Обзор американских кардиологических журналов за неделю (ссылки)

[Chevychelov]

Trial Summary COGENT
Title: Clopidogrel and the Optimization of Gastrointestinal Events Trial
Trial Sponsor: Cogentus Pharmaceuticals
Year Presented: 2009
Year Published: 2010
Topic(s): General Cardiology, Interventional Cardiology
Summary Posted: 10/6/2010
Writer: Dharam J. Kumbhani, M.D., S.M.
Author Disclosure: NOTHING TO DISCLOSE
Reviewer: Peter C. Block, M.D., F.A.C.C.
Reviewer Disclosure: CONSULTING FEES/HONORARIA: QuantumCor, Medtronic, Intervalve EQUITY INTERESTS/STOCK OPTIONS: Direct Flow Medical RESEARCH/RESEARCH GRANTS: Edwards Lifesciences

Description:

A few platelet studies have indicated that proton pump inhibitors (PPIs), specifically omeprazole, are associated with reduced antiplatelet efficacy of clopidogrel, when used together. In addition, the use of dual antiplatelet therapy is often fraught with problems of gastrointestinal (GI) bleeding in patients at higher risk for bleeding. The current trial sought to study clinical GI and cardiovascular (CV) outcomes in patients on dual antiplatelet therapy with aspirin and clopidogrel, who had no indication for a PPI.
Hypothesis:

PPIs would be associated with a lower risk of bleeding as compared with placebo in patients at average risk for bleeding from antiplatelet therapy. This would be achieved without a significant increase in adverse clinical outcomes resulting from possible reduced antiplatelet efficacy of clopidogrel.
Drugs/Procedures Used:

Patients were randomized to receive either a fixed dose of clopidogrel 75 mg along with omeprazole 20 mg (CGT-2168), or clopidogrel with placebo.
Concomitant Medications:

All patients received enteric coated aspirin at a dose of 75-325 mg daily; statins (68%); nonsteroidal anti-inflammatory drugs (NSAIDs; 9%)
Principal Findings:
A total of 3,761 patients were randomized, 1,876 to clopidogrel + omeprazole, and 1,885 to clopidogrel alone. The trial was terminated early when the sponsor lost financing. Baseline characteristics were fairly similar between the two groups. About 49% of the patients were H. pylori positive, and 9% had used NSAIDs. History of myocardial infarction (MI) or stroke was noted in 30% and 8% of the patients, respectively. About 13% were current smokers, 52% consumed alcohol, and 4% had a history of GI bleeding or an ulcer in the past.

The primary endpoint of GI events at 180 days was significantly lower in the clopidogrel + omeprazole arm, as compared with the clopidogrel alone arm (1.1% vs. 2.9%, hazard ratio 0.34, 95% confidence interval 0.18-0.63, p < 0.001). There was no interaction when stratified by H. pylori or NSAID use status. Of the individual components of the primary endpoint, overt gastroduodenal bleeding (0.1% vs. 0.6%, p = 0.03) and overt upper GI bleeding of unknown origin (0.1% vs. 0.6%, p = 0.03) were both significantly reduced in the combination arm, as compared with the placebo arm.

CV events, including any CV event (4.9% vs. 5.7%, p = 0.98), MI (1.2% vs. 1.5%, p = 0.83), revascularization (4.0% vs. 4.6%, p = 0.70), stroke (0.2% vs. 0.3%, p = 0.43), CV mortality (0.4% vs. 0.3%, p = 0.49), and all-cause mortality (0.4% vs. 0.5%, p = 1.0) were similar between the combination and placebo arms, respectively. In addition, there were no cases of stent thrombosis in the clopidogrel + omeprazole arm, as compared with two in the clopidogrel + placebo arm.

Serious adverse events were similar (10.1% vs. 9.4%, p = 0.48). Diarrhea was more frequent in patients receiving omeprazole (3.0% vs. 1.8%, p = 0.01).
Interpretation:
The results of this landmark trial indicate that the concomitant use of clopidogrel with omeprazole is associated with a reduction in composite GI events when used in patients who were not at high risk for GI bleeding, including overt upper GI bleeding. This is achieved without an increase in adverse CV events, contrary to what has been suggested by ex vivo platelet assays, and a few observational studies.

Similar concerns from ex vivo platelet assays had been raised for atorvastatin when used with clopidogrel, but had not borne out when tested for clinical outcomes in randomized controlled trial data sets. This highlights the importance of clinical outcomes over surrogate measures, such as platelet assays, and also the importance of well-conducted randomized controlled trials over observational studies.

One issue is that it is unknown if clopidogrel and omeprazole taken together would have the same lack of interaction as the fixed dose combination tested in this trial. This will need to be tested in future trials, since the company making this fixed dose combination is now defunct. Also, since homozygosity for loss of function of the CYP2C19 gene has been shown to be associated with reduced transformation of clopidogrel to active metabolite, future studies will also need to focus on the effect of PPIs in this subgroup of patients.
Conditions:
Coronary heart disease
Prevention/Secondary
Therapies:
Antiplatelet agent / Clopidogrel
Study Design:
Blinded. Parallel. Placebo Controlled. Randomized. Stratified.
Patients Screened: 4,444
Patients Enrolled: 3,761
Mean Follow Up: 180 days
Mean Patient Age: Median: 68.6 years
Female: 32%
Primary Endpoints:
Composite GI events, defined as upper GI bleeding; bleeding of presumed occult GI origin with decrease in hemoglobin of ≥2 g/dl or decrease in hematocrit ≥10%; symptomatic gastroduodenal ulcer confirmed by endoscopy or radiography; pain of presumed GI origin with underlying multiple erosive disease confirmed by endoscopy, obstruction, or perforation
Composite of CV death, nonfatal MI, coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), or ischemic stroke
Secondary Endpoints:
Occurrence of gastroesophageal reflux disease, as evidenced by symptomatic, endoscopically confirmed erosive esophagitis
Patient Population:
Age ≥21 years
Clopidogrel therapy with concomitant aspirin was anticipated for at least the next 12 months
o Acute coronary syndrome
o Undergoing placement of a coronary stent
Exclusions:
Hospitalized patients for whom discharge was not anticipated within 48 hours of randomization
Requirement for current or chronic use of a PPI, H2 receptor blocker, sucralfate, or misoprostol
Erosive esophagitis, esophageal, or gastric variceal disease, or non-endoscopic gastric surgery
Receipt of >21 days of clopidogrel or another thienopyridine prior to randomization
Oral anticoagulation that cannot be safely discontinued for duration of study
Recent fibrinolytic therapy
Scheduled PCI or recent (<30 days prior to randomization) CABG
Active bleeding or a history of a hemostatic disorder
Systemic corticosteroids except low-dose oral corticosteroids equivalent to prednisone ≤5 mg/day
References:

Bhatt DL, Cryer BL, Contant CF, et al., on behalf of the COGENT Investigators. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;Oct 6:[Epub ahead of print].

Presented by Dr. Deepak Bhatt at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2009), San Francisco, CA, September 24, 2009.

[Chevychelov]

Title: Chest Compression-Only CPR by Lay Rescuers and Survival From Out-of-Hospital Cardiac Arrest
Date Posted: October 5, 2010
Authors: Bobrow BJ, Spaite DW, Berg RA, et al.
Citation: JAMA 2010;304:1447-1454.

