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Monday, October 25, 2010


Title: Proton-Pump Inhibitors Are Associated With Increased Cardiovascular Risk Independent of Clopidogrel Use: A Nationwide Cohort Study
Date Posted: October 8, 2010
Authors: Charlot M, Ahlehoff O, Norgaard ML et al.
Citation: Ann Intern Med 2010;153:378-386.

Clinical Trial:
Clopidogrel and the Optimization of Gastrointestinal Events Trial

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)?

This was a nationwide cohort study based on linked administrative registry data. The primary outcome was a composite of rehospitalization for MI or stroke or cardiovascular death. Patients were examined at several assembly time points, including 7, 14, 21, and 30 days after MI. Follow-up was 1 year.

Of 56,406 included patients, 9,137 (16.2%) were rehospitalized for MI or stroke or experienced cardiovascular death. Of the 24,702 patients (43.8%) who received clopidogrel, 6,753 (27.3%) received concomitant PPIs. The hazard ratio for cardiovascular death or rehospitalization for MI or stroke for concomitant use of a PPI and clopidogrel among the cohort assembled at day 30 after discharge was 1.29 (95% confidence interval, 1.17-1.42). The corresponding ratio for use of a PPI in patients who did not receive clopidogrel was 1.29 (CI, 1.21-1.37). No statistically significant interaction occurred between a PPI and clopidogrel (p = 0.72).

The authors concluded that PPIs seem to be associated with increased risk for adverse cardiovascular outcomes after discharge, regardless of clopidogrel use for MI.

This study found no evidence that concomitant PPI therapy increases risk for adverse cardiovascular events in patients who receive clopidogrel and is consistent with the results of the COGENT trial. PPIs appear to be associated with an increased risk for adverse cardiovascular outcomes regardless of clopidogrel use, and this increased cardiovascular risk is likely explained by unmeasured confounders. These results seem to refute concerns about increased risk for ischemic events during concomitant PPI and clopidogrel therapy, and provide further reassurance about safety of PPIs in patients on dual antiplatelet therapy when such therapy is indicated.

Thursday, October 21, 2010


Title: Long-Term Effects of a Lifestyle Intervention on Weight and Cardiovascular Risk Factors in Individuals With Type 2 Diabetes Mellitus: Four-Year Results of the Look AHEAD Trial
Date Posted: September 30, 2010
Authors: The Look AHEAD Research Group.
Citation: Arch Intern Med 2010;170:1566-1575.

Study Question:
Does a lifestyle modification intervention result in long-term changes in weight and cardiovascular disease risk factors among patients with type 2 diabetes?

The Look Ahead Study is a multicenter randomized clinical trial comparing the effects of an intensive lifestyle intervention versus diabetes support and education. Patients all had type 2 diabetes and were between the ages of 45 and 76 years. Additional inclusion criteria included a body mass index (BMI) of 25 or greater. The intensive intervention included diet modification for a goal weight loss of 7% over the first year, with weight loss maintenance over the following years. Participants met with study members weekly in the first 6 months, then three times per month for the next 6 months, followed by once per month for the following study follow-up period. The control group had three group sessions each year.

A total of 5,145 overweight or obese patients with diabetes (mean age 58.7 years, 59.5% female) were included in the study. Over the 4-year follow-up, patients in the intensive lifestyle modification group had greater weight loss compared to the control group (-6.15% vs. -0.88%, p < 0.001) and greater improvement in treadmill fitness (12.74% vs. 1.96%, p < 0.001). The intensive intervention also resulted in lower glycated hemoglobin levels, and lower systolic and diastolic blood pressure compared to the control group. Lipid profiles among those in the intensive group also improved with great increases in high-density lipoprotein (HDL) cholesterol (3.67 vs. 1.97, p < 0.001) and reductions in triglyceride levels (-25.56 vs. 19.75 mg/dl, p < 0.001). Reductions in low-density lipoprotein cholesterol were greater in the control group, as compared to the intensive lifestyle group (-11.27 vs. 12.84 mg/dl, p = 0.009); however, lipid-lowering medication use was higher in the control group, which may explain this finding. At 4 years, those patients in the intensive intervention group had greater improvements in weight, fitness, glycated hemoglobin, systolic blood pressure, and HDL cholesterol compared to those in the control group.

