tract infection, nasopharyngitis, upper respiratory tract infection, headache, and bronchitis.

During the initial 24-week period, patients were advised to maintain stable insulin doses, which could be decreased to reduce the risk of hypoglycemia. Patients with hyperglycemia or with substantially increased insulin had a rescue visit and remained in the study on a flexible insulin regimen.

During the extension period, all patients were able to adopt a flexible insulin regimen. Sixty-nine percent of patients were treated with metformin, and the dose could not be changed during the study.

Fleming reported that 21.3% of patients on saxagliptin achieved a therapeutic glycemic response of HbA1c less than 7%, while 8.7% of patients on placebo achieved that goal.

Mean body weight increase 0.8 kg on saxagliptin and 0.5 kg on placebo. The difference was not statistically significant, Fleming reported.

"Saxagliptin was well tolerated when added to insulin with or without concomitant metformin," Fleming said. "Consistent efficacy results were observed regardless of metformin use."

[Chevychelov]

ASD: Gestational Diabetes Guidelines Controversial

By Kristina Fiore, Staff Writer, September 14, 2011

Review

LISBON -- International guidelines on screening for gestational diabetes that will likely raise the prevalence of the condition have sparked questions over appropriate diagnostic tools and cost efficacy, researchers said here.

During a press briefing at the European Association for the Study of Diabetes meeting here, some researchers said that recommendations from the International Association of Diabetes and Pregnancy Study Groups released in 2010 are cost-effective.

But others are concerned that the two-step screening process, which could raise the prevalence from about 7% of pregnant women to 16% or more, may be too costly and too demanding.

Ob/Gyns and diabetologists have long recognized a need for more consensus on diagnosis and screening for gestational diabetes, but not all medical associations, including the American Congress of Obstetricians and Gynecologists, have accepted the international guidelines.

The 2010 guideline recommends an initial oral glucose tolerance test (OGTT) at the first prenatal visit, and a follow-up at 24 to 28 weeks' gestation if diabetes is not diagnosed initially.

Disease is diagnosed if the 75-g OGTT readings at 0, 1, and 2 hours exceed 5.1 mmol/L (126 mg/dL), 10.0 mmol/L (180 mg/dL), or 8.5 mmol/L (153 mg/dL), respectively.

Sue Kirkman, MD, senior vice president of medical affairs and community information at the American Diabetes Association, said her organization adopted the recommendations into its standards of care last January.

But some researchers have argued that this type of testing is too demanding -- and much more costly -- for pregnant women, especially when a fasting plasma glucose (FPG) test is simpler and may be more accurate, thus reducing the potential problem of overdiagnosis.

In fact, the World Health Organization (WHO) and recommends using FPG levels to diagnose gestational diabetes, which is diagnosed at an FPG of 4.4 mmol/L or higher.

And ACOG said it has declined to adopt the guidelines because of concerns with a lack of randomized controlled trials for the diagnostic criteria.

But Peter Damm, MD, of the University of Copenhagen in Denmark, who was on the international guideline writing committee, said during a press briefing that the group's conclusions were based on the best evidence available -- the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study.

Robert Fraser, MD, of the University of Sheffield in England, added that several subsequent studies also have vouched for the benefits of screening and treating the condition.

Those include the 2005 ACHOIS study and the 2009 Maternal-Fetal Medicine Units Network Trial, which both found that treatment reduces perinatal complications such as increased rates of cesarean section, increased fetal size, neonatal hypoglycemia, and shoulder dystocia, he said.

As well, a meta-analysis of both studies showed a reduction in preeclampsia, birth weight, and the proportion of large-for-gestational-age infants, though there were no effects on C-section rates or neonatal hypoglycemia, Fraser said.

And a cost-efficacy study published in Diabetologia, based on two treatment trials, found screening with FPG and OGTT in which risk was found to be 1% to 4.2% was "most likely" cost-effective and risk higher than 4.2% was cost-effective for universal glucose tolerance testing, he added.

Treatment typically involves diet and lifestyle modification, with a move to insulin if the diabetes is not controlled, Fraser said. Oral diabetes medications, particularly sulfonylureas or metformin, also have been supported by short-term studies.

__________________________________________________ _______________________
BMI Not Greatest Heart Failure Risk Factor

By Crystal Phend, Senior Staff Writer, Published: September 14, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Explain that normal-weight individuals with that grouping of metabolic risk factors were 2.33 times more likely to develop heart failure over six years than those without metabolic syndrome, suggesting that metabolic syndrome may be a more important heart failure risk than obesity alone.


Point out that in the absence of metabolic syndrome, obese individuals were at lower risk than individuals of normal weight with metabolic syndrome.

Metabolic syndrome may be a more important heart failure risk than obesity alone, Greek researchers found.

Normal-weight individuals with that grouping of metabolic risk factors were 2.33 times more likely to develop heart failure over six years than those without metabolic syndrome (P=0.007) in a study by Christina Voulgari, MD, PhD, of Athens University Medical School, and colleagues.

But neither overweight nor obesity in the absence of metabolic syndrome had a significant impact on the incidence of heart failure, the group reported in the Sept. 20 issue of the Journal of the American College of Cardiology.

Obese individuals who did not have metabolic syndrome were actually at the lowest heart failure risk in the cohort study.

"Their findings give credence to the existence of a 'metabolically healthy population' and raises concern about those with metabolic syndrome," Eileen Hsich, MD, of the Cleveland Clinic, wrote in an accompanying editorial.

The reason for this obesity paradox may be that each component of metabolic syndrome is a known risk factor for heart failure, making it not surprising that they better predict risk together than a single variable alone, she suggested.

But that's not cause to lay off lifestyle recommendations for obese individuals who don't meet criteria for metabolic syndrome, Hsich noted, pointing out that "At an older age, they probably are no longer healthy."

The better message may be to not overlook metabolic syndrome status regardless of weight, the researchers added.

Their study included 550 individuals without diabetes or baseline macrovascular complications, studied over a median of six years of follow-up within a larger prospective, community-based study.

Among them, 271 met National Cholesterol Education Program Adult Treatment Panel III criteria for metabolic syndrome based on insulin resistance, abdominal obesity, hypertension, high triglycerides, and low HDL cholesterol.

Echocardiographic follow-up pointed to 2.5-fold higher risk of heart failure onset with metabolic syndrome overall (95% confidence interval 1.68 to 3.40).

Higher body mass index (BMI) was linked to higher rates of metabolic syndrome (38.4% at 25 kg/m2 and under to 69% at 30 kg/m2 and over) and of the individual components.

But higher BMI alone wasn't predictive of heart failure.

Heart failure incidence was highest, at 15.6%, in those with a normal BMI, 14.2% among overweight individuals, and lowest -- at 9.3% -- among the obese.

In the absence of metabolic syndrome, obese individuals were at lower risk of heart failure than individuals of normal weight with metabolic syndrome (P<0.001).

With metabolic syndrome, all three groups had relatively similar heart failure risk, with adjusted hazard ratios of 2.33, 2.66, and 2.13 versus no metabolic syndrome in a normal-weight individual.

These patterns persisted through adjustment for age, sex, smoking status, physical inactivity, lipids, glucose levels, and inflammatory marker profile.

The researchers cautioned that the relatively few heart failure cases that developed -- 185 in total, likely because they had excluded patients with diabetes and macrovascular complications -- may have limited the study's statistical power despite its longer-term follow-up.

[Chevychelov]

Long-QT Syndrome
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Predicting mortality and hospital admission in patients with COPD: significance of NT pro-BNP, clinical and echocardiographic assessment
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Serum thrombin activatable fibrinolysis inhibitor levels in patients with newly diagnosed multiple myeloma
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[Chevychelov]

HFSA: Statins Tied to Lower Mortality in Afib

By Todd Neale, Senior Staff Writer, September 21, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that among patients with atrial fibrillation, those who are taking a statin may be less likely to die during follow-up than those who are not taking a statin.


Note that statin use was not associated with reductions in all-cause or heart failure hospitalization.
Review
BOSTON -- Among patients with atrial fibrillation, those who are taking a statin may be less likely to die during follow-up than those who are not taking a statin, a retrospective study showed.

Through four years, patients who were admitted to the hospital for atrial fibrillation and were started on a statin had a significantly lower rate of all-cause death (28% versus 42%, P<0.001), according to Jason Salamon, MD, of the Albert Einstein College of Medicine in New York City.

But statin use was not associated with reductions in all-cause or heart failure hospitalization, he reported at the Heart Failure Society of America meeting here.


"The study is an indication of the strong pleiotropic effects of statins," Salamon said in an interview.

"I think it solidifies the fact that there is an inflammatory-mediated process in atrial fibrillation and I think that this may give us a chance to do prospective trials to see if statins, in the future, will decrease mortality in patients with atrial fibrillation and may give us another way of managing the condition."

He noted that increasing evidence points toward inflammation playing a role in the pathogenesis of atrial fibrillation, and that some studies have suggested that statins, which have anti-inflammatory properties separate from their lipid-lowering capabilities, may prevent atrial fibrillation.

That is supported by a 2008 meta-analysis in which statins significantly reduced the risk of atrial fibrillation in patients with a history of the condition and in other high-risk populations, including those undergoing cardiac surgery and those with acute coronary syndromes.

In addition, another study reported in 2008 showed that among women with a history of coronary artery disease, those who took statins had a lower risk of developing atrial fibrillation.

But studies have not looked at whether statins are associated with reduced mortality in patients with atrial fibrillation, Salamon said.

He and his colleagues performed a retrospective cohort analysis of patients treated for atrial fibrillation at Montefiore Medical Center over a 12-year period. The study included adult patients with a normal left ventricular ejection fraction and an LDL cholesterol level of less than 130 mg/dL.

Patients with known coronary artery disease or hyperlipidemia were excluded.

At baseline, there were no significant differences between the patients who were started on a statin and those who were not. The mean age was about 70. The mean LDL cholesterol level was 97 mg/dL in patients who were started on a statin and 92 mg/dL in those who were not.

Statin use was associated with a 40% relative reduction in the risk of dying through four years of follow-up (RR 0.6, 95% CI 0.5 to 0.7).

The reduction was not explained by a difference in LDL cholesterol levels, which were similar after the index hospitalization in the patients who were started on a statin (84 mg/dL) and those who were not (85 mg/dL).

Serum creatine phosphokinase levels -- an indication of muscle injury, a potential side effect of statins -- were not significantly different in the two groups.

Salamon and his colleagues acknowledged some limitations of the study, including the retrospective design, the fact that left ventricular ejection fraction was measured by echocardiogram, and the lack of stratification based on the type of atrial fibrillation.

[Chevychelov]

HFSA: Longer Look Confirms Nesiritide's Flop

By Todd Neale, Senior Staff Writer, September 22, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Note that this study presenting 180-day follow-up essentially confirms data previously published after 30-day follow-up indicating there was no effect of nesiritide compared with placebo on clinical outcomes of patients presenting with acute decompensated heart failure.
Review

BOSTON -- Six-month follow-up in the ASCEND-HF trial confirmed a lack of significant clinical benefit -- or harm -- from nesiritide (Natrecor) in patients with acute decompensated heart failure, researchers found.

At 180 days, the overall rate of all-cause mortality was 12.5%, with no significant difference between the placebo and nesiritide groups (HR 0.96, P=0.52), according to Randall Starling, MD, MPH, of the Cleveland Clinic.

Mortality was significantly predicted by all-cause rehospitalization during the first 30 days of follow-up (HR 1.87, 95% CI 1.50 to 2.34), he reported at the Heart Failure Society of America meeting here.

"The implications for this, we believe, are that rehospitalization is a meaningful endpoint in heart failure trials," Starling said.

Nesiritide -- a recombinant human B-type natriuretic peptide -- was approved by the FDA in 2001 on the basis of the VMAC trial, which compared IV nesiritide with nitroglycerin or placebo in 489 patients with acute decompensated heart failure. The results showed that nesiritide improved pulmonary capillary wedge pressure versus placebo and nitroglycerin and dyspnea versus placebo at three hours.

Approval was met by enthusiasm in the clinical community, but that was dampened in 2005 after two meta-analyses raised concerns about risks of mortality and worsening renal function.

An independent panel convened by the maker of nesiritide, Scios, and chaired by Eugene Braunwald, MD, of Brigham and Women's Hospital in Boston, recommended that a large clinical trial be conducted to definitively assess the safety and efficacy of IV nesiritide.

The result was the ASCEND-HF trial, which compared nesiritide and placebo added to usual care in about 7,000 patients with acute decompensated heart failure.

The main results -- first reported at the American Heart Association meeting last year and later published in the New England Journal of Medicine -- did not reveal any substantial safety concerns but failed to show a significant benefit for nesiritide in reducing the composite of heart failure hospitalization or all-cause death through day 30 or in improving dyspnea at six or 24 hours.

The 180-day analysis that Starling presented was consistent with those findings, in that there were no significant differences in clinical outcomes between the nesiritide and placebo groups.

Cardiovascular death occurred in 8.2% and 8% of the placebo and intervention arm, respectively, and worsening heart failure occurred in 4.9% and 4.6%, respectively.

"When added to usual treatment in unselected patients with acute decompensated heart failure, nesiritide is as safe as placebo, as Dr. Starling pointed out, it is also as effective as placebo, and in this era of comparative effectiveness it's important to recognize it is more expensive than placebo," William Little, MD, of Wake Forest University in Winston-Salem, N.C., said in comments following the presentation, to laughter from the audience.

So despite the strong physiologic rationale for nesiritide, Little added, the translation of that rationale into proven therapies is going to require more work.
__________________________________________________ ________________________

[Chevychelov]

HFSA: Depressed Spouse Affects HF Patient, Too

By Todd Neale, Senior Staff Writer, September 22, 2011

Today Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that for patients with heart failure, their quality of life suffers most when both they and their caregivers are depressed.


Note that the next lowest physical and mental quality of life scores occurred when only the patient was depressed.
Review

BOSTON -- Heart failure patients' quality of life suffers most when both they and their caregivers are depressed, researchers found.

In a study of 91 patient-caregiver pairs, a patient's physical and mental quality of life scores were lowest when both the patient and his or her caregiver were depressed (P<0.05), according to Misook Chung, PhD, RN, of the University of Kentucky in Lexington.

The next lowest scores occurred when only the patient was depressed, she reported at the Heart Failure Society of America meeting here.

In this study, nearly three-quarters of the caregivers were spouses, and 76% of them were women.

From the caregiver's perspective, quality of life scores were similarly low when both the patient and the caregiver were depressed and when the caregiver was the only one who was depressed.

The findings indicate that healthcare professionals in a heart failure program should be focusing on both the patient's and the caregiver's well-being, which is not generally done, Chung said.

"Because caregivers are hidden patients, too, and a lot of caregivers of heart failure patients have stress, especially emotional stress. And they also have a lot of comorbidity because they are burdened," she said. "So I think the dyadic approach must be done."

Previous studies have shown that up to three-quarters of patients with heart failure report at least some depressive symptoms; up to 35% of those report high levels.

But depression is common among the caregivers as well, with studies indicating that 23% to 47% of spouses of patients of heart failure have mild-to-moderate depressive symptoms.

To explore the impact of depression in both the patient and the caregiver, Chung and her colleagues assessed depression, quality of life, and family function among 91 patient-caregiver dyads in Kentucky.

The caregivers were an average of 5.4 years younger than the patients with heart failure (56.7 versus 62.1, P<0.001). About half of all caregivers and patients had less than a high school education and most were white.

Nearly one-third of caregivers had at least one comorbidity, but information documenting comorbidities was missing for 23% of caregivers, so the rate could have been higher. Also, 30.8% of caregivers worked full or part-time outside the home.

All of the participants underwent screening with the Beck Depression Inventory, the McMaster Family Assessment Device, and the Short Form-36 to measure levels of depressive symptoms, family function, and quality of life, respectively.

Overall, 30% of patients and 25% of caregivers had at least mild depressive symptoms. On average, the level of depressive symptoms was higher in the patients (P=0.011).

The caregivers and patients gave similar scores on all three subscales of family function -- problem solving ability, communication, and general family function.

Physical quality of life scores were lower in the patients, although scores on mental quality of life were similar in the two groups.

On a scale of 0 (poor) to 100 (best), when neither party was depressed, patients reported a score of 34.6 compared with 26.0 when both were depressed (P<0.001). Scores for caregivers were 45.5 and 39.8, respectively (P<0.001).

In general, family function and quality of life were harmed most when both the patient and caregiver were depressed and least when neither was depressed.

For example, on a scale of 1 (healthy function) to 4 (unhealthy function), the general family function when neither party was depressed was 1.8 from both the patient and caregiver's perspective. When both parties were depressed, the scores rose to 2.3 and 2.4 for patient and caregiver, respectively (P=0.001 and P=0.05).

Chung said that she and her colleagues are conducting a pilot study among 38 dyads to see whether an intervention targeting both patients with heart failure and their caregivers can improve outcomes for both compared with usual care. The intervention involves cognitive behavioral therapy and the teaching of self-management skills.

[Chevychelov]

HFSA: Novel IV Drug No Help in Acute HF

By Todd Neale, Senior Staff Writer, September 22, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Note that the use of intravenous cinaciguat, an activator of soluble guanylate cyclase, in patients with acutely decompensated heart failure, was not associated with improved clinical outcome and was associated with significant hypotension as an adverse event.
Review
BOSTON -- An investigational IV agent for acute decompensated heart failure does not appear to reduce dyspnea, although some questions remain about whether development should continue, researchers found.

In a series of three phase IIb trials, cinaciguat -- an activator of soluble guanylate cyclase -- failed to show substantial benefits over placebo, and resulted in a higher rate of severe hypotension, according to Mihai Gheorghiade, MD, of Northwestern University School of Medicine in Chicago.

That risk resulted in the premature termination of two of the three trials -- COMPOSE 1 and COMPOSE EARLY -- after only 74 patients were enrolled, he reported at the Heart Failure Society of America meeting here.


The third trial -- COMPOSE 2 -- was stopped early after only four patients enrolled because of indications that the trial could not be completed in a reasonable amount of time.

"Short-term treatment with intravenous cinaciguat in heart failure should no longer be investigated given its hypotensive effects at relatively low doses without a substantial benefit in terms of dyspnea, wedge pressure, or cardiac output," Gheorghiade concluded.

But in comments following Gheorghiade's presentation, John Burnett Jr., MD, of the Mayo Clinic in Rochester, Minn., said that the potential benefits of lower doses of cinaciguat could not be determined because that trial -- COMPOSE 2 -- only enrolled four patients before stopping.

He called for further research, perhaps in a chronic heart failure population instead of an acute population.

"I think we're premature in calling an end at this point with this small number of patients in a trial that's been terminated early," Burnett said.

But Gheorghiade stuck with his conclusion that it would be futile to continue looking at the short-term use of cinaciguat, and that there have to be options to stop investigating agents early in the process of development when they fail to show any signs of benefit.

"In the future, given the fact that we have so many molecules now in heart failure, we need to develop methods where we can stop early," he said.

"We cannot afford another ASCEND trial," he added, referring to the ASCEND-HF trial that showed nesiritide (Natrecor) -- widely used for acute decompensated heart failure at one time -- was no help or harm in that population.

The COMPOSE program included three randomized, placebo-controlled, phase IIb trials of cinaciguat in patients with chronic heart failure who were hospitalized with dyspnea and congestion.

The program was started based on preclinical studies that showed cardiorenal protective effects from the agent, independent of its powerful vasodilatory effects.

COMPOSE 1 (12 patients) and COMPOSE 2 (four patients) evaluated the hemodynamic effects of five IV doses of cinaciguat administered over 24 to 48 hours -- 10 and 25 µg/h (COMPOSE 1) and 50, 100, and 150 µg/h (COMPOSE 2). All of the patients in these two trials required invasive hemodynamic monitoring, and the primary outcome was an effect on pulmonary capillary wedge pressure at eight hours.

COMPOSE EARLY (62 patients) evaluated the three higher doses in patients hospitalized with worsening heart failure who were randomized within 12 hours of presentation. The primary outcome was an effect on dyspnea at eight hours.

Because of the low patient numbers, Gheorghiade presented descriptive analyses for COMPOSE 1 and COMPOSE EARLY only.

In COMPOSE 1, the hemodynamic study, each of the three doses of cinaciguat was associated with a greater reduction in systolic and diastolic blood pressure at eight, 24, and 48 hours, compared with placebo. There were no major changes in heart rate, cardiac index, right atrial pressure, or pulmonary capillary wedge pressure, Gheorghiade said.

In COMPOSE EARLY, there was also a substantial drop in blood pressure with each dose of cinaciguat, with no major changes in heart rate, renal function, creatinine, B-type natriuretic peptide (BNP), or N-terminal pro-BNP.

Dyspnea was not affected, although Gheorghiade noted that even though the average time to randomization was well within the 12-hour limit (5 hours 36 minutes), most patients did not have severe dyspnea when the infusions started.

Most of the treatment-emergent adverse events were related to severe hypotension, which was more frequent with cinaciguat than with placebo both in COMPOSE 1 (22% versus 0%) and COMPOSE EARLY (28% versus 5%).

Although Gheorghiade said cinaciguat should no longer be investigated, he said chronic cyclic guanosine monophosphate modulation with available oral soluble guanylate cyclase activators and stimulators should continue because of the cardiorenal protective effects seen in preclinical studies that were separate from their vasodilatory effects.

[Chevychelov]

Platelet Testing Not Ready for Prime Time

By Chris Kaiser, Cardiology Editor, September 22, 2011

Action Points
Note that this study found that high residual platelet reactivity during clopidogrel treatment is a poor prognostic sign, but treatment adjustment based upon this finding did not improve clinical outcome.


Note that the editorialist concluded that the currently available evidence does not support routine use of testing platelet function with subsequent adjustment of antiplatelet dosing in clinical practice.
Review
Patients undergoing percutaneous coronary interventions who have high residual platelet reactivity following clopidogrel (Plavix) loading are at an increased risk for adverse outcomes, but that study finding is not necessarily an argument for routine platelet testing, according to an outside commentator.

The primary endpoint rate -- a composite of cardiac death, myocardial infarction, any urgent coronary revascularization, and stroke at two years -- was greater in patients with high residual platelet reactivity (HRPR) compared with those with low residual platelet reactivity (LRPR) (14.6% versus 8.7%, P=0.003), reported David Antoniucci, MD, from Careggi Hospital in Florence, Italy, and colleagues.

Stent thrombosis, part of the secondary endpoint, also was higher in the HRPR group compared with the low reactivity group (6.1% versus 2.9%, P=0.01), according to the study, which was published in the Sept. 21 issue of the Journal of the American Medical Association.


While high platelet reactivity is prognostic for adverse events in this patient population, there are varying platelet function tests and cutoff values that make broad pronouncements about routine testing difficult to make, said Dominick J. Angiolillo, MD, PhD, of the University of Florida College of Medicine-Jacksonville, in an accompanying editorial.

For example, Antoniucci and colleagues in this study, called RECLOSE 2–ACS, used the gold standard platelet function test of light transmittance aggregometry, but this test is not user-friendly and "is limited only to experienced research laboratories," Angiolillo said.

It would have been of greater practical value to use a point-of-care assay, especially considering the large number of patients (1,789) with acute coronary syndrome (ACS) that were evaluated, he said.

In addition, the cutoff value of platelet aggregation of 70% or greater that investigators used was one they had previously defined, but they had derived it from a patient population with a different risk profile, Angiolillo said. He also had concerns about using one platelet measurement shortly after PCI rather than serial measurements.

More importantly, however, the platelet testing and subsequent titrating of clopidogrel or ticlopidine did not result in improved outcomes, similar to the result seen in the GRAVITAS trial.

While Angiolillo praised this and similar studies, he said that platelet function testing should be reserved for research, at least until "appropriately powered randomized controlled trials demonstrate efficacy and safety (in particular, low bleeding risk)."

In the Responsiveness to Clopidogrel and Stent Thrombosis 2–ACS (RECLOSE 2–ACS) study, researchers followed 1,789 patients from a single center for a median of 2.8 years. The incidence of HRPR was 14% and these patients tended to be older, have a higher incidence of diabetes and hypercholesterolemia, and were more likely to have a history of previous MI, compared with those with LRPR.

Even after antiplatelet treatment adjustment for those with HRPR, nearly 40% still had platelet aggregation values greater than 70%.

Researchers said the dual antiplatelet compliance rate at six months was above 97% in groups with and without HRPR, but the rate dropped to 63% and 68% in the low and high groups, respectively, at the median follow-up.

The absolute 5.9% difference in primary endpoint rates was mostly a factor of cardiac mortality, which was nearly 10% in the HRPR group compared with 4.3% in the LRPR group (P<0.001).

Kaplan-Meier curves showed that those with HRPR had twice the rate of primary endpoint and cardiac death at six months (P<0.001 for both), which remained significant out to two years (P=0.001 and P=0.002, respectively).

The stent thrombosis rate was also twice as high in the HRPR group compared with the low reactivity group, although the study was not powered for this adverse event, Antoniucci and colleagues said.

After multivariable analysis, researchers found HRPR to be independently associated with the primary endpoint (HR 1.49, 95% CI 1.08 to 2.05, P=0.02) and with cardiac mortality (HR 1.81, 95% CI 1.18 to 2.76, P=0.006).

The study is limited by its nonrandomized design. Also, the researchers cannot rule out the possibility of other medications having an effect on platelet responsiveness. They also noted that these results should be considered "hypothesis generating for further studies of tailored therapy using new antithrombotic agents" such as prasugrel (Effient) or ticagrelor (Brilinta).

[Chevychelov]

Cardiac Rehab Lowers Risk After Mild Stroke, Too

By Crystal Phend, Senior Staff Writer, September 22, 2011

Action Points
Note that coronary heart disease and stroke share many modifiable risk factors, and cardiovascular disease is often a comorbidity in patients presenting with TIA or stroke.


Point out that in this study, investigators were able to show that comprehensive cardiac rehabilitation successfully reduced multiple risk factors in patients presenting with TIA or mild stroke.
Review
Comprehensive cardiac rehabilitation may help patients who've had a transient ischemic attack (TIA) or a mild stroke avoid a second event, a feasibility study suggested.

The program of exercise, counseling, and medical management reduced key risk factors, including cholesterol and weight, significantly compared with baseline, according to Neville Suskin, MBChB, MSc, of the London Health Sciences Center Cardiac Rehabilitation & Secondary Prevention Program in London, Ontario, and colleagues.

The six-month intervention also shifted 25.6% of individuals into the lowest mortality risk category on the Duke Treadmill Score (P<0.001), the group reported in the November issue of Stroke: Journal of the American Heart Association.


Those benefits "could potentially play out into a reduction in strokes and TIAs and coronary events as well, although we have to follow up and validate that," co-author Peter L. Prior, PhD, told MedPage Today in an interview.

A randomized clinical trial is now under way to compare safety and efficacy with a control group, which the feasibility study did not include.

It shouldn't be difficult to expand such rehabilitation programs from their traditional cardiac population to include stroke patients as well, the researchers suggested.

"We're looking at a commonality of risk factors and physiology between cerebrovascular and cardiovascular populations," said Prior, a psychologist at the London Health Sciences Center Cardiac Rehabilitation & Secondary Prevention Program.

Basic secondary prevention at stroke prevention clinics typically includes only medical management and fairly low intensity counseling on risk factors, referring out for exercise, diet, and other interventions, he noted.

But putting all the aspects together in a single comprehensive program likely would improve participation and adherence rates, Prior speculated.

The study included 110 consecutive patients with at least one vascular risk factor who agreed to join such a program after a TIA or mild, nondisabling stroke in the prior 12 months.

These patients joined heart patients in a six-month outpatient cardiac rehab program that included an education component, depression screening and referral, encouragement to join an on-site smoking cessation program, and nutritional counseling with a registered dietitian emphasizing the Mediterranean diet.

Also part of the program was exercise four times a week -- supervised on-site, followed up at home, or both -- and medical management following clinical guidelines.


Patients also got standard secondary prevention clinic care.

At six months, significant changes from baseline included:
A 31.4% boost in aerobic capacity by 2.05 METs, considered clinically relevant (P<0.001)
A 0.30 mmol/L drop in total cholesterol (P=0.008)
An 11.6% reduction in total cholesterol to HDL ratio (P<0.001)
A 0.27 mmol/L decrease in triglycerides (P=0.003)
Loss of an average 2.44 cm in waist circumference (P<0.001)
A drop in body mass index by 0.53 kg/m2 (P=0.003)
Weight loss of 1.43 kg (3.15 pounds, P=0.001)
Fewer participants continued to smoke (P=0.008)


LDL fell by 10.3% (P=0.015) and HDL rose by 4.4% (P=0.069), while systolic and diastolic blood pressure also improved by 3.21 and 2.34 mm Hg, respectively, although none of those changes met the P=0.01 level required for statistical significance in the study.

Use of secondary prevention medications didn't improve, which may point to a need for better management, the researchers noted.

The average Duke Treadmill Score -- validated for prediction of mortality risk in outpatients suspected of having cardiovascular disease although not for stroke -- improved from 4.49 at baseline to 7.88 at the end of the six months (P<0.001).

Overall, the annualized rate of stroke recurrence was 4.6%, which fit in the low end of published risk estimates for this population and supported the safety of cardiac rehab for them, Suskin's group wrote.

They cautioned that without a control group the study couldn't rule out the possibility that usual care interventions accounted for the benefits seen over the course of cardiac rehab.

But Prior noted that the patient experience in Ontario was likely representative of that in the U.S. and elsewhere.

[Chevychelov]

Europe Eyes Afib Drug Restriction

By Chris Kaiser, Cardiology Editor, September 22, 2011

Review

The European Medicines Agency (EMA) today recommended restricting the use of the antiarrhythmic drug dronedarone (Multaq) because of its adverse event profile.

The drug has been associated with an increased risk of liver, lung, and cardiovascular adverse events.

The EMA's Committee for Medicinal Products for Human Use (CHMP) said dronedarone should be prescribed only for maintaining sinus rhythm after successful cardioversion in patients with paroxysmal or persistent atrial fibrillation or after alternative treatment options have been considered and rejected.

In January, the FDA said it would require a warning about the potential for liver injury added to the drug's label.

Then in July, drugmaker sanofi-aventis pulled the plug on the PALLAS trial because of an increase in cardiovascular events. PALLAS was testing dronedarone in patients with permanent atrial fibrillation, for which it is not approved.

The EMA committee initiated its review of the drug following reports of severe liver injury and the discontinuation of the PALLAS trial.

The committee acknowledged, however, that dronedarone remains a useful treatment option for some patients.

It also cautioned that the drug must not be used in patients with permanent atrial fibrillation, heart failure, or left ventricular systolic dysfunction and that doctors should consider discontinuation of treatment if atrial fibrillation reoccurs.

Patients on amiodarone should have regular monitoring of lung and liver function and heart rhythm. It's especially important to monitor liver function closely during the first few weeks of treatment, according to the committee.

The European Commission will consider the committee's recommendation.

[Chevychelov]

Cardiac Echo: There Is an App for That

By Todd Neale, Senior Staff Writer, September 23, 2011

Action Points
Explain that a field study of portable echocardiography in Honduras found that remote expert interpretation could be performed at both a workstation and smartphone with more than 90% agreement.

Note that diagnoses made by a cardiology fellow in the field performing the echocardiograms were overridden by the experts in more than one-third of cases.
Review

Remote interpretation of echocardiograms on a smartphone may help expand the use of such tests to previously inaccessible settings, researchers found.

There was relatively little loss of accuracy when electrocardiographic data transmitted from a remote Honduran village by a nonexpert was interpreted in the U.S. using a specially equipped smartphone instead of a full workstation, according to Brian Choi, MD, MBA, of George Washington University in Washington, D.C., and colleagues.

Among two expert echocardiographers, the intertechnology agreement between interpretations done on the smartphone and the workstation was 90% (P<0.01), the researchers reported online in the Journal of the American Society of Echocardiography.

"Our study does show that although pocket-size cardiac ultrasound may be inferior to complete echocardiographic evaluation, given the concordance of interpretation by expert readers using different methods to review the transmitted images, pocket-size cardiac ultrasound as an adjunct to traditional physical examination and with remote expert overread may provide additional diagnostic capability in remote or hostile environments," they concluded.

To test the accuracy of using a smartphone running medical imaging software compliant with the Health Insurance Portability and Accountability Act to interpret echocardiographic data from a remote location, the researchers conducted a study using 89 patients in a remote Honduran village and two expert echocardiographers in the U.S.

All of the Honduran patients (mean age 54; 58% female) underwent echocardiography by a nonexpert cardiology fellow who was on a humanitarian mission using a pocket-size ultrasound device.

The most common indications for echocardiography were arrhythmia (33%), cardiomyopathy (28%), and syncope or presyncope (15%).

The fellow, who had completed a three-month rotation in an academic echocardiography lab, provided a point-of-care diagnosis before transmitting the images to the U.S. by dial-up modem. The electronic files were sent by broadband from an urban center when field connectivity was unavailable.

The two expert echocardiographers in the U.S. first interpreted the findings on a workstation. After a minimum of four weeks, the studies were randomized and stripped of identifying information and sent to the readers via their smartphones, which had pinch zoom capabilities for both still images and cine loops.

Using the workstation, point-of-care diagnoses from the cardiology fellow were changed in 38% of patients; 41% of the changes were left ventricular function correction and 38% were valvulopathy correction. Another 18% of the changes involved poor image quality that prevented confirmation of the diagnosis.

The two U.S. experts agreed on the interpretation of the point-of-care diagnosis in 82% of cases (P<0.0001), which was excellent, according to the researchers.

"Smartphone interpretations by expert echocardiographers agreed with the point-of-care diagnoses in 61% of cases," they said. Further analysis comparing interpretations on workstations and the smartphone found excellent agreement of 90%.

Choi and colleagues noted that, because of the ubiquity of Internet access in the healthcare environment, the costs of starting a system involving remote interpretation of echocardiographic data on smartphones are limited to the point-of-care device, the smartphone, and the special software.

"Furthermore, as we find ourselves domestically to be in an era of more aggressive cost containment and care shifting more to mid-level practitioners, mobile consultation could provide improved access to specialists with advanced training, which may help limit cost growth without compromise of care," they wrote.

The researchers acknowledged some limitations of the study, including the fact that the indications for echocardiography were heavily weighted toward three conditions; the possibility that the point-of-care diagnostic accuracy would have been improved by having an expert echocardiographer there; significant transmission delays from the field; and the fact that the device used did not have spectral Doppler, electrocardiographic, or M-mode capabilities.

"Although larger, more robust echocardiographic equipment may have been more capable of acquiring superior data, such machines may not be practical in inaccessible locations, whether it be an austerely equipped humanitarian mission environment or in a crowded room at the bedside of a critically ill patient," the authors noted.

[Chevychelov]

Heart Failure Society of America
Boston • September 18 - 21, 2011
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Novel IV Drug No Help in Acute HF
BOSTON -- An investigational IV agent for acute decompensated heart failure does not appear to reduce dyspnea, although some questions remain about whether development should continue, researchers found.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]


Depressed Spouse Affects HF Patient, Too
BOSTON -- Heart failure patients’ quality of life suffers most when both they and their caregivers are depressed, researchers found.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]


Longer Look Confirms Nesiritide’s Flop
BOSTON -- Six-month follow-up in the ASCEND-HF trial confirmed a lack of significant clinical benefit -- or harm -- from nesiritide (Natrecor) in patients with acute decompensated heart failure, researchers found.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]


Statins Tied to Lower Mortality in Afib
BOSTON -- Among patients with atrial fibrillation, those who are taking a statin may be less likely to die during follow-up than those who are not taking a statin, a retrospective study showed.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]


CABG Has Benefit in Ischemic Heart Failure
BOSTON -- Adding CABG to guideline-based medical therapy improved quality of life in patients with ischemic heart failure, although the clinical significance of the findings remains unclear, an analysis of the STICH trial showed.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]


Remote HF Monitoring Cuts Readmissions
BOSTON -- Monitoring heart failure patients remotely -- either through simple telephone calls or more complex telemonitoring -- can improve outcomes, with particular benefits in driving down hospital readmissions, a subanalysis of a Cochrane review showed.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]


HF Outcome Better With Biomarker Panel
BOSTON -- A panel of seven biomarkers was highly predictive of adverse outcomes in patients with chronic heart failure, researchers found.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]


Heart Failure Risk Rises as the Blood Boils
BOSTON -- Individuals who are prone to getting angry may have a higher risk for heart failure, researchers found.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]


Tracking Fluid Build-Up Fails to Help HF Patients
BOSTON -- Measuring intrathoracic impedance in patients with heart failure -- and alerting the patients at a certain threshold -- did not improve outcomes, researchers found.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]


Controversy Highlighted at Upcoming Meeting
BOSTON -- Much progress has been made in managing heart failure, but there are still some areas of controversy that will be highlighted at the upcoming meeting of the Heart Failure Society of America here.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]

[Chevychelov]

European Association for the Study of Diabetes
Lisbon • September 12 - 16, 2011
--------------------------------------------------------------------------------
Gliptin Tx Works Long-Term for Glycemic Control
LISBON -- Long-term treatment of type 2 diabetes with dipeptidyl peptidase-4 (DPP-4) inhibitors for two years appeared to maintain improvement in glycosylated hemoglobin A1c levels, researchers reported here.
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Debate Brings Incretin Risks to Forefront
LISBON -- Whispered concerns about a higher risk of certain cancers linked with incretin therapies for diabetes have become more audible after a debate here between top researchers.
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Meta-Analysis Confirms Value of CGM in Type 1 Diabetes
LISBON -- Despite its limitations, continuous glucose monitoring (CGM) appears to improve glycemic control compared with self-monitoring in type 1 diabetes patients, researchers reported here.
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Closed-loop System on Par With Open-loop for Glucose Control
LISBON -- A bihormonal closed-loop system in patients with diabetes that delivers rescue glucagon as well as insulin may be comparable with open-loop administration of the two hormones, researchers said here.
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Breast Cancer in Diabetes May Be Artifactual
LISBON -- An apparent risk of breast cancer in postmenopausal women recently diagnosed with type 2 diabetes may in fact be related to detection bias, researchers reported here.
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’Gliptin’ Diabetes Drugs May Be Heart Savers
LISBON -- While searching for potential cardiovascular risks among studies involving dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetics, researchers made a surprising discovery -- treatment with the so-called gliptin class appears to protect the heart.
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Contest Offers $100K for "New Insulin"
LISBON -- One diabetes advocacy group is betting that the next big thing in treatment, especially for type 1 disease, will come not from within the field, but from putting together many heads from various disciplines.
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Novel Drug BRIGHTENs Diabetes Research
LISBON -- The investigational drug ipragliflozin improved glycemic control and decreased body weight and blood pressure, according to the phase III BRIGHTEN study.
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Once-Weekly Exenatide Flops Against Liraglutide
LISBON -- A trial failed to prove that once-weekly injections of exenatide (Bydureon) were equal to daily injections of liraglutide (Victoza) in reducing glycosylated hemoglobin A1c in type 2 diabetes patients, researchers reported here.
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No Microvascular Benefit With Intense BP, Glucose Control
LISBON -- Aggressively lowering blood pressure and blood glucose together won’t provide any microvascular benefits to type 2 diabetes patients, researchers said here.
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Biomarkers May Predict CAD, Death in Diabetics
LISBON -- Two biomarkers may be associated with cardiovascular events and death in type 2 diabetes patients, researchers reported here.
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Liraglutide Plus Insulin Does Not Add Weight
LISBON -- The addition of insulin to the treatment regimen of type 2 diabetes patients on liraglutide (Victoza) doesn’t wipe out previously seen weight loss -- and insulin appears to help these patients achieve glycemic control, researchers said here.
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Gestational Diabetes Guidelines Controversial
LISBON -- International guidelines on screening for gestational diabetes that will likely raise the prevalence of the condition have sparked questions over appropriate diagnostic tools and cost efficacy, researchers said here.
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Intensive Glucose Control Cuts Renal Risks
LISBON -- Intensive glucose-lowering may protect against end-stage renal disease (ESRD) in diabetic patients, according to an analysis of data from the ADVANCE trial.
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Diabetes, MI, Feeling Bad Add Up to Shorter Life
LISBON -- Men with type 2 diabetes and an acute myocardial infarction who score lower on quality-of-life measures have a greater mortality risk than other men with these conditions whose scores indicate they feel better about their health, researchers reported here.
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Diabetes Estimate Now 366 Million
LISBON -- About 366 million people worldwide have diabetes, according to the latest figures from the International Diabetes Federation, released in advance of a United Nations summit on non-communicable diseases in New York next week.
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Hot Controversies, but No Hot-Line Sizzlers
LISBON -- Though there’s "no major endpoint trial" being presented at this year’s European Association for the Study of Diabetes meeting here, executive director Viktor Joergens, MD, said there will be plenty of debate over several recent controversies.
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[Chevychelov]

Dabigatran: A New Option for Anticoagulation in Atrial Fibrillation and Venous Thromboembolism
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"Smart" Coaching to Promote Physical Activity, Diet Change, and Cardiovascular Health
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What should be the blood pressure target for diabetic patients?
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[Chevychelov]

Focus on: Antiplatelet therapies

The evolution of antiplatelet therapy in cardiovascular disease
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The pharmacogenetics of antiplatelet agents: towards personalized therapy?
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Cost-effectiveness of oral antiplatelet agents—current and future perspectives
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Managing adverse effects and drug–drug interactions of antiplatelet agents
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The role of aspirin for stroke prevention in atrial fibrillation
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[Chevychelov]

Appropriate ICD interventions found in half of ARVD/C patients

Bhonsale A. J Am Coll Cardiol. 2011;58:1485-1496.

About one-half of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy after placement of an implantable cardioverter defibrillator for primary prevention experience appropriate interventions, new data suggest.

The study included patients from the Johns Hopkins registry with definite or probable arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), defined by the presence of major and minor diagnostic criteria according to the 2010 revised Task Force Criteria, who underwent ICD implantation for primary prevention. Researchers obtained detailed phenotypic, genotype and ICD event information and assigned appropriate ICD therapies based on patients’ intracardiac electrograms.

There were 84 ARVD/C patients who received an ICD for primary prevention of sudden cardiac death, and 48% of patients received appropriate ICD therapy during a mean of 4.7 ± 3.4 years. According to researchers, proband status (HR=6.4; 95% CI, 2.3-18.2), the presence of nonsustained ventricular tachycardia (HR=3.8; 95% CI, 1.9-7.6), inducibility at electrophysiologic study (HR=3.1; 95% CI, 1.4-6.9) and Holter premature ventricular complex count of more than 1,000/24 hours (HR=3.1; 95% CI, 1.1-8.3) were predictors of appropriate ICD therapy; and nonsustained ventricular tachycardia (HR=10.54; 95% CI, 2.40-46.18) and inducibility at electrophysiologic study (HR=4.5; 95% CI, 1.37-14.96) were predictors of appropriate ICD interventions on multivariable analysis.
__________________________________________________ _______________________
Coronary CTA bested MPI in patients with acute chest pain

Goldstein J. J Am Coll Cardiol. 2011;58:1414-1422.

The use of coronary CTA resulted in a more rapid, cost-efficient diagnosis than rest-stress myocardial perfusion imaging in ED acute, in low-risk patients with chest pains, according to study results.

From June 2007 to November 2008, patients with acute chest pain admitted to the ED were randomly assigned to a coronary CTA group or a myocardial perfusion imaging (MPI) group. According to researchers, patients included in the study had chest pain suspicious for angina; were aged 25 years or older; had a time from onset of chest pain to presentation of 12 hours or less; had a time from ED presentation to randomization of 12 hours or less; had normal or nondiagnostic rest electrocardiogram evidence of ischemia; and had a thrombolysis in MI risk score of 4 or less for unstable angina or non-STEMI. Researchers defined the primary outcome as diagnostic efficiency starting when patients were randomly assigned into coronary CTA or MPI groups and ending when test results were called to ED physicians; secondary outcomes were defined as ED cost of care and safety.

Researchers reported a 54% reduction in time to diagnosis when using the coronary CTA diagnostic strategy demonstrating a more rapid diagnosis vs. MPI (P<.0001). In secondary outcomes, there was a 38.2% reduction in total ED costs of care in the coronary CTA diagnostic strategy vs. MPI (P<.0001), and the safety endpoint showed that both strategies had similar low number of cases with adjudicated major adverse cardiac events (P=.29) and that there were no deaths in either group.

Overall, 361 patients were enrolled in the coronary CTA group. More than minimal CAD was ruled out in 82.2% of coronary CTA patients, more than 70% stenosis was detected in 3.6% of patients, intermediate stenosis was found in 10.2% of patients, and 3.9% of cases had scans that were not fully interpretable, according to researchers. Of the 37 coronary CTA patients who had rest-stress MPI performed, 23 had either intermediate lesions or nondiagnostic scans, 10 had normal CCTA, and four showed more than 50% narrowing. Index testing among 338 MPI patients was normal or probably normal in 89.9%, and 89.1% were discharged within 6 hours. Invasive coronary angiography was performed in 24 coronary CTA cases vs. 21 MPI cases.

