Abstract 398: Pharmacogenetic Therapeutic Enhancement of a Prespecified Composite Morbidity-Mortality Measurement in BEST
In the Beta-Blocker Evaluation of Survival Trial (BEST), there were 8 secondary endpoints (SEPs) in the FDA-negotiated bucindolol efficacy analysis plan (EAP). By regulatory agreement reached over 1 year prior to the trial’s end, from a clinical efficacy standpoint, the highest order SEPs was a composite morbidity-mortality measure (CMM), added in the EAP to the 7 SEP described in the protocol. The components of CMM were: cardiovascular death, cardiac transplantation, heart failure hospitalization and emergency room visits for treatment of heart failure. Shown in the table⇓ are the # of events, bucindolol:placebo hazard ratios (95% confidence limits) for time-to-event for CMM, for the entire cohort and for the β1 and α2c adrenergic receptor (AR) gene polymorphism subgroups of the 1040-patient DNA substudy. These genetic subgroups were previously shown to have heterogeneous outcomes for total mortality. The β1-AR 389 Arg/Arg variant leads to gain of function (by 3– 4 fold), with greater cardiomyopathic effects in transgenic mice and a greater degree of total mortality reduction with the bucindolol, while α2c 322–325 Del variant leads to loss of prejunctional adrenergic inhibitory function, exaggerated sympatholysis from bucindