Обзор американских кардиологических журналов за неделю (ссылки)

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Drug-eluting stents reduced major adverse cardiac event rate
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Drug-eluting stents in patients with STEMI reduced the long-term rate of major adverse cardiac events vs. bare metal stents, according to the 3-year follow-up findings of the DEDICATION trial.

The study population consisted of 626 patients with STEMI referred within 12 hours who were randomly assigned to have a drug-eluting stent or a bare metal stent implanted in the infarct-related lesion with or without distal protection during primary percutaneous coronary intervention.
After 3 years, target lesion revascularization was 6.1% in the drug-eluting stent group vs. 16.3% in the bare metal stent group (P<.001), and the rate of major adverse cardiac events was 11.5% vs. 18.2%, respectively (P=.02). Although all-cause mortality did not differ significantly, the rate of cardiac death was higher in the drug-eluting stent group, 6.1% vs. 1.9%, than for the bare metal stent group (P=.01). Reinfarction, stroke and stent thrombosis occurrence was similar between groups.
This study, researchers wrote, “shows that in patients with STEMI, implantation of a drug-eluting stent, compared with a bare metal stent, significantly reduces the rate of major adverse cardiac events and the need for revascularization. Despite this reduction, patients with STEMI who have a drug-eluting stent implanted seem to have a higher risk of cardiac death that cannot be attributed to reinfarction or stent thrombosis.” – by Brian Ellis

Kaltoft A. J Am Coll Cardiol. 2010;56:doi:10.1016/j.jacc.2010.05.009.

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WISE: Coronary flow reserve improved adverse outcome prediction over angiographic CAD severity
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Coronary microvascular reactivity to adenosine improved the prediction of major adverse outcomes over angiographic coronary artery disease severity among women with suspected ischemia and atherosclerosis risk factors, results from the WISE study suggested.

Researchers from several U.S. cities investigated relationships between major adverse outcomes and baseline coronary flow reserve after intracoronary adenosine in 189 women referred for suspected ischemia. Baseline evaluation included a physical examination and the collection of clinical and laboratory data. Researchers observed associations between coronary flow reserve and major adverse outcomes, such as death, nonfatal MI, nonfatal stroke or hospital stay for HF, at a mean follow-up of 5.4 years.

During follow-up, 79 women (42%) had an adverse outcome, and there were 138 events, which included 11 deaths. An exploratory receiver-operator characteristic analysis suggested that coronary flow reserve <2.32 was the best discriminating threshold for adverse outcomes (event rate, 26.7%; and ≥2.32 event rate, 12.2%; P=.01). Lower coronary flow reserve was associated with increased risk for major adverse outcomes (HR=1.16; 95% CI, 1.04-1.30), a finding that held true among the 152 women without obstructive CAD (HR=1.20; 95% CI, 1.05-1.38).
“In women undergoing coronary angiography to further evaluate suspected ischemia, a limited coronary microvascular response to adenosine is associated with increased risk for major adverse outcomes, even in the absence of significant obstructive CAD,” the researchers wrote. “This finding supports the need for more investigation of altered coronary smooth muscle reactivity and the smaller vessels in women with suspected ischemia. Long-term follow-up of new cohorts of women should help to determine whether coronary microvascular dysfunction and its link with adverse outcomes can be confirmed and modified.”

Pepine C. J Am Coll Cardiol. 2010;55:2825-2832.

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Mediterranean diet positively linked with cardiac autonomic function
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A Mediterranean dietary pattern among middle-aged men was associated with higher heart rate variability, leading researchers to conclude that it may lower the rate of CV events.
The group of U.S. researchers administered the Willett Food Frequency Questionnaire to 276 middle-aged male twins. Ninety-four percent were non-Hispanic white, 3% African-American and 3% other race/ethnic group. The researchers derived a score measuring the extent to which an individual’s diet conformed to the Mediterranean diet. This diet incorporated seven desirable components: cereals, vegetables, fruits and nuts, legumes, fish, a high dietary ratio of monounsaturated to saturated fatty acids (as reflected in high olive oil consumption) and moderate alcohol consumption; and two undesirable components: meat and dairy food products.
After adjusting for energy intake, other nutritional factors, shared genes and common environment, a one-unit higher Mediterranean diet score was associated with 3.9% to 13% higher time and frequency domain heart rate variability parameters. This positive association was independent of genes, shared environmental factors and known CV risk factors. Additionally, dizygotic twin pairs had larger differences in several heart rate variability measures than monozygotic twin pairs, implying what the researchers said they believe is a shared genetic pathway between the diet and heart rate variability. Further controlling for known CV risk factors and consumption of fish oil supplements and medications did not significantly change estimates.
“Our study demonstrates for the first time a positive association between the Mediterranean dietary pattern and heart rate variability” and suggests “that autonomic tone may be one of mechanisms linking the Mediterranean diet to a lower rate of CV events,” the researchers concluded.

Dai J. Circ Cardiovasc Qual Outcomes. 2010;doi:10.1161/CIRCOUTCOMES.109.905810.

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HF-ACTION: Cost incurred for exercise and usual care in HF patients similar
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Patients with symptomatic HF randomly assigned to exercise training exhibited no cost benefit nor a decreased hospitalization rate vs. patients randomly assigned to usual care, results from the HF-ACTION study suggested.
The researchers assigned 2,331 outpatients with medically stable HF to either an exercise training or usual care group. They collected extensive data on medical resource use and hospital bills for estimates of direct medical costs.
During the mean follow-up of 2.5 years, there were 2,297 hospitalizations in the exercise group and 2,332 in the usual care group. The mean number of inpatient days was 13.6 (standard deviation, 27 days) in the exercise group and 15 (standard deviation, 31.4 days) in the usual care group. Other measures of resource use were similar between groups, including ED and urgent care visits, except for trends that suggested that fewer patients in the exercise group underwent high-cost inpatient procedures.
Estimated total direct medical cost per participant was $50,857 (standard deviation, $81,488) in the exercise group and $56,177 (standard deviation, $92,749) in the usual care group. The direct cost of exercise training was an estimated $1,006 (standard deviation, $337), whereas patient time costs, including supervised training and home exercise time, were an estimated $5,018 (standard deviation, $4,600).
According to the researchers, “Relative to the overall cost of HF to the health care system, costs associated with exercise training are small. However, in this economic evaluation, we found little systematic benefit in terms of overall medical resource use with this intervention.”

Reed S.Circ Cardiovasc Qual Outcomes. 2010;doi:10.1161/CIRCOUTCOMES.109.907287.

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Follow-up appointments not linked with improved readmission rate
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Improved discharge processes, such as arranging hospital follow-up appointments, did not approve readmission rate or survival in general medicine patients, according to study data.
Minnesota-based researchers analyzed hospital dismissal instructions for general medicine patients dismissed in 2006 from Mayo Clinic hospitals in Rochester, Minn., (n=4,989) and noted whether appointment details for follow-up were documented. They developed survival analysis and propensity score-adjusted proportional hazards regression models to investigate the relationship between follow-up appointment arrangements and hospital readmission, ED visits and mortality at 30 and 180 days after discharge.
Of the dismissal summaries, 3,037 (60.9%) contained instructions for a follow-up appointment. No difference was found between those with a documented follow-up appointment vs. those without 30 days after dismissal. However, within 180 days of dismissal, those with a documented follow-up appointment were more likely to have a hospital readmission or an ED visit (HR=1.10; 95% CI, 1.01-1.20).
“Despite our original hypothesis that specific instructions regarding a hospital follow-up appointment would be associated with fewer hospital readmissions, we found that having documented specific follow-up instructions at dismissal was actually associated with a slightly higher likelihood of having either an emergency department visit or hospital readmission 180 days after dismissal,” the researchers concluded. “Before health care payers such as CMS reduce hospital payment for readmissions that are thought to be avoidable, a clearer understanding of the factors that may reduce hospital readmission is needed. Efforts to ensure follow-up for all patients after dismissal may not be beneficial or cost-effective.” – by Brian Ellis
Grafft C. Arch Intern Med. 2010;170:955-960.

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MESA: Increased risk for coronary artery calcification in patients with microalbuminuria
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Asymptomatic individuals demonstrated an increased risk for incident coronary artery calcification, as well as greater coronary artery calcification progression, among those with microalbuminuria, according to the findings of a prospective cohort analysis of participants in the MESA study.
The MESA study included 6,814 self-identified white, African-American, Hispanic or Chinese participants who were free of clinical CVD at entry. Of the 6,775 individuals with available urine albumin data, researchers excluded those who had macroalbuminuria or were missing follow-up coronary artery calcification (CAC) data, leaving them with the final study population of 5,666 participants.
At baseline, individuals with microalbuminuria were more likely to have CAC >0 compared with those without microalbuminuria (62% vs. 48%, P<.0001). During a mean follow-up of 2.4 years, patients with microalbuminuria and no CAC at baseline compared with those without microalbuminuria in demographic-adjusted analyses were more likely to develop CAC (RR=2.05; 95% CI, 1.41-3.02). After multivariant adjustment, the relationship was attenuated but remained significant (RR=1.76; 95% CI, 1.19-2.61). Additionally, among those with CAC at baseline, those with microalbuminuria vs. those without had a 15-volume-units higher median increase in CAC in demographic adjusted analyses.
“This large, population-based study demonstrates an increased risk of incident CAC as well as greater CAC progression among those with microalbuminuria,” the researchers wrote. “Further study is needed to determine the degree to which macroalbuminuria precedes and predicts progression of atherosclerosis and how this information can be used to reduce CV events.”
DeFilippis A. J Am Coll Cardiol Img. 2010;3:595-604.

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High lifetime risk of CVD predicative of increased LV mass
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Patients with low short-term/high lifetime predicted risk for CVD appear to be at a greater risk of concentric left ventricular hypertrophy and increased aortic wall thickness than those with low short-term/low lifetime risk.
Researchers divided 1,804 patients from the Dallas Heart Study who were between the ages of 30 and 50 years and had cardiac magnetic resonance into three groups: low short-term (<10% 10-year risk of CHD)/low lifetime predicted risk (<39% lifetime risk of CVD), low short-term (<10%)/high lifetime risk (≥39%) and high short-term risk (≥10%; prevalent diabetes, previous stroke or MI).
Participants with low short-term/high lifetime risk had greater LV mass (men: 95 ± 17 g/m² vs. 90 ±12 g/m² and women: 75 ± 14 g/m² vs. 71 ± 10 g/m²; P<.001 for both) vs. those with low short-term/low lifetime risk. LV wall thickness, concentricity, aortic wall thickness and prevalent coronary artery calcium were also greater in those with high lifetime risk (P<.001 for all), but LV end-diastolic volume was not. These associations remained even among subjects without detectable coronary artery calcium.
“We demonstrated for the first time that participants with low short-term/high lifetime predicted risk of atherosclerotic CVD compared with those with low short-term/low lifetime predicted risk had a 1.6- to 3.3-fold greater prevalence of LV hypertrophy; significantly increased LV mass of a concentric phenotype; and increased aortic wall thickness,” researchers wrote. “These data, coupled with our previous findings, suggest that an assessment of lifetime risk of CVD can aid in the identification of a subgroup of individuals 30 to 50 years of age who are at low risk over a 10-year period but nevertheless have a significant subclinical CVD burden.”
Gupta S. J Am Coll Cardiol Img. 2010;3:605-613.

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Noninvasive imaging shown useful in predicting outcomes in patients with AF
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Delayed-enhancement MRI and echocardiographic assessment were able to discriminate between paroxysmal vs. persistent atrial fibrillation in a cross-sectional, retrospective study performed at the University of Utah Hospital.
The study population included 65 patients aged 61.2 ± 14.2 years with paroxysmal or persistent AF in which researchers employed 3-D delayed-enhancement MRI. Researchers also used velocity vector imaging to obtain 2-D echocardiography and longitudinal left atrium strain and strain rate during ventricular systole. Of the 55 patients included in the final analysis, 44% had paroxysmal and 56% had persistent AF.
Mean fibrosis was 17.8 ± 14.5%. Log-transformed fibrosis inversely corresponded with left atrium midlateral strain (r=–0.5; P=.003) and strain rate (r=–0.4; P<.005). Patients with persistent AF had higher fibrosis (22 ± 17% vs. 14 ± 9%; P=.04) and lower midseptal (27 ± 14% vs. 38 ± 16%; P=.01) and midlateral (35 ± 16% vs. 45 ± 14%; P=.03) strains vs. those with paroxysmal AF. Multivariable stepwise regression indicated midlateral strain (r=–0.5; P=.006) and strain rate (r=–0.4; P=.01) inversely predicted the extent of fibrosis independent of other echocardiographic parameters and the rhythm during imaging.
According to researchers, combined noninvasive imaging techniques may be helpful in predicting outcomes and guiding therapeutic strategies in patients with AF. “Novel imaging strategies such as those described in this report may allow us to identify patients earlier in their disease process, before the development of severe or irreversible abnormalities,” they reported. “Echocardiographic strain imaging of the atria may be particularly useful in centers where delayed-enhancement MRI is unavailable or in patients who are not candidates for MRI.”
Kuppahally S. Circ Cardiovasc Imaging. 2010;3:231-239.

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Tissue characterization by CV magnetic resonance predictive of future CV events
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Tissue characterization of infarct core and border zone with CV magnetic resonance was associated with future CV events in patients with ischemic cardiomyopathy, study data indicated.
Researchers retrospectively studied a population of 70 patients with CAD and left ventricular dysfunction (LV ejection fraction, <50%; mean LVEF, 25 ± 11%) who were considered for revascularization or medication therapy with or without an implantable cardioverter defibrillator. Patients underwent diagnostic coronary angiography before CV magnetic resonance examination. Researchers from California and New York institutions used MRI to acquire cine and delayed enhancement images.
Twenty-nine patients (41%) who had CV events showed a larger infarct border zone and its percentage of myocardium (median, 13.3 g vs. 8 g; P=.02), according to the results. “The core infarct zone and its percentage of myocardium, LV end-diastolic volume, LV end-systolic volume, and LVEF were not statistically significant,” researchers said in the study.
Following a sub-analysis of the medical management and revascularization patients with CV events, the researchers reported that the medically managed group had a larger border zone, although there was no difference between border and core zones in the revascularization group (P<.05).