[Chevychelov]

American Society of Nuclear Cardiology
Denver • September 8 - 11, 2011

Criteria to Guide Stress SPECT Need Work
DENVER -- Wide variations in the predictive power of appropriateness criteria for SPECT myocardial perfusion imaging warrants further research before lab accreditation becomes mandatory next year, researchers said here.
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Guidelines for Stress SPECT Improve Outcomes
DENVER -- Adherence to the appropriateness criteria for stress SPECT myocardial perfusion imaging (MPI) can lead to better utilization and outcomes, but inappropriately ordered tests offer a less useful diagnostic yield, a single-center study found.
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Stress Tests Clarified With CT Angiography
DENVER -- In patients with prior inconclusive stress tests and recurring chest pain, the use of coronary CT angiography (CCTA) can reduce downstream tests, a single-center retrospective study found.
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Stress Imaging Drug Works As-Needed
DENVER -- The use of regadenoson (Lexiscan) is safe and can lead to cost and time efficiencies in patients undergoing exercise SPECT myocardial perfusion imaging.
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Imaging Agent May Target LV Ablation Hot Spots
DENVER -- An imaging radiotracer used for cardiac innervation may identify left ventricular (LV) areas linked to tachyarrhythmic events, subsequently aiding ablation procedures, a small study found.
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IV Drug KOs GI Discomfort of Stress Imaging
DENVER -- Aminophylline is safe and feasible with the newer generation vasodilator regadenoson (Lexiscan) in patients undergoing myocardial perfusion imaging (MPI), a new study demonstrated.
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More Patients May Be Candidates for Exercise Stress
DENVER -- Primary care physicians appear more likely to select patients for pharmacological stress testing, even though these patients may be capable of an exercise stress test, a single-center study found.
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Gender, Language May Sway Selection for Exercise MPI
DENVER -- English-speaking men are more likely to be referred for an exercise stress with SPECT myocardial perfusion imaging (MPI) versus a pharmacological stress test, a large database study found.
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Age Alone May Put Symptom-Free People at Risk for Silent Ischemia
DENVER -- Traditional risk factors were predictive of silent ischemia in younger individuals, while age seemed to be the main predictor in those ages 74 and up, researchers found.
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Workforce Challenges, Novel Tracers Top Meeting
DENVER -- It’s an interesting time to be a nuclear cardiologist, with both challenges and exciting new developments on the horizon, said the Mayo Clinic’s Todd Miller, MD, program chair of American Society of Nuclear Cardiology meeting.
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[Chevychelov]

A review of the 2011 ESC guidelines on cardiovascular disease in pregnancy
An article from the e-journal of the ESC Council for Cardiology Practice.

Ferreira R.
Topics: Pregnancy and Heart Disease
Authors: Ferreira, R.
Increasing prevalence of hypertension, obesity and diabetes, coupled with a rise in the age of expectant mothers, have contributed to increasing the burden of cardiac disease during pregnancy. The new ESC 2011 guidelines for the management of cardiovascular disease during pregnancy (1) provide physicians with new recommendations that come to update the 2003 ESC consensus document on this subject (2) and this paper aims to review its main recommendations.

A review of Recommendations
I - General

a- Childbearing age
cardiac disease
Risk assessment

b- Pre-pregnancy
In known or suspected congenital or acquired cardiovascular and aortic disease
Risk assessment and counseling

c- Pre-pregnancy and during pregnancy
cardiac disease
Risk assessment; with high risk patients to be treated in specialised centres by a multidisciplinary team
In congenital heart disease or congenital arrhythmia, cardiomyopathies, aortic disease or genetic malformations associated with CVD
Genetic counseling

d- During pregnancy
in unexplained or new cardiovascular signs or symptoms
Echocardiography; if echocardiography is insufficient for diagnosis gadolinium-free MRI to be considered

e- Delivery
in dilatation of the ascending aorta >45mm, severe aortic stenosis, Eisenmenger syndrome or severe heart failure
C-Section (Cesarean section) to be considered
in Marfan patients with an aortic diameter 40-45mm
C-section may be considered; but avoiding prophylactic antibiotic therapy during delivery.
II - Pulmonary Arterial Hypertension (PAH)

PAH as described (5) includes 1) all idiopathic and heritable forms of the disease
and 2) pulmonary hypertension associated with congenital heart disease with or without previous corrective surgery.

a- Child-bearing age
in pulmonary hypertension or in those with oxygen saturation below 85% at rest
to be advised against becoming pregnant
in suspicion of pulmonary embolism as causing or suspected to partly having caused pulmonary hypertension
associated anticoagulant treatment to be considered

b- During Pregnancy
In pulmonary arterial hypertension before becoming pregnant
continuation to be considered after delivering information regarding associated teratogenic effects
III - Aortic Disease

Heritable disease such as Marfan syndrome, bicuspid aortic valve, Ehlers Danlos syndrome, Turner syndrome and other forms of congenital heart disease predispose to both aneurysm formation and aortic dissection.

a- Child-bearing age
to be counseled on the risk of aortic dissection and the recurrence risk for the offspring

b- Pre-pregnancy
Marfan syndrome or other known aortic disease
imaging of the entire aorta (CT/MRI)
if ascending aorta >45mm
surgical treatment required
aortic disease associated with a bicuspid aortic valve when the aortic diameter is >50mm
surgical treatment to be considered

c- Pregnancy
with ascending aorta dilatation
echocardiographic imaging every 4-8 weeks
with dilatation of distal ascending aorta, aortic arch or descending aorta
gadolinium-free MRI

d- Delivery
for patients with ascending aorta >45mm
C-section to be considered
IV - Acquired and congenital valvular heart disease

a- Child-bearing age
atrial fibrillation, left atrial thrombosis or prior embolism
therapeutic anticoagulation
in 1) severe MS or 2) asymptomatic severe AS with symptoms development during exercise test or 3) severe aortic or mitral regurgitation and symptoms or impaired ventricular function or dilatation

b- Pregnancy
severe symptoms or systolic pulmonary artery pressure >50mmHg despite medical therapy
percutaneous mitral commissurotomy to be considered
severe aortic stenosis -symptomatic or LVEF<50%-
intervention
in patients with mechanical valves - until the 36th week
OAC recommended from second trimester
in patients with mechanical valves - after the 36th week and having stopped OAC
dose- adjusted UFH or LMWH
LMWH to be replaced by iv UFH at least 36 hours before planned delivery.

c- Delivery
If delivery starts while in OAC
C-section
V - Coronary Artery Disease

a- Pre-Pregnancy
in known CAD
pregnancy may be considered in the absence of residual ischemia and LV dysfunction

b- During pregnancy (9):
ACS is rare and strongly related to the major CAD risk factors
chest pain,
ECG and troponin levels to be taken
STEMI,
coronary angioplasty is preferred reperfusion therapy
non ST-elevation ACS without risk criteria,
conservative management is to be considered
VI - Acquired and inherited cardiomyopathies and heart failure

a- Child-bearing age
information to be delivered on the risk of deterioration of the condition during gestation and peripartum

b- During pregnancy
intracardiac thrombus, detected by imaging, or with evidence of systemic embolism
Anticoagulation
hypertrophic cardiomyopathy (HCM)
with atrial fibrillation
therapeutic AC with LMWH or oral vitamin K antagonists, according to the stage of pregnancy
with persistent AF
cardioversion to be considered

c- During pregnancy and after delivery
Peripartum cardiomyopathy (PPCM) is a form of dilated CM presented as heart failure with LV systolic dysfunction towards the end of pregnancy or in the months following delivery. It is a diagnosis of exclusion (10).
heart failure treatment according to general guidelines for the treatment of acute and chronic heart failure, - while avoiding ACE inhibitors, angiotensin II receptor blockers and rennin inhibitors

d- Delivery
In hypertrophic cardiomyopathy.
Delivery under Beta-blocker protection

VII - Arrhythmias

a- Before or during pregnancy
Ventricular tachycardia (VT)(11):
implantation of an ICD, if clinically indicated

b- During pregnancy
Episodes of tachyarrhythmia
DC conversion to restore sinus rhythm - all antiarrhythmic drugs to be considered toxic for the fetus
Atrial flutter and fibrillation in relation with structural heart disease leading to haemodynamic instability
electrical cardioversion
haemodynamicaly stable patients
pharmacological treatment to be considered

supraventricular tachycardia (12):
acute conversion of paroxysmal SVT
vagal maneuvre followed by i.v. adenosine
acute treatment of any tachycardia with haemodynamic instability
Immediate electrical cardioversion
pharmacological conversion of paroxysmal SVT i.v.
metoprolol or propranolol to be considered
pharmacological conversion of paroxysmal SVT i.v.
verapamil to be considered

sustained, unstable and stable VT
immediate electrical cardioversion with implantation of permanent pacemaker or ICD with echocardiographical guidance to be considered, especially if the foetus is beyond 8 weeks gestation
drug-refractory and poorly tolerated tachycardias
catheter ablation to be considered
VIII - Hypertensive Disorders

Includes (13) 1) Pre- pregnancy hypertension: BP>140/90 mmHg or developing before 20 weeks of gestation 2) Gestational hypertension - Develops after 20 weeks’ gestation and resolves in most cases within 42 days postpartum 3) pre-eclampsia - when associated with significant proteinuria 4) Pre-existing hypertension with further worsening of BP and protein excretion >3g/day in 24 hour urine collection after 20 weeks’ gestation 5) Antenatal unclassifiable hypertension. When BP is first recorded after 20 weeks of gestation and hypertension is diagnosed.

a- During pregnancy (14):
SBP of 140-150 mmHg or DBP of 90-99mmHg
non-pharmacological management
SBP>170mmHg
emergency hospitalisation
In pre-eclampsia associated with pulmonary edema,
infusion i.v. nitroglycerine
In severe HT
drug treatment with i.v. labetalol or oral methyldopa or nifedipine
With continued pre-pregnancy HT
pre-pregnancy medication to be continued- provided ACE inhibitors, angiotensin II antagonists and direct renin inhibitors be kept under close BP control

b- For delivery
in gestational HT with proteinuria with adverse conditions
Induction
IX - Venous thromboembolism including pulmonary embolism

a- Pre-pregnancy and early pregnancy
risk factors for VTE to be assessed - mainly previous history of unprovoked DVT or PE and thrombophilias forming high, intermediate and low risk groups
- high risk
to receive antenatal profilaxis with LMWH as well as 6 weeks postpartum
- intermediate risk
postpartum prophylaxis with LMWH to be given for at least 7 days or longer, if >3 risk factors persist

b- During pregnancy
in suspected VTE
D-Dimer measurement and compression ultrasonography
in acute VTE
pregnancy UFH is in high risk and LMWH in non-high risk patients

c- During pregnancy and puerperium
increased incidence of venous thromboembolism (VTE) and its clinical manifestations (PE).
Conclusion
Suspected cardiac disease in childbearing age should prompt physician to offer counseling and special care
Cardiac disease during pregnancy to be managed by interdisciplinary teams
High risk patients to be sent for treatment in specialised centers
Diagnostic procedures and interventions to be performed by specialists with great expertise in the individual techniques
Registries and prospective studies to be implemented to improve current state of knowledge.

[Chevychelov]

Bayer Claims ACS Benefit for Xarelto

By Peggy Peck, Executive Editor, Reviewed by
September 29, 2011

Review

Rivaroxaban (Xarelto) plus standard therapy reduced death, myocardial infarction, and stroke in a study of acute coronary syndrome, according to Bayer, which announced the topline results.

But, the company said the drug, an oral direct factor Xa inhibitor, was associated with an increased risk of bleeding.

Earlier this week Astellas announced it was halting development of darexaban maleate, its entry in the oral anticoagulant field, after an acute coronary syndrome study revealed a higher bleeding risk associated with the drug -- and almost a year ago a trial of apixaban (Eliquis) in ACS was halted when excess bleeding was observed.

Bayer said it "intended to present these data as soon as possible at a forthcoming scientific congress as well as to file for market authorization by the end of this year."

Rivaroxaban, which is marketed in the U.S. under a collaboration with Johnson & Johnson, is FDA approved for prevention of deep vein thrombosis in patients undergoing joint surgery. The FDA is currently considering the company's application to market the drug for the prevention of stroke in patients with nonvalvular atrial fibrillation.
__________________________________________________ _____________________

CMS to Decide on Paying for New Valve Procedure

By Emily P. Walker, Washington Correspondent, Reviewed by
September 29, 2011

Review

WASHINGTON -- Responding to requests from two major cardiology groups, the Centers for Medicare and Medicaid Services (CMS) has started the process of determining whether it should have an official payment policy for transcatheter aortic valve replacement (TAVR) to treat aortic stenosis.

The American College of Cardiology (ACC) and the Society of Thoracic Surgeons (STS) formally petitioned CMS to open a "National Coverage Analysis" on the new procedure -- more familiarly known as TAVI -- during which an artificial valve is inserted percutaneously into the patient's own aortic valve.

The procedure is intended as an alternative for patients with severe aortic stenosis who are too frail for open-heart surgery.

Opening a National Coverage Decision is a highly unusual move on CMS' part because there is not yet an FDA-approved valve to use in the procedure. The agency hardly ever starts investigating whether Medicare should cover a device or drug before it's been approved.

There are a number of TAVI devices in development, but Edwards Lifesciences' Sapien transcatheter heart valve is expected to hit the market first. In July, the FDA's Circulatory System Devices panel voted 9-0, with one abstention, to recommend approval for Sapien.

Although the FDA has yet to make its decision, the company is expecting approval in October. The agency doesn't have to follow the advice of its advisory committees, although it often does.

While members of the advisory panel were concerned with the stroke risk observed in the Edwards Lifescience's two-part PARTNER trial, they ultimately felt the benefits of the device -- 20% more patients were alive one year after receiving the Sapien device than with standard therapy -- outweighed the risks.

Those risks are reduced when the procedure is performed in a specialized heart center by a multidisciplinary team in which each member has appropriate training and credentialing; in a modified cardiac lab or hybrid operating room with the necessary specialized equipment; and when the team uses a pre-planned approach on how to manage the decision-making during the procedure, the presidents of the ACA and TCT wrote in a Sept. 22 letter to Louis Jacques, MD, director of the coverage and analysis group for CMS.

The groups urged CMS to make coverage contingent on the procedure being performed in an optimal setting.

In addition, the groups said it's "critical" that long-term follow-up be performed (most data in Partner only went up to two years) and that all patients undergoing TAVI be enrolled in a registry to track long-term outcomes. They said CMS should not cover the procedure unless it's reported in a mandatory registry.

It its announcement, CMS said it is particularly interested in a definition of when TAVI is "reasonable and necessary" -- the standard the agency adheres to when deciding whether Medicare will cover a procedure. The agency also said the question has been raised of how generalizable the study data are to a "real world" setting.

The Partner trial tested the transcatheter technology in patients too frail to undergo surgery as well as in patients who were candidates for surgical repair. The primary endpoint was a comparison of survival through the full duration of the study. Patients with the Sapien device had better survival rates at one year than those in the control group -- 69% compared with 50% (P<0.0001).

However, there was a higher incidence of stroke observed in the trial: After 30 days, 13 patients in the TAVI group had a stroke, compared with just three in the standard treatment arm. After one year, 25 patients in the TAVI group had had a stroke, compared with eight in the control group.

CMS will accept public comments on transcatheter aortic valve replacement through Oct. 28 and is slated to issue a final decision by March 28, 2012.

[Chevychelov]

Afib Patients Often Uninformed About Stroke Risk

By Chris Kaiser, Cardiology Editor, Reviewed by September 29, 2011

Review

People with atrial fibrillation were more concerned about heart attacks than stroke, and only half of more than 500 Afib patients said they considered themselves at risk for having a stroke, according to a survey by the American Heart Association.

Out of 502 respondents (236 men), 42% said heart disease and myocardial infarction are their main health concerns, while stroke was cited as the greatest concern by only 8%. Beating out stroke were cancer (13%), obesity (11%), and diabetes (10%).

Twenty-five percent of those who answered the emailed survey said they were not at risk of stroke, while another 25% were not sure about the risk. More women than men were "not sure" (29% versus 20%), but there were no significant differences between men and women who said either they were or were not at risk.

Interestingly, only two-thirds of respondents said they discussed stroke risk with a healthcare professional, with men reporting that they were more likely to have discussed stroke risk with their doctors -- 74% versus 60% -- despite the fact that there were more high-risk women in the sample than high-risk men.

"The systems of healthcare are such that practitioners are under pressure to see patients quickly," Mark Estes III, MD, a professor of medicine at Tufts University School of Medicine in Boston and a spokesperson for the AHA, told MedPage Today. "In that context, both patients and physicians have to be proactive. Physicians can give patients written material and direct them to various websites."

When respondents were asked which health concern they "feared" the most, the top answer was stroke, even though heart disease and myocardial infarction were ranked as the leading health concerns.

Twenty-six percent of those surveyed said they feared stroke versus 15% who said they feared heart attack.

The fear of stroke increased with age so that only 16% of people younger than 55 said they worried about stroke versus 31% of those who were older than 65.

This is not surprising as the risk of stroke increases with age, Estes said. "Generally, the age cutoff where the risk of stroke increases substantially is 65, and over 75 is where we feel the risk is significant."

Other health concerns that were feared included heart failure (14%), disability (12%), and death (12%).

Another indication of a knowledge gap for those with atrial fibrillation was when respondents were asked whether they agreed with this statement: "Everyone with atrial fibrillation is at risk for a stroke." Only two-thirds agreed with it, but perhaps more troubling was the answer given by 17% of those surveyed -- they called the statement false.

Estes said that it is not just patients who are confused or misinformed about atrial fibrillation, noting that many healthcare providers overestimate the risk associated with warfarin therapy. That, coupled with the inconvenience of warfarin maintenance, leads many physicians to assume that patients won't want to initiate therapy.

But open communication between physicians and patients often solves these problems.

"Physicians can have a discussion with patients, give them information, outline the options, and let them know that a decision has to be made and work with them to select the best option for their particular situation," Estes said. "Ongoing discussions can help answer concerns and address compliance issues."
__________________________________________________ ____________________
Left Atrium Key to Stroke Risk After Afib Ablation

By Crystal Phend, Senior Staff Writer,
September 29, 2011

Action Points
This single center cohort study examined the risk of stroke after radiofrequency and cryoablation Maze procedure in 150 patients who were in sustained sinus rhythm post-procedure.


Lack of left atrial mechanical contractility was associated with a five-fold increased risk of stroke, and increased left atrial size was associated with a threefold increased risk of stroke.


Echocardiographic evaluation of the left atrium may be useful for risk stratification after Maze procedure; however, further study is needed to validate these findings.
Review

Stroke risk may remain high for atrial fibrillation patients despite a successful Maze procedure if the left atrium doesn't regain mechanical function, researchers found.

Lack of left atrial contractility predicted a persistent five-fold elevation in stroke risk (P=0.02) in a single center study by David Luria, MD, of the Sheba Medical Center in Tel Hashomer, Israel, and colleagues.

A large left atrium was another substantial post-Maze stroke risk factor, the group reported in the Oct. 4 issue of the Journal of the American College of Cardiology.

"Anticoagulant treatment should be strongly considered" for patients with the two risk factors, the group suggested in the paper.

This simple noninvasive echocardiographic approach would be reasonable as a first step to identifying anticoagulant candidates, Shunichi Homma, MD, and Marco Di Tullio, MD, both of Columbia University Medical Center in New York City, agreed in an accompanying editorial.

It could point to patients who need further assessment for more direct stroke risk indicators, such as spontaneous echo contrast or thrombus in the surgical stump of the appendage, they noted.

However, further validation in prospective studies is needed before initiating anticoagulation solely on the basis of large atrial volume or lack of left atrial mechanical contraction, they argued.

The study included 150 patients in sustained sinus rhythm after a modified Maze procedure using a combination of radiofrequency and cryoablation without the use of atrial incisions done from 2004 through 2009.

At three-month echocardiographic follow-up, 31% had no evidence of left atrial mechanical contraction. None of these 47 patients later regained contractile function.

During a mean follow-up of 24.5 months, ischemic stroke occurred in 15 patients (10%), most of whom had no left atrial contractility (10 patients, 21% of the 47).

Cumulative probability of surviving to year two without a stroke was thus only 43% for patients who had no left atrial mechanical contraction versus 95% for those who had atrial contractility (P=0.003).

In an analysis separating out patients on anticoagulants and with prosthetic mechanical valves that could influence stroke risk independently of left atrial mechanics, the researchers again showed an effect of absent contractility on stroke risk with 45% versus 95% cumulative stroke-free survival probability (P=0.01).

For patients with left atrial volume index of 33 mL/m2 or greater, the cumulative probability of going without a stroke was 55% compared with 94% in those with smaller left atria (P=0.01).

The multivariate-adjusted stroke risk associated with large atrial volume was 3.23-fold (P=0.03).

Notably, the CHADS2-VASc score wasn't predictive in patients without left atrial mechanical contraction, which Luria's group pointed to as evidence that "left atrial mechanical standstill is an independent and powerful risk factor for thromboembolic stroke."

The researchers noted that they did not consider risk in patients with decreased, rather than absent, left atrial contraction.

Other limitations included the nonrandomized, retrospective design and small number of thromboembolic strokes that occurred, leaving it underpowered to detect interactions, they added.

The editorialists warned about generalizability given the "unusually high" stroke incidence compared with other studies (10% versus 1.6% in one comparable study), "possibly indicating the selection of a population at especially high baseline risk and likely reflecting the absence of anticoagulation."

Also, only five of the 15 stroke patients had transesophageal echo confirmation that the left atrial appendage was effectively obliterated, "leaving the possibility that thrombus in the surgical stump may have contributed to the clinical event in the others," they noted.

But since all five cases checked affirmed successful obliteration, the single surgeon who did nearly all the obliterations likely had similar success on those that weren't checked, the researchers argued.

[Chevychelov]

Drugmaker Pulls Plug on Oral Anticoagulant

By Peggy Peck, Executive Editor, Reviewed by
September 29, 2011

Review

Astellas Pharma has announced it is shutting down global development of darexaban maleate, a direct factor Xa inhibitor, after an acute coronary syndrome study revealed a higher bleeding risk associated with the drug.

The company said the ACS results reported at the European Society of Cardiology meeting last month in Paris, coupled with its inability to find a development partner for darexaban made further development impractical.

In the ACS study there was a significant dose-dependent increase in major bleeding and clinically relevant nonmajor bleeding at six months among patients treated with darexaban.

But darexaban is not the first direct factor Xa inhibitor to demonstrate safety concerns when used to treat ACS patients -- apixaban failed in phase III for that patient population. And a third factor Xa inhibitor, rivaroxaban (Xarelto), is currently being evaluated for ACS.