Study Question:
Does compression-only cardiopulmonary resuscitation (COCPR) by bystanders improve outcomes after sudden cardiac arrest (SCA)?
Methods:
This was a prospective, observational cohort analysis of 4,415 patients (mean age 65 years) with SCA in 2005-2009 in Arizona. A public education campaign promoting COCPR was initiated in Arizona in 2005. The 1º endpoint was survival to hospital discharge.
Results:
Fifteen percent of patients received conventional bystander CPR, 19% received COCPR, and 66% did not receive any bystander CPR. Overall survival to hospital discharge was 7.1%. COCPR was a significant independent predictor of survival compared to no CPR (odds ratio [OR], 1.6) and compared to conventional CPR (OR, 1.6). The percentage of patient who survived with good neurologic status was significantly higher in the COCPR group (7.6%) than in the conventional CPR group (5.2%) or no-CPR group (3.0%).
Conclusions:
Compared to no CPR or conventional CPR, bystander COCPR significantly improves outcomes after SCA.
Perspective:
COCPR is associated with improved survival after SCA because it avoids several of the problems associated with conventional CPR, including: 1) the cessation of cardiac output during interruptions in chest compressions, 2) the long interval needed to restore cardiac output after resumption of chest compressions, 3) the reduction in venous return associated with positive pressure ventilation, and 4) the reluctance of bystanders to perform mouth-to-mouth ventilation.
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Title: Downloadable Software Algorithm Reduces Inappropriate Shocks Caused by Implantable Cardioverter-Defibrillator Lead Fractures. A Prospective Study
Date Posted: October 6, 2010
Authors: Swerdlow CD, Gunderson BD, Ousdigian KT, Abeyratne A, Sachanandani H, Ellenbogen KA.
Citation: Circulation 2010;122:1449-1455.

Print
Study Question:
Does software that detects oversensing or high lead impedance lower the risk of inappropriate shocks in patients with an implantable cardioverter-defibrillator (ICD) and a fractured Medtronic Fidelis lead?
Methods:
The subjects of this study were 426 patients (mean age 61 years) with an ICD and a Fidelis lead confirmed to be fractured at the time of explantation. Software that provides a lead-integrity alert (LIA) triggered by oversensing or high impedance was implanted in 213 patients at the discretion of the treating physician. The other 213 patients were monitored by automated daily impedance measurements and served as a control group.
Results:
The prevalence of inappropriate shocks was significantly lower in the LIA group (38%) than in the control group (70%). There was a 50% relative reduction in the prevalence of patients with ≥5 inappropriate shocks in the LIA group. The proportion of patients with no inappropriate shocks or ≥3 days of warning was significantly higher in the LIA group (72%) than in the control group (50%).
Conclusions:
Inappropriate shocks caused by a lead fracture are reduced by a LIA software upgrade.
Perspective:
The most common clinical manifestation of lead fractures is inappropriate shocks. This study demonstrates that downloadable software improves the sensitivity with which a non-physiological event such as electrical noise caused by a fracture is detected, thereby making inappropriate shocks less likely. In addition to demonstrating the efficacy of the new algorithm, the study demonstrates the feasibility of downloading software upgrades to previously implanted ICDs.

[Chevychelov]

Vitamin D and Heart Failure
by Charley Hepfinger, PharmD

Accumulating evidence suggests that vitamin D deficiency (serum levels <20 ng/mL) and insufficiency (serum levels between 20 ng/mL and 30 ng/mL) may play a role in the development of a variety of conditions, including HF. Several studies have demonstrated an association between low vitamin D levels and worse outcomes among patients with HF. The prevalence of hypovitaminosis D is high, with as much as 57% of the U.S. adult population affected. This has potentially far-reaching implications for the optimal management of patients with HF.

There are many risk factors for the development of vitamin D deficiency. Some of the more common include: lack of sun exposure, pigmented skin, older age, institutionalization, obesity, kidney and liver disease, and the use of certain drugs (eg, anticonvulsants, glucocorticosteroids).

One major source of vitamin D is sunlight. Photosynthesis in the epidermis results in the conversion of endogenous 7-dehydrocholestol to cholecalciferol (vitamin D3). Vitamin D can also be obtained through the diet or by supplementation. The two major forms of dietary (or supplementary) vitamin D are ergocalciferol (vitamin D2) and cholecalciferol. Vitamins D2 and D3 are precursors of the hormonally active form known as 1,25-dihydroxycholecalciferol (ie, calcitriol), which plays an important role in CVD.

Low levels of calcitriol have been associated with activation of the renin-angiotensin aldosterone system, elevated levels of proinflammatory cytokines such as tumor necrosis factor alpha, and an increase in parathyroid hormone, all of which may increase the risk for CVD. Besides these systemic effects, there may be local implications as well. The vitamin D receptor, which is widely distributed throughout human tissues, has been identified in human cardiomyocytes, where it regulates many important physiologic processes, including calcium influx and myocyte proliferation and hypertrophy. In addition, enzymes necessary for the conversion of vitamin D precursors to calcitriol have been isolated in heart tissue.

Vitamin D trials

Many observational studies and some randomized trials have been performed to further elucidate the role of vitamin D in HF. One of the first human studies demonstrating the possible benefit of vitamin D supplementation in HF involved a randomized, controlled trial among 123 patients treated for 9 months with cholecalciferol 2,000 IU daily vs. placebo. Although results demonstrated no differences in survival rates in this relatively small, short-term study, patients who received cholecalciferol achieved significant reductions in parathyroid hormone and tumor necrosis factor alpha, as well as significant increases in the anti-inflammatory cytokine interleukin-10. As expected, serum vitamin D levels increased in the treatment group by 26.8 ng/mL.

In another more recent trial, investigators examined the relationship between vitamin D deficiency and various assessments associated with HF, including HF mortality. In this study, 3,299 patients who had been referred for cardiac angiography had baseline serum vitamin D levels measured. They were categorized into four groups based on vitamin D status: severe deficiency (<10 ng/mL), moderate deficiency (10 to 19.99 ng/mL), insufficiency (20 to 29.99 ng/mL) and optimal (≥30 ng/mL). During the 7.7-year follow-up period, there were significantly more HF-related deaths among those with severe vitamin D deficiency (6.6%) vs. those with optimal levels (1.8%). Even after adjusting for multiple potential confounders, the HR remained significant at 2.84 for those with severe deficiency. Other findings included a significant negative correlation between vitamin D serum levels and N-terminal pro-B-type natriuretic peptide, as well as significant inverse associations between vitamin D levels and impaired left ventricular function and NYHA functional classification.

Although currently available evidence does not support widespread vitamin D screening for all patients with HF, consideration should be given for assessment in some HF subgroups. Clearly, those with concomitant disease states necessitating optimal vitamin D levels (eg, osteoporosis) should be screened and treated. Other patients with HF who may benefit from screening include those with multiple risk factors for deficiency and those with persistent HF-related symptoms despite the use of optimal drug therapy (eg, ACE inhibitors/angiotensin receptor blockers, beta-blockers). Although calcitriol is the active form of vitamin D, the most reliable predictor of bodily stores is 25-hydroxyvitamin D (25-OH vitamin D) and is thus the preferred method for assessing vitamin D status.

Repletion regimens

For patients with vitamin D deficiency or insufficiency, there are a variety of repletion regimens that have been used. Dosing should be individualized based on a given patient’s 25-OH vitamin D level and risk factors. Vitamin D supplements are available in two forms: plant-derived ergocalciferol, and cholecalciferol, which is animal-based. Although some experts favor the use of cholecalciferol because of greater potency, once consumed, both forms are ultimately converted to 25-OH vitamin D. One strategy for replacement in deficiency includes ergocalciferol 50,000 IU orally once weekly for 8 to 12 weeks. Insufficiency can generally be treated for shorter durations or with lower daily doses (eg, cholecalciferol 1,000 IU by mouth daily). Depending on the cause, most patients with deficiency will likely require long-term, lower daily dosing to maintain body stores. As with all drug therapy, patients should receive appropriate monitoring to ensure safety. Although rare, hypercalcemia and hyperphosphatemia may occur and could be measured, along with a repeat 25-OH vitamin D level after replacement.

Data from future randomized, controlled trials will help to establish more definitive guidelines regarding vitamin D supplementation in patients with HF or other CV and renal diseases. According to ClinicalTrials.gov, there are currently at least eight studies in various stages examining the effects of vitamin D in patients with HF, and many other ongoing vitamin D trials in patients with heart disease and/or chronic kidney disease. One of the largest is the Paricalcitol Capsules Benefits in Renal Failure-Induced Cardiac Morbidity in Chronic Kidney Disease (PRIMO) trial. This study will randomly assign 220 patients with chronic kidney disease to treatment with paricalcitol (an activated vitamin D analogue) vs. placebo for 48 weeks to assess the potential effects of paricalcitol on LV hypertrophy. An even larger trial, the Vitamin D and Omega-3 Trial (VITAL) is a 5-year study that will enroll 20,000 patients and will measure several important outcomes, including CVD, stroke and cancer. Results from studies such as PRIMO, VITAL and others will help further clarify the role of vitamin D in many high-risk conditions.

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Folic acid supplementation for homocysteine reduction yields no effect on vascular outcomes
Clarke R. Arch Intern Med. 2010;170:1622-1631.

Data from a meta-analysis of eight randomized trials demonstrated that folic acid supplementation to reduce homocysteine levels did not significantly affect CV events, cancer or mortality in patients at higher risk for CVD.

“Elevated plasma total homocysteine has been suggested as a potentially modifiable risk factor for CHD, stroke and other occlusive vascular conditions,” the researchers wrote.

However, the researchers found that lowering homocysteine levels by 25% for 5 years did not significantly affect the incidence of major vascular events during the treatment period.

The meta-analysis included eight randomized, placebo-controlled trials of 37,485 patients at high risk for CVD. Participants were randomly assigned to receive folic acid (n=18,723) in doses ranging from 0.8 mg per day to 40 mg per day or to placebo or a small dose of folic acid (n=18,762). Median duration of treatment was 5 years.

During the treatment period, 3,990 major coronary events, 1,528 strokes and 5,068 revascularizations occurred, as well as 3,010 cancers and 5,125 deaths. Folic acid supplementation resulted in an average reduction of 25% in homocysteine levels but was not associated with significant effects on vascular outcomes. The rate ratios were 1.01 (95% CI, 0.97-1.05) for major vascular events, 1.03 (95% CI, 0.97-1.10) for major coronary events and 0.96 (95% CI, 0.87-1.06) for stroke.

Similarly, there was no significant effect on cancer outcomes during the treatment period. The rate ratio was 1.05 (95% CI, 0.98-1.13) for overall cancer incidence, 1.00 (95% CI, 0.85-1.18) for cancer mortality and 1.02 (95% CI, 0.97-1.08) for all-cause mortality.

Additionally, folic acid supplementation did not significantly affect vascular outcomes in any subgroups and did not affect overall vascular mortality, according to the researchers. Participants who experienced larger reductions in homocysteine levels did not experience any benefit, and longer duration of treatment did not trend toward increasing benefit.

“Although the lack of any other benefits is disappointing (albeit fairly definitive), the lack of any significant adverse effects on vascular events, cancer incidence, cancer mortality and overall mortality provides reassurance about the safety of population-wide folic acid fortification,” the researchers wrote.
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Periaortic fat linked with PAD, low ankle-brachial index
Fox CS. Circ Cardiovasc Imaging. 2010;3:515-519.

Researchers have demonstrated an association between periaortic fat and both peripheral arterial disease and low ankle-brachial index in more than 1,000 members from a community-based population.

“Central obesity is associated with PAD, suggesting that ectopic fat depots may be associated with localized diseases of the aorta and lower-extremity arteries,” the researchers wrote. “We hypothesized that persons with greater amounts of periaortic fat are more likely to have clinical PAD and a low ankle-brachial index (ABI).”

This hypothesis culminated in an analysis of 1,205 individuals (53.7% women; mean age, 65.9 ± 8.9 years) from the Framingham Heart Study Offspring cohort. Researchers measured periaortic fat surrounding the thoracic aorta using a volumetric quantitative approach and also quantified visceral abdominal fat. They defined clinical PAD as a history of intermittent claudication and dichotomized ABI as low (≤0.9) or lower-extremity revascularization vs. normal (>0.9 to <1.4).

Study results indicated that the OR for the combined endpoint per one standard deviation increase in periaortic fat was 1.52 (P=.004), which was heightened with additional adjustment for BMI (OR=1.69; P=.002) or visceral abdominal fat (OR=1.67; P=.009); however, no association was observed for visceral abdominal fat (P=.16). No association was also reported per standard deviation increase in BMI or waist circumference after accounting for visceral abdominal fat (BMI, P=.35; waist circumference, P=.49).

Study limitations included the strictly white study population, which limited generalizability to other races, and the use of thoracic periaortic fat as a proxy measure of perivascular fat through the entire arterial tree due to the researchers’ inability to quantify perifemoral artery fat.

“We demonstrated that periaortic fat is associated with low ABI and intermittent claudication. We did not observe a similar association with BMI, waist circumference or visceral abdominal fat,” the researchers concluded. “Our findings suggest a potential role for periaortic fat in the pathogenesis of PAD.”

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Type 2 diabetes increased risk for sudden cardiac death in patients after MI
Junttila M. Heart Rhythm. 2010;7:1396 -1403.

Patients with type 2 diabetes may be at a higher risk for sudden cardiac death after MI than nondiabetic patients, new data from Hearth Rhythm suggests.
“Type 2 diabetes mellitus is a well-established risk factor for atherosclerosis, but its contribution to sudden cardiac death risk after MI is not well defined,” the researchers wrote. “Sudden cardiac death in the post-MI patient is of special interest because of the magnitude of risk, the challenge of individual risk profiling and the potential for prevention in high-risk individuals.”
The study included 3,276 patients (mean age, 60 ± 11 years) who were enrolled at the time of acute MI between 1996 and 2005, and they were followed until 2009. At baseline, 629 patients (19.2%) had type 2 diabetes based upon WHO criteria. Patients with type 1 diabetes and patients with cardiac arrest during or before MI were excluded from the study.
Among patients with type 2 diabetes, rate of sudden cardiac death was notably higher than for nondiabetic patients (5.9% vs. 1.7%; adjusted HR=2.3; 95% CI, 1.4-3.8). The incidence of sudden cardiac death in diabetic patients with left ventricular ejection fraction of more than 35% was nearly identical to nondiabetic patients with LVEF of 35% or less (4.1% vs. 4.9%; P=.48).
Researchers also noted that an excess in the incidence of non-sudden cardiac death among diabetic patients started to appear within the first 6 months of follow-up (P<.001). This was not the case for both the incidence and excess of sudden cardiac death for diabetic patients, which did not begin to appear until more than 6 months after the index event.
“Patients with type 2 diabetes are at higher risk for sudden cardiac death after MI than are nondiabetic patients. The incidence of sudden cardiac death in post-MI type 2 diabetic patients with LVEF >35% is equal to that of nondiabetic patients with LVEF <35%,” the researchers concluded. “Further prospective information on post-MI diabetic patients is needed to evaluate indications for, and efficacy of, implantable cardioverter defibrillators and other therapies for this higher-risk subgroup.”
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FDA requests withdraw of sibutramine from U.S. market

The FDA has issued a recommendation against the continued prescription and use of sibutramine due to elevated CV risks to certain patients taking the drug, according to a press release.
The agency determined that the CV risks outweighed the marginal benefits associated with the drugs and requested that the manufacturer of sibutramine (Meridia, Abbott Laboratories) voluntarily withdraw the product from the market in the U.S. Abbott Laboratories agreed to the request.
The withdraw came after new data from the approximately 10,000-patient Sibutramine Cardiovascular Outcomes (SCOUT) trial indicated a 16% increased risk for major adverse CV events (a composite of nonfatal MI, nonfatal stroke, resuscitation after MI and CV death) in patients taking sibutramine vs. placebo (HR=1.16; 95% CI, 1.03-1.31). The primary endpoint of the trial was driven, according to data cited in an FDA press release, by nonfatal MI (HR=1.28; 95% CI, 1.04-1.57) and nonfatal stroke (HR=1.36; 95% CI, 1.04-1.77).
The agency recommended in a press release that patients currently taking sibutramine cease taking the medication and consult their physicians about alternative weight loss management strategies and programs.
Sibutramine was approved by the FDA in 1997 for weight loss and maintenance of weight loss in patients with a BMI ≥30 kg/m2 or for patients with a BMI ≥27 kg/m2 with other CV risk factors. The FDA announced the continued review of clinical trial data regarding sibutramine in November 2009 and January 2010 due to reports of adverse effects on the heart following use of the drug.

[Chevychelov]

Title: Downloadable Software Algorithm Reduces Inappropriate Shocks Caused by Implantable Cardioverter-Defibrillator Lead Fractures. A Prospective Study
Date Posted: October 6, 2010
Authors: Swerdlow CD, Gunderson BD, Ousdigian KT, Abeyratne A, Sachanandani H, Ellenbogen KA.
Citation: Circulation 2010;122:1449-1455.

Study Question:
Does software that detects oversensing or high lead impedance lower the risk of inappropriate shocks in patients with an implantable cardioverter-defibrillator (ICD) and a fractured Medtronic Fidelis lead?
Methods:
The subjects of this study were 426 patients (mean age 61 years) with an ICD and a Fidelis lead confirmed to be fractured at the time of explantation. Software that provides a lead-integrity alert (LIA) triggered by oversensing or high impedance was implanted in 213 patients at the discretion of the treating physician. The other 213 patients were monitored by automated daily impedance measurements and served as a control group.
Results:
The prevalence of inappropriate shocks was significantly lower in the LIA group (38%) than in the control group (70%). There was a 50% relative reduction in the prevalence of patients with ≥5 inappropriate shocks in the LIA group. The proportion of patients with no inappropriate shocks or ≥3 days of warning was significantly higher in the LIA group (72%) than in the control group (50%).
Conclusions:
Inappropriate shocks caused by a lead fracture are reduced by a LIA software upgrade.
Perspective:
The most common clinical manifestation of lead fractures is inappropriate shocks. This study demonstrates that downloadable software improves the sensitivity with which a non-physiological event such as electrical noise caused by a fracture is detected, thereby making inappropriate shocks less likely. In addition to demonstrating the efficacy of the new algorithm, the study demonstrates the feasibility of downloading software upgrades to previously implanted ICDs.

[Chevychelov]

Identification of a High-Risk Population for Esophageal Injury During Radiofrequency Catheter Ablation of Atrial Fibrillation: Procedural and Anatomical Considerations
Martinek M, Meyer C, Hassanein S, et al.
Heart Rhythm 2010;7:1224-1230.
Study Question: What factors predispose to esophageal injury during radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF)?

Prognostic Value of E/E’ Ratio in Patients With Unoperated Severe Aortic Stenosis
Biner S, Rafique AM, Goykhman P, Morrissey RP, Naghi J, Siegel RJ.
J Am Coll Cardiol Img 2010;3:899-907.
Study Question: Are there clinical or echo/Doppler parameters that have prognostic power among patients with unoperated severe aortic stenosis (AS)?

Analysis of Risk Factors for Abdominal Aortic Aneurysm in a Cohort of More Than 3 Million Individuals
Kent KC, Zwolak RM, Egorova NN, et al.
J Vasc Surg 2010;52:539-548.
Study Question: Who should be screened for abdominal aortic aneurysms (AAAs), and what is the overall prevalence of AAAs in the United States?

Severe Hypoglycemia and Risks of Vascular Events and Death
Zoungas S, Patel A, Chalmers J, et al., on behalf of the ADVANCE Collaborative Group.
N Engl J Med 2010;363:1410-1418.
Study Question: What is the relationship between severe hypoglycemia and adverse clinical outcomes?

Proton-Pump Inhibitors Are Associated With Increased Cardiovascular Risk Independent of Clopidogrel Use: A Nationwide Cohort Study
Charlot M, Ahlehoff O, Norgaard ML et al.
Ann Intern Med 2010;153:378-386.
Study Question: What is the risk for adverse cardiovascular outcomes related to concomitant use of proton pump inhibitors (PPIs) and clopidogrel compared with that of PPIs alone in adults hospitalized for myocardial infarction (MI)?

Clopidogrel With or Without Omeprazole in Coronary Artery Disease
Bhatt DL, Cryer BL, Contant CF, et al., on behalf of the COGENT Investigators.
N Engl J Med 2010;Oct 6:[Epub ahead of print].
Study Question: What is the efficacy and safety of concomitant administration of clopidogrel and proton pump inhibitors (PPIs) in patients with coronary artery disease who are receiving clopidogrel plus aspirin?

Unrecognised Myocardial Infarction and Long-Term Risk of Heart Failure in the Elderly: The Rotterdam Study
Leening MJ, Elias-Smale SE, Felix JF, et al.
Heart 2010;96:1458-1462.
Study Question: What is the long-term risk of heart failure in patients with electrocardiographic (ECG) evidence of unrecognized myocardial infarction (MI)?

Comparison of AngioJet Rheolytic Thrombectomy Before Direct Infarct Artery Stenting With Direct Stenting Alone in Patients With Acute Myocardial Infarction: The JETSTENT Trial
Migliorini A, Stabile A, Rodriguez AE, et al.
J Am Coll Cardiol 2010;56:1298-1306.
Study Question: What is the effect of rheolytic thrombectomy (RT) before direct infarct artery stenting, as compared with direct stenting (DS) on myocardial reperfusion, and clinical outcome in patients with acute myocardial infarction (AMI)?

Prognostic Significance of Myocardial Fibrosis in Hypertrophic Cardiomyopathy
O’Hanlon R, Grasso A, Roughton M, et al.
J Am Coll Cardiol 2010;56:867-874.
Study Question: What is the relationship between myocardial fibrosis detected by late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) for prediction of clinical events in patients with hypertrophic cardiomyopathy (HCM)?

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DANPACE: All-cause mortality in patients with sick sinus syndrome did not differ with AAIR, DDDR pacing

Nielsen J. Session 708001–708002.
European Society of Cardiology Congress 2010

Data from a new study has suggested no significant difference in all-cause mortality for the use of single-lead atrial pacing or dual-chamber pacing in patients with sick sinus syndrome. However, the rate of paroxysmal atrial fibrillation and re-operation was significantly higher in the single-lead atrial pacing group.

The DANPACE trial was a Danish multicenter study consisting of 1,415 patients (73.0 ± 11.3 years, 64.5% women) with sick sinus syndrome who were randomly allocated to either rate adaptive single-lead atrial (AAIR; n=707) pacing or rate adaptive dual-chamber (DDDR, n=708) pacing. Patients were followed for a mean of 5.4 ± 2.6 years.

According to study researchers, all-cause mortality was 29.6% in the AAIR group and 27.3% in the DDDR group (for DDDR, HR=0.94; 95% CI, 0.77-1.14). The incidence of paroxysmal AF was lower in the DDDR group than in the AAIR group (HR=0.79; 95% CI, 0.64-0.97), even after correction for relevant baseline variables. Incidence of chronic AF, stroke and HF did not differ between groups; however, there was a significantly less rate of patients in the DDDR group who underwent re-operation during follow-up than the AAIR group (HR=0.50; 95% CI, 0.39-0.66).

This led the researchers to conclude that DDDR pacing should be the preferred pacing mode in patients with sick sinus syndrome to reduce AF and re-operations.

However, in the presentation’s discussant, Carina Blomström-Lundqvist, MD, with the department of cardiology at Uppsala University Hospital, Uppsala, Sweden, said she was not as convinced by the results.

“In the DANPACE study, the percent of atrial pacing was similar in the AAIR group (58 ± 29%) and the DDDR group (59 ± 31%, P=.52), but the percentage of ventricular beats that were paced in the DDDR group was only 65 ± 33%, which is lower than in the SAVE-PACE trial (99%) and thus may partly explain the lack of deleterious effects usually observed with ventricular pacing regarding occurrence of AF and increased mortality,” she said.

“The study further demonstrated that the vast majority (83%) of sick sinus syndrome patients with AAIR devices remained as randomized, at last follow-up,” Blomström-Lundqvist said. “Further studies with long-term outcomes and economic evaluation of the most optimal pacing modes are therefore needed to identify the preferred pacing device for patients with sick sinus syndrome without evident need for ventricular pacing.”
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COGENT: PPI use reduced rate of gastrointestinal bleeding in patients given clopidogrel, aspirin
Bhatt D. N Engl J Med. 2010;doi:10.1056/nejmoa1007964.

Patients given a proton pump inhibitor besides clopidogrel and aspirin had a reduced rate of upper gastrointestinal bleeding, new results from the COGENT trial have indicated. Furthermore, researchers also reported no apparent CV interaction between clopidogrel and omeprazole.

“Proton pump inhibitors are believed to decrease the risk of [gastrointestinal] complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel,” the researchers wrote.

They initiated the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) to bring further clarification to this concern by assessing the efficacy and safety of administration of proton pump inhibitors in patients (n=3,761) with CAD who were receiving clopidogrel plus aspirin. Patients were included if they were at least 21 years and anticipating use of clopidogrel therapy with concomitant aspirin for at least 12 months.

Overall, 51 patients had a gastrointestinal event, with an event rate at 180 days of 1.1% in the omeprazole arm and 2.9% in the placebo arm (omeprazole HR=0.34; 95% CI, 0.18-0.63). Study results also indicated reduction in the rate of overt upper gastrointestinal bleeding with omeprazole vs. placebo (HR=0.13; 95% CI, 0.03-0.56).

Similarly, in the 109 patients who had a CV event, the event rate was lower in the omeprazole group (4.9% vs. 5.7%); however, this reduction was not statistically significant (omeprazole HR=0.99; 95% CI, 0.68-1.44).

Limitations of note, according to the researchers, were the premature termination of the trial, the wide CI around the HR for CV events, leading to an indefinite finding, and the single-pill formulation used that differs from generic omeprazole with respect to its release kinetics.

This randomized assessment, the researchers concluded, “provides reassurance that there is no clinically significant CV interaction between proton pump inhibitors and clopidogrel, whereas there is a significant reduction in gastrointestinal bleeding with PPI use as compared with placebo. Further research will be necessary to determine the optimal approach to reducing the risk of gastrointestinal adverse events among patients receiving potent antithrombotic therapy, but prophylactic proton pump inhibition appears to be promising.”

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Title: Effects of Diet and Physical Activity Interventions
Date Posted: October 12, 2010
Authors: Goodpaster BH, DeLany JP, Otto AD, et al.
Citation: JAMA 2010;Oct 9:[Epub ahead of print].

Study Question:
What are the effects of weight loss and physical activity intervention on the adverse health risks of severe obesity?
Methods:
A single-blind randomized trial was conducted from February 2007 through April 2010 at the University of Pittsburgh. Participants were 130 (37% African American) severely obese (class II or III) adult participants without diabetes recruited from the community. Patients were provided a 1-year intensive lifestyle intervention consisting of diet and physical activity. One group (initial physical activity) was randomized to diet and physical activity for the entire 12 months; the other group (delayed physical activity) had the identical dietary intervention, but with physical activity delayed for 6 months. Primary outcome was change in weight. Secondary outcomes were additional components comprising cardiometabolic risk, including waist circumference, abdominal adipose tissue, and hepatic fat content.
Results:
There was no difference between groups for: mean age 46 years, 10% men, mean body mass index 43.5 kg/m2, and 75% had class III obesity. Of 130 participants randomized, 101 (78%) completed the 12-month follow-up assessments. Although both intervention groups lost a significant amount of weight at 6 months, the initial-activity group lost significantly more weight in the first 6 months compared with the delayed-activity group (10.9 kg, 95% confidence interval [CI], 9.1-12.7 vs. 8.2 kg, 95% CI, 6.4-9.9; p = 0.02 for group × time interaction). Weight loss at 12 months, however, was similar in the two groups (12.1 kg, 95% CI, 10.0-14.2 vs. 9.9 kg, 95% CI, 8.0-11.7; p = 0.25 for group × time interaction). Waist circumference, visceral abdominal fat, hepatic fat content, blood pressure, and insulin resistance were all reduced in both groups. The addition of physical activity promoted greater reductions in waist circumference and hepatic fat content.
Conclusions:
Among patients with severe obesity, a lifestyle intervention involving diet combined with initial or delayed initiation of physical activity resulted in clinically significant weight loss and favorable changes in cardiometabolic risk factors.
Perspective:
The findings are intuitive. Experience in our center is that patients who commit to both exercise and diet do better with weight loss and metabolic parameters, at least in part because of improved diet compliance in those who exercise.
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Title: Effect of a Free Prepared Meal and Incentivized Weight Loss Program on Weight Loss and Weight Loss Maintenance in Obese and Overweight Women: A Randomized Controlled Trial
Date Posted: October 12, 2010
Authors: Rock CL, Flatt SW, Sherwood NE, Karanja N, Bilge Pakiz, Thomson CA.
Citation: JAMA 2010;Oct 9:[Epub ahead of print].

Study Question:
Does a free meal plan, together with an incentivized weight loss program, allow women to lose significant amounts of weight and maintain that weight loss long-term?
Methods:
Women over the age of 18 with a body mass index between 25 and 40 who were not pregnant or planning a pregnancy were included in this study. Additional exclusion criteria included women with food allergies, active involvement in another diet study, and history of significant psychiatric disorder and/or eating disorder. The study was a randomized controlled trial in which women were randomized to either in-person center-based or telephone-based one-to-one weight loss counseling together with free prepared meals or usual care. Weight was measured over a 2-year period. Meals were low-fat, energy reduced. Additional goals included regular physical activity of 30 minutes per day for 5 or more days of the week.
Results:
A total of 442 women were included in this trial (mean age 44 years). At 2 years, weight data were available for 407 women (92% of the subjects). Based on an intention-to-treat analysis, mean weight loss was 7.4 kg (95% confidence interval [CI], 6.1-8.7 kg) or 7.9% (95% CI, 6.5%-9.3%) of initial weight at 24 months for the center-based group. Weight loss was 6.2 kg (95% CI, 4.9-7.6 kg) or 6.8% (95% CI, 5.2%-8.4%) for the telephone-based group, and 2.0 kg (95% CI, 0.6-3.3 kg) or 2.1% (95% CI, 0.7%-3.5%) for the usual care control group after 24 months. The difference between the three groups was statistically significant (p < 0.001). All three groups demonstrated improvements in physical fitness and reductions in total cholesterol; however, no intervention effect was observed. Levels of C-reactive protein were reduced to a greater degree among women in the two intervention arms compared to usual care.
Conclusions:
The investigators concluded that a structured weight loss plan with free meals resulted in greater weight loss and maintenance of weight loss over 2 years compared to usual care.
Perspective:
These data suggest that a structured plan including prepared meals may assist overweight and obese adults to lose weight. A careful transition from prepared meals to the subject’s ad lib diet, together with continued counselor support, is likely key to the continued maintenance of weight loss observed in this study.

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Trial Summary TRACS
Title: Transfusion Requirements After Cardiac Surgery
Year Published: 2010
Topic(s): Cardiovascular Surgery, General Cardiology
Summary Posted: 10/13/2010
Writer: Anthony A. Bavry, M.D., M.P.H., F.A.C.C.
Author Disclosure: NOTHING TO DISCLOSE
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Reviewer Disclosure: RESEARCH/RESEARCH GRANTS: Astra Zeneca, Heartscape, Eisai, Sanofi Aventis, The Medicines Company, Ethicon, Bristol Myers Squibb Cogentus, PLx Pharma, Takeda

Description:

The goal of the trial was to evaluate a strategy of restrictive red blood cell (RBC) transfusion compared with a strategy of liberal RBC strategy among patients undergoing surgery with the use of cardiopulmonary bypass.
Hypothesis:

Restrictive RBC transfusion will be noninferior in preventing death and severe morbidity.
Drugs/Procedures Used:

Patients undergoing surgery with cardiopulmonary bypass were randomized to a restrictive RBC transfusion strategy if the hematocrit was <24% (n = 249) versus a liberal RBC transfusion strategy if the hematocrit was <30% (n = 253).
Concomitant Medications:

Clopidogrel and anticoagulants were held for at least 5 days prior to surgery. During surgery, unfractionated heparin was administered at a dose of 500 U/kg.
Principal Findings:
Overall, 502 patients were randomized. There was no difference in baseline characteristics between treatment groups. In the restrictive strategy group, the mean age was 59 years, 40% were women, 35% had diabetes, left ventricular ejection fraction (LVEF) ≥60% was present in 55%, median EuroSCORE was 4, and preoperative hemoglobin/hematocrit values were 13.4 g/dl and 39.9%.

Mean hematocrit values in the intensive care unit (ICU) were 28% in the restrictive strategy group versus 32% in the liberal strategy group (p < 0.001). RBC transfusion was performed in 47% versus 78% (p < 0.001), respectively. Most transfusions were given in the operating room or within 3 days of surgery.

The primary outcome, all-cause mortality, cardiogenic shock, acute respiratory distress syndrome, or renal failure requiring dialysis occurred in 11% of the restrictive strategy group versus 10% of the liberal strategy group (p = 0.85).

Mortality occurred in 6% versus 5% (p = 0.93), cardiogenic shock occurred in 9% versus 5% (p = 0.42), acute respiratory distress syndrome occurred in 2% versus 1% (p > 0.99), and renal failure requiring dialysis occurred in 4% versus 5% (p > 0.99), respectively.

In a multivariate model, regardless of treatment strategy, transfusion of more than 5 RBC units was associated with increased mortality.
Interpretation:
Among patients undergoing surgery with cardiopulmonary bypass, a restrictive RBC transfusion strategy was associated with similar outcomes compared with a more liberal transfusion strategy. In the restrictive RBC strategy, the target to transfuse was a hematocrit of 24% and the mean hematocrit value attained in the ICU was 28%, whereas in the liberal RBC strategy, the target to transfuse was a hematocrit of 30% and the mean hematocrit value attained was 32%. Independent of treatment strategy, the transfusion of >5 RBC units was associated with increased mortality.

Many studies have now called into question the practice of transfusing RBCs after invasive procedures to an arbitrary hematocrit target. This study documents that a hematocrit target as low as 24% is safe. Transfusion requirements should be based on evidence of impaired oxygen carrying capacity.
Study Design:
Randomized. Parallel.
Primary Endpoints:
30-day all-cause mortality or severe morbidity defined as cardiogenic shock, acute respiratory distress syndrome, or renal failure requiring hemodialysis
Secondary Endpoints:
All respiratory, cardiac, neurologic, and infectious complications
Inflammatory complications
Bleeding requiring reoperation
ICU and hospital length of stay
Patient Population:
Patients at least 18 years of age undergoing surgery with cardiopulmonary bypass

Number of screened applicants: 1,765
Number of enrollees: 502
Duration of follow-up: 30 days
Mean patient age: 59 years
Percentage female: 40%
Ejection fraction: 55% with LVEF ≥60%
NYHA class: I-7%, II-41%, III-42%, IV-10%
Exclusions:
Emergency procedures, ascending and descending thoracic aortic procedures, or LV aneurysm resection
Inability to receive blood products
Participation in another study
Anemia, thrombocytopenia, or coagulopathy
Pregnancy
Neoplasm
Endocarditis
Congenital heart defect
Hepatic dysfunction
End-stage renal disease
Inability to provide informed consent
References:
Hajjar LA, Vincent JL, Galas FR, et al. Transfusion Requirements After Cardiac Surgery: The TRACS Randomized Controlled Trial. JAMA 2010;304:1559-1567.

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Title: Effects of Lowering Homocysteine Levels With B Vitamins on Cardiovascular Disease, Cancer, and Cause-Specific Mortality: Meta-Analysis of 8 Randomized Trials Involving 37 485 Individuals
Date Posted: October 12, 2010
Authors: Clarke R, Halsey J, Lewington S, et al., on behalf of the B-Vitamin Treatment Trialists’ Collaboration.
Citation: Arch Intern Med 2010;170:1622-1631.

Study Question:
Does dietary supplementation with folic acid to lower homocysteine levels reduce risk for cardiovascular events, cancer, or all-cause mortality?
Methods:
Trials were included in this meta-analysis if they were randomized, double-blind studies comparing B-vitamin supplements containing folic acid with placebo for the prevention of vascular disease, which randomized at least 1,000 participants for treatment duration of 1 year or more. Folic acid doses ranged from 0.8-5.0 mg/day, except for one trial using 40 mg/day. Study populations included those with a prior history of heart disease or at risk for heart disease. Individual participant data were obtained for a meta-analysis of eight large, randomized, placebo-controlled trials of folic acid supplementation involving individuals at increased risk of cardiovascular disease. The analyses involved intention-to-treat comparisons of first events during the scheduled treatment period.
Results:
A total of 37,485 adults were included in this meta-analysis of eight randomized clinical trials. Two-thirds of subjects were men (mean age 65 years). Over the follow-up period, 9,326 vascular events were observed including 3,990 major coronary events, 1,528 strokes, and 5,068 revascularizations. A total of 3,010 cancers and 5,125 deaths were also observed. Supplementation with folic acid led to an average reduction in homocysteine levels of 25%. During a median follow-up of 5 years, folic acid allocation had no significant effects on vascular outcomes, including major vascular events (relative risk [RR], 1.01; 95% confidence interval [CI], 0.97-1.05), major coronary events (RR, 1.03; 95% CI, 0.97-1.10), and stroke (RR, 0.96; 95% CI, 0.87-1.06). There were no significant effects on vascular outcomes in any of the subgroups (age, sex, pretreatment levels of folate, or homocysteine) studied or on overall vascular mortality. No difference in overall cancer incidence was observed for folic acid versus placebo (RR, 1.05; 95% CI, 0.98-1.13), cancer mortality (RR, 1.00; 95% CI, 0.85-1.18), or all-cause mortality (RR, 1.02; 95% CI, 0.97-1.08).
Conclusions:
The authors concluded that dietary supplementation with folic acid to lower homocysteine levels had no significant effects on cardiovascular events or on overall cancer or mortality.
Perspective:
These data add to prior studies, which have suggested the lack of benefit for vitamins. Clinicians can point to such studies when discussing supplementation with their patients.
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Title: Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies
Date Posted: October 8, 2010
Authors: Assimes TL, Holm H, Kathiresan S, et al
Citation: J Am Coll Cardiol 2010;Oct 7:[Epub ahead of print].

Study Question:
How strong and reproducible is the association between the Trp719Arg polymorphism in kinesin-like protein 6 (KIF6) and risk of clinical coronary artery disease (CAD)?
Methods:
The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.
Results:
A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. They also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls, as well as all non-European subgroups.
Conclusions:
The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
Perspective:
Previous large genome-wide association studies have reported several significant, but typically modest, single nucleotide polymorphism associations with complex diseases. A polymorphism in KIF6 has been shown to be associated with increased CAD risk, a risk that was subsequently shown to be present only in nonstatin users. Even though the mechanism(s) by which this variant may affect CAD risk and response to stating treatment is unknown, a commercially available assay has been marketed and sold to physicians hoping to identify patients most likely to benefit from statin therapy. Before encouraging widespread testing and treatment strategies based on common polymorphisms, it is critical to understand just how robust these associations are. Although genome-wide association study data will provide important clues to the biology of complex diseases and may be used to risk-stratify some patients, the current study is a sobering reminder to proceed with caution before using this information to guide patient care.

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FDA advisory panel recommends darbepoetin alpha remain on market

The Cardiovascular and Renal Drugs Advisory Committee voted 15 to 1 to recommend keeping darbepoetin on the market, despite an increased risk for stroke with the drug documented in the TREAT trial.

Darbepoetin alpha (Aranesp, Amgen Inc.), an erythropoiesis-stimulating agent (ESA), was initially approved in 2001 for the treatment of anemia associated with chronic renal failure for patients both on and off dialysis. The TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) was designed to test darbepoetin with anemia associated with chronic kidney disease (CKD) and with type 2 diabetes. The objectives of the randomized, double-blind, placebo-controlled, multi-center, international trial was to demonstrate the benefit of darbepoetin treatment of the anemia to a target hemoglobin level of 13 g/dL by reducing the occurrence of either of two primary endpoints: the composite CV endpoint of all-cause mortality or a specified CV event (myocardial ischemia, chronic HF, MI and stroke); and the composite renal endpoint of all-cause mortality or progression to end-stage renal disease vs. placebo.