The investigators concluded that an intensive lifestyle modification program can result in reductions in weight and improvements in cardiovascular disease risk factors and fitness over several years.

Lifestyle modification can result in significant improvements of risk factors, including blood pressure and lipids. These findings are encouraging in that the intervention resulted in long-term improvements, which have the potential to result in reductions in cardiovascular disease events. However, the ability to implement such intensive programs in the community remains unclear.

Monday, October 18, 2010


The hottest topic this week in Washington at the annual TCT is percutaneous valves. Beaumont will be one of the sites participating and Steven Almany will be one of the investigators. The therapy offers great promise to many with aortic stenosis where the risk of surgery might be prohibitive. It is of course early and there are risks which are described in the summary below about the trial presented.

As many as one-third of patients with severe aortic stenosis (AS) are high-risk surgical candidates and are conservatively managed. However, nonsurgical management of symptomatic AS is associated with a median survival of about 2 years. The PARTNER trial sought to compare outcomes between standard therapy and transcatheter aortic valve implantation (TAVI) in patients with inoperable AS. TAVI is a new procedure in which a bioprosthetic aortic valve is inserted through a catheter and implanted within the diseased native aortic valve.

TAVI would be superior to standard therapy in patients who are at high risk for mortality with aortic valve surgery.

Drugs/Procedures Used:
TAVI was performed under general anesthesia, and under transesophageal echocardiographic guidance. A standard balloon aortic valvuloplasty (BAV) was initially performed, followed by transfemoral insertion of either a 22- or 24-French sheath (for a 23 or 26 mm valve, respectively). The valve itself was part of the Edwards SAPIEN heart-valve system, which consists of a trileaflet bovine pericardial valve mounted on a balloon-expandable, stainless steel support frame. This system was advanced across the native aortic valve. The valve and support frame were then balloon expanded across the native valve during rapid ventricular pacing. Standard therapy consisted of medical management and BAV alone if deemed necessary.

Concomitant Medications:
All patients undergoing TAVI received heparin during the procedure, and dual antiplatelet therapy consisting of aspirin and clopidogrel for 6 months after the procedure.

Principal Findings:
Of the more than 3,000 patients with severe AS who were screened, a total of 358 patients (12%) were randomized across 21 sites, 179 to TAVI, and 179 to standard therapy. Baseline characteristics were fairly similar between the two arms. The mean Society of Thoracic Surgeons (STS) score was 11.6%, with a corresponding mean logistic EuroSCORE of 28.4. Other conditions contributing to a high-risk designation included heavily calcified (“porcelain”) aorta in 15.1%, chest wall deformity or irradiation (13.1%), oxygen-dependent respiratory insufficiency (23.5%), and frailty based on prespecified criteria (23.1%).

About 93% of the patients had New York Heart Association (NYHA) class III or IV symptoms, with a mean aortic valve area of 0.6 cm2, and a mean aortic valve gradient of 44 mm Hg. The mean left ventricular ejection fraction (LVEF) was 52%, with moderate to severe mitral regurgitation present in about 23% of the patients. Pulmonary hypertension was present in about 43% of the patients. Coexisting coronary artery disease was noted in about 71% of the patients, with 41% having undergone prior coronary artery bypass grafting, and 27% prior percutaneous coronary intervention. About 20% of patients had undergone BAV at some point prior to randomization.

There was no difference in 30-day mortality between the TAVI and standard therapy arms (5.0% vs. 2.8%, p = 0.41). However, at 1 year, the primary endpoint of all-cause mortality was significantly lower in the TAVI arm (30.7% vs. 50.7%, hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.40-0.74, p < 0.001).

