ARCA biopharma, Inc. has announced that a comparative analysis of primary endpoint data from four beta blocker trials was presented at the American College of Cardiology 58th Annual Scientific Session being held March 29-31, 2009.
Results of the analysis, which compared all-cause mortality in participants in the COPERNICUS, MERIT-HF, CIBIS-II and BEST trials, suggest that differences in survival associated with beta-blocker treatment observed in clinical trials may be significantly influenced by inclusion of varying geographic populations (U.S. vs. Rest of World, or ROW) and that genetic diversity should be considered in the relevance of cardiovascular trials and interpretation of results.
Large randomized, controlled trials have shown that beta-blockers reduce mortality by 34 to 35 percent in heart failure patients with moderate to severe systolic dysfunction. The majority of patients enrolled in these trials were from outside the U.S. In contrast, the Beta-Blocker Evaluation of Survival Trial (BEST), the only intention-to-treat mortality trial which enrolled almost exclusively U.S. patients, showed a 13 percent reduction in all-cause mortality.
The magnitude of the effect on survival of beta-blocker therapy was either reduced (HR 0.80) or neutral (HR 1.05) in large U.S. populations included in COPERNICUS and MERIT-HF, respectively. These effects are more comparative to BEST trial results with bucindolol in U.S. patients. The “Very Favorable” (beta1-adrenergic receptor 389 Arginine homozygous) genotype subgroup in BEST showed significantly improved mortality reduction compared to other beta-blockers. Such findings suggest that differences in beta-blocker survival benefit observed in clinical trials may be significantly influenced by inclusion of varying geographic populations. Genetic diversity should be considered in the relevance of cardiovascular trials and interpretation of results.
BEST included a prospectively-designed DNA substudy that identified a subgroup of approximately 47 percent of participants who had the Very Favorable response genotype. This genotype subgroup of BEST was compared to the overall study cohorts. Comparisons were not prospectively defined at the time of the randomized trials. There is no adjustment for differences in baseline characteristics of the trial populations. The beta1-adrenergic receptor 389 Arginine/Glycine polymorphism is known to be influenced by racial differences that vary in European versus American populations, and other adrenergic receptor polymorphisms that could influence beta-blocker response also exhibit racial differences in allele frequencies.