All subjects (n=4,038) of the trial were randomized to either subcutaneous treatment with darbepoetin (n=2,012) to achieve a hemoglobin level of 13 g/dL or to receive matching placebo injection (n=2,026). According to a press release, efficacy and safety favored the placebo group. The CV composite HR (1.05; 95%CI, 0.94-1.17) and the renal composite HR (1.05; 95% CI, 0.95-1.19) both slightly favored placebo.

Furthermore, the risk of stroke was nearly twofold higher in the darbepoetin group when compared to placebo (5% vs. 2.6%).

Following presentations by the sponsor and the FDA, the advisory panel voted not to recommend withdraw of the use of darbepoetin in patients with chronic kidney disease not on dialysis, with one member abstaining from voting.

“I voted no,” said Peter Kaboli, MD, MS, associate professor, University of Iowa Carver College of Medicine, Iowa City VA Medical Center, Iowa City, Iowa. “I believe the drug has considerable safety concerns, but to answer this question there is not compelling evidence that it should be withdrawn for any indication. More discussion is needed for where it should be modified.”

“Clearly, TREAT and the other trials suggest that the high-dose aggressive regimen is not desirable,” Allan Coukell, director, The Pew Prescription Project, Washington, said on his vote to recommend withdraw. “The current labeling of a goal of 10-12 g/dL seems to me still rather close to the aggressive treatment that we’ve seen. I don’t think we know how best to use this drug in this population, nor am I fully convinced that the control arm tells us how best to use it.”

In an additional question taken at the end of the meeting, the panel also voted 10-4 with 3 members abstaining to not recommend avoiding use of darbepoetin in all patients with CKD with a prior history of stroke.

“I voted no,” said Darren K. McGuire, M.D., associate professor of medicine, University of Texas Southwestern Medical Center, Dallas. “There is a real possibility that these patients would derive particular benefit of elevated hemoglobin compared with a lower one. One consideration is to do a written informed consent to initiate darbepoetin therapy.”

On his vote yes, David Stroncek, MD, chief of cell processing, department of transfusion medicine, Clinical Center, National Institutes of Health, Bethesda, Md, explained that while he did recommend to avoid using darbepoetin in all patients with a history of stroke, it shouldn’t be prohibited in these patients either. “If it is given, it should be given with appropriate discussion and informed consent,” he added. – by Brian Ellis
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Severe hypoglycemia increased risk for major macrovascular, microvascular events
Zoungas S. N Engl J Med. 2010;363:1410-1418.

Patients with severe hypoglycemia experienced increased risks for a range of adverse clinical outcomes, including macrovascular and microvascular events, and CV and all-cause mortality, according to findings presented in The New England Journal of Medicine.

Researchers involved in the study examined 11,140 patients with type 2 diabetes to determine the relationship between severe hypoglycemia and the risks for macrovascular and microvascular events. Patients were at least 55 years of age and were recruited from 215 centers in 20 countries between June 2001 and March 2003. Researchers split patients into two arms — intensive glucose control (n=5,571) and standard glucose control (n=5,569) — and followed them for a median of 5 years.

During follow-up, 231 patients (2.1%) had at least one severe hypoglycemic episode, 150 in the intensive glucose group (2.7%) and 81 in the standard glucose group (1.5%). Severe hypoglycemia was associated with the following increases in adjusted risks: major macrovascular events (HR=2.88; 95% CI, 2.01-4.12), major microvascular events (HR=1.81; 95% CI, 1.19-2.74), death from a CV cause (HR=2.68; 95% CI, 1.72-4.19) and death from any cause (HR=2.69; 95% CI, 1.97-3.67).

In the concluding remarks of their study, the researchers commented that although their findings cannot exclude the possibility that severe hypoglycemia has a direct causal link with these outcomes, the findings suggest that it is as likely to be a marker of vulnerability to a wide range of adverse clinical outcomes.

“In either case, the presence of severe hypoglycemia should raise clinical suspicion of the patient’s susceptibility to adverse outcomes and prompt action to address this possibility,” they added. – By Brian Ellis

This is an extremely important study in the field of diabetes. It shows the strong association between hypoglycemia and the risk of CV events and death. That itself is a very interesting observation. Even more interesting, nonvascular adverse events were also significantly increased in those with hypoglycemia. This finding raises the possibility that hypoglycemia is a marker of increased risk in general, more so than directly causing CV events. Future studies will need to examine if the findings regarding hypoglycemia noted here are consistent in other diabetic populations.

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Metabolic syndrome no more predictive of adult type 2 diabetes, atherosclerosis than BMI alone
Magnussen CG. Circulation. 2010;122:1604-1611.

Youth with metabolic syndrome were two to three times more likely to develop type 2 diabetes and atherosclerosis later in life, according to study findings; however, this association was no more indicative of later-in-life disease than BMI alone.

The study included data from the population-based, prospective, observational Bogalusa Heart and Cardiovascular Risk in Young Finns studies that featured 1,781 participants. Researchers investigated the utility of four categorical definitions of youth metabolic syndrome and their components in predicting adult high carotid intima-media thickness and type 2 diabetes among those aged 9 to 18 years at baseline (1984-1988) who were then examined 14 to 27 years later (2001–2007).

Researchers reported that compared with participants free of metabolic syndrome at youth, those with early metabolic syndrome were two to three times more likely of having carotid intima-media thickness and type 2 diabetes in their adult years. Risk estimates with the use of high BMI, however, were similar to those of metabolic syndrome phenotypes in predicting adult outcomes, leading researchers to recommend screening for high BMI or overweight and obesity in the pediatric setting as a simpler, equally accurate alternative.

“Our findings have direct clinical relevance because they suggest that in the clinical setting, efforts to identify youth with heightened future risk of meaningful outcomes can be minimally achieved with the use of body mass index only, thus avoiding cost and other barriers associated with testing and classification of youth metabolic syndrome,” the researchers wrote. “However, clinicians who use high BMI to identify youth at increased future risk need to keep in mind that a large proportion of contemporary youth will be classified as at risk and that our analyses are unable to discount that youth metabolic syndrome may be useful in identifying and possibly treating other cardiometabolic disorders.”
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Cardiomyocyte-specific microRNA presents diagnostic potential for CV disorders
Corsten M. Circ Cardiovasc Genet. 2010;doi:10.1161/CIRCGENETICS.110.957415.

Plasma levels of select microRNA were found to be significantly higher in patients with such conditions as acute MI and viral myocarditis, leading researchers of the Circulation: Cardiovascular Genetics study to credit the RNA molecules as being possible biomarkers in cardiology.

“It was recently discovered that small RNAs, called microRNAs, circulate freely and stably in human plasma. This finding has sparked interest in the potential of microRNAs as biomarkers, because microRNAs are strongly implicated in CVD and RNA molecules can be detected with high specificity and sensitivity using novel molecular techniques,” the researchers wrote.

To test this hypothesis, they isolated microRNAs from plasmas taken from patients with varying degrees of cardiac damage from such conditions as acute MI, viral myocarditis, diastolic dysfunction and acute HF. They used real-time percutaneous coronary revascularization to determine plasma levels of selected microRNAs, including those associated with the heart (microRNA-1, -133a, -208b and -499), fibrosis (microRNA-21 and -29b) and leukocytes (microRNA-146, -155 and -223).

In plasma from acute MI patients, researchers found significantly higher levels of microRNA-208b (1,600-fold; P<.005) and microRNA-499 (100-fold; P<.0005) when compared with controls. For viral myocarditis, they observed less extreme but still statistically significant elevations of microRNA-208b (30-fold; P<.01) and microRNA-499 (sixfold; P<.01) vs. controls.

No significant changes were reported in microRNAs for diastolic dysfunction and only microRNA-499 was elevated (twofold; P<.05) in acute HF patients. Researchers said plasma microRNA levels were not affected by a number of clinical confounders, including age, gender, BMI, kidney function, systolic BP and white blood cell count.