Earlier this year, Astellas abandoned plans to seek approval from the Japanese regulatory agency to market the drug for use after surgery.
__________________________________________________ ___________________

Featured Commentary

Issue No. 6, 2011
CETP inhibition in perspective

The sixth in a series of regular Commentaries highlighting topical issues relevant to EAS activities
Cholesteryl ester transfer protein (CETP) inhibition has been a ‘hot topic’ in recent news. At the European Society of Cardiology (ESC) Congress in Paris 27-31 August, two trials with dalcetrapib were presented –dal-PLAQUE and dal-VESSEL. Results and implications from these trials are discussed here.
Dal-PLAQUE
The findings from this small trial, presented as a poster at the ESC Paris, were subsequently published in The Lancet.1 Dal PLAQUE was designed to investigate the effects of dalcetrapib treatment on structural and inflammatory markers of plaque burden, using innovative multimodality imaging techniques.

In this phase IIb, double-blind trial 130 patients (mean age 63 years, 82% male and mean HDL cholesterol 1.2 mmol/L or 46 mg/dL at baseline) with coronary heart disease (CHD) or CHD risk equivalents and treated to a LDL cholesterol level of <2.6 mmol/L (mean 1.9 mmol/L or 74 mg/dL) were randomly allocated to treatment with dalcetrapib 600 mg/day or placebo for 24 months. The primary endpoints were indices of plaque burden from the carotid and abdominal aorta (total vessel area, wall area, wall thickness and normalised wall index) at 24 months measured using magnetic resonance imaging (MRI). Plaque inflammation was also assessed at 6 months using 18F fluoro-deoxyglucose uptake measured by positron emission tomography/computed tomography (FDG-PET/CT).

Treatment with dalcetrapib increased plasma levels of HDL cholesterol levels by 31%, consistent with previous phase II data.2

Dalcetrapib treatment was associated with reduction in structural markers of plaque burden at 24 months, as indicated by:
Significant reduction in total vessel area (absolute change from baseline corrected for placebo, -4.01 mm2, 90%CI -7.23 to -0.80, p=0.041)
A trend for reduction in average wall area (-2.20 mm2, 90%CI -4.54 to 0.13, p=0.12).
The dalcetrapib placebo-corrected changes in total vessel area, average wall area and normalised wall index were either below the pre-specified ‘no harm’ boundary, or the change was numerically lower in the dalcetrapib group than the placebo group.

FDG-PET/CT results showed no evidence of increased vascular inflammation with dalcetrapib at 6 months. The target to background ratio (TBR) for the most diseased segment decreased over 6 months in the dalcetrapib group but did not change in the placebo group (average absolute change 0.19, 90% CI -0.29 to -0.09, p=0.001 versus -0.043, 90% CI -0.14 to 0.06, p=0.51). Exploratory analyses showed that the change in HDL cholesterol level appeared to be inversely correlated with the change in TBR for the most diseased segment at 6 months. A 4.3% reduction in arterial inflammation was observed with each increase in HDL cholesterol tertile (p=0.04).

Dalcetrapib treatment was not associated with any increase in blood pressure. There were 15 adjudicated cardiovascular events (13 on dalcetrapib vs. 2 on placebo).

It is acknowledged that the study was exploratory and therefore no correction was made for multiple statistical analyses. Additionally, patients were only randomised if they had a sufficient PET signal at baseline. Despite these methodological limitations, the data support the hypothesis that HDL cholesterol raising associated with dalcetrapib treatment might reduce inflammation in turn leading to favourable changes in structural vascular changes.

[Chevychelov]

OBESITY: Stepped Approach to Weight Loss Works

By Todd Neale, Senior Staff Writer, October 02, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that stepping up the intensity of a weight-loss intervention only for those patients who fail to reach their goal may be a viable alternative to standard lifestyle approaches.

Point out that this study used a stepped-care approach in which the intensity is increased only if the participant fails to reach a pre-specified goal.
Review

ORLANDO -- Stepping up the intensity of a weight-loss intervention only for those patients who fail to reach their goal may be a viable alternative to standard lifestyle approaches, a randomized trial showed.

There was no significant difference in the percentage of patients who achieved a 10% reduction in weight after 18 months between the stepped-care group and the standard group (26% versus 32%, P>0.05), according to John Jakicic, PhD, of the University of Pittsburgh.

The average percent weight loss was also similar in the two groups (5.8% versus 6.8%, P>0.05), Jakicic reported at the Obesity Society meeting here.

"So the stepped-care approach may present an effective alternative to standard behavioral weight loss interventions," he said.

He added that 30% to 40% of the patients in the stepped-care group remained at one of the first two steps, which involved monthly group meetings, weekly mailed lessons, and mailed feedback on a self-monitoring diary (for both steps), and one phone call per month (for the second step only).

Although behavioral interventions involving lifestyle changes have been shown to be effective at getting patients to lose weight, the intensity of such approaches generally remains the same regardless of whether the participants are responding.

A stepped approach, in which the intensity is increased only if the participant fails to reach a pre-specified goal, has been proposed as an alternative, but the strategy had not been compared with a standard behavioral weight loss intervention in a randomized trial, according to Jakicic.

He and his colleagues designed the Step Up study, which randomized 364 overweight and obese individuals to a stepped-care or standard intervention. The mean age of the participants was 42.2 and the mean body mass index was 33 kg/m2 (ranging from 25 to 39.9 kg/m2). Most of the participants were female (82.7%).

Those in both groups were prescribed dietary goals, with the aim of reducing calories and fat intake, and physical activity targets progressing to 300 minutes of moderate-to-vigorous intensity exercise per week.

The standard behavioral weight loss program involved group sessions weekly for the first six months, twice a month for the next six months, and monthly sessions for the final six months. The program remained consistent for all participants regardless of weight loss achieved.

In the stepped-care group, however, participants were scheduled to attend one group session per month throughout the study and to receive weekly mailed lessons, as well as mailed feedback on their diaries. Those who failed to achieve various weight loss goals -- 5% at three months, 7% at six months, and 10% at nine months and every three months thereafter -- received more frequent contact.

The intensified steps included up to two phone calls per month, up to two individual sessions to discuss weight loss per month, and the provision of meal replacements.

Although participants in both groups lost weight, the absolute loss was significantly greater in the standard group for the first six months (22 pounds versus 17.6 pounds, P<0.05), as was the percent weight loss (9.2% versus 7.6%, P<0.01). At each time point beyond six months, however, there was no significant difference between the two groups for either measure.

Jakicic said that there was more work to be done to evaluate a stepped-care intervention for weight loss, including looking at:
Whether any of the steps were more effective than others
Who responded to the approach
Different approaches for stepping up care
The effect of diet and physical activity behaviors

In addition, he and his colleagues will conduct a cost-effectiveness analysis and examine whether the weight loss thresholds for stepping up care need to be adjusted.

[Chevychelov]

Collateral Blood Supply May Cut Death Risk in CAD

By Todd Neale, Senior Staff Writer,
October 02, 2011

Action Points
Explain that patients who have coronary artery disease (CAD) and strong coronary collateral circulation appear to have improved survival.


Point out that the risk reduction was more pronounced in studies in which most patients underwent percutaneous coronary intervention, and those in which the collateral circulation was assessed using intracoronary pressure measurements versus visual inspection.
Review

Patients who have coronary artery disease (CAD) and strong coronary collateral circulation appear to have improved survival, a meta-analysis showed.

For patients with stable or acute CAD, a high degree of collateralization was associated with a 36% reduction in the risk of dying during follow up for as long as 10 years (RR 0.64, 95% CI 0.45 to 0.91), according to Christian Seiler, MD, of the University Hospital Bern in Switzerland, and colleagues.

The risk reduction was more pronounced in two types of studies: those in which most patients underwent percutaneous coronary intervention (PCI) versus those with no PCI (RR 0.42 versus 0.70), and those in which the collateral circulation was assessed using intracoronary pressure measurements versus visual inspection (RR 0.38 versus 0.71), the researchers reported online in the European Heart Journal.

Coronary collateral circulation is found in individuals with and without coronary artery disease. If one of the epicardial arteries becomes blocked, the collateral arteries can enlarge to provide an alternative source of blood to the heart.

"The coronary collaterals may represent a useful prognostic marker," they wrote. "Patients with a low collateralization have an increased mortality risk and may be monitored more closely."

They added that diagnostic angiography remains important to define the coronary anatomy and the degree of collateralization, which is best accomplished by measuring the intracoronary pressure; an alternative is to use an intracoronary ECG.

The researchers stated that for patients with an MI, increased collateralization has been associated with the following:
Smaller infarct size
Preserved cardiac function after an acute infarction
Reduced post-infarct ventricular dilatation
Reduced post-infarct aneurysm formation


But the relationship between increased collateralization and mortality is less clear.

Seiler and colleagues performed a meta-analysis of 12 studies that included 6,529 patients with stable or acute CAD and reported the degree of coronary collateralization and mortality statistics.

The lower mortality risk with a high degree of collateralization was consistent in patients with stable disease (RR 0.59, 95% CI 0.39 to 0.89), those with subacute MI (RR 0.53, 95% CI 0.15 to 1.92), and those with acute MI (RR 0.63, 95% CI 0.29 to 1.39). The differences among the relative risks were not statistically significant (P=0.149).

The researchers noted that the lack of statistical significance for the relationship in the MI groups was mostly due to limited power from a small sample size.

Although a causal relationship between better collateralization and mortality could not be established, the authors speculated on some possible underlying mechanisms.

Collateral circulation has been shown to reduce QT interval prolongation resulting from acute myocardial ischemia, which puts patients at risk for fatal arrhythmias, they wrote.

In addition, they noted that reductions in infarct size and post-infarct ventricular dilatation and preservation of cardiac function likely have mortality benefits.

"The results of this study highlight the importance of finding means to induce collateral growth," Seiler and colleagues wrote, adding that experimental studies have shown that promoting growth is feasible.

"We further need larger-scale interventional studies which test whether the therapeutic promotion of collaterals translates into improved clinical outcomes," they wrote.

They acknowledged that the analysis was limited in that all of the included studies were observational and most were small and retrospective.

The study was supported by the Swiss National Science Foundation.

The authors reported that they had no conflicts of interest.
Primary source: European Heart Journal
Source reference:
Meier P, et al "The impact of the coronary collateral circulation on mortality: A meta-analysis" Eur Heart J 2011.

[Chevychelov]

OBESITY: Mother, Baby Risk Factors Predict Child's Obesity

By Todd Neale, Senior Staff Writer,
October 03, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Note that at age 7, children with four maternal and infant risk factors had a substantially greater risk of obesity than other children.
Review
ORLANDO -- Targeting four modifiable maternal and infant risk factors may make a large impact on reducing childhood obesity, researchers found.

The four factors were maternal smoking during pregnancy, gestational weight gain, breastfeeding duration, and infant sleep duration, according to Matthew Gillman, MD, of Harvard Medical School in Boston.

At age 7, children with adverse levels of all four risk factors had a substantially greater risk of obesity than those with healthy levels of all four (28% versus 4%). Gillman reported those findings at the Obesity Society meeting here.


"These four factors, which are potentially modifiable, explain a large proportion of obesity in childhood, and the implication is that, if we can mount interventions to change these things, we can go a long way toward preventing childhood obesity," Gillman said.

Several pre- and postnatal risk factors for childhood obesity have been identified, Gillman said, but there have been few studies that have examined the predictive value of combinations of risk factors.

To explore the issue, he and his colleagues turned to Project Viva, a longitudinal cohort study in Massachusetts looking at the health of women and their children.

The current analysis included 948 mother-child pairs who provided information both at baseline and when the child was 7-years-old.

The researchers chose to examine four factors -- all dichotomized for adverse and healthy conditions -- for their relationship with childhood obesity:
Maternal smoking during pregnancy (yes/no)
Gestational weight gain (excessive/not excessive)
Breastfeeding duration (less than 12 months/at least 12 months)
Infant sleep duration (less than 12 hours a day/at least 12 hours a day)


During pregnancy, 9% of the mothers smoked and 58% gained excessive weight. Most of the infants (71%) were breastfed for less than one year and 31% slept less than 12 hours a day.

All four of the risk factors were individually associated with an increased likelihood of obesity when the child was 7 (ORs 1.55 to 2.01), although the relationship reached statistical significance for infant sleep duration only (OR 2.01, 95% CI 1.24 to 3.25).

Overall, 6.9% of the children had adverse levels of none of the risk factors, 36.1% had one risk factor, 40.8% had two, 14.5% had three, and 1.9% had all four.

The overall rate of obesity at age 7 was 10.8%, ranging from a low of 4% for children with healthy levels of all four risk factors to a high of 28% for adverse levels of all four risk factors.

Similar trends were seen for body mass index (BMI) z-score, which ranged from 0.07 to 0.79, and percent body fat, which ranged from 23.2% to 26.5%.

The model was adjusted for maternal BMI and education, child race/ethnicity, and household income. Further adjustment for sugary drink intake, fast food intake, TV screen time, and physical activity did not have substantial effect on the findings.

The researchers calculated that if the population shifted from having two to four of these adverse risk factors to zero or one, 55% of the cases of childhood obesity would be avoided.

Gillman said that some studies of interventions to modify these factors have been performed and some are ongoing.

Infant sleep is modifiable, at least on a population level, by adjusting how parents put their babies to sleep, he said. An example would be teaching parents to rock their babies until they are almost asleep, putting them in their cribs, and allowing them to put themselves to sleep, rather than rocking them until they fall sleep.

More work needs to be done on reducing smoking during pregnancy, Gillman said. Most mothers will stop smoking when they know they are pregnant, but there is room for interventions for smoking cessation at or before the time of conception.

Support interventions using lactation consultants have been shown to be effective for increasing the initiation and duration of breastfeeding.

Although there is not one strategy proven to reduce gestational weight gain, many trials are ongoing, and Gillman said that he expects to see some consensus about effective approaches develop in the coming years.

[Chevychelov]

ECG 'Noise' Predicts Death After MI

By Chris Kaiser, Cardiology Editor,
October 03, 2011

Action Points
Explain that three computational biomarkers analyzing data from long-term Holter monitoring identifies individuals with non-ST-segment elevation acute coronary syndromes (NSTEMI ACS) at risk for cardiovascular death.


Note that these biomarkers rely on data already being collected and appear to independently add to traditional predictors.
Review
Certain ECG signals that were once considered "noise" are associated with a higher risk of death following a non-ST-segment elevation acute coronary syndrome (NSTEMI ACS), according to computational ECG analysis of the MERLIN-TIMI36 trial.

Each of three computational biomarkers derived from long-term Holter ECG signals were strongly associated with cardiovascular death, Zeeshan Syed, PhD, from the University of Michigan in Ann Arbor, and colleagues reported.

After adjusting for TIMI risk score, ejection fraction, and other ECG-based metrics, the computationally-generated biomarkers were still independently associated with cardiovascular death, according to the study published online in Science Translational Medicine.


"The main point of our study is that we are able to make better use of data that we're already collecting," Syed told MedPage Today.

"There's prognostic information buried in the noise, and it's almost invisible because of the sheer volume of the data," Syed said. "The sophisticated computational techniques allow us to home in on truly abnormal ECG signals. These patients with unstable hearts are at a greater risk of dying. Identifying them would allow physicians to initiate more aggressive treatment."

Researchers noted that current metrics such as echocardiography and left ventricular ejection fraction (LVEF) don't always correctly stratify ACS patients into high and low risk. The three computational biomarkers, when added to existing predictors, improved classification by 7% to 13%, they wrote.

About 2.5% of patients die within 90 days following an NSTEMI ACS. The rate increases to about 6% within a year.

The use of echo and a conservative threshold of less than 40% LVEF identifies 31.7% of these deaths, according to the study.

Although the majority of the patients identified by echo are at high risk, we are still missing more than two-thirds of these patients who will die," Syed said.

To better help identify these patients, Syed and colleagues used data mining and machine learning techniques to retrospectively search through 24-hour continuous ECGs from 4,557 heart attack patients enrolled in the MERLIN-TIMI36 trial.

They found that the ECG signals from many of the patients who later suffered cardiovascular death contained similar errant patterns that until now were dismissed as noise or simply undetectable.

The three computational biomarkers are:
Morphologic variability, which assesses myocardial instability by quantifying low-amplitude probabilistic variability in the shape of the ECG waveform over long periods of time
Symbolic mismatch, which quantifies the degree to which long-term ECG signals of individual patients are anomalous relative to those of other patients with a similar clinical history
Heart rate motif, which integrates the frequency with which high- or low-risk heart rate patterns reflecting autonomic function appear in a patient's ECG over long time periods.


In the unadjusted analysis, morphologic variability was the strongest predictor of death (HR 3.31, 95% CI 2.49 to 4.40, P<0.001), followed by symbolic mismatch (HR 2.36, 95% CI 1.73 to 3.22, P<0.001) and heart rate motif (HR 2.21, 95% CI 1.65 to 2.97, P<0.001).

Even after adjusting for traditional risk stratifying techniques, the computational biomarkers were still independently associated with dying compared with the other techniques and as well as compared with each other.

But Syed is not ready to do away with conventional risk stratifying techniques.

"Just as disease is multifactorial, we need to continue to apply multiple risk stratifying approaches including functional and electrical activity," Syed told MedPage Today.

One potential area where these biomarkers might help is in identifying candidates for implantable cardioverter defibrillators, he said.

But there is a spectrum of treatments, including drugs, stents, and devices, which are initiated based on assessment from traditional metrics. The hope of Syed and colleagues is that the computational biomarkers will help "to better stratify patients and define where they should fall within the spectrum of treatment."

Syed said he wants to test these biomarkers prospectively on patients in the hospital, and also on asymptomatic people at an increased risk for heart disease.

The study was limited because about 2,000 patients in the MERLIN-TIMI36 trial did not have continuous ECG data available.

In addition, some of the conventional risk metrics could not be assessed in the patient data, which reduced the size of the multivariate model.

Also, these findings are not generalizable to other populations, such as those with STEMI or heart failure, for example.

[Chevychelov]

OBESITY: Weight Counseling by PCPs Found Lacking

By Todd Neale, Senior Staff Writer,
October 04, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Note that this study of primary care visits documents that despite increases in the prevalence of obesity in the population, there were significant declines in the percentage of adult primary care visits with counseling for weight reduction, diet, and exercise.
Review
ORLANDO -- Even as rates of overweight and obesity rise, primary care physicians appear to be cutting back on weight counseling for their adult patients, researchers found.

From 1995 to 2008 -- when rates of overweight and obesity are estimated to have increased from 52% to 63% -- the percentage of primary care visits that included weight counseling dropped from 7.8% to 6.2% (OR 0.62, P<0.001), according to Chris Sciamanna, MD, MPH, of Penn State College of Medicine in Hershey, Pa.

The reduction was consistent in patients recognized by the physician to have hypertension, diabetes, or obesity, he reported at the Obesity Society meeting here.


During the same time period, there was not a drop-off in the percentage of visits that included tobacco counseling, which Sciamanna said indicates that one of the possible explanations for the reduction in weight counseling is a perception that it does not work.

To back that up, he pointed to a 2003 survey of primary care physicians that found that the treatment of obesity was rated as significantly less effective than therapies for nine out of 10 other chronic conditions.

"I think some of the problem is that we really don't know what works in primary care," Sciamanna said, adding that physicians need effective tools, including websites and programs, to guide the treatment of obese patients.

"Doctors really need to know what to say ... because these things are complicated and we're not trained to counsel," he said. "Unless you're going to change the way doctors are educated, we really need to know what exactly to say and what exactly to do."

In 2003, the U.S. Preventive Services Task Force recommended screening all adult patients for obesity and offering intensive counseling and behavioral interventions to promote weight loss for those who were obese.

The federal government has also set a Healthy People 2020 goal of increasing the proportion of obese-adult office visits that include counseling and education related to losing weight and living a healthy lifestyle.

But despite the guidance, previous studies have shown counseling rates to be low, Sciamanna said. To see if there's been an increase in recent years, he and his colleagues looked at data from the National Ambulatory Medical Care Survey, comparing 15,753 adult patients treated in 1995 to 1996 to 16,766 patients treated in 2007 and 2008.

The analysis was restricted to office-based visits to family physicians, general practitioners, and general internists.

As part of the study, physicians checked off services provided at each visit and what conditions each patient had.

After adjustment for patient and provider characteristics, the percentage of visits that included weight counseling fell by a relative 38% from the earlier to the later time period (OR 0.62, 95% CI 0.50 to 0.77), even for obese patients (from 39.9% to 29.9%).

There were similar trends for diet and exercise counseling as well.

Sciamanna noted some limitations of the analysis, including the uncertainty of the actual body mass index of the patients and the unclear definition of weight counseling as selected by the physicians.

In addition, he said, it is assumed that physicians under-reported the rate of obesity -- about 11% for both time periods.

[Chevychelov]

OBESITY: When Kids Are Young Moms Exercise Less

By Todd Neale, Senior Staff Writer,
October 04, 2011

Action Points
Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Note that these studies indicate that having young children present in the home significantly reduced the physical activity level of parents.
Review
ORLANDO -- Mothers of young children get less exercise than women who do not have children at home, researchers found.

Women with a dependent child younger than 6 participated in an average of 6.38 minutes less moderate-to-vigorous intensity physical activity each day (P<0.05), according to Kristi Adamo, PhD, of the Children's Hospital of Eastern Ontario Research Institute.

That works out to about 45 minutes less exercise per week, she reported at the Obesity Society meeting here.

"I think, at least clinically, that's pretty important," Adamo said, noting that the Canadian national guidelines call for at least 150 minutes of moderate-to-vigorous physical activity per week for adults.


"Future research should continue to focus on strategies to encourage women with young children to establish or re-engage in a physically active lifestyle," she added.

Having dependent children at home has been proposed as a contributing factor to the low physical activity levels observed around the world, although results of previous studies have been mixed regarding the impact of children's age, the number of children, and the sex of the parent, according to Adamo.

To explore the issue, she and her colleagues turned to the Canadian Health Measures Survey for 2007 to 2009. Their analysis included 2,315 men and women ages 20 to 65 who agreed to wear an accelerometer to assess physical activity levels. Only those who wore the device for at least 10 hours a day for at least four days were included.

Overall, 47% of women and 42% of men had a dependent child at home.

When children of all ages were grouped together, having a child at home or having more than one child at home was not associated with the level of physical activity in either men or women.

However, when a child at home was younger than 6, women got significantly less exercise than women with no children at home in a univariate analysis.

The significant difference held up in a model that adjusted for parental age, marital status, household income, hours worked per week, and body mass index.

Women with a child younger than 6 were also significantly less likely to meet the Canadian national recommendation for moderate-to-vigorous physical activity (OR 0.50).

In a univariate analysis, men with a child ages 6 to 11 participated in significantly less physical activity compared with those with no children at home (P<0.05). After adjustment for potential confounders, however, the difference no longer reached statistical significance.