“Quantitative tissue characterization of the border zone mass and border zone percentage of infarcts was associated with a higher likelihood of future CV events in patients with ischemic cardiomyopathy,” the researchers concluded. “On the basis of our study, a more detailed analysis of the injured myocardium with cardiac MR to analyze infarct heterogeneity might provide therapeutic guidance in patients with chronic, severe ischemic cardiomyopathy.”
Heidary S. J Am Coll Cardiol. 2010; 55:2762-2768.

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Atrial Fibrillation Management Strategies and Early Mortality After Myocardial Infarction: Results From the Valsartan in Acute Myocardial Infarction (VALIANT) Trial
Nilsson KR Jr, Al-Khatib SM, Zhou Y, et al.
Heart 2010;96:838-842.
Study Question: Does a rhythm-control strategy for atrial fibrillation (AF) affect outcomes compared to a rate-control strategy early after myocardial infarction (MI)?

Continuing Warfarin Therapy Is Superior to Interrupting Warfarin With or Without Bridging Anticoagulation Therapy in Patients Undergoing Pacemaker and Defibrillator Implantation
Ahmed I, Gertner E, Nelson WB, et al.
Heart Rhythm 2010;7:745-749.
Study Question: Is therapy with warfarin safer than heparin in patients undergoing device implantation?

Warfarin Genotyping Reduces Hospitalization Rates: Results From the MM-WES (Medco-Mayo Warfarin Effectiveness Study)
Epstein RS, Moyer TP, Aubert RE, et al.
J Am Coll Cardiol 2010;55:2804-2812.
Study Question: Does genotype testing for functional variants of CYP2C9 and VKORC1 in patients initiating warfarin therapy lead to reduced hospitalizations?


Outcomes in Patients With De Novo Left Main Disease Treated With Either Percutaneous Coronary Intervention Using Paclitaxel-Eluting Stents or Coronary Artery Bypass Graft Treatment in the Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) Trial
Morice MC, Serruys PW, Kappetein AP, et al.
Circulation 2010;121:2645-2653.
Study Question: What are the outcomes in the prespecified subgroup of patients with left main (LM) disease in the SYNTAX trial?

Geographic Variation in Medicare Drug Spending
Zhang Y, Baicker K, Newhouse JP.
N Engl J Med 2010;Jun 9:[Epub ahead of print].
Study Question: Do Medicare patients who spend more on pharmaceuticals to control chronic conditions have fewer physician visits?

Genetic Determinants of Treatment Benefit of the Angiotensin-Converting Enzyme-Inhibitor Perindopril in Patients With Stable Coronary Artery Disease
Brugts JJ, Isaacs A, Boersma E, et al.
Eur Heart J 2010;Jun 10:[Epub ahead of print].
Study Question: Do sequence variations involving genes in angiotensin-converting enzyme (ACE)-related pathways affect clinical response to ACE therapy in patients with stable coronary artery disease (CAD)?

Cardiac Performance Measure Compliance in Outpatients: The American College of Cardiology and National Cardiovascular Data Registry’s PINNACLE (Practice Innovation And Clinical Excellence) Program
Chan PS, Oetgen WJ, Buchanan D, et al.
J Am Coll Cardiol 2010;56:8-14.
Study Question: What are the results of the first large office-based quality improvement study of outpatients with coronary artery disease (CAD), heart failure, and atrial fibrillation?


Mid-Region Pro-Hormone Markers for Diagnosis and Prognosis in Acute Dyspnea: Results From the BACH (Biomarkers in Acute Heart Failure) Trial
Maisel A, Mueller C, Nowak R, et al.
J Am Coll Cardiol 2010;55:2062-2076.
Study Question: What is the diagnostic utility of mid-regional pro–atrial natriuretic peptide (MR-proANP) for the diagnosis of acute heart failure (AHF) and the prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with AHF?

Patients With Acute Coronary Syndromes and Elevated Levels of Natriuretic Peptides: The Results of the AVANT GARDE-TIMI 43 Trial
Scirica BM, Morrow DM, Bode C, et al.
Eur Heart J 2010;June 17:[Epub ahead of print].
Study Question: What is the effect of early inhibition of the renin–angiotensin–aldosterone system (RAAS) in acute coronary syndrome (ACS) patients with preserved left ventricular function on hemodynamic stress?


Randomized Trial of Paclitaxel- Versus Sirolimus-Eluting Stents for Treatment of Coronary Restenosis in Sirolimus-Eluting Stents: The ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) Study
Mehilli J, Byrne RA, Tiroch K, et al., on behalf of the ISAR-DESIRE 2 Investigators.
J Am Coll Cardiol 2010;55:2710-2716.
Study Question: What is the comparative efficacy of repeat sirolimus-eluting stent (SES) versus implantation with paclitaxel-eluting stent (PES) for patients with SES restenosis requiring reintervention?


Aspirin for the Primary Prevention of Cardiovascular Events in People With Diabetes
Pignone M, Alberts MJ, Colwell JA, et al., on behalf of the American Diabetes Association, American Heart Association, and American College of Cardiology.
J Am Coll Cardiol 2010;55:2878-2886.
Perspective: The following are 10 points to remember about this expert consensus document.

Prognostic Implications of the Urinary Albumin to Creatinine Ratio in Veterans of Different Ages With Diabetes
O’Hare AM, Hailpern SM, Pavkov ME, et al.
Arch Intern Med 2010;170:930-936.
Study Question: Albuminuria is associated with an increased risk of death independent of level of renal function. Is this association similar for adult diabetics of all ages?

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Nature Reviews Cardiology 7, 358 (July 2010) | doi:10.1038/nrcardio.2010.75

Subject Category: Arrhythmias

New test for long QT syndrome
Bryony M. Mearns

long Qt syndrome (lQts) is potentially lethal if left untreated. accurate diagnosis is, therefore, vital. Patients with lQts have
impaired adaptation of the Qt interval in response to changes in heart rate. a study by Dr sami Viskin and colleagues has now shown that this maladaptation is exaggerated upon standing—an action associated with a sudden increase in heart rate. a test has been proposed on the basis of this observation. according to
Dr Viskin, from the tel aviv Medical center in israel, “the test is very easy to do and should be performed in addition to (not instead of) all the tests that we perform to confirm or exclude a diagnosis of lQts.” the multinational study cohort included 68 patients with lQts and 82 control individuals. sudden standing after resting in a supine position resulted in a similar acceleration of heart rate in both study groups: 28 ± 10 bpm in controls and 26 ± 11 bpm in patients with lQts. in controls, the Qt interval decreased by
21 ± 19 ms; however, since the Qt interval decreased less than the rr interval, the Qt interval corrected for heart rate (Qtc interval) actually increased by 50 ± 30 ms. By contrast, the Qt interval
did not decrease in patients with lQts (it lengthened by 4 ± 34 ms) and so the Qtc interval was increased by 89 ± 47 ms, which was significantly more than in the controls (P <0.001). Patients with various types of lQts were included in the study. although
patients with lQt1 (n = 31) and those with lQt2 (n = 28) had similar Qt and Qtc intervals at baseline, as well as similar increases in heart rate upon standing, individuals with lQt2 had a larger increase in their Qtc interval upon standing than patients with lQt1
(114 ± 42 ms versus 67 ± 41 ms). Finally, Qt-related ventricular ectopy occurred in some patients upon standing and the investigators warn that this observation “suggests that untreated
patients are at risk for more serious arrhythmias every time they stand up.” Bryony M. Mearns
Original article Viskin, S. et al. The response of the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome. J. Am. Coll. Cardiol. 55, 1955–1961 (2010)