Other outcomes such as cardiovascular death at 1 year (20.5% vs. 44.6%, HR 0.39, 95% CI 0.27-0.56, p < 0.001) and death or rehospitalization at 1 year (42.5% vs. 71.6%, HR 0.46, 95% CI 0.35-0.59, p < 0.001) were also lower in the TAVI arm. Major strokes at 30 days (5.0% vs. 1.1%, p = 0.06) and at 1 year (7.8% vs. 3.9%, p = 0.18) were numerically higher in the TAVI arm. Major vascular complications were significantly higher in the TAVI arm, both at 30 days (16.2% vs. 1.1, p < 0.001) and at 1 year (16.8% vs. 2.2%, p < 0.001). Similarly, major bleeding was higher in the TAVI arm at 30 days (16.8% vs. 3.9%, p < 0.001) and at 1 year (22.3% vs. 11.2%, p = 0.007).

Other complications such as acute kidney injury, endocarditis, and new pacemaker requirement were similar between the two arms. BAV was necessary in 36.9% of the patients in the standard therapy arm over 1 year of follow-up, whereas repeat TAVI was necessary in three (1.7%) patients in that time frame.

Echocardiographic parameters such aortic valve area (0.6-1.5 cm2) and mean aortic valve gradient (44.5-11.1 mm Hg) showed significant improvement in the TAVI arm at 30 days (p < 0.001 for both). Moderate or severe paravalvular and valvular aortic regurgitation were noted in 11.8% and 1.3% of the patients at 30 days, respectively, in the TAVI arm. NYHA class demonstrated significant improvements in the TAVI arm at 30 days and at 1 year, as compared with the standard therapy arm (p < 0.001).

PARTNER is a landmark trial in the field of structural heart disease and in the management of patients with severe AS. Patients in this trial were very high risk to begin with, as evidenced by >50% mortality at 1 year in the standard therapy arm. The results of the inoperable group of patients (cohort B) are reported here. TAVI resulted in 45% reduction in all-cause mortality and 61% reduction in cardiovascular mortality at 1 year in these high-risk AS patients compared with standard therapy. Echocardiographic criteria such as aortic valve area and mean aortic valve gradients, and symptom criteria such as NYHA class, also demonstrated a significant improvement.

The procedure is complex and fraught with numerous complications, however, as evidenced by a significantly higher risk of major vascular complications and major bleeding, and a trend towards a higher risk of major stroke in the TAVI arm. Thus, while the overall results are very encouraging, the high complication rate should temper any tendencies toward the overaggressive use of TAVI (if FDA approved for the treatment of AS) in lower-risk patients, and surgical AVR should still be considered the gold standard for treatment of AS in these patients. The availability and performance of smaller profile TAVI delivery systems, a comparison of transfemoral to transapical TAVI (cohort A patients), and long-term follow-up are eagerly awaited.

On another note, the design and execution of the PARTNER trial highlight the importance of close collaboration between interventional cardiologists and cardiac surgeons in the management of this complex group of patients.

Friday, October 15, 2010



In a small study, allopurinol improved exercise tolerance in patients with CAD.

Experimental evidence suggests that allopurinol lowers myocardial oxygen consumption. To assess whether this effect might benefit patients with cardiac ischemia, U.K. investigators randomized 60 patients with chronic stable exertion- induced angina, angiographically proven coronary artery disease, and positive exercise stress tests to add daily allopurinol (600 mg) or placebo to their baseline angina medications for 6 weeks; patients then crossed over to the opposite treatment for 6 weeks.

Exercise stress testing was performed after randomization and at the end of each treatment period. Compared with placebo recipients, allopurinol recipients exhibited significantly longer mean total exercise time (393 vs. 307 seconds), mean time to ST depression (298 vs 249 seconds), and mean time to symptoms (304 vs. 272 seconds). No adverse treatment effects were noted.

The anti-ischemic effect of allopurinol that was demonstrated in this study is comparable to that of other drugs such as amlodipine and nitrates, but its mechanism remains obscure. The authors speculate that allopurinol might reduce oxidative stress, thereby making more molecular oxygen available to ischemic myocardium and improving endothelial function. Although allopurinol generally is tolerated well, serious adverse effects occur occasionally. Thus, in future trials, researchers should compare allopurinol to other anti-anginal agents and include more patients and clinical outcomes.

Noman A et all. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: A randomized, placebo controlled crossover trial.
Lancet 2010 Jun 19; 375:2161