As a possible explanation for the apparently stronger influence of children on the level of physical activity in women compared with men, Adamo said that mothers are typically the primary caregivers when children are young and, in many cultures, the expectations placed on mothers are different from those placed on fathers.

She noted some limitations of the study, including the cross-sectional design, the low response rate and accelerometry compliance in the national survey, and the limited number of variables that could be included in the models.

The findings appear to gain some support from another analysis presented at the meeting by Brooke Tompkins, MA, of the University of North Carolina at Chapel Hill.

She and her colleagues looked at the association between having children in the home and adherence to a standard behavioral weight loss intervention. The study included 127 participants in the control arm of the Step Up study. The intervention included periodic group sessions, a reduction in the intake of calories and fat, and a progression to 300 minutes of moderate-to-vigorous physical activity per week.

Most of the participants (83.5%) were female.

Through six months, the average percentage of weight lost was greater in the participants who did not have children at home after adjustment for gender, race, and marital status (12.32% versus 9.87%, P=0.03).

Those with children attended significantly fewer group sessions, submitted fewer self-monitoring diaries, recorded fewer days of diet, and reported fewer days of exercise (P<0.05 for all).

"If you're expected to come to a weight loss intervention in person, then it might not be feasible for parents," Tompkins said. "So we need to look for other interventions, maybe something online, that are just a little bit easier for parents to do."

[Chevychelov]

OBESITY: Three Questions May Peg Type 2 Diabetes Risk

By Todd Neale, Senior Staff Writer,
October 05, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that a study found that being age 55 or older, having a body mass index (BMI) greater than 30, and having a family history of diabetes predicted a higher risk of developing type 2 diabetes over five years, compared with those who were under 55 with a BMI less than 25 and no family history of diabetes.


Note that although the three-item tool was simpler than the seven-item instrument advocated by the American Diabetes Association, the two instruments were not directly compared in this study.
Review

ORLANDO -- A simple, three-item instrument may be enough to accurately identify those individuals who are at high risk for type 2 diabetes in the next five years, researchers found.

Individuals who were 55 or older, were obese -- with a body mass index (BMI) greater than 30 -- and had a family history of diabetes had a 19.9% risk of developing type 2 diabetes over five years of follow-up, according to Harold Bays, MD, of the Louisville Metabolic and Atherosclerosis Research Center in Kentucky.

Younger individuals with a BMI less than 25 and no family history of the disease, however, had an almost negligible five-year risk (0.3%), Bays reported at the Obesity Society meeting here.

The three-item screener might have advantages over more established tools that use seven or more variables because it might be a less cumbersome way for patients to identify undiagnosed diabetes and start treatment, he said.

The simplified tool emphasizes that weight loss is an option that patients can use to reduce their risk of type 2 diabetes, Bays said.

"I think that's a crucial message to be sent to patients," he said. "It's something that they can proactively address in order to reduce their risk of a serious disease."

There are several algorithms available to estimate the risk of developing type 2 diabetes, including the American Diabetes Association's (ADA's) Diabetes Risk Test, which includes seven variables -- age, race, family history of diabetes, obesity, physical activity, hypertension, and gestational diabetes.

To look at whether it would be feasible to simplify that score with just three variables -- age, family history, and obesity -- Bays and his colleagues turned to the Study to Help Improve Early Evaluation and Management of Risk Factors Leading to Diabetes (SHIELD), a five-year population-based survey.

A baseline survey was sent in 2004 to 22,001 adults in the U.S, with annual follow-up questionnaires sent through 2009.

From the respondents who were free from diabetes at baseline and provided information at the five-year follow-up, the researchers identified high-risk and low-risk groups according to age, family history, and obesity.

Overall, there were 290 high-risk individuals who were 55 or older, were obese, and had a family history of diabetes, and 408 low-risk individuals who were younger than 55, with a BMI less than 25 and no family history of diabetes.

Through five years of follow-up, 19.9% of the high-risk individuals reported developing type 2 diabetes, compared with only 0.3% of the low-risk individuals (P<0.0001).

In an interview, Peter Katzmarzyk, PhD, of the Pennington Biomedical Research Center in Baton Rouge, commented that the simplified algorithm "would certainly expedite the identification of higher-risk patients for type 2 diabetes."

However, the evidence is still preliminary, he said, and future studies should compare the discriminatory ability of the full ADA algorithm with the three-item tool and also test the proposed instrument in a more diverse patient population, as more than 90% of the participants in SHIELD were white.

"But I do think it's a very good first step," Katzmarzyk said.

Bays noted that if a clinician is not currently doing any assessment for type 2 diabetes risk, then whether the simplified tool is inferior or superior to the full algorithm is irrelevant. Those using the full model should probably keep using it, he said, but those who are not using anything might be motivated to start using the simpler option.

Bays and colleagues noted that the analysis was limited in that the diagnosis of diabetes and other conditions was self-reported, and because household panels like SHIELD tend to under-represent very wealthy and very poor populations and do not include military personnel or institutionalized individuals.

[Chevychelov]

Parsing Rivaroxaban Data Raises Efficacy Questions

By Chris Kaiser, Cardiology Editor,
Reviewed by
October 05, 2011

Review

Whether rivaroxaban (Xarelto) is noninferior to warfarin for preventing strokes in patients with atrial fibrillation could depend on how you read the data, two physicians charge.

In the ROCKET-AF trial, the overall rate of stroke and blood clots per 100 patient-years was 2.12 in the once-daily 20 mg rivaroxaban arm compared with 2.42 in the warfarin arm, which reached significance for noninferiority but not for superiority.

The trial showed similar positive data for the per-protocol analysis: rivaroxaban was superior to warfarin with a stroke/blood clot rate of 1.71 per 100 patient-years versus 2.16, again being significant for noninferiority but not for superiority.

However, an analysis of the data by an FDA reviewer "identified important issues affecting interpretation of these results," Thomas R. Fleming, PhD, and Scott S. Emerson, MD, PhD, from the University of Washington in Seattle, wrote in a Perspective piece in the Oct. 6 issue of the New England Journal of Medicine.

Fleming and Emerson noted the importance of the "constancy assumption" in noninferiority trials and how ROCKET-AF might have violated this.

For example, they wrote, patients in the trial were at a higher risk than those who participated in the reference trial.

Other concerns about nonconstancy include the 5% of patients lost to follow-up and the lower-than-average number of patients in the therapeutic range for those on warfarin (55%).

The writers suggested that the "noninferiority margin might need to be modified" because of nonconstancy problems.

Fleming and Emerson also stressed the need for per-randomization analyses in noninferiority trials.

"The importance of per-randomization analyses is very apparent in ROCKET-AF," they wrote, because the on-treatment analysis followed observation at two days after randomization treatment stopped. They said that this time frame is "likely to miss events related to inadequate coagulation during the transition to alternative treatment."

In fact, those in the rivaroxaban arm had higher rates of stroke and blood clots compared with the warfarin arm between two and seven days after stopping treatment with the direct oral factor Xa inhibitor.

Superiority was not established in the per-randomization analysis (RR 0.88, 95% CI 0.78 to 1.03) and a "positive trend seen in the per-protocol analysis of myocardial infarctions was similarly attenuated."

They also noted that a rise in mortality after stopping rivaroxaban treatment "further complicates the noninferiority assessment in ROCKET-AF."

The two commenters compared ROCKET-AF to the RE-LY trial, which compared different doses of twice-daily dabigatran (Pradaxa) in patients with atrial fibrillation with warfarin.

Not only did more patients on warfarin in the RE-LY trial (66%) have a higher average time in therapeutic range compared with ROCKET-AF, but the per-randomization relative risk of stroke or blood clot for those on dabigatran was 0.66 (95% CI 0.53 to 0.82).

"The results robustly support the superiority of dabigatran over warfarin" and Fleming and Emerson asked whether rivaroxaban should now be required to show noninferiority to the direct oral thrombin inhibitor dabigatran.

"The RE-LY results and uncertainty about the validity of the constancy assumption in ROCKET-AF raise concerns that rivaroxaban could be inferior to either dabigatran or warfarin, particularly when the latter is 'used skillfully,'" they wrote.

The FDA analysis also questioned the once-daily dosing of rivaroxaban, saying it wasn't "supported by the available pharmacokinetic and pharmacodynamic data."

All of these problems with ROCKET-AF "could lead to an unproven treatment displacing an effective treatment on the basis of overzealous promotion of more convenient once-daily dosing," they said.

Despite the negative analysis by one of the FDA reviewers, the panel as a whole recommended approval of rivaroxaban. The FDA is expected to make a ruling by Nov. 5.

[Chevychelov]

OBESITY: Teens Clueless About Fast Food Content

By Todd Neale, Senior Staff Writer,
October 05, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that the vast majority of adolescents underestimate the calorie content of meals purchased at fast food restaurants.


Point out that a greater actual calorie count was associated exponentially with a greater underestimate on the part of the participants.
Review
ORLANDO -- The vast majority of adolescents underestimate the number of calories contained in the meals they purchase at fast food restaurants, researchers found.

Of those ages 11 to 20 surveyed outside of fast food chains in four U.S. cities, 80% underestimated the actual calorie content, and 30% misjudged the amount by at least 500 calories, Jason Block, MD, of Harvard Medical School in Boston, reported at the Obesity Society meeting here.

Only 14% of the participants noticed any nutritional information in the restaurant, and fewer still -- 3% -- saw and used the information when ordering.


The findings, Block said, raise concerns that even when calorie information is available on the menus of restaurant chains with at least 20 locations nationwide, as mandated by the Affordable Care Act, people might not use it.

That concern is supported by a similar study conducted in New York City, which found that although most teens noticed the calorie information on menus after such a policy was adopted, only 9% said they considered the information when choosing their food.

As part of the baseline phase of a study to evaluate the new federal regulation, Block and his colleagues surveyed adolescents at fast food restaurants in Boston, Springfield, Mass., Providence, R.I., and Hartford, Conn.

In each city, the researchers visited 10 restaurants three times each, for a total of 120 visits during the study. The chains included McDonald's, Burger King, Subway, Dunkin' Donuts, and Wendy's.

Overall, 36% of the 547 individuals approached agreed to participate in the study. Their mean age was 16 and they were ethnically diverse -- 16% white, 36% black, 28% Hispanic, 6% Asian, and 14% other or multiracial. Based on self-reported height and weight, 26% were overweight or obese, which Block acknowledged seemed low.

The researchers collected the participants' receipts to calculate the calorie content of their meal and administered a short survey on the awareness and use of nutritional information in the restaurant, as well as on the estimated calorie content of the food purchased.

The average actual calorie content of the meals was 746, with 28% of the participants purchasing 1,000 calories or more.

The average estimated calorie content, however, was only 464. The underestimation was consistent across restaurant chains.

A greater actual calorie count was associated exponentially with a greater underestimate on the part of the participants. Those who consumed 1,000 calories, for example, underestimated their meal by an average of 350 calories. For those who consumed 1,500 calories, the estimate was short by 700 calories.

The researchers also asked the participants to estimate how many calories are needed each day to maintain a healthy diet. According to lenient standards, 68% of them were accurate (1,000 to 3,000 calories), 23% underestimated, and 9% overestimated.

Those who underestimated the daily requirement underestimated their meal content by 28% compared with those who were accurate.

On the flip side, those who overestimated the daily requirement overestimated the calorie count by 39%.

These findings, Block said, support the use of an anchoring statement on menus, which, according to federal law, will tell customers that the recommended daily intake is 2,000 calories.

The study "suggests that perhaps this might be a promising, helpful thing for people to put into context the calorie content of meals," Block said.

He noted some limitations of the analysis, including the low response rate and the inability to measure the actual consumption of food. The researchers also were not able to randomly select participants or to sample customers at the drive-thru window.

[Chevychelov]

OBESITY: Sleep Apnea Cut With Weight-Loss Program

By Todd Neale, Senior Staff Writer,
October 06, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that patients with obesity and type 2 diabetes participating in a sleep substudy lost significantly more weight with an intensive lifestyle intervention program than those in the control group and also significantly reduced their apnea-hypopnea index.


Note that improved apnea-hypopnea index tracked with the amount of weight lost but still remained significantly improved for the lifestyle intervention group compared with controls at four years despite gaining back about half the weight lost in the first year.
Review

ORLANDO -- An intensive lifestyle intervention to get obese patients with type 2 diabetes to lose weight had long-lasting effects on obstructive sleep apnea as well, according to results from an ancillary study to the Look AHEAD trial.

Through four years, patients undergoing the intensive intervention maintained about a four-point reduction in apnea-hypopnea index, compared with a sustained four-point increase in the control group, according to Gary Foster, PhD, of Temple University in Philadelphia.

Patients with the most severe obstructive sleep apnea at baseline had the largest gains through four years (P<0.0001), he reported at the Obesity Society meeting here.

Foster noted, however, that with a mean apnea-hypopnea index of 20.5 -- indicating moderate obstructive sleep apnea -- at baseline among the patients, the reductions seen over the course of the study would not, on average, be enough to replace other treatments.

"I don't want to give you the impression that this is an alternative treatment to [continuous positive airway pressure]," he said. "It's probably a complementary treatment."

The findings came from Sleep AHEAD, an ancillary study of the Look AHEAD trial, which compared an intensive lifestyle intervention with diabetes support and education for weight loss in obese patients with type 2 diabetes.

The sleep study was designed to evaluate whether weight loss would be associated with improvements in sleep-disordered breathing, which had been demonstrated in observational studies and smaller randomized trials.

Participants in Look AHEAD were screened with a questionnaire designed to identify patients at increased risk for obstructive sleep apnea. The researchers excluded patients currently being treated for the condition or who had undergone surgery for it, but included those with untreated obstructive sleep apnea.

All 305 patients selected for the sleep study underwent overnight polysomnograms at home. Those with an apnea-hypopnea index of less than 5 were considered free from obstructive sleep apnea. Scores of 5 to less than 15 were considered mild, 15 to less than 30 moderate, and 30 or more severe.

The mean score was 20.5. Only 13.4% of the patients did not have obstructive sleep apnea. Another 33.5%, 30.5%, and 22.6% had mild, moderate, and severe symptoms, respectively.

After one year, patients undergoing the intensive lifestyle intervention lost an average of 24 pounds, whereas those in the control group had no weight loss (P<0.0001).

At the same time, patients in the intervention group had about a six-point reduction in apnea-hypopnea index, compared with a four-point increase in the controls (P<0.0001).

Through four years, patients in the intervention group gained back about half of the weight that was lost, although they sustained a four-point reduction in apnea-hypopnea index. The controls sustained a four-point increase in the index.

At four years, a greater percentage of patients in the intervention group improved their obstructive sleep apnea category from baseline (about 40% versus 15%) and had a remission of apnea symptoms (20% versus 3%).

Although the change in apnea-hypopnea index was significantly related to the weight change, there was still a significant reduction in symptoms even after the change in weight was accounted for (P=0.001).

That indicates that the intervention had an effect on obstructive sleep apnea that was separate from the weight loss, Foster said.

"The likely hero, I think, is fitness," he said, noting that another study has shown that even in the absence of weight loss, changes in fitness can drive changes in apnea-hypopnea index.

[Chevychelov]

OBESITY: CVD Risk Cut With Rejected Weight-Loss Drug

By Todd Neale, Senior Staff Writer,
October 06, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Note that this study demonstrates that weight loss with combination naltrexone/bupropion was associated with improved 10-year risk for overall CV disease, CHD, MI, and CHF as measured by published risk equations.


Point out that confirmation that reduced CV risk is actually associated with improved outcomes will require a prospective trial.
Review
ORLANDO -- It appears that the investigational weight-loss combination of naltrexone standard release and bupropion standard release (Contrave) reduces the predicted 10-year risk of cardiovascular events, an analysis of four phase III trials showed.

Using an average of six major risk prediction models, one year of treatment with the combination in low-risk overweight and obese patients reduced the absolute 10-year risk of cardiovascular events by 0.17%, compared with a reduction of 0.05% with placebo (P<0.05), according to Robert Chilton, DO, of the University of Texas Health Science Center at San Antonio.

Significant reductions were also seen with the combination in the predicted 10-year risk of coronary heart disease, MI, and congestive heart failure relative to placebo (P<0.01 for all), he reported at the Obesity Society meeting here.


The findings, he said, provide confidence that the drug combination will show a benefit in an upcoming cardiovascular outcomes trial.

Naltrexone/bupropion has been shown in randomized trials to be effective in getting overweight and obese patients to lose weight compared with placebo.

The FDA, however, went against the recommendations of one of its advisory committees and did not approve the combination because of concerns about increases in blood pressure in patients taking the active treatment.

The agency told the maker of the drug, Orexigen, that it would need to conduct a cardiovascular outcomes trial to ease doubts about safety before the drug could be approved.

Initially, Orexigen was hesitant to conduct such a trial and said it would no longer seek approval for the combination in the U.S., saying the requested trial "is unprecedented and would generate significantly more information than is necessary or feasible."

The company continued meeting with the FDA, however, and said in a Sept. 20 statement that the design requirements for a cardiovascular outcomes trial "are reasonable and feasible and provide the certainty required to reinitiate development of Contrave."

The proposed trial would enroll a population of overweight and obese individuals with an estimated annual risk of major cardiovascular events of 1 to 1.5%.

According to Orexigen, the FDA said that the drug could be approved if an interim analysis of the trial excludes any unacceptable cardiovascular risk.

"Both FDA and Orexigen estimate that such a study would require approximately 87 total events by the interim analysis to enable resubmission of the New Drug Application for approval," according to a statement from the company. "Orexigen estimates that the entire study would require fewer than 10,000 patients and less than two years from study start to the interim analysis."

The trial is expected to start in the first half of 2012.

According to Chilton, he and his colleagues planned to look at the effect of treatment with naltrexone/bupropion on the predicted 10-year risk of cardiovascular events even before the company submitted data to the FDA for consideration.

The analysis reported at the meeting pooled data on 3,363 patients who participated in the phase III Contrave Obesity Research program, which included four randomized, placebo-controlled trials lasting 56 weeks. Patients on active treatment received 32 mg naltrexone SR/360 mg bupropion SR.

The researchers estimated the change in 10-year risk of cardiovascular events after one year of treatment using six established risk prediction tools -- the Framingham, Fremantle, QRisk2, Reynolds, SCORE, and U.K. Prospective Diabetes Study scores.

The patient population had a low cardiovascular risk at baseline. The mean age was about 46, the mean body mass index was 36 kg/m2, and 12 to 13% had type 2 diabetes.

Averaging the six risk scores together, the predicted 10-year cardiovascular risk at baseline was 5.8% in the drug group and 5.6% in the placebo group.

As seen previously, there was significantly greater weight loss in the active treatment group after one year (7% versus 2.3%, P<0.001).

Using all six of the risk scores, the predicted 10-year risk of cardiovascular disease events dropped to a greater extent with active treatment than with placebo after one year in the overall population, as well as in patients with type 2 diabetes and those without the disease.

There was no significant effect on the predicted risk of ischemic heart disease, cardiovascular mortality, or stroke.

Chilton said that the findings suggest that a cardiovascular outcomes trial will show that the drug combination is safe.

"In a year, we do show risk benefits for cardiovascular reduction in events, so the drug would be something worthwhile," he said, adding that he would prefer having his patients lose weight without drugs.

"Weight loss is very important. If you can do it without the drug, that'd be better yet, but if you need a crutch for a short time this is not a bad option and these are drugs [naltrexone and bupropion] that are both well known," he said. "But I think long term you still need to make a new plan in life and change your entire lifestyle."

Although he did not address the naltrexone/bupropion combination specifically, Jonathan Purnell, MD, an endocrinologist at Oregon Health & Science University in Portland, said that the recent rejections of three investigational weight-loss drugs -- including topiramate/phentermine (Qnexa) and lorcaserin (Lorqess) -- is "very discouraging."

"We lack tools to effectively help people maintain weight loss, even if we have the time and the resources to talk about lifestyle, and we know that lifestyle alone has a very modest impact on sustained weight loss," said Purnell, a spokesman for the Obesity Society.

"Lacking very effective tools -- and a lot of the studies show that these drugs are effective -- is very frustrating for both us as clinicians as well as patients."

[Chevychelov]

FDA Okays Combo Pill for Diabetes, Cholesterol
The FDA has approved a fixed-dose combination tablet that combines the diabetes drug sitagliptin with simvastatin, under the brand name Juvisync.
[Ссылки могут видеть только зарегистрированные и активированные пользователи]

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Higher HDL Lowers Cardiovascular Risk in Type 2 Diabetes

By Charles Bankhead, Staff Writer,
October 07, 2011

Today Action Points
Explain that a study found that patients with type 2 diabetes who had higher baseline HDL levels or increased HDL from baseline by whatever means had a lower risk of hospitalization for cardiovascular disease than those with lower HDL levels.


Note that while an observational study cannot prove causality, type 2 diabetics whose HDL decreased by ≥6.5 mg/dL showed a significantly increased risk of hospitalization for cardiovascular disease.
Review
Higher HDL levels in patients with type 2 diabetes significantly reduced the odds of hospitalization related to cardiovascular disease, data from a large cohort study showed.

Every 5 mg/dL increase in baseline HDL was associated with a 6% reduction in the CVD hospitalization risk. During a mean follow-up of 55.8 months, each 5 mg/dL increase in HDL was associated with a 4% lower risk.

A categorical analysis centered on a baseline HDL showed that a ≥6.5 mg/dL decrease was associated with an 11% increase in CVD risk, whereas a ≥6.5 mg/dL increase reduced the CVD hazard by 8%, as compared with individuals who remained within 6.4 mg/dL of baseline values.


"Our results add to the growing body of evidence that increasing the HDL cholesterol levels might be an important strategy for CVD risk reduction," Gregory A. Nichols, PhD, of Kaiser Permanente Center for Health Research in Portland, Ore., and co-authors wrote in an article published online in the American Journal of Cardiology.

"The prevention of HDL cholesterol decreases could be equally important," they said.

Patients with type 2 diabetes have a substantially elevated risk of CVD, with estimates ranging as high as 87% greater compared with nondiabetic adults. Reduction of LDL cholesterol remains the focus of lipid management to reduce CVD risk.

However, clinical trials of intensive LDL-lowering with statin drugs have shown that at least 10% of patients have major CVD events, the authors noted in their introduction.

Glycemic control remains the focus of diabetes management, although intensive hypoglycemic treatment has failed to reduce CVD risk in type 2 diabetics, they continued. The findings suggest that treatment targets other than LDL and hemoglobin A1c deserve consideration.

HDL cholesterol offers one potential target for CVD risk reduction in patients with type 2 diabetes. About half of diabetic patients have low HDL levels, an observation that has generated speculation that raising HDL levels might substantially reduce CVD risk in that patient population.