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Gene Variant, PPI Use Increase Mortality in Clopidogrel-Treated Patients

Key Points:
Carrying CYP2C19*2 allele and/or using PPI increases MACE risk by 42%
Stent thrombosis over 3 times more likely in CYP2C19*2 carriers
But PPI impact seen only in high-risk patients
By Kim Dalton
Monday, June 28, 2010

Clopidogrel-treated patients who carry a loss-of-function gene variant for the key enzyme needed to metabolize the drug and/or use a proton pump inhibitor (PPI) face an increased risk of cardiovascular events and death, according to a meta-analysis published in the July 5, 2010, issue of the Journal of the American College of Cardiology. However, the impact of PPIs appears to be limited to those at high baseline risk.
Investigators led by Gilles Montalescot, MD, PhD, of Hôpital Pitié-Salpètrière (Paris, France), reviewed the literature for studies that looked at the impact of the CYP2C19*2 loss-of-function allele or PPI use on MACE or mortality in stented patients on long-term clopidogrel therapy. Of 23 studies that met the inclusion criteria, 10 focused on CYP2C19*2 and involved 11,959 participants, while 13 focused on the effect of PPI coadministration and involved 48,674 patients.
Analysis of pooled data from studies about the influence of CYP2C19*2 status showed that being a carrier of this variant was associated with higher rates of MACE (all 10 studies) and all-cause mortality (5 studies) as well as a nearly 3-fold increased risk of Academic Research Consortium-defined stent thrombosis (4 studies) compared with noncarriers (table 1). The majority of stent thrombosis cases (47 of 71) occurred within 30 days of implantation.
The relative impact of carrying 1 vs. 2 loss-of-function alleles was evaluable in just under half of the 11,959 patients. While homozygotes were found to face a significant increased risk of MACE (OR 2.05, 95% CI 1.15-3.63) compared with noncarriers, heterozygotes exhibited only a trend toward increased risk (OR 1.59, 95% CI 0.88-2.88). On the other hand, stent thrombosis was significantly more likely to occur in both heterozygotes (OR 3.34, 95% CI 1.84-5.93)) and homozygotes (OR 4.68, 95% CI 1.55-14.11).
Among studies that looked at PPI use, analysis showed that coadministration increased the risk of both MACE and all-cause mortality (table 2).
Omeprazole was the PPI most frequently used in the study populations (50.3%), followed by pantoprazole (19.8%) and esomeprazole (19.3%). In a separate analysis restricted to data on omeprazole use, the increased MACE risk was comparable to that seen with any PPI use.
The researchers used a weighted regression model to investigate whether there was a relationship between the incidence of MACE in the study population and PPI use. The results suggested that the impact of PPIs depends on the overall population’s baseline risk, as indicated by the incidence of adverse events among patients who did not use PPIs. When the investigators looked only at the 6 studies in which the MACE rate was higher than 10% (the median value for all 13 PPI studies) in PPI nonusers, coadministration had a clear impact on MACE risk (OR 1.49, 95% CI 1.41-1.57; P < 0.001). No effect of PPI use was seen in the remaining studies, in which patients were at lower baseline risk.
When all data were combined, patients who either carried a CYP2C19*2 allele and/or used a PPI had a 42% increase in the risk for MACE and a 20% increase in the risk for death (both P < 0.001).
The authors note that considerable evidence points to a negative interaction between clopidogrel and PPIs, but thus far studies on the clinical relevance of such interaction have been inconsistent. In an e-mail communication with TCTMD, Dr. Montalescot wrote, “One of the major contributions of our analysis is to provide an explanation for the high heterogeneity among studies of the estimate of PPI influence in clopidogrel-treated patients.
“We were unable to find any significant interaction in low-risk patients, so there is no obvious reason to restrain PPI use in these patients,” Dr. Montalescot continued. “However, a high-risk patient taking a PPI will have a higher thrombotic risk than a similar patient not taking a PPI. Some risk factors (like age) are common for thrombosis and bleeding, but others are specific. For example, prior episodes of stent thrombosis or MI are strong predictors of further ischemic events (not of bleeding),” suggesting PPIs should be withheld.
Moreover, a causal link between PPI use and clopidogrel response has not been established, the investigators observe. “Whether the detrimental impact of PPI use in high-risk patients is related to CYP2C19 inhibition or another mechanism remains to be determined,” they write, adding, “Our study also strongly suggests a need to further characterize particular risk factors that may promote PPI interaction in these high-risk patients.”
In a telephone interview with TCTMD, Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), was skeptical of the PPI conclusions. “I’m not convinced the investigators have made their argument,” he said. “The dataset is inferior. Some of the studies showing the greatest impact of PPIs are either based on claims data or on retrospective observational studies where you can’t possibly correct for all the confounding variables. And if you look at the post hoc analyses of the randomized TRITON and COGENT trials, they found no impact.”
One problem is that PPIs tend to be given to people at higher risk, Dr. Bates said, and the researchers did not adjust for that when they performed their meta-analysis. Moreover, he said, “the drug-drug interaction [between clopidogrel and PPIs] is very dynamic. There are a lot of variables that make the PPI story less impressive. I don’t think it will be confirmed,” he concluded.
An Entrée for Genotyping?
On the other hand, Dr. Bates was enthusiastic about the genetic side of the meta-analysis. “This may be an entrée for genotyping in clinical cardiology,” he said. “This is the first instance where you clearly have demonstrated that a variant allele is associated with worse outcomes and should be identified and it should alter your treatment. [As such,] it may be the breakthrough that the visionaries talking about individualized medicine have been waiting for.”
The findings are likely to change practice, Dr. Bates suggested, either through the impact of the outcome data themselves or their influence on insurance companies, “which will eventually demand [genetic testing] when generic clopidogrel comes out. . . . If you’re wild type [ie, a normal metabolizer], you get generic clopidogrel for financial reasons, and if you have one of the loss-of-function alleles they’ll pay for prasugrel or ticagrelor [if it’s approved]. I think economics is going to drive [adoption of genetic testing].”
Dr. Bates noted that point-of-care genetic tests soon will be available that will make it possible to genotype patients when they first check into the cath lab and to then have the results by the end of the procedure or at least by discharge.
Dr. Montalescot agreed that having such tests is key, especially since much of the excess stent thrombosis risk imparted by carrying a CYP2C19*2 allele occurs early after stenting. “The near future lies in a rapid and low-cost test allowing genotype-guided antiplatelet therapy. Rapid genetic testing should allow us to get the genetic profile as fast as we get a troponin level,” he wrote.
In his e-mail, Dr. Montalescot said it will be important to ascertain whether there is a gene-dose effect associated with CYP2C19*2 since heterozygotes represent 20% to 25% of the general population while only about 3% are homozygous for the allele. “Whereas many data argue for a complete resistance profile in homozygotes, heterozygotes display a more intermediate response to clopidogrel—although significantly worse than that observed in wild-type patients,” he wrote, adding, “The optimal management of these patients needs to be determined.”
Dr. Bates agreed, and reported that a forthcoming study by another group is expected to show more clearly that the clinical impact of CYP2C19*2 applies to heterozygous patients, making its clinical relevance difficult to ignore.
Study Details
For the meta-analysis, the investigators conducted a systematic search of Medline (1966 to October 1, 2009) and the Cochrane Library (1980 to October 1, 2009) and reviewed abstracts from selected scientific meetings. The primary endpoint was MACE, as defined in each study by the occurrence of death, nonfatal MI, stroke, or urgent revascularization. Endpoints were evaluated at the longest follow-up available.
Sensitivity analyses to assess the influence of publication status, sample size, and study quality on the impact on MACE showed heterogeneity among the studies of both the CYP2C19*2 variant (P = 0.003) and PPI coadministration (P < 0.001).
Source:
Hulot J-S, Collet J-P, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration. J Am Coll Cardiol. 2010:56:134-143.