“We report that cardiac damage in diverse cardiac diseases initiates massive release of cardiomyocyte-specific microRNAs into the circulation, and that these microRNAs are highly insensitive to clinical characteristics in a cardiovascular patient population,” researchers wrote. “Our findings suggest a potential role for microRNAs as biomarkers in cardiology and mandate subsequent investigations to define their clinical applicability in early detection of myocardial damage.”

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Prevention of Atrial Fibrillation Recurrence With Corticosteroids After Radiofrequency Catheter Ablation: A Randomized Controlled Trial
Koyama T, Tada H, Sekiguchi Y, et al.
J Am Coll Cardiol 2010;56:1463-1472.
Study Question: Does steroid therapy reduce the probability of recurrent atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA) of paroxysmal atrial fibrillation (PAF)?

Cardiorespiratory Fitness Is Related to the Risk of Sudden Cardiac Death: A Population-Based Follow-Up Study
Laukkanen JA, M?kikallio TH, Rauramaa R, Kiviniemi V, Ronkainen K, Kurl S.
J Am Coll Cardiol 2010;56:1476-1483.
Study Question: Does cardiopulmonary fitness predict one’s risk for sudden cardiac death (SCD)?

Improvements in Symptoms and Quality of Life in Patients With Paroxysmal Atrial Fibrillation Treated With Radiofrequency Catheter Ablation Versus Antiarrhythmic Drugs
Reynolds MR, Walczak J, White SA, et al.
Circ Cardiovasc Qual Outcomes 2010;Oct 12:[Epub ahead of print].
Study Question: Does radiofrequency catheter ablation (RFCA) of paroxysmal atrial fibrillation (AF) improve quality of life (QOL) to a greater extent than antiarrhythmic drug therapy?

Heart Failure Reversal by Ventricular Unloading in Patients With Chronic Cardiomyopathy: Criteria for Weaning From Ventricular Assist Devices
Dandel M, Weng Y, Siniawski H, et al.
Eur Heart J 2010;Oct 7:[Epub ahead of print].
Study Question: What are correlates of long-term success following ventricular assist device (VAD) wean for myocardial recovery?

Arteriotomy Closure Devices for Cardiovascular Procedures: A Scientific Statement From the American Heart Association
Patel MR, Jneid H, Derdeyn CP, et al.
Circulation 2010;Oct 4:[Epub ahead of print].
Perspective: The following are 10 points to remember about this scientific statement.

Follow-up After Pulmonary Valve Replacement in Adults With Tetralogy of Fallot: Association Between QRS Duration and Outcome
Scherptong RW, Hazekamp MG, Mulder BJ, et al.
J Am Coll Cardiol 2010;56:1486-1492.
Study Question: Is QRS duration before and after pulmonary valve replacement (PVR) related to long-term outcomes in patients with tetralogy of Fallot (TOF)?

Pilot Study of the Antiplatelet Effect of Increased Clopidogrel Maintenance Dosing and Its Relationship to CYP2C19 Genotype in Patients With High On-Treatment Reactivity
Barker CM, Murray SS, Teirstein PS, Kandzari DE, Topol EJ, Price MJ.
JACC Cardiovasc Interv 2010;3:1001-1007.
Study Question: Does doubling the dose of clopidogrel from 75-150 mg/day reduce platelet reactivity in patients with high on-treatment platelet reactivity (OTR)? Does this response differ based on CYP2C19 status?

Multicenter Validation of the Diagnostic Accuracy of a Blood-Based Gene Expression Test for Assessing Obstructive Coronary Artery Disease in Nondiabetic Patients
Rosenberg S, Elashoff MR, Beineke P, et al., on behalf of the PREDICT (Personalized Risk Evaluation and Diagnosis in the Coronary Tree) Investigators.
Ann Intern Med 2010;153:425-434.
Study Question: What is the predictive ability of a 23-gene expression-based classification test for diagnosis of obstructive coronary artery disease (CAD) in nondiabetic patients?

Enhanced External Counterpulsation Improves Peripheral Artery Flow-Mediated Dilation in Patients With Chronic Angina. A Randomized Sham-Controlled Study
Braith RW, Conti CR, Nichols WW, et al.
Circulation 2010;122:1612-1620.
Study Question: What are the mechanisms responsible for clinical and anti-ischemic benefits of enhanced external counterpulsation (EECP)?

Association Between Visceral Adipose Tissue Area and Coronary Plaque Morphology Assessed by CT Angiography
Ohashi N, Yamamoto H, Horiguchi J, et al.
J Am Coll Cardiol Img 2010;3:908-917.
Study Question: Is visceral adipose tissue area associated with coronary plaque morphology?

Magnetic Resonance Imaging and Troponin Elevation Following Percutaneous Coronary Intervention: New Insights Into Myocyte Necrosis and Scar Formation
Schoenhagen P, White HD.
J Am Coll Cardiol Intv 2010;3:959-962.
Perspective: The universal definition of myocardial infarction (MI) designates biomarker increase (with troponin preferred) from a normal baseline to a level 3 times the 99th percentile as percutaneous coronary intervention (PCI)-related MI (Type 4a).

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Dabigatran etexilate approved to prevent stroke in AF

Today the FDA announced approval of dabigatran etexilate for the prevention of stroke and blood clots in patients with atrial fibrillation. The drug will be available in 75 mg and 150 mg capsules.

The approval was based on data from a trial comparing dabigatran etexilate (Pradaxa, Boehringer Ingelheim Pharmaceuticals, Inc.) with warfarin (Coumadin, Bristol-Myers Squibb). Patients assigned to dabigatran etexilate had fewer strokes compared with those assigned to warfarin, according to the press release.

In contrast to warfarin, patients taking dabigatran etexilate will not require periodic monitoring with blood tests, according to Norman Stockbridge, MD, PhD, director of the Division of Cardiovascular and Renal Products at the FDA’s Center for Drug Evaluation and Research.

The most common adverse events reported in the trial were life-threatening and fatal bleeding. Dyspepsia, stomach pain, nausea, heartburn and bloating were also reported, according to the press release. A medication guide explaining the risk for bleeding will be distributed with the drug each time a prescription is filled.
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Guideline changes for CPR led to higher neurologically-intact hospital discharge rates
Aufderheide TP. Heart Rhythm. 2010;7:1357–1362.

American Heart Association guideline changes for CPR resulted in significantly higher neurologically-intact hospital discharge rates in patients with out-of-hospital cardiac arrest, suggested data from Heart Rhythm.

“In 2005, AHA recommended multiple ways to improve circulation during CPR. Little is known about the impact of this new approach on survival rates for patients with out-of-hospital cardiac arrest,” the researchers wrote.

They tested this hypothesis that the new changes — including a renewed emphasis on more hard and fast compressions, fewer ventilations and complete chest wall recoil – could improve outcome by analyzing conglomerate quality assurance data during prospective implementation of the 2005 AHA Guidelines in five emergency medical services (EMS) systems. The EMS personnel were all trained in the new aspects of the guidelines and the primary outcome was defined as survival to hospital discharge.

According to study results, demographics, rate of bystander CPR, and time from the 911 call for help to arrival of EMS personnel were similar between the intervention (n=1,605) and historical control (n=1,641) groups. Researchers recorded a survival to hospital discharge rate of 10.1% in the control group vs. 13.1% in the intervention group (P=.007).

Additional study data indicated that the survival to discharge in patients presenting with a rhythm of ventricular fibrillation/ventricular tachycardia was 20% in controls vs. 32.3% the intervention group (P<.001), while the intervention group also had an advantage in survival to discharge with a CPC classification or 1 or 2 (intervention, 59.6% vs. control, 33.3%; P=.038).

“These findings support the importance of implementing an optimized sequence of therapeutic interventions during the performance of CPR for patients in cardiac arrest,” the researchers concluded. – by Brian Ellis

While the results are in concert with an increasing body of data supporting benefit of the 2005 guidelines, which includes an emphasis on minimizing interruptions in chest compressions, [this study] is not a randomized trial and some advances in care after resuscitation, including implementation of hypothermia and revascularization, could explain the greater survival to hospital discharge.