Clinical studies have yet to produce clear evidence that increasing HDL levels will reduce CVD risk in type 2 diabetes, possibly because of the lack of safe and effective agents, the authors continued.

Attempts to use drugs to raise HDL have generally been unsuccessful. Several trials of HDL-raising drugs have been stopped because of an increase in cardiovascular events and mortality including ILLUMINATE and AIM-HIGH.

The search continues, however, for a safe HDL-raising drug. Researchers reported at this year's European Society of Cardiology meeting positive results for such a drug in the phase IIb dal-VESSEL trial, and the DEFINE trial, reported at last year's American Heart Association meeting, showed good results for anacetrapib in terms of safety and efficacy.

In addition, the FDA on Oct. 7 approved Juvisync (sitagliptin and simvastatin), the first combination drug to treat type 2 diabetes and high cholesterol in one tablet.

In an effort to inform on the association between HDL level and CVD risk in type 2 diabetes, Nichols and colleagues performed a retrospective cohort study of 30,067 members of the Kaiser Permanente Northwest and Georgia regions. All patients had type 2 diabetes and had at least two HDL cholesterol measurements during 2001 to 2006.

Investigators analyzed clinical data on the patients through 2009 to determine whether change in HDL cholesterol influenced subsequent risk of CVD-related hospitalization. They examined HDL cholesterol continuously and by three categories: HDL increase ≥6.5 mg/dL from baseline, decrease ≥6.5 mg/dL, and no increase or decrease >6.4 mg/dL.

During follow-up, 61% of the patients had HDL levels that remained within 6.4 mg/dL of baseline values, 21.6% had ≥6.5 mg/dL increases in HDL, and 17% had ≥6.5 mg/dL decreases.

The authors found that 3,023 (10.1%) patients had CVD-related hospitalizations during the follow-up period. After multivariate adjustment, they found that every 5 mg/dL greater baseline HDL level was associated with a statistically significant 6% reduction in the hazard for CVD hospitalization (P<0.0001), and each 5 mg/dL increase from baseline was associated with a 4% reduction in CVD risk (P<0.003).

The categorical analysis showed that every 6.5 mg/dL increase in HDL during follow-up was associated with an 8% reduction in CVD risk, which did not achieve statistical significance (P=0.077). However, each 6.5% or greater decrease in HDL was associated with a significant 11% increase in the CVD hospitalization hazard (P=0.047).

Acknowledging the study's limitations, the authors wrote that an observational study cannot prove causality. They also noted that they could not determine the reasons for changes in HDL levels or whether the changes were maintained throughout the follow-up period.

In addition, 24% of patients with type 2 diabetes could not be included in the study because they did not have two HDL measurements.

"Despite these limitations, we have concluded that the changes in HDL cholesterol are associated with changes in the risk of CVD hospitalizations," the authors wrote in conclusion. "Additional study is needed to understand the role of improving HDL cholesterol in a multifactorial prevention strategy."

[Chevychelov]

OBESITY: No-Cal Drinks Yield Bigger Weight Loss

By Todd Neale, Senior Staff Writer,

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Point out that in this study, obese patients who replaced caloric beverages with water or diet beverages were more likely than controls to achieve a clinically meaningful weight loss at six months.
Review

ORLANDO -- Replacing calorie-laden beverages with water or diet drinks may be effective at shedding weight and improving other cardiometabolic parameters in the short term, a randomized trial showed.

In the three-arm trial, there were no significant between-group differences in the percentage of weight lost over six months, but participants in the combined substitution groups were significantly more likely to lose at least 5% of their body weight (OR 2.1, P<0.05) than those who were told only to make healthy dietary choices (the control group), according to Deborah Tate, PhD, of the University of North Carolina's Gillings School of Global Public Health in Chapel Hill.

Participants in the substitution groups were told to replace at least two caloric drinks a day with either water or diet beverages.

Those in the water group had significantly greater improvements in systolic blood pressure and fasting glucose compared with the controls (P<0.05 for both), Tate reported at the Obesity Society meeting here.

"Replacing caloric beverages with noncaloric alternatives, without intensive monitoring of other diet and physical activity, resulted in small but significant weight changes that may be substantial if applied at a population level," Tate said.

Data from the National Health and Nutrition Examination Survey (NHANES) have shown that about 60% of adults report drinking sugar-sweetened beverages, and that adults consume an average of 300 calories per day from such drinks.

To see whether substituting noncaloric alternatives for caloric drinks could make a difference in weight loss, Tate and colleagues conducted the CHOICE (Choose Healthy Options Consciously Everyday) study.

Participants were overweight or obese (body mass index 25 to less than 50 kg/m2) and ages 18 to 65 (mean 42). To enter the study, they had to report consuming at least 280 calories per day from caloric beverages at baseline, not counting unsweetened milk.

The researchers randomized 315 people -- 105 in the control group, 104 in the diet beverage group, and 106 in the water group.

All three groups attended a monthly group session. The control group received information on making healthy dietary and lifestyle choices, but no guidance was given regarding drinks.

The focus of the sessions in the two substitution groups was on replacing at least 200 calories per day from drinks as a means to lose weight. The participants received handouts covering the information that was being discussed in the sessions with the control group. The researchers provided monthly supplies of either bottled water or diet beverages of the participants' choosing.

Through six months, participants in the diet beverage group cut an average of 218 drink calories per day, those in the water group cut an average of 148, and those in the control group cut an average of 86. The differences between the substitution groups and the control group were both significant (P<0.05).

Food intake decreased slightly in all three groups.

Looking at the substitution groups individually, only the participants in the diet beverage group were more likely to lose 5% or more of their body weight (OR 2.3, P<0.05). That is likely the result of better adherence to drink replacement compared with the water group, Tate said.

Blood pressure, fasting glucose, and hydration improved in both substitution groups, although the only significant differences versus the control group were in the water group -- for systolic blood pressure and fasting glucose.

Tate acknowledged that the study was limited by the predominantly female patient population (85%), the use of self-reported measures of diet, and the short duration.

[Chevychelov]

OBESITY: Girls Happy With Their Bodies Don't Binge Eat

By Todd Neale, Senior Staff Writer,
October 07, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that among overweight adolescent girls, those who are more satisfied with their bodies appear to be less likely to develop binge eating disorder.


Note that girls who were satisfied with their bodies gained significantly less body mass than their less-satisfied peers.
Review
ORLANDO -- Among overweight adolescent girls, those who are more satisfied with their bodies appear to be less likely to develop binge eating disorder, researchers found.

Through 11 years of follow-up, girls who said they were pretty much, a lot, or totally satisfied with their bodies had 61% lower odds of meeting criteria for the eating disorder compared with those who were only a little or not at all satisfied (OR 0.39, 95% CI 0.24 to 0.64), according to Kendrin Sonneville, ScD, RD, of Children's Hospital Boston.

They also gained significantly less body mass (0.1 kg/m2 less per year), Sonneville reported at the Obesity Society meeting here.


"This study builds on the existing literature that recognizes body dissatisfaction as a risk factor for negative outcomes during adolescence," she said. "Body satisfaction may be a salient target for both obesity and eating disorder prevention."

Dissatisfaction with one's body -- which is common and even normative in adolescent girls, according to Sonneville -- has been associated with various adverse outcomes, including disordered eating, low self-esteem, and depressive symptoms. Rates of dissatisfaction are particularly high among girls who are overweight or obese.

Body satisfaction, on the other hand, has been associated with fewer unhealthy weight control behaviors and higher levels of physical activity. It also has been tied to less weight gain among overweight and obese adolescent girls, who, nevertheless, are more likely to report binge eating.

To explore the relationship between body satisfaction and binge eating disorder, Sonneville and her colleagues examined data from the Growing Up Today Study (GUTS), an ongoing study of the offspring of women in the Nurses Health Study II. All GUTS participants were 9 to 15 years old when the study began in 1996.

The current analysis included 1,559 girls from the 1996 to 2007 waves of GUTS who were overweight or obese at baseline. Their mean age was 11.8 and the mean BMI was 23.7 kg/m2.

Body satisfaction was assessed using a single question: "In the past year, how happy have you been with the way your body looks?"

Answers ranged from not at all to totally. The 57.2% answering pretty much, a lot, or totally were considered to be satisfied with their bodies.

Binge eating disorder was defined as at least weekly binges that involved eating an amount of food that the girl would be embarrassed about if someone saw her eating it, accompanied by a feeling of being out of control. Overall, 1.7% of girls had the disorder at baseline and were excluded from further analysis.

During the 11-year follow-up, the mean BMI change was 5.1 kg/m2.

About one in every 10 girls (9.5%) met criteria for binge eating disorder at least once during follow-up.

After adjustment for age, BMI, TV viewing, and maternal overweight or obesity, girls who were satisfied with their bodies gained less weight and were less likely to develop binge eating disorder during follow-up compared with their less satisfied peers.

The level of satisfaction seemed to matter, as the attenuation of the BMI increase and the reduction in the odds of developing binge eating disorder were greater as satisfaction increased (P<0.05 for both trends).

For example, girls who were a lot or totally satisfied with their bodies gained 0.13 fewer BMI units than those who were not at all satisfied, and were 85% less likely to develop binge eating disorder (OR 0.15, 95% CI 0.06 to 0.37).

Sonneville acknowledged some limitations, including the use of self-reported data, the measurement of body satisfaction using a single question, and the lack of racial/ethnic diversity in the sample (94% of participants were white).

[Chevychelov]

FDA approves combination sitagliptin, simvastatin
By

The FDA today announced approval of a fixed-dose combination therapy containing sitagliptin and simvastatin for the treatment of adults with type 2 diabetes and high cholesterol.

“This is the first product to combine a type 2 diabetes drug with a cholesterol-lowering drug in one tablet,” Mary H. Park, MD, director of the division of metabolism and endocrinology products in the FDA Center for Drug Evaluation and Research, said in a press release. “However, to ensure safe and effective use of this product, tablets containing different doses of sitagliptin and simvastatin in fixed-dose combination have been developed to meet the different needs of individual patients. Dose selection should factor in what other drugs the patient is taking.”

The combination tablet (Juvisync; Merck) was approved in sitagliptin/simvastatin dosage strengths of 100 mg/10 mg, 100 mg/20 mg and 100 mg/40 mg. According to the FDA, treatment should only be prescribed when patients require treatment with both sitagliptin (Januvia, Merck) and simvastatin (Zocor, Merck).
__________________________________________________ _______________________

MRI deemed safe for patients with selected implanted cardiac devices

Nazarian S. Ann Intern Med. 2011;155:415-424.
Reynolds MR. Ann Intern Med. 2011;155:470-472.
By

MRI can be performed safely in patients with selected pacemaker and implantable cardioverter defibrillators when using device selection and programming protocol, new data suggest.

Patients with clinical indication for MRI and an implantable device were enrolled in a study between February 2003 and April 2010. Researchers enrolled 438 patients (54% had a pacemaker; 46% had ICDs) who underwent 555 MRI examinations. Most MRIs were of the brain, 22% of the spine, 16% of the heart, 13% of the abdomen or pelvis and 9% of an extremity.

Immediately after MRI, right ventricular sensing (median change, 0 mV), and atrial (median change, –2 Ù) and right (median change, –4 Ù) and left (–11 Ù) ventricular lead impedances were reduced, according to researchers. At long-term follow-up, 61% of patients had decreased right ventricular sensing (median, 0 mV), right ventricular lead impedance (median, –3 Ù), battery voltage (median, –0.01 V) and increased right ventricular capture threshold (median, 0 V).

Three patients had their device reverted to a transient backup programming mode, with no long-term effects. According to the researchers, this was the “primary clinically significant event attributable to MRI.”

They concluded that “MRI was performed safely in all patients.” However, image distortion, signal voids or bright areas, and poor fat suppression were noted when the device was located in the MRI field of view. “Given the potential for changes in device variables and programming, monitoring by device experts is necessary,” they wrote.

The researchers said patients were selected and treated based on previous safety studies. Only patients with pacemakers manufactured after 1998 and defibrillators manufactured after 2000 were enrolled, and researchers followed programming and monitoring protocol.

“The risks and benefits of MRI in a patient with a cardiac rhythm management device should be assessed on an individualized basis, as with any important medical decision,” Matthew R. Reynolds, MD, MSc, and Peter Zimetbaum, MD, of the division of cardiology, Beth Israel Deaconess Medical Center, wrote in an accompanying editorial. “The authors have not demonstrated that MRI in these patients is risk-free, only that the risks are quantitatively small. Therefore, before permitting a patient to have MRI, the potential benefits of the MRI relative to alternative diagnostic strategies should be established.
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600-mg loading dose of clopidogrel reduced infarct size in STEMI patients

Patti G. J Am Coll Cardiol. 2011;58:1592-1599.
By

A reduction of infarct size and improvement of angiographic results, residual cardiac function and 30-day major adverse CV events were associated with pretreatment with a 600-mg loading dose of clopidogrel vs. a 300-mg loading dose before primary percutaneous coronary intervention in STEMI patients, according to an analysis of the ARMYDA-6 MI study.

Patients with STEMI undergoing primary PCI were enrolled in the study. Researchers randomly assigned a 600-mg or 300-mg loading dose of clopidogrel to patients before the procedure. The primary endpoint was defined as the evaluation of infarct size, and secondary endpoints were the prevalence of thrombolysis in MI flow grade of more than 1 before PCI and less than 3 after PCI; left ventricular ejection fraction by transthoracic echocardiography at discharge; incidence of major adverse CV events at 30 days; and occurrence of bleeding or entry site complications.

Overall, the primary endpoint concluded that infarct size was lower in patients assigned to the 600-mg dose. Looking at secondary endpoints, TIMI flow grade of more than 1 at diagnostic coronary angiography before PCI was found in 21.4% of patients in the 600-mg arm vs. 12.2% in the 300-mg arm, whereas a lower incidence of TIMI flow grade of less than 3 was associated with the 600-mg dose (P=.031). Study results showed that LVEF early after PCI was similar in the two arms (P=.42), but was higher in the 600-mg dose at discharge (P=.026). The 600-mg group also had a reduced incidence of 30-day major adverse CV events vs. the 300-mg group (P=.049).

Researchers also found that symptom-to-balloon (P=.86) time and clopidogrel load-to-balloon time (P=.45) were similar in the two arms.

The results are somewhat limited by a small sample, but having said that, they are significant. Furthermore while 600 mg improved non fatal outcomes, the important fact was the benefit was achieved without an increase in bleeding or other measured side effect. Furthermore, there appears to be a finite number of receptors bound by a P2Y12 inhibiter so increasing the dosage improves the possibility of achieving an important therapeutic level early while not paying a price for the higher loading dose.

[Chevychelov]

Statins Protect Brain in Head Trauma

By Crystal Phend, Senior Staff Writer, October 11, 2011

Action Points
Explain that seniors on a statin at the time of moderate-to-severe head trauma were 76% less likely to die in hospital although the study could not imply a direct causal effect of statins.

Note that statin users were 13% more likely to have made a good functional recovery by 12 months.
Review
Statins may make traumatic brain injury much more survivable for older adults, a national study suggested.

Seniors on a statin at the time of moderate-to-severe head trauma were 76% less likely to die in hospital (relative risk 0.24, 95% confidence interval 0.08 to 0.69), Eric B. Schneider, PhD, of Johns Hopkins, and colleagues found.

Statin users were also 13% more likely to have made a good functional recovery by 12 months (RR 1.13, 95% CI 1.01 to 1.26), the group reported in the October issue of the Journal of Trauma.

Although cardiovascular comorbidities appeared to eliminate any protective advantage, statins warrant further study as possible protective agents to be given when patients of any age present with head trauma, the researchers suggested.


After the damage from direct impact or acceleration and deceleration of the brain, secondary injury occurs from inflammatory and immune processes, the group explained.

Statins' pleiotropic effects on inflammation, thrombosis, and endothelial function may help prevent that secondary injury, although their primary role in lowering cholesterol likely has little impact, Schneider and colleagues suggested.

Animal studies have suggested a protective effect even when statins are started soon after brain injury.

"Right now there really isn't anything that can be prescribed to help people with a serious brain injury, and this is a glimmer of hope," Schneider told MedPage Today in an interview.

However, he recommended against administering the drugs for traumatic brain injury until further confirmation of benefit and safety.

Schneider's group examined outcomes through the National Study of Costs and Outcomes of Trauma database, which receives reports from 69 U.S. hospitals.

They excluded deaths within 24 hours of hospitalization and cases admitted with fixed dilated pupils indicating likely nonsurvivable injury that statins wouldn't reasonably be expected to affect. The cohort was also limited to the age group more likely to be taking statins.

Among the 523 individuals in the database 65 and older with a head injury and Abbreviated Injury Score of at least 3, statin use at the time of injury was recorded for 22%.

Death before discharge occurred among 9.1% of statin users as compared with 15.4% of nonstatin users (P=0.047), an advantage that remained significant at 76% after adjustment for other factors remained.

At three months, statin users were a nonsignificant 23% more likely to have made a good functional recovery (RR 0.77, 95% CI 0.42 to 1.41).

Although the 13% advantage at 12 months was statistically significant overall, it wasn't among statin users who had cardiovascular comorbidities (RR 1.11, 95% CI 0.82 to 1.50).

For inhospital mortality, the same pattern emerged, with a significant benefit only among those without cardiovascular comorbidities (RR 0.17, 95% CI 0.05 to 0.63).

"If statin-induced peri-injury endothelial homeostasis in fact underlies the improved outcomes seen in this and other studies, we suspect that statins may not benefit head trauma victims with significantly compromised endothelium (e.g., cardiovascular disease)," Schneider's group wrote in the paper.

They cautioned that the observational study could not imply a direct causal effect of statins, as the results could have been confounded by a "healthy user bias."

Another limitation was the lack of data on statin type, indication, dose, or duration of treatment, the group added.

[Chevychelov]

Heart Rate in Afib No Guarantee for Quality of Life

By Crystal Phend, Senior Staff Writer,
Published: October 11, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Explain that a study randomizing patients with permanent atrial fibrillation to lenient or strict rate control did not result in differences in perceived quality of life between the groups.

Note that many patients were not symptomatic at baseline in either group and that quality of life was determined by answers to a questionnaire.

Stricter rate control for patients with permanent atrial fibrillation doesn't improve quality of life, a clinical trial showed.

More lenient control to a resting heart rate under 110 beats per minute showed no difference on any quality-of-life measure compared with strict control to less than 80 bpm, Isabelle C. Van Gelder, MD, of the University Medical Center Groningen, the Netherlands, and colleagues found.

Factors that did matter for well-being were symptoms, sex, age, and underlying disease severity, they reported in the Oct. 18 issue of the Journal of the American College of Cardiology.

These substudy results from the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) trial add to the primary endpoint showing no advantage to strict control for adverse outcomes.

Those findings go against common clinical assumptions, noted Paul Dorian, MD, MSc, of St. Michael's Hospital, and Andrew C.T. Ha, MD, of Toronto General Hospital, both in Toronto.

"For example, many physicians may assume that a rapid and irregular heart rate is undesirable, and implicitly subjectively undesirable, compared with a slower, more well-controlled rate," they wrote in an accompanying editorial.

That this wasn't the case for the study population -- largely those with "long-standing and not terribly symptomatic atrial fibrillation" -- points to the need to individualize decisions to intensify rate control, Dorian and Ha argued.

"Clinicians need to be aware that patient personality, treatment expectations, and factors unrelated to the arrhythmia itself will have important, potentially determining influences on the extent to which atrial fibrillation causes suffering," they wrote.

The researchers agreed that different groups, such as highly symptomatic patients, might feel better with tighter rate control.

RACE II included 614 permanent atrial fibrillation patients randomized to rate control classified as lenient or strict based on a target of less than 110 bpm at rest versus less than 80 bpm or less than 110 bpm if exercising moderately.

The substudy included the 437 who completed quality-of-life questionnaires at baseline, one year, and at the end of study after a median of three years.

The prevalence of symptoms -- largely dyspnea, fatigue, and palpitations -- declined somewhat during follow-up to 48% from 58% at baseline, though without a difference between rate control groups.

Initial heart rate didn't predict quality of life at baseline, nor did change in quality-of-life correlate with heart rate.

The strict and lenient rate control groups came out similar for all quality of life measures at 12 months and at the end of the study on the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) questionnaire.

The atrial fibrillation severity scale and the Multidimensional Fatigue Inventory-20 likewise showed no differences between rate control strategies at any point and a lack of correlation with heart rate.

The lack of relative improvement with stricter control of heart rate may have reflected that patients were already at a relatively low symptom level at baseline and so had little room for improvement whatever the treatment strategy, the researchers noted.

Indeed one of the determinants of improvement on the SF-36 and atrial fibrillation severity scale was symptoms at baseline.

Other predictors of improvement on the SF-36 included absence of symptoms at the end of the study, higher left ventricular ejection fraction, younger age, and a thinner septum, and younger age alone for the atrial fibrillation severity scale.

Possible explanations for the findings also may have been that symptoms driven more by underlying heart disease or by ventricular irregularity weren't impacted by degree of rate control or that the higher doses of rate control drugs in the strict control group actually adversely affected quality of life.

Van Gelder's group cautioned that the results could not be generalized to patients without permanent atrial fibrillation or who are highly symptomatic.

Other limitations were that strategies to achieve heart rate targets differed between groups and the quality of life questionnaires may not have been sensitive enough, they added.

[Chevychelov]

Diabetes Drug May Have Plaque Benefit


This report is part of a 12-month Clinical Context series.By Todd Neale, Senior Staff Writer, MedPage Today
Published: October 12, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
for reading medical news

Pioglitazone (Actos) may reduce atherosclerotic plaque inflammation, independent of its glucose-lowering effects, a small randomized trial showed.

In patients with impaired glucose tolerance or type 2 diabetes accompanied by carotid atherosclerosis, pioglitazone and glimepiride reduced fasting plasma glucose to a similar extent after four months of treatment, according to Nobuhiro Tahara, MD, PhD, of Kurume University in Japan, and colleagues.

But only pioglitazone reduced atherosclerotic plaque inflammation (P<0.01), as assessed with serial 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, the researchers reported in the October issue of JACC: Cardiovascular Action Points
Explain that pioglitazone (Actos) may reduce atherosclerotic plaque inflammation, independent of its glucose-lowering effects.

Note that the sole independent predictor of a reduction in inflammation was an increase in HDL cholesterol level, which occurred with pioglitazone, but not glimepiride.
Imaging.Action Points
Explain that pioglitazone (Actos) may reduce atherosclerotic plaque inflammation, independent of its glucose-lowering effects.


Note that the sole independent predictor of a reduction in inflammation was an increase in HDL cholesterol level, which occurred with pioglitazone, but not glimepiride.