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Professional Societies Respond to New Clopidogrel 'Black Box' Warning
Key Points:
FDA revised clopidogrel label in March 2010
Highlights impact of genetic factors on clopidogrel metabolism
New guidelines help clinicians understand issues that affect practice
By Caitlin E. Cox
Monday, June 28, 2010

This March, the Food and Drug Administration (FDA) revised the product label of clopidogrel, highlighting how genetic differences could affect response to the antiplatelet drug and listing options for patient management. To help physicians interpret the new FDA warning, the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) issued a joint clinical alert on June 28, 2010.
The document written by David R. Holmes Jr, MD, of the Mayo Clinic (Rochester, MN), and colleagues is being published online ahead of print in both the Journal of the American College of Cardiology and Circulation.
The FDA’s “boxed warning” outlines 3 issues related to clopidogrel responsiveness:
Warning that clopidogrel has reduced effectiveness in patients who are poor metabolizers
Specifying that genetic tests are available to detect polymorphisms in CYP2C19, one of several genotypes associated with enzyme activity in the P450 system that are responsible for converting clopidogrel to its active metabolite
Advising health care professionals to consider use of other antiplatelet medications or alternative dosing strategies in patients identified as poor responders
An Evolving Landscape
Coauthor Gregory J. Dehmer, MD, of Texas A&M College of Medicine (College Station, TX), told TCTMD in a telephone interview that as recently as 5 years ago, knowledge about genetic variation—and its impact on clopidogrel responsiveness and platelet inhibition—was “incredibly immature.” But since then the field has evolved very rapidly, such that “the average, very busy interventional cardiologist is probably aware of many of these issues,” he said.
“We don’t quite know everything that needs to be known at this point, but certainly the FDA has done an important thing by issuing their ‘black box’ statement,” Dr. Dehmer commented, explaining that while the agency appropriately raised the issue of clopidogrel metabolism, it left decisions about what to do with that information up to individual health care providers. Thus, the joint statement aims to “further help clinicians at least at this point, even realizing our knowledge in this area is incomplete.”
In addition to summarizing the literature, the ACCF/AHA report provides specific recommendations for practice.
Number 1 among them, Dr. Dehmer advised, is “always emphasize to patients the importance of compliance with clopidogrel therapy. Noncompliance is still a huge issue. . . . Overall, that message is now pretty clearly out there, as people have understood the hazards of not taking your clopidogrel as prescribed.” He pointed out that all discussions about genetic and platelet function testing are done under the assumption of compliance, without which testing results would be irrelevant.
“Number 2 is still to stick with the [existing evidence-based] guideline recommendations in terms of using clopidogrel,” Dr. Dehmer continued. “Number 3 is to realize that there are other drugs out there that are alternatives.” Prasugrel is a currently available option, he said, specifying that its potential ischemic benefit must be balanced against higher bleeding risk. While not yet on the market, ticagrelor also seems promising, Dr. Dehmer added.
Increasing the loading or maintenance doses of clopidogrel may be another way to improve platelet inhibition, the ACCF/AHA paper suggests.
No Clear Path for Testing
Another element of clinical practice addressed by the report is whether patients should undergo tests that might reveal information about clopidogrel response. “The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time,” Dr. Holmes and colleagues write, noting that the various CYP2C19 polymorphisms account for only about 12% of differences in platelet response to clopidogrel. “There is no information that routine testing improves outcome in large subgroups of patients. In addition, the clinical course of the majority of patients treated with clopidogrel without . . . testing is excellent.” Thus, clinical judgment is required, they note.
For example, if a patient who is compliant with clopidogrel has an adverse event, either genetic or platelet function testing would make sense, Dr. Dehmer explained, cautioning that a drawback to this selective approach is that if the event in question is mortality, then testing may come too late. This idea lies behind arguments for routine testing, he said, but that strategy may not be feasible in cases where prompt treatment is crucial, such as acute MI.
There is also the question of cost, he added, pricing genetic tests at approximately $500. In an era of heightened concern about health care expenditures, “it would be an enormous undertaking” to recommend testing for every patient on clopidogrel, Dr. Dehmer said.
Source:
Holmes DR Jr, Dehmer GJ, Kaul S, et al. ACCF/AHA clopidogrel clinical alert: Approaches to the FDA “boxed warning.” J Am Coll Cardiol. 2010;Epub ahead of print.

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Repeat SES More Effective Than Balloon Angioplasty for SES Restenosis

Key Points:
For SES restenosis, recurrent TLR lower with SES vs. balloon angioplasty Mortality, stent thrombosis rates equal at 2 years
IVUS guidance, patient-centered approach key in lieu of definitive data
By Caitlin E. Cox
Friday, June 25, 2010

Repeat implantation of sirolimus-eluting stents (SES) after SES-associated restenosis is more effective at preventing a recurrence than balloon angioplasty, reports a Japanese registry study published online June 21, 2010, ahead of print in Circulation. Moreover, 2-year mortality and stent thrombosis rates are similar between the treatments, providing reassurance that repeat SES use is a safe option.
Researchers led by Takeshi Kimura, MD, of Kyoto University (Kyoto, Japan), looked at 990 patients enrolled in the physician-initiated, prospective j-Cypher registry who experienced SES-related restenosis during the course of 3-year follow-up after their initial stent implantation. A total of 1,094 lesions required TLR. At physician discretion, 537 of those lesions were treated with SES and 557 with balloon angioplasty (471 “plain old balloon angioplasty” and 86 cutting balloon).
More Different Than Alike
Baseline characteristics were similar between SES and balloon angioplasty patients, with the exception of diabetes prevalence, which was higher in the balloon angioplasty group (58% vs. 47%; P = 0.0007). Lesions treated with SES were more often saphenous vein graft and de novo. They were also more likely to have been treated under intravascular ultrasound (IVUS) guidance and with direct stenting. Balloon angioplasty-treated lesions, meanwhile, were more likely to be in the left circumflex coronary artery, to be at least 30 mm long, to have in-stent restenosis as the original lesion morphology, and side branch stenting. They were treated with a higher number of stents and with longer stents.

