Abstract 10438: Prevention of Atrial Fibrillation by Bucindolol is Completely Dependent on the Beta-1 389 Arg/Gly Adrenergic Receptor Polymorphism
Beta blockers have modest efficacy for the prevention of atrial fibrillation (AF) in chronic heart failure/reduced ejection fraction (HFREF) populations, with risk reductions on the order of 20-40%. We assessed the ability of the beta-blocker/sympatholytic agent bucindolol to prevent AF in the BEST trial, identifying new onset AF from AE/SAE case report forms as well as routinely measured ECGs in patients not in AF on study entry, and constructing Kaplan Meier curves using Cox regression. In the entire 2708 patient cohort there were 115/1190 (9.7%) new onset AF episodes in baseline sinus rhythm patients in the placebo group, and 75/1202 (6.2%) in the bucindolol group. The time to event hazard ratio (95% CIs) was 0.59 (0.44, 0.79), p = 0.0004. In the 1040 patient DNA substudy based on 80 total events the hazard ratio was 0.57 (0.36, 0.90), p = 0.014) and the therapeutic effect was completely dependent on the beta-1 389 Arg/Gly polymorphism: [Figure 1]
Conclusions: 1) bucindolol produced substantial prevention of AF in the entire BEST population, with a risk reduction of 41%; 2) the risk reduction for new onset AF was pharmacogenetically determined, with patients who were homozygous arginine at beta-1 389 having a 74% risk reduction and patients having any glycine at this position having no effect. This effect differentiation is greater than for heart failure mortality or hospitalization endpoints, where the 389 Arg/Arg genotype is associated with risk reductions of 34-48% vs. 8-22% in Gly carriers.
- © 2011 by American Heart Association, Inc.