The sole independent predictor of a reduction in inflammation was an increase in high-density lipid (HDL) cholesterol level, which occurred with pioglitazone, but not glimepiride.

"These findings suggest that HDL-cholesterol-increasing effects of pioglitazone could mainly be involved in the suppression of atherosclerotic plaque inflammation in our patients," Tahara and colleagues wrote, adding that they could not exclude the possibility of some other mechanism.

They noted that previous studies, including AIM-HIGH, have failed to show any benefit from raising HDL cholesterol levels on hard cardiovascular events.

In an accompanying editorial, Ahmed Tawakol, MD, of Massachusetts General Hospital in Boston, and Aloke Finn, MD, of Emory University in Atlanta, added that "it is important to note that it remains unclear whether lowering plaque inflammation is the mechanism by which statins and pioglitazone therapy decrease cardiovascular events or even whether, in general, reductions in inflammation would translate into clinical benefit."

Pioglitazone has been shown to be better than glimepiride for preventing the progression of atherosclerosis in patients with diabetes, and the PROactive trial suggested that the drug might have a plaque-stabilizing effect. But there are no data on whether any specific oral hypoglycemic agent is preferred for preventing atherosclerotic plaque inflammation.

To compare pioglitazone and glimepiride (Amaryl), Tahara and colleagues recruited 52 patients with impaired glucose tolerance or type 2 diabetes. All also had evidence of carotid atherosclerosis.

The patients were randomized to 15 mg to 30 mg of pioglitazone or 0.5 mg to 4 mg of glimepiride for four months, with titration of the doses to maintain a fasting plasma glucose of 110 mg/dL or lower.

Plaque inflammation was measured at baseline and at the completion of the study using FDG-PET. Scans were done on the carotid arteries and the ascending aorta of the aortic arch because those areas are associated with atherothrombotic stroke, according to the researchers.

At baseline, there was no between-group difference in the target-to-background ratio, which is a measure of plaque inflammation.

After four months, both pioglitazone and glimepiride reduced fasting plasma glucose and hemoglobin A1c similarly.

Pioglitazone increased weight and waist circumference and decreased high-sensitivity C-reactive protein (hs-CRP). Glimepiride increased hs-CRP.

There were no significant changes in blood pressure, fasting plasma insulin, low-density lipid cholesterol, or triglycerides in either group.

Pioglitazone significantly decreased atherosclerotic plaque inflammation according to FDG-PET, whereas glimepiride treatment resulted in a nonsignificant increase in inflammation.

Thus, the researchers wrote, "pioglitazone may be a promising strategy for the treatment of atherosclerotic plaque inflammation in impaired glucose tolerant or type 2 diabetic patients."

They acknowledged some limitations of the study, including the small sample size; the possibility of confounding by the use of nonstudy medications; the short duration; and the lack of statistical power to detect differences in cardiovascular endpoints.

The study was supported in part by a grant for the Academic Frontier Project from the Ministry of Education, Science, Sports, Culture, and Technology in Japan.

The study authors reported that they had no conflicts of interest.

Tawakol reported receiving research grants and/or consulting income from Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Roche, VBL Therapeutics, Siemens Medical Systems, and the NIH. Finn reported having sponsored research agreements with Medtronic and St. Jude Medical.

[Chevychelov]

CREST substudy: Carotid artery stenting associated with better quality of life

Cohen D. J Am Coll Cardiol. 2011;58:1557-1565.
By

Carotid artery stenting is associated with better health-related quality of life during the early recovery period of carotid revascularization vs. carotid endarterectomy, according to an analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial, or CREST.

Patients undergoing carotid revascularization were randomly assigned to either carotid artery stenting (CAS) or carotid endarterectomy (CEA) groups. Health-related quality of life was measured at baseline, 2 weeks, 1 month and 1 year by using standardized questionnaires and assessed using the Medical Outcomes Study Short-Form 36 (SF-36).

Between December 2000 and July 2008, there were 1,262 patients randomly assigned to CAS and 1,240 to CEA. SF-36 subscale scores were similar at baseline, but by 2 weeks, CAS patients had better scores vs. CEA patients (all P<.01). There were only three of eight subscales with better scores in the CAS group vs. CEA by the 1-month follow-up, and no differences for any SF-36 subscales at 1 year, according to researchers. At 1 year, worse health-related quality-of-life scores were reported in patients who had periprocedural stroke and periprocedural MI vs. patients who had no periprocedural events.

Less difficulty eating or swallowing, less difficulty driving and less impairment from headaches and neck pain, but more walking difficulty and more impairment from leg pain, were reported by CAS patients vs. CEA patients at 2 weeks. These results were similar by the 1-month follow-up. For ratings of overall pain, patients who had CAS and CEA had reported similar scores at baseline (P=.23), and by 2 weeks assessment, CAS patients reported lower pain score vs. CEA patients (P<.01). By 1-month (P=.16) and 12-month (P=.86) assessment, the difference was no longer present. The CAS group also reported less need for pain medication around the 2-week assessment (P<.01), but this difference was also no longer present by 1-month (P=.90) and 12-month (P=.57) evaluation.

“Finding that the choice between these two therapeutic options is a toss-up considering both clinical and quality-of-life outcomes means primarily that, for the clinician, whose primary role is to provide expert advice to the patient, there is no ‘wrong decision,’” Daniel B. Mark, MD, MPH, Manesh R. Patel, MD, and Kevin J. Anstrom, PhD, all of the Duke Clinical Research Institute and the division of cardiology at the Duke University School of Medicine in Durham, N.C., said in an accompanying editorial. “Neither risk can be completely avoided as both events occur after each procedure, but the incremental risks are too low to affect the expected quality-of-life results of either treatment.”

Disclosure: Dr. Cohen received research support from Boston Scientific, Abbott Vascular, Medtronic, Edwards Lifesciences, MedRad, Merck/Shering-Plough,and Eli Lilly-Daiichi Sankyo; is a consultant to Merck/Schering-Plough, Eli Lilly, Medtronic and Cordis; and has served on the speakers’ bureau for Eli Lilly and The Medicines Company. Dr. Mark reports no relevant financial disclosures.





David
Faxon


While carotid stenting patients had better initial quality of life measures by one year there was no difference. This is consistent with the SAPPHIRE trial and not surprising since recover is longer after surgery. It is reassuring since there was a small but significant difference in stroke rate in favor of carotid endarterectomy which might have lead to a lower QoL in the stenting group but this was not seen. It does mean that both techniques are equivalent. Quality of life is often more important to patients than adverse events so this type of study is important in assessing any treatment options.

[Chevychelov]

FDA Device Panel Gives Nod to New Stent for PAD

By Emily P. Walker, Washington Correspondent,
Reviewed by
October 13, 2011

Review

GAITHERSBURG, Md. -- An FDA advisory committee has voted 11-0 to endorse the first-ever drug-eluting stent for treatment of symptomatic peripheral arterial disease, agreeing unanimously that the Zilver PTX stent appears safe and effective.

The vote came at the end of Thursday's meeting of the FDA's Circulatory System Devices Advisory Committee. The FDA does not have to follow the advice of its advisory committees, but it often does.

If approved, the Zilver PTX stent, which was developed by Cook Medical, will be the first drug-eluting stent approved for treatment of peripheral artery disease (PAD), a condition that affects roughly 30 million people annually.

Current treatment options for PAD include percutaneous transluminal balloon angioplasty and bare metal stents, but both methods are associated with high rates of restenosis. About 50% of patients who have bare metal stents implanted in their leg arteries have to have another procedure after a year.

In Cook Medical's randomized clinical trial, 12-month restenosis rates were decreased by 50% in patients with a Zilver stent compared with those who received a bare metal stent.

The FDA panel spent Thursday discussing the company's two Zilver studies, which together included more than 1,000 patients.

The first study was a randomized, controlled trial that enrolled 479 patients and compared treatment of de novo or restenotic lesions of the femoropopliteal artery up to 140 mm in length using the Zilver PTX stent or percutaneous transluminal angioplasty (PTA).

At 12 months, 83% of the Zilver patients achieved primary efficacy versus just 33% of the PTA patients (P<0.01). Almost half of the controlled patients failed PTA on the initial attempt and were then randomized to either Zilver PTX or bare Zilver stents.

Adverse event rates -- including excess deaths, stent thrombosis, or stent fracture -- were about the same between the two groups after one year.

According to two-year follow-up data presented at the International Symposium on Endovascular Therapy last January, nearly 87% of the patients receiving the paclitaxel-eluting stent were still alive and had not needed amputation or another procedure after 24 months of follow-up, compared with just 78% of the patients treated with angioplasty alone who remained event-free (P<0.01).

The second study that the panel reviewed was a global registry of 787 patients treated with de novo or restenotic lesions of the femoropopliteal artery with no restriction on lesion length and was intended to answer the safety question. Patients from 50 centers in Europe, Canada, and Korea treated with the Zilver PTX stent were enrolled and followed for two years.

After one year, about 90% of the patients with the PTX stent had experienced no major adverse events.

Advisory panel chairman Clyde Yancy, MD, chief of cardiology at Northwestern University Feinberg School of Medicine in Chicago, called the new device "a technology that would not just benefit, but greatly benefit, these patients."

Cook Medical is asking the FDA to approve the stent to treat lesions no longer than 140 mm per limb for a total of 280 mm per patient.

"This is going to be a paradigm shift in how we treat the superficial femoral artery," Gary Ansel, MD, co-principal investigator in the Zilver PTX randomized trial, told MedPage Today after the meeting.

Ansel, who is the director of the Center for Critical Limb Care at Riverside Methodist Hospital in Columbus, Ohio, said if the FDA approves the device, endovascular specialists can provide their PAD patients with a treatment option that is less likely to require them to undergo another procedure one year out.

The panel discussed whether the device should be used in patients who can't tolerate antiplatelet therapy, because all patients in the trial took clopidogrel 24 hours prior to the procedure and for 60 days after the procedure. In addition, 90% of the patients in the trial took aspirin for one month to a year after the procedure.

However, panelists did not think being unable to tolerate clopidogrel should necessarily make a patient ineligible for the Zilver PTX.

The Zilver PTX stent is currently used in Asia, Europe, the Middle East/Africa, and South America for treatment of PAD.

[Chevychelov]

VA: Novel Ablation Catheter Tackles Persistent Afib

By Chris Kaiser, Cardiology Editor,
October 13, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


In this clinical trial subjects with persistent atrial fibrillation who were randomized to RF ablation were more likely to achieve a 90% reduction in episodes of atrial fibrillation than those on medical therapy.


Complications occured in 12.3% of subjects, including four periprocedural strokes. The trial was not designed to assess efficacy with respect to long-term stroke prevention.
Review
A radiofrequency ablation catheter system with a multi-electrode design was better at reducing atrial fibrillation (Afib) in patients with persistent or long-standing Afib compared with those on medical management, a randomized trial found.

Of the 138 patients randomized to ablation, 55.8% had an atrial fibrillation and atrial flutter burden reduction of greater than 90% and were free of antiarrhythmic drug therapy at six months, compared with 26.4% of the 72 patients in the medical management arm, according to a study presented at the Venice Arrhythmias 2011 conference this week in Venice, Italy.

The rate of seven-day acute procedural events in the ablation arm was 12.3%, "a rate comparable to other persistent Afib studies," reported Lucas Boersma, MD, PhD, from St. Antonius Ziekenhuis in the Netherlands, and colleagues.


The acute event rate had an upper 95% confidence interval of 19%, which did not meet the prespecified performance goal of 16%. However, the prespecified acute safety endpoint was established in 2006 and was based on patients with paroxysmal atrial fibrillation, John Hummel, MD, director of clinical electrophysiology research at the Ohio State Medical Center in Columbus and an investigator in the trial, told MedPage Today in an interview.

"The patients in this trial were much sicker and had more complex disease than those on whom we modeled our prespecified acute safety endpoint," Hummel said. He also noted that some of the acute events, such as urinary tract infection and pneumonia, had little to do with the catheter system.

"Patients with persistent or long-standing atrial fibrillation, especially those refractory to drug therapy, are particularly challenging, and this new technology holds promise as an option for them," Hummel said.

For the TTOP-AF trial (Tailored Treatment of Persistent Atrial Fibrillation), researchers enrolled 210 patients who were symptomatic and drug refractory. Patients came from 23 sites in the U.S. and one in the Netherlands.

Patients were randomized 2:1 to ablation or medical management. Follow-up was at one, three, and six months in both arms. At three months, those in the ablation arm could be sent for retreatment with ablation if needed. After four months, those in the medical arm could cross over to ablation if needed.

Researchers defined persistent atrial fibrillation as continuous Afib for more than seven days but less than one year, or Afib recurrence within seven days of direct current cardioversion.

They defined long-standing persistent atrial fibrillation as continuous Afib for more than a year but less than four years.

The protocol included the use of three investigational ablation catheters, each designed for specific anatomic targets: pulmonary vein, left atrial septum, and left atrial body. The catheters apply "linear lesions through multiple neighboring electrodes at the same time," Hummel said, as opposed to the conventional point-by-point ablative technique.

The acute safety endpoint involved the use of all three catheters, which included isolating the pulmonary vein, ablating the complex atrial fractionated electrograms, and having the patient in sinus rhythm.

There were no significant differences at baseline between the two arms of the study, including with CHADS2 score, ejection fraction, and number of failed antiarrhythmic drugs.

A total of 93% of patients in the ablation arm had acute success and 35% required retreatment at three months. In the medical arm, 83% received a therapeutic intervention, 78% underwent cardioversion, and 86% had a change in drug dose or type.

The primary effectiveness endpoint included acute safety, chronic safety, and chronic effectiveness. In the intention-to-treat analysis, 55.8% of the ablation patients met the primary effectiveness endpoint at six months versus 26.4% of those being medically managed. The difference was significant at P<0.0001.

"That's a huge difference and a welcome finding because these patients are among the more difficult patients to ablate," Hummel said.

Acute safety events in the ablation arm included four strokes, two cases ofcardiac tamponade, two pseudoaneurysms, and two cases of heart failure with one resulting in death. Hummel noted that the acute stroke rate of 2.7% in TTOP-AF is comparable to other studies.

Chronic safety events in the ablation arm included four asymptomatic pulmonary vein stenoses, one symptomatic pulmonary vein stenosis, one stroke, one persistent atrial septal defect secondary to septal puncture, and one pericardial effusion. The medically managed arm had two cases of gastrointestinal bleeding and one case of atrial fibrillation with rapid ventricular response.

There was "very little difference" in the number of chronic safety adverse events between the two arms when analyzed by cumulative follow-up per patient per month, Hummel said. The ablative arm had 1,243 cumulative follow-up months, whereas the medical arm had 420 months. The number of adverse events per patient per month was 0.008 versus 0.007.

"Prolonged duration atrial fibrillation is a more difficult condition to provide meaningful therapy [for] than patients with shorter episodes of atrial fibrillation," Bruce Wilkoff, MD, president of the Heart Rhythm Society, told MedPage Today. "Medications have not been very effective in this situation, and this new procedure shows significant promise as an alternative."

Medtronic, who sponsored the study, has sent these data to the FDA for review. The catheter system is not available in the U.S, although it has been available in Europe and Canada for several years.

[Chevychelov]

Gut Bacteria May Keep Statin Response in Check

By Todd Neale, Senior Staff Writer,
October 16, 2011

Action Points
Explain that pretreatment levels of secondary bile acids, produced by intestinal bacteria, were found to correlate with the lowering of LDL cholesterol in response to simvastatin.


Note that higher pretreatment levels of these bacterial-derived bile acids were found in good responders to simvastatin but not in poor responders.
Review
Various bacterial-derived bile acids appear to influence the response to statin treatment, researchers found.

Pretreatment levels of several primary and secondary bile acids were strongly associated with the low-density lipoprotein (LDL) cholesterol-lowering ability of simvastatin in healthy individuals, according to Rima Kaddurah-Daouk, PhD, of Duke University, and colleagues.

The findings, reported online in PLoS ONE, "warrant further evaluation of interactions of specific markers for gut microbiota and therapeutic response to statins," the researchers wrote. "Identification of the basis for such interactions may in turn lead to dietary or other interventions that can improve statin efficacy by altering gut microflora."

There is variability among individuals in the therapeutic response to statins, and previous studies have shown that genetics can only account for part of it.


Kaddurah-Daouk and colleagues turned to the field of metabolomics, which incorporates the interactions between a person's genome, microbiome, and environment in explaining response to treatments.

To search for biomarkers that might help predict response to statin therapy, the researchers used two groups of participants from the Cholesterol and Pharmacogenetics Study. The latter was designed to identify factors related to the response to six weeks of treatment with simvastatin 40 mg in healthy, drug-naive volunteers.

One group consisted of 100 randomly selected individuals across the spectrum of LDL cholesterol-lowering response to statin therapy and constituted the full-range group.

The second group was made up of 48 individuals -- 24 from the top 10% and 24 from the bottom 10% in terms of response to statin therapy, who were the good and poor performers, respectively.

In all of these participants, the researchers used a metabolomics platform to measure a panel of metabolites related to cholesterol synthesis, dietary sterol absorption, and bile acid formation.

In the full-range group, there was a correlation between lower pretreatment levels of five primary and secondary bile acids:
Taurocholic acid (TCA)
Glycocholic acid (GCA)
Taurochenodeoxycholic acid (TCDCA)
Glycochenodeoxycholic acid (GCDCA)
Glycoursodeoxycholic acid (GUDCA)


The full-range group had a greater LDL cholesterol-lowering response to simvastatin (P<0.02 for all).

In the good and poor responders, higher pretreatment levels of three secondary bile acids -- lithocholic acid (LCA), taurolithocholic acid (TLCA), and glycolithocholic acid (GLCA) -- were associated with a better response to statin therapy (P<0.05 for all). These secondary bile acids are produced by intestinal bacteria.

Bile acids and statins use the same transporters in the liver and intestine, and the researchers observed that an increased plasma concentration of simvastatin was associated with higher levels of several secondary bile acids in the study groups.

"Bile acids are known to be important endocrine signals, functioning in the systemic control of lipid levels, muscle function, and immune cell regulation," the authors wrote. "It has not escaped our attention that all of these pathways are affected by statins, either as therapeutic targets or side effects, suggesting that bile acids may be important mediators of statin activities."

They concluded that the findings, "along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome, and environmental influences should be considered in the study and management of cardiovascular disease."

The investigators noted that their results could only be applied to simvastatin as metabolites and pathways for other statins might differ.

[Chevychelov]

FDA advisory panel backs drug-eluting stent for PAD

The FDA Circulatory System Devices Panel of the Medical Devices Advisory Committee voted 11-0 today for approval of a new paclitaxel-eluting stent designed for the improvement of luminal diameter for the treatment of de novo or restenotic symptomatic vascular disease of above-the-knee femoral arteries.

The self-expanding nitinol stent (Zilver PTX, Cook Medical) is coated on its outer surface with paclitaxel without any polymer, binder or excipient at a dose density of 3 mcg/mm2. If approved, this device would be the first-ever paclitaxel-eluting stent available in the US for the treatment of symptomatic peripheral arterial disease.

The committee unanimously agreed that the stent is safe for use in patients who meet the proposed indication criteria of maximum lesion length of 140 mm per limb and 280 mm per patient. The 11 panel members further voted that there is reasonable assurance that the stent is effective for patients who meet the aforementioned criteria. Overall, the committee said the benefits of this stent outweigh the risks for use in patients who meet the criteria specified in the proposed indication.

Post-approval trial

Along with the recommended approval, the advisory committee also discussed whether a post-approval study would be necessary for further safety and efficacy data.

The sponsor proposed a long-term follow-up of the randomized control trial that enrolled 479 patients with symptomatic de novo or restenotic superficial femoral artery lesions to be used as a post-approval study. The post-approval study would require 900 patients and would analyze a non-inferiority comparison of the rate of event-free survival between percutaneous transluminal angioplasty and paclitaxel-eluting stent groups at 5 years. The proposed primary endpoint is event-free survival and the rate of stent fracture and late stent thrombosis for patients is the proposed secondary endpoint.

Some panel members questioned whether the post-approval study would require a patient population of 900, or if a cohort that large is necessary. Committee member Richard Lange, MD, from the University of Texas Health Science Center, said finishing the 5-year randomized control trial would provide enough results for the paclitaxel-eluting stent. "I am less convinced that the long-term data will give us any information we don't have already," Lange said during the meeting. "I think the current study going on for 5 years probably tells us enough about stent thrombosis."

John C. Somberg, MD, a panel member from Rush University Medical Center, said a larger study would provide the sponsor with more sufficient data. He suggested continuation of the cohort study, but added that the committee "should advance the idea that there is need for a larger study follow-up that can look for smaller effects, such as stent thrombosis and … whether diabetics are equally benefited from the stent [as are] other populations, such as females.

Other recommended additions for post-approval study included inclusion of bleeding risks and the addition of more women and patients with diabetes.

Although the FDA is not required to follow the recommendations of the advisory committees, it usually does.

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CHD remains leading cause of death in Americans, despite recent decline


Although self-reports of coronary heart disease have declined from 2006 to 2010, CHD remains the leading cause of death in the US, with rates varying from state to state and by race and ethnicity, according to recent data published in the CDC’s Morbidity and Mortality Weekly Report.

“We’re all at risk for heart disease and stroke,” Jing Fang, MD, epidemiologist in the CDC’s Division of Heart Disease and Stroke Prevention, said in a press release. “People of all ages, genders, races and ethnicities are affected. However, certain groups, including American Indians/Alaska natives, African Americans and older adults, are at higher risk than others.”

CDC researchers analyzed data from Behavioral Risk Factor Surveillance System surveys conducted between 2006 and 2010, a state-based, random digit-dialed telephone survey of the US civilian, noninstitutionalized population aged 18 years or older. Administered in all 50 states, the District of Columbia, and the US territories of Guam, Puerto Rico and the US Virgin Islands, the survey estimates state-specific CHD prevalence and recent trends by age, sex, race/ethnicity and education.

Overall, the number of participants who reported being told they have CHD by a health care professional declined from 6.7% to 6%. By 2010, participants aged 65 years and older had a higher CHD prevalence (19.8%) vs. participants aged 45 to 64 years (7.1%) and 18 to 44 years (1.2%). CHD prevalence was also greater in participants with less than a high school education (9.2%) vs. high school graduates (6.7%), participants with some college education (6.2%) and participants with a college degree (4.6%).

Among the states, age-adjusted CHD prevalence from 2006 to 2010 showed the greatest declines in West Virginia (23.1%; from 10.4% to 8%) and Missouri (22.1%; from 7.7% to 6%). By 2010, CHD prevalence by state varied widely, from 3.7% in Hawaii and 3.8% in Washington, D.C. to 8% in West Virginia and 8.2% in Kentucky. Researchers generally observed the greatest regional prevalences in the South.