Cumulative incidence of recurrent TLR, the primary endpoint, was significantly lower in SES-treated lesions than in those who underwent balloon angioplasty. Late catch-up was observed in both groups between years 1 and 2, although the degree of catch-up appeared to be similar regardless of treatment strategy (table 1).
But of 33 baseline variables evaluated, only 2 remained independent predictors of recurrent TLR on multivariable analysis. SES treatment reduced the odds of reintervention (OR 0.44; 95% CI 0.32-0.61; P < 0.0001), while hemodialysis increased the risk (OR 1.61; 95% CI 1.02-2.53; P = 0.04).
Overall mortality did not differ between SES- and balloon angioplasty-treated patients at 1 year (4.5% and 6.6%) or at 2 years (10.4% and 10.8%; P = 0.4). Cumulative rates of definite stent thrombosis also were similar for the SES and balloon angioplasty groups at 1 year (0.2% and 0.6%). By 2 years, the incidence was 0.6% in both groups.
In terms of angiographic results, mean reference vessel diameter was significantly higher in SES-treated lesions than balloon angioplasty-treated lesions (2.95 ± 0.48 mm vs. 2.88 ± 0.45 mm; P = 0.02). Percent diameter stenosis and minimal lumen diameter, on the other hand, were similar between the 2 groups. Focal pattern was more prevalent than nonfocal pattern. In balloon-angioplasty treated lesions, nonfocal restenosis was associated with higher incidence of recurrent TLR compared with focal restenosis. SES-treated lesions did not show any difference in recurrent TLR related to pattern. For both focal and nonfocal lesions, SES treatment resulted in significantly fewer TLR events than did balloon angioplasty.
Researchers Advise Sticking with SES
The analysis of j-Cypher reveals “a very strong treatment effect of repeated SES implantation over [balloon angioplasty] in preventing recurrent TLR in a large number of patients with adjustment for differences in baseline characteristics,” Dr. Kimura and colleagues conclude. “Until otherwise proven by adequately sized randomized trials, our current observation supports the choice of repeated SES implantation for SES-associated restenosis.”
Optimal treatment of SES-related restenosis has not yet been defined, in part because the restenotic efficacy of these stents is so high that it can be difficult to obtain sufficiently large study populations, the investigators note. “However, with expanding indication of SES to more complex lesions, management of restenosis has emerged as a clinically relevant issue,” they write.
Future research should focus on determining predictors of refractory restenosis after SES treatment, they add. Such factors could guide the choice between PCI and CABG in patients with complex lesions.

Restenosis Issue Not Yet Eliminated

Paul S. Teirstein, MD, of the Scripps Clinic (La Jolla, CA), writes in an editorial accompanying the paper that “[i]n 2010, despite all the promising technology and all the research, creativity, effort, and dollars poured into the field, the problem of restenosis, although vastly reduced, has not been eliminated.” An estimated 200,000 repeat revascularizations are performed in the United States every year, he reports.
There are numerous treatment options—including simple balloon dilatation; cutting balloon; scoring balloon; restenting with the same DES or one with a newer design or different mechanism of action; redilation plus brachytherapy or oral sirolimus; and CABG—but data to guide decisions are sparse, Dr. Teirstein notes.
The j-Cypher paper contributes “another helpful but less than perfect data set to this troubled field. . . . Unfortunately, despite its size, owing to its many confounders and other limitations, the results of this large study are only modestly helpful to the physician community,” he said, adding that beyond significant differences in baseline characteristics between the 2 treatment groups “this study also suffers from a lack of randomization, a lack of study monitoring, and a lack of independent core laboratory assessment.”
In a telephone interview, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), told TCTMD, “As far as registry studies go, this one’s done very well and is a very good analysis.” He stressed 2 major caveats: lack of randomization and limitation of the study population to Japanese patients. “While I don’t think the fundamental biology would be any different in terms of restenosis or the response to the drug-eluting stents, there is potentially the issue of [antiplatelet] compliance being good in Japan,” which might substantially lower stent thrombosis rates compared with those within a heterogeneous American population, he explained.
With those caveats, “I still think it’s an important contribution to the literature and shows that the results of using a drug-eluting stent to treat drug-eluting stent restenosis are pretty good, both with respect to safety and efficacy,” Dr. Bhatt said, “though it also does show we’ve got some more work to do because the repeat revascularization rates were still not in the single digits after treatment.”
There are many treatment modalities available, “so what we need at this point is good exploration of those options with large, adequately powered randomized trials. That’s really the missing piece,” he commented. “Drug-coated balloons, for example, seem very appealing and are a nice way of tackling the restenosis without committing the patient to added layers of metal. That is something that is really quite exciting.”
Focus on Good Clinical Judgment
For now, “it’s a matter of trying to use best available data and good clinical judgment,” said Dr. Bhatt. He advised using IVUS to guide treatment decisions for DES restenosis. If IVUS indicates the initial stent was under-deployed or not sized appropriately for the artery, balloon angioplasty would be the likely choice. “On the other hand, if it was diffuse neointimal hyperplasia, I likely would elect to put in another drug-eluting stent,” he said, noting that patient-specific factors such as antiplatelet compliance, bleeding disposition, and potential need for noncardiac surgery should also be considered.
Dr. Teirstein offered additional advice for clinicians treating patients with DES in-stent restenosis:
In order to ease the emotional impact of repeat procedures, reassure patients that they do not have an incurable, lethal disease
Explain to them the mechanism of restenosis
Make every repeat PCI experience as patient-centered as possible, performing outpatient and radial access procedures when feasible
Sources:
Abe M, Kimura T, Morimoto T, et al. Sirolimus-eluting stent versus balloon angioplasty for sirolimus-eluting stent restenosis: Insights from the j-Cypher registry. Circulation. 2010;Epub ahead of print.
Teirstein PS. Drug-eluting stent restenosis: An uncommon yet pervasive problem. Circulation. 2010;Epub ahead of print.

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Rosiglitazone increased risk for serious CV events
By
When compared with pioglitazone, rosiglitazone prescription led to an increased risk of stroke, HF and all-cause mortality in patients aged 65 years and older, according to study findings.
The study consisted of a nationwide, observational, retrospective, inception cohort of 227,571 patients aged 65 years and older (mean age, 74.4 years) who began treatment with rosiglitazone (Avandia, GlaxoSmithKline) or pioglitazone (Actos, Takeda) through a Medicare Part D prescription drug plan from July 2006 to June 2009 and who underwent follow-up up to 3 years after thiazolidinedione initiation. The individual endpoints of acute MI, stroke, HF and all-cause mortality were the main outcome measures.
During the study period, researchers recorded 8,667 endpoints. The adjusted HR for rosiglitazone vs. pioglitazone was 1.06 (95% CI, 0.96-1.18) for acute MI; 1.27 (95% CI, 1.12-1.45) for stroke; 1.25 (95% CI, 1.16-1.34) for HF; and 1.14 (95% CI, 1.05-1.24) for all-cause mortality. For the composite of acute MI, stroke, HF or death, the adjusted HR was 1.18 (95% CI, 1.12-1.23) with the attributable risk for the composite endpoint being 1.68 (95% CI, 1.27-2.08) excess events per 100 person years of treatment with rosiglitazone vs. pioglitazone.
David N. Juurlink, MD, PhD,with the department of medicine, Sunnybrook Health Science Centre, Toronto, wrote in an accompanying editorial that although he did not regard the findings as being novel, the study’s strengths included that it was large, rigorously conducted and exceptionally timely.
“Accumulating concerns about rosiglitazone make it difficult to advance a cogent argument regarding why, exactly, a patient might want to receive the drug or why a physician would choose to prescribe it when there is an available and quite possibly safer alternative,” Juurlink wrote.
Graham DJ. JAMA. 2010;304:doi:10:1001/jama.2010.920.