Declines among racial/ethnic populations from 2006 to 2010 were observed among whites (6.4% to 5.8%) and Hispanics (6.9% to 6.1%). CHD prevalence was greatest among American Indians/Alaska natives (11.6%), followed by blacks (6.5%), Hispanics (6.1%), whites (5.8%), and Asians or native Hawaiians/ Pacific Islanders (3.9%). Analysis of race and sex revealed that in 2010 American Indian/Alaska natives (14.3%) and whites (7.7%) had the greatest CHD prevalence among men, while American Indian/Alaska natives (8.4%) and blacks (5.9%) had the greatest CHD prevalence among women.

Fang J. MMWR. 2011;60:1377-1381.

[Chevychelov]

FDA proposes lower risk classification for external pacemakers

The FDA has issued a proposed rule and draft special controls guidance lowering the risk classification for external pacemaker pulse generators from Class III to Class II.

External pacemaker pulse generators were placed on the market before the Medical Device Amendments Act of 1976, making them a pre-amendment device still being reviewed under premarket notification because the FDA did not issue regulations requiring applications for premarket approval. The FDA has proposed general controls and special controls, making external pacemaker pulse generators safer and more effective for the temporary treatment of regulating heartbeat and controlling irregular heartbeats.

"The FDA has assessed the benefits and risks of external pacemaker pulse generators," Christy Foreman, director of the Office of Device Evaluation at the FDA's Center for Devices and Radiological Health, said in a press release. "The special controls outline in this draft guidance, along with general controls, will assure the safety and efficacy of these devices and provide manufacturers with a more predictable path to market."

The proposed rule and draft special controls guidance provide manufacturers with clarity and specific guidance on what information is needed in a premarket notification for external pacemaker pulse generators, although it will not significantly change the FDA's review of the product.
__________________________________________________ ___________________________
Same-day discharge after PCI not associated with higher risk for death, rehospitalization

Rao S. JAMA. 2011;306:1461-1467.

Among selected low-risk Medicare patients who underwent an elective percutaneous coronary intervention, same-day discharge was rarely implemented, but was not associated with an increased risk for death or rehospitalization at 2 days or at 30 days when compared with patients who remained in the hospital overnight, according to a recent study published in the Journal of the American Medical Association.

“Risks associated with PCI are highest within the first 24 to 48 hours after the procedure,” according to background information in the article. “However, short- and long-term outcomes after PCI have improved because of the evolution in device technology and pharmacotherapy. Despite this improvement, patients are usually observed overnight in the hospital after elective PCI to monitor for PCI-related complications.”

Sunil V. Rao, MD, of the Duke Clinical Research Institute, and colleagues examined the prevalence of same-day discharge among older individuals following PCI and the rates of death or rehospitalization. The study included data from more than 107,000 patients aged 65 years and older who underwent elective PCI procedures at 903 sites participating in the CathPCI Registry between November 2004 and December 2008; these data were linked with Medicare Part A claims. Patients were divided into two groups based on length of stay at the hospital after PCI: same-day discharge or overnight stay.

Overall, the prevalence of same-day discharge was 1.25% (n=1,339), with significant variation across facilities. Rates of procedural success were not significantly different between the two groups. Patient characteristics were similar with same-day discharge vs. overnight stay, although same-day discharge patients underwent shorter procedures with less multivessel intervention. Patients who were discharged the same day as surgery were more often categorized in the lowest quintile of predicted risk for death or rehospitalization, while there were approximately equal proportions of lower- and higher-risk patients observed overnight, according to a JAMA press release.

The researchers found no significant differences in rates of death or rehospitalization at 2 days (same-day discharge 0.37% vs. overnight stay 0.5%) or at 30 days (same-day discharge 9.63% vs. overnight stay 9.7%). Additionally, median time to death or rehospitalization did not differ significantly between the two groups in patients with adverse outcomes (same-day discharge 13 days vs. overnight stay 14 days). When the researchers adjusted for patient and procedure characteristics, same-day discharge was not associated with death or rehospitalization at 30 days.

The researchers noted, however, that despite the apparent safety of same-day discharge for selected patients, this approach is rarely practiced at sites represented in the National Cardiovascular Data Registry. “This may reflect reluctance on the part of clinicians to discharge patients the same day as the PCI procedure because of concerns over early post-PCI complications. Although these concerns are well founded, the rates of vascular or bleeding complications were extremely low (less than 1%) among the patients in our analysis, with no clinically significant differences between groups,” the researchers wrote.

They added, that according to published guidelines, same-day discharge can be considered for patients undergoing PCI who have low-risk clinical features, successful procedures without prolonged postprocedure use of parenteral (by injection) antithrombotic agents, and adequate social support.

[Chevychelov]

Sharp Drop in Heart Failure Admissions, First Ever

By Crystal Phend, Senior Staff Writer,
October 18, 2011

Action Points
Explain that a Medicare claims analysis found admissions for heart failure over the period from 1998 to 2008 decreased significantly, although less in black men than in other groups.


Note that one-year mortality following heart failure hospitalization also decreased significantly during this same period but by a more modest percentage.
Review
Heart failure hospitalizations dropped 29.5% nationally over the past decade, largely because fewer patients were admitted rather than fewer admissions per patient, researchers found.

The risk-adjusted rate of heart failure hospitalization fell from 2,845 to 2,007 per 100,000 person-years from 1998 to 2008 (P<0.001) in a fee-for-service Medicare claims analysis by Jersey Chen, MD, MPH, of Yale University, and colleagues.

That decline -- the first ever documented in the U.S. -- likely saved $4.1 billion in Medicare costs since 1998, they reported in the Oct. 19 issue of the Journal of the American Medical Association.


Lower incidence of heart failure risk factors; modest improvements in blood pressure control; better use of evidence-based therapies; and a shift toward outpatient management of heart failure may have been contributing factors, the group suggested.

The main reason for the drop in hospitalizations was fewer unique patients hospitalized for heart failure, down from 2,014 per 100,000 in 1998 to 1,462 per 100,000 in 2008.

One-year mortality after heart failure hospitalization also dropped modestly by a relative 6.6% over the same period, from a risk-adjusted rate of 31.7% to 29.6% (P<0.001).

That is good news, according to Clyde W. Yancy, MD, of Northwestern University in Chicago and a past president of the American Heart Association.

"Research, implementation of best practices, and quality-focused initiatives, such as Get With The Guidelines, have had a positive return on investment," he said in a statement to MedPage Today.

An accompanying editorial also pointed to the results as a sign of hope, though with plenty of room for improvement.

The "persistently" and "unacceptably" high one-year mortality rates suggested a need for immediate attention to heart failure postdischarge practices, wrote Mihai Gheorghiade, MD, of Northwestern University, and Eugene Braunwald, MD, of Brigham and Women's Hospital and Harvard in Boston.

They suggested the following strategies:
Using more aggressive treatment for subclinical congestion
Taking a mechanistic approach to underlying cardiac abnormalities
Boosting use of digoxin and mineralocorticoid antagonists
Scheduling an early postdischarge visit


"There is more work to be done," agreed Ralph Brindis, MD, immediate past-president of the American College of Cardiology, in a statement. While overall trends are on the right track, not all groups benefited equally, he noted.

When Chen's group analyzed all heart failure hospitalizations nationally in a complete sample of Medicare fee-for-service claims from 1998 to 2008, they found that all sex and race groups showed reductions in heart failure hospitalizations.

But black men had the lowest rate of decline, with heart failure hospitalizations falling from 4,142 to 3,201 per 100,000 person-years over the study period. This improvement was a significant 19% less than other groups after adjusting for age.

The rates didn't fall evenly across states either.

Heart failure hospitalization changes happened significantly slower than the national mean in three states: Connecticut, Rhode Island, and Wyoming. One-year mortality rates actually increased in five states: South Dakota, Arizona, Alaska, Louisiana, and Kentucky.

"We must continue to work to understand the causes of these disparities in outcomes and continue to apply what we learn through research to improve care and prevention across the board," Brindis said in the statement.

The researchers cautioned that the study could not determine causality for any of the findings.

Other limitations were sole inclusion of a Medicare population, which may differ in heart failure hospitalization and mortality trends from a younger population with different insurance, and use of administrative codes not confirmed clinically.

[Chevychelov]

No First Trimester Pregnancy Risk for ACE Inhibitors

By Todd Neale, Senior Staff Writer,
October 18, 2011

Action Points
Explain that it is likely that any teratogenic effects previously attributed to ACE inhibitors taken during the first trimester of pregnancy are the result of the underlying hypertension and not the medications themselves.

Note that untreated hypertension was associated with greater risks of any malformation, congenital heart defects, and neural tube defects.
Review

It is likely that any teratogenic effects previously attributed to ACE inhibitors taken during the first trimester of pregnancy are the result of the underlying hypertension and not the medications themselves, researchers found.

Compared with women who did not have hypertension, use of either ACE inhibitors or other anti-hypertensives in the first trimester was associated with greater odds of any malformation when the child was born (ORs 1.20 and 1.22, respectively), according to De-Kun Li, MD, PhD, of Kaiser Permanente's Division of Research in Oakland, Calif., and colleagues.

However, the presence of hypertension in the absence of drug treatment was also associated with greater odds of any malformation (OR 1.25, 95% CI 1.19 to 1.31), the researchers reported online in BMJ.

Compared with women who had untreated hypertension, those exposed to either ACE inhibitors or other anti-hypertensives were not more likely to give birth to a child with a malformation.

"Our finding suggests that it is likely the underlying hypertension, rather than use of anti-hypertensive drugs in the first trimester, that increases the risk of malformations in offspring," Li and colleagues wrote.

ACE inhibitors have been designated by the FDA as category D drugs -- meaning that they carry known fetal risks -- when used during the second and third trimesters of pregnancy. The effects of ACE inhibitors during the first trimester are not as well known, however.

A 2006 study raised concerns about an increased risk of congenital anomalies when ACE inhibitors, but not other anti-hypertensives, were used during the first trimester, although two subsequent analyses failed to find such an association consistent with the current study.

"On the basis of all these findings, it is reasonable to conclude that exposure to ACE inhibitors during the first trimester poses no greater risk of birth defects than exposure to other anti-hypertensives," wrote Allen Mitchell, MD, of Boston University, in an accompanying editorial.

Li and colleagues examined data from 465,754 mothers and their offspring born from 1995 to 2008 within the Kaiser Permanente Northern California region.

During the study period, the prevalence of ACE inhibitor use in the first trimester was only 0.9 per 1,000 pregnancies. The rate for other anti-hypertensives was 2.4 per 1,000.

Among women who did not have hypertension, the rate of congenital malformation was 5.4%. The rate was higher for women who took an ACE inhibitor during the first trimester (8.5%), those who took any other anti-hypertensive (6.9%), and those with untreated hypertension (7.2%).

After adjustment for maternal age, ethnicity, parity, pre-existing diabetes, and overweight, that worked out to a 20% to 25% greater relative risk of birth defects across those three groups. The risk did not differ, however, between the medication groups and the untreated hypertension group.

The researchers then looked into two specific malformations: congenital heart defects and neural tube defects.

The results of the analysis for congenital heart defects mirrored those from the analysis looking at overall malformations, with increased relative risks of 41% to 54% among women taking ACE inhibitors, those taking other anti-hypertensives, and those with untreated hypertension when compared with women without hypertension.

Similarly, when the comparison group was women with untreated hypertension, use of ACE inhibitors or other anti-hypertensives during the first trimester only was not associated with an increased risk of congenital heart defects.

The use of ACE inhibitors or other anti-hypertensives was not associated with neural tube defects, although untreated hypertension carried a higher risk compared with the nonhypertensive controls (1% versus 0.6%; OR 1.43, 95% CI 1.26 to 1.62).

The authors noted some limitations of the study, including unknown compliance to dispensed medications, the inability to track prescriptions filled outside of the Kaiser Permanente system, and the limited information on the characteristics of women with treated and untreated hypertension.

[Chevychelov]

Biomarker Levels May Be Key to Heart Failure Decline

By Chris Kaiser, Cardiology Editor,
October 18, 2011

Action Points
Note that current treatment of chronic CHF due to left ventricular systolic dysfunction consists of the use of beta-adrenergic blockers and vasodilators, with the addition of aldosterone blockade or cardiac resynchronization therapy for those with persistent symptoms. Therapy is guided by ascertainment of clinical stability and volume status.


Note also that persistently elevated levels of NT-proBNP have been shown to be predictive of poor outcomes.


Point out that this study demonstrates that biomonitoring of NP-proBNP levels in combination with aggressive treatment based upon results can lead to significantly improved outcomes in patients with CHF.
Review
Monitoring levels of amino-terminal pro–B-type natriuretic peptide (NT-proBNP) and keeping them below a certain threshold proved to be more beneficial for heart failure patients than the standard of care, the PROTECT study found.

Those in the NT-proBNP monitoring arm had significantly fewer cardiovascular events (58 versus 100, P=0.009) at a mean follow-up of 10 months, James L. Januzzi Jr., MD, from Massachusetts General Hospital in Boston, and colleagues reported.

In addition, patients in the biomarker-monitored arm had fewer events per patient (0.77 versus 1.3, P=0.03) and a longer duration before their first event, according to the study in the Oct. 25 Journal of the American College of Cardiology.


At an interim analysis of the 151 patients thus far enrolled in PROTECT (75 in the NT-proBNP arm), the recommendation was made to stop enrollment because of a statistically significant reduction in the primary endpoint of total cardiovascular events favoring the NT-proBNP arm.

"We found a remarkable reduction in heart failure complications, primarily driven by improvements in worsening heart failure [27 versus 54, P=0.001] and reduced heart failure hospitalizations [11 versus 27, P=0.002]," Januzzi told MedPage Today in an interview.

"NT-proBNP levels are powerfully prognostic and allow therapeutic changes in those at highest risk. This is a very necessary step toward personalized healthcare in the heart failure space," Januzzi said.

The standard drug therapy for patients with chronic heart failure due to left ventricular systolic dysfunction (ejection fraction ≤40%) includes beta-adrenergic blockers and vasodilators, with the addition of an aldosterone blockade or cardiac resynchronization therapy reserved for those with persistent symptoms, Januzzi and colleagues wrote.

They also noted that "ascertainment of clinical stability and volume status in chronic heart failure can be challenging in inexperienced hands," and managing medication dosage is often suboptimal.

With that background, the investigators initiated the PROTECT (Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting) study, a single-center randomized controlled trial.

The goal in the interventional arm was to lower NT-proBNP levels to 1,000 pg/mL or below and sustain them there.

The primary clinical endpoint was total cardiovascular events, which was a composite of worsening heart failure, hospitalization for heart failure, clinically significant ventricular arrhythmia, acute coronary syndromes, cerebral ischemia, and cardiac death.

The mean age of patients was 63 years, with 21% older than 75. The older patients averaged slightly more clinic visits than the younger patients (7.5 versus 5.0), and those in the NT-proBNP arm averaged one more clinic visit than those in the standard-of-care arm (6.0 versus 5.0).

Investigators saw a similar average therapy adjustment between the two arms (7 versus 6), but noted that those in the interventional arm had more aggressive dosing changes.

Levels of the biomarker were similar at baseline between the two arms, but declined significantly by the end of the study for those in the NT-proBNP arm (2,344 to 1,125 pg/mL, P=0.01) compared with the standard of care (1,946 to 1,844 pg/mL, P=0.61).

Researchers found a linear relationship between the levels of NT-proBNP and events. Those below 1,000 pg/mL had the lowest mean frequency of events (0.45 events) compared with those between 1,000 and 2,000 pg/mL (1.1 events), between 2,000 and 3,000 pg/mL (1.25 events), and above 3,000 pg/mL (2.0 events) (P<0.001 for trend).

Those in the interventional arm also reported higher quality of life scores. "Not only did they have fewer events, but they also felt better and had favorable reverse cardiac remodeling as seen with echocardiography," Januzzi said.

In an accompanying editorial, Alan Maisel, MD, from the VA San Diego Healthcare System, wrote that PROTECT proves that lowering NT-proBNP levels is "indeed possible, is safe (the kidneys still work, the blood pressure is fine), and may lead to more benefits compared with simple non-biomonitored up-titration of therapies."

Despite the study being single-center and unblinded, it had "strong adherence to study protocol with consistent biomonitoring of NT-proBNP levels, allowing aggressive therapeutic efforts at NT-proBNP lowering," Maisel said.

Because of the relatively small sample size, brief duration of follow-up, and rigorous protocols, these results must be proven in a real-world setting, Maisel said.

In fact, Januzzi said the researchers are readying for a larger multicenter randomized trial. In addition, he and others are researching home-based finger-prick NT-proBNP testing.

[Chevychelov]

Bariatric Surgery Benefits the Whole Family

By Kristina Fiore, Staff Writer,
October 18, 2011

Action Points
Explain that a study found that obese relatives living with a patient who undergoes bariatric surgery had a significant drop in weight a year after the procedure.


Note that adult family members improved their eating habits, with significantly less uncontrollable eating and emotional eating.
Review
When one family member has bariatric surgery, the others lost weight as well, researchers found.

Obese relatives living with the surgery patient had a significant drop in weight a year after the procedure (P=0.01), John Morton, MD, PhD, of Stanford University, and colleagues reported in the October issue of the Archives of Surgery.

Bariatric surgery may be able to "induce weight loss and healthy behaviors in people surrounding the patient," they wrote.

Studies have shown that weight loss is socially contagious, they explained, since spouses who enroll in weight loss programs together tend to shed more pounds, as do those who join a support group.


Thus, if one family member makes lifestyle changes after surgery, it's possible that other family members will do so as well, Morton and colleagues wrote.

They looked at changes in weight and healthy behaviors in 35 patients who had Roux-en-Y gastric bypass, along with 35 adult family members and 15 children, in a single-center, prospective, longitudinal study between Jan. 1, 2007, and Dec. 31, 2009.

Family members were required to attend three patient preoperative educational sessions and all postoperative visits where lifestyle modification was emphasized.

Before the operation, 60% of adult family members and 73% of children were obese.

The researchers found that the mean weight of adult family members fell overall, from 220 lbs. to 198 lbs., but the decline wasn't significant.

However, when family members were divided up based on their level of obesity before the surgery, there was a significant drop in weight for obese adults after one year -- from 234 lbs. to 226 lbs. (P=0.01).

There was also a significant decline in waist circumference for this group, from 119 cm to 111 cm (P=0.03).

As expected, children gained weight in the year after surgery, due to natural growth. Yet their expected one-year mean body mass index (BMI) was higher than the observed one-year BMI, the researchers reported.

In obese children, the expected BMI of 31.2 was higher than the observed BMI of 29.6, but the trend wasn't significant.

In kids who weren't obese, the expected BMI was lower than the observed BMI, they added, and waist circumference remained the same in all children.

Kids did have small but non-significant increases in quality of life, as well as non-significant declines in the number of hours spent in front of the TV.

Similarly, they significantly increased their physical activity levels (P=0.04), as did adult family members (P=0.005).

Adults also improved their eating habits, with significantly less uncontrollable eating (P=0.01) and emotional eating (P=0.04) at one year.

They also drank less alcohol, falling from 11 drinks per month to just one drink per month (P=0.009).

"These data suggest that following surgery, family members were conscious of and attempting to limit maladaptive eating patterns," they wrote.

They concluded that "having a family member undergo weight loss surgery is a powerful reminder for dietary modification."

They added that bariatric surgery programs should encourage family members to participate in patient support groups and education sessions in order to "capitalize on the halo effects" of the procedure.

[Chevychelov]

Obesity, Diabetes and Poverty Share a Common Zip Code

By Kristina Fiore, Staff Writer,
October 19, 2011

Action Points
Explain that helping people move out of poor neighborhoods into those that are better off may help reduce levels of obesity and diabetes.


Note that in a dose-response model, adults who spent more time in lower-poverty housing had greater improvements in diabetes and BMI outcomes.
Review
Helping people move out of poor neighborhoods into those that are better off may help reduce levels of obesity and diabetes, researchers found.

In a large social experiment, people who used vouchers to move to an area with better socioeconomic conditions were significantly less likely to have a high body mass index (BMI) and elevated glycated hemoglobin (HbA1c) levels than those who remained in poor neighborhoods, Jens Ludwig, PhD, of the University of Chicago, and colleagues reported in the Oct. 20 issue of the New England Journal of Medicine.


Moving from high-poverty to low-poverty areas is associated "with modest but potentially important reductions in the prevalence of extreme obesity and diabetes," Ludwig and colleagues wrote.

Researchers have long questioned whether a person's neighborhood directly contributes to the development of obesity and diabetes. Observational studies have shown that neighborhood factors such as poverty or racial separation are associated with greater risks of these conditions.

To look more closely at the association, Ludwig and colleagues looked at data from a Department of Housing and Urban Development (HUD) program conducted between 1994 and 1998.

The department randomly assigned 4,498 women with children who were living in public housing in high-poverty urban areas to one of three groups:
1,788 received rent-subsidy housing vouchers earmarked for a move to a low-poverty area, as well as counseling 'to help with their housing search'
1,312 got rent-subsidy vouchers with no requirement as to where they could live and no special counseling
1,398 were assigned to a control group that wasn't offered either opportunity


The researchers then looked at participants' health outcomes -- including height, weight, and HbA1c levels -- between 2008 and 2010.

Overall, 48% of the families given the vouchers to move to a low-poverty area used them; 63% used the no-restriction vouchers.

Ludwig and colleagues found that using a voucher to move to a low-poverty area was associated with a decreased risk of extreme obesity and diabetes among the female heads-of-households.

Among these women there was a significantly lower prevalence of the following factors than in the control group:
BMI of 35 or higher, absolute difference of 4.61 percentage points (P=0.02), relative reduction of 13%
BMI of 40 or higher, absolute difference of 3.38 percentage points (P=0.03), relative reduction of 19.1%
HbA1c of 6.5% or higher, absolute difference of 4.31 percentage points (P=0.02), relative reduction of 21.6%

There were no significant differences between those in the traditional voucher group and controls.

The difference in outcomes between the two voucher groups wasn't significant for any BMI threshold, but there was a trend toward a significant difference in the prevalence of HbA1c 6.5% or higher at P=0.05, the researchers reported.

This finding suggests that low-poverty vouchers and traditional ones have different associations with neighborhood attributes that may affect health, they wrote.

In a dose-response model, adults who spent more time in lower-poverty housing had greater improvements in diabetes and BMI outcomes, they added.

The study was limited by loss to follow-up, lack of baseline health information, and because subjects volunteered to participate.

Still, the researchers concluded that the results "raise the possibility that clinical or public health interventions that ameliorate the effects of neighborhood environment on obesity and diabetes could generate substantial social benefits."

The mechanisms underlying the associations are unclear and warrant further investigation, they added.