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ACE inhibitor and amlodipine combo efficacious in patients with diabetes and hypertension
By

An ACE inhibitor when combined with amlodipine was more effective in preventing fatal and nonfatal CV outcomes in patients with hypertension and diabetes than when combined with hydrochlorothiazide, study data indicated.

Researchers analyzed patients with diabetes (n=6,946) who were randomly assigned to treatment with benazepril combined with either amlodipine (B+A) or hydrochlorothiazide (B+H) in the ACCOMPLISH trial. They also analyzed a subgroup of patients with diabetes at a very high risk (n=2,842) and patients without diabetes (n=4,559). A composite of CV death, stroke, MI, resuscitated arrest, hospitalization for angina and coronary revascularization was the primary endpoint.

The mean achieved BP in the full diabetes group was 131.5 mm Hg/72.6 mm Hg in the B+A treatment group and 132.7 mm Hg/73.7 mm Hg in the B+H group. During 30 months, the B+A group experienced 307 primary events while the B+H group had 383 (HR=0.79; 95% CI, 0.68-0.92). The patients with a very high risk of diabetes given B+A had 195 primary events, whereas those given B+H had 244 (HR=0.77; 95% CI, 0.64-0.93). In patients without diabetes, there were 245 primary events in the B+A group and 296 in the B+H group (HR=0.82; 95% CI, 0.69-0.97).
“For the large proportion of diabetic patients whose blood pressure can be controlled with a two-drug combination, the use of amlodipine with a blocker of the renin-angiotensin system should now be considered,” the researchers concluded.
Weber M. J Am Coll Cardiol. 2010;doi:10.1016/j.jacc.2010.02.046.

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No improvement on all-cause mortality in patients given statins
By

Patients at high risk who received statins showed no evidence of all-cause mortality improvement, study data indicated.

Researchers of this meta-analysis compiled trials through searches of the Medline and Cochrane databases that were dated January 1970 to May 2009, using terms related to statins, CV endpoints and clinical trials. The prospective, randomized controlled trials of statin therapy involved patients free from CVD at baseline and provided data on all-cause mortality.

In the 11 selected trials (n=65,229), patients were followed for about 244,000 person-years. During this time, 2,793 deaths took place, of which 1,447 deaths occurred among placebo patients (n=32,606) and 1,346 deaths among those treated with a statin (n=32,623). The RR for all-cause mortality associated with statin use was 0.91 (95% CI, 0.83-1.01). Researchers also reported no statistical evidence of heterogeneity between the studies (I²=23%; 95% CI, 0%-61%).
“We observed that statin therapy for an average period of 3.7 years had no benefit on all-cause mortality in a high-risk primary prevention population,” the researchers wrote. “Current prevention guidelines endorse statin therapy for subjects at high global risk of incident CVD as a means to reduce fatal and nonfatal vascular events. Due consideration is needed in applying statin therapy in lower-risk primary prevention populations.”
Ray KK. Arch Intern Med. 2010;170:1024-1031.

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CASES-PMS: With formalized training, physicians with varied experience achieved similar results to those highly experienced in carotid stenting
By
The varied experience level of physicians in the CASES-PMS trial did not prevent them from attaining similar stenting results as the highly experienced physicians from the SAPPHIRE trial, new study data suggested.
Carotid Artery Stenting With Emboli Protection Surveillance – Post-Marketing Study (CASES-PMS) researchers included patients in their study who were older than 18 years and had de novo atherosclerotic or post-endarterectomy restenotic obstructive lesions in native carotid arteries with either ≥50% carotid stenosis if symptomatic or≥80% carotid stenosis if asymptomatic; and patients with at least one anatomic or physiologic risk factor placing them at high risk for surgery. The primary endpoint was a composite of 30-day major adverse events, which included death, any stroke or MI. The patients (n=1,492) were enrolled at 73 sites from August 2003 to October 2005.
The rate of the primary endpoint was 5%, which met criteria for noninferiority to the prespecified objective performance criteria set by the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial. The 1-year cumulative percentage of major adverse events was 12.5%, and all strokes to 30 days plus ipsilateral stroke between 31 and 360 days were similar in the CASES-PMS trial (5.4%) vs. the SAPPHIRE cohort (4.9%).
“With the formalized training program utilized in this study, physicians with varied experience in carotid stenting can achieve short- and longer-term results similar to the highly experienced SAPPHIRE investigators,” the researchers concluded. “One-year outcomes with CASES-PMS showed little additional neurological morbidity and mortality beyond an acceptable 30-day outcome previously reported, and largely reflects the natural history of a large cohort of patients with a high prevalence of advanced cardiovascular disease at baseline.”
Schreiber TL. J Am Coll Cardiol. 2010;56:49-57.
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No difference in strut coverage reported between zotarolimus-eluting or bare metal stents
By
A comparison of strut coverage between zotarolimus-eluting stents and bare metal stents resulted in no significant differences between the two devices, findings from the Optical Coherence Tomography in Acute Myocardial Infarction study indicated.
Forty-four patients with STEMI who underwent primary percutaneous coronary intervention were randomly assigned zotarolimus-eluting stents (Endeavor, Medtronic; n=33) or bare metal stents (n=11). Researchers conducted angiographic, IVUS and optical coherence tomography at 6 months and clinical follow-up at 1 year.
According to researchers, there were no differences between zotarolimus-eluting and bare metal stents in uncovered struts, maximum length of uncovered segments, percentage of malapposed struts and maximum length of malapposed segments. They also reported a similar response between zotarolimus-eluting and bare metal stents in neointimal response. In addition, there were no deaths, MI or stent thrombosis at clinical follow-up, and no late acquired malapposition in either group.
Study limitations included the lack of endothelial cell level resolution and inability to provide functional tissue differentiation in the intravascular optical coherence tomography, the small group of patients, and the fact that researchers did not perform pre-PCI or post-PCI optical coherence tomography, mainly due to concerns over patient safety.
“This [optical coherence tomography] study found similar 6-month strut coverage and vessel response in zotarolimus-eluting stents and bare metal stents implanted during primary PCI,” the researchers concluded. “Long-term follow-up in more patients is required to establish the clinical significance of these imaging findings regarding stent thrombosis and restenosis.”
Guagliumi G. J Am Coll Cardiol Intv. 2010;3:680-687.

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Title: Screening Asymptomatic Subjects for Subclinical Atherosclerosis: Can We, Does It Matter, and Should We?
Date Posted: June 29, 2010
Authors: Shah PK.
Citation: J Am Coll Cardiol 2010;56:98-105.

Print
Conclusions:
The following are 10 points to remember about this viewpoint and commentary.

1. Approximately 40-60% of major occlusive atherosclerotic cardiovascular events (i.e., myocardial infarction, sudden death) occur as the first manifestation (unheralded events), accounting for >700,000 such events annually in the United States. The identification of subjects at risk of such events is obviously important, if identification leads to implementation of and compliance with effective preventive measures that reduce such risk.

2. Guidelines suggest using the Framingham Risk Score (FRS) to help decide prevention strategies, but are limited by underestimation of lifetime risk, misclassification of high-risk subjects as low or intermediate risk, and misclassification of very low-risk subjects into higher strata of risk. A highly significant number of low- and intermediate-risk persons have preclinical atherosclerosis.

3. The currently available biomarkers, specifically high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2, provide statistically significant but clinically modest incremental prognostic value and, thus, are not sufficiently precise to markedly improve the discriminant value of FRS.

4. Noninvasive imaging techniques can identify atherosclerosis in various vascular beds. To date, the most extensively studied are coronary calcium, a validated measure of atherosclerotic plaque, by noncontrast computed tomography, and B-mode ultrasonography to detect carotid intima-media thickness (CIMT) and carotid plaque.

5. Absence of coronary calcium (coronary calcium score [CCS] = 0), while not excluding the presence of noncalcified plaque, virtually excludes significant coronary atherosclerosis, but more importantly is associated, in an asymptomatic population, with an extremely low risk of cardiovascular events in the ensuing 5-10 years, ranging from 0.0% to 0.6%. The absence of calcium does not infer a low risk of coronary disease in symptomatic persons.

6. An increase in CIMT (over 75th percentile for a person’s age, sex, and race) is associated with future risk of cardiovascular events independent of risk factors, and the presence of carotid plaque (50% greater than adjacent wall or >1.5 mm) is more significant than simply an increase in CIMT. CCS appears to have incremental prognostic value over CIMT, with the exception of CIMT being more predictive of strokes.

7. Despite the lack of randomized clinical trial evidence, the totality of observational evidence supports imaging-guided management because: 1) detecting disease is likely better than simply identifying risk factors that have only a modest specificity and a highly variable relationship to the development of disease; 2) imaging can reclassify intermediate- and low-risk FRS subjects into higher risk strata for which more aggressive medical therapy and lower cholesterol targets would be recommended, thereby tangibly altering benefit; and 3) imaging-based identification of at-risk subjects may improve compliance and adherence to risk-modifying interventions.

8. The SHAPE (Screening for Heart Attack Prevention and Education) Task Force screening guidelines recommend noninvasive atherosclerosis imaging of all asymptomatic men (ages 45-75 years) and women (ages 55-75 years), except those at very low risk, to augment conventional cardiovascular risk assessment algorithms. Using SHAPE guidelines, between 35-48% of persons are placed in a higher risk stratum, making them eligible for lipid-lowering therapy, and the number needed to reclassify one individual as newly eligible (or no longer eligible) for lipid-lowering therapy ranged from 4.1 to 7.8, depending on the CCS threshold used.

9. Studies have suggested a cost-effectiveness of the SHAPE guideline, particularly if the cost is decreased from the $400 used for the analysis and if compliance is increased as has been seen in observational studies. There could be a small increase in lifetime risk of cancer from the median radiation exposure of 2.3 mSv.

10. Although randomized, controlled, prospective data to prove the efficacy of imaging-guided risk assessment in improving clinical outcomes are not available and such studies should be encouraged, the large amount of observational cohort and prospective longitudinal data support selective use of imaging-based risk assessment, especially in intermediate-risk groups identified by the FRS.
Perspective:
Our group strongly supports screening all but the very low-risk patient, as per the SHAPE guidelines, and we consider screening younger men and women with a low high-density lipoprotein cholesterol or family history of premature coronary artery disease. We have convinced our institution to provide screening CCS at cost ($260).
Author(s):
Melvyn Rubenfire, M.D., F.A.C.C.
Topic(s):
General Cardiology, Prevention/Vascular, Noninvasive Cardiology

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Title: Hypertension 2008—Awareness, Understanding, and Treatment of Previously Diagnosed Hypertension in Baby Boomers and Seniors: A Survey Conducted by Harris Interactive on Behalf of the Preventive Cardiovascular Nurses Association
Date Posted: June 17, 2010
Authors: Miller NH, Berra K, Long J.
Citation: J Clin Hypertens 2010;12:328-334.
Study Question:
How do cardiovascular disease (CVD) risk factors, relationships with health care providers, and rates of adherence to therapy differ between a cohort of hypertensive American adults ages 44-62, and those ages 63 and older?
Methods:
In June 2008, a Harris Interactive online survey was conducted with 1,548 hypertensive persons ages 44 and older, who were asked 124 closed-ended questions including demographics, medication use and adherence, and relationship with health care provider.
Results:
The survey confirms the findings of earlier research demonstrating suboptimal rates of adherence to antihypertensive recommendations, both medication and lifestyle regimens, despite awareness of the health risks associated with uncontrolled hypertension. Analysis by age group (baby boomers, ages 44-62 years, and seniors ages 63 years and older) revealed that nonadherence was higher in the baby boomer cohort, although the boomers reported a higher level of concern than the seniors. Gaps in provider-patient communication appear to contribute to suboptimal adherence to treatment recommendations.
Conclusions:
The age of the patient plays an important role in both attitude and behavior regarding chronic disease management, as well as preferences as to type of educational materials considered helpful and the vehicle by which the education is delivered.
Perspective:
Because of the large number of those in the cohort born between 1946 and 1964, additional further research is warranted to evaluate attitudes, knowledge, and behaviors concerning the identification and treatment of hypertension. Understanding these factors will contribute to the development of potential strategies to address treatment adherence.
Author(s):
Suzanne Hughes, MSN, RN
Topic(s):
General Cardiology, Prevention/Vascular

Title: Statins and All-Cause Mortality in High-Risk Primary Prevention: A Meta-Analysis of 11 Randomized Controlled Trials Involving 65,229 Participants
Date Posted: June 29, 2010
Authors: Ray KK, Kondapally Seshasai SR, Erqou S, et al.
Citation: Arch Intern Med 2010;170:1024-1031.
Study Question:
Does statin use for primary prevention reduce risk of all-cause mortality?
Methods:
This was a meta-analysis of randomized controlled trials identified from literature searches of MEDLINE and Cochrane databases. Trials were published between January 1970 and May 2009. Inclusion criteria were a study design, which was prospective and randomized with the use of a control arm. The study population was free of cardiovascular disease (CVD) at baseline. Data on all-cause mortality were published or available.
Results:
A total of 1,226 citations were identified, of which 17 full-text articles were reviewed and 11 studies were included in this analysis. A total of 65,229 participants were included; over 244,000 person-years of follow-up, 2,793 deaths occurred. Subjects were primarily from western countries, with an age range of 51-75 years. The proportion of women in these studies ranged from 0-68%. The average low-density lipoprotein (LDL) cholesterol at baseline was 138 mg/dl and the average follow-up LDL was 94 mg/dl for subjects randomized to statins. Mean follow-up was 3.7 years. Statin use was not associated with a reduction in all-cause mortality (relative risk, 0.91; 95% confidence interval, 0.83-1.01) or an estimated 7 fewer deaths for every 10,000 person-years of treatments. There was no statistical evidence of heterogeneity among studies.
Conclusions:
The authors concluded that statin therapy does not appear to reduce all-cause mortality among men and women with no prior history of CVD and only modestly elevated LDL cholesterol levels.
Perspective:
This meta-analysis suggests that among patients with no prior history of CVD, in particular those at lower risk, statins may not provide significant benefit.
Author(s):
Elizabeth A. Jackson, M.D., F.A.C.C.
Topic(s):
Prevention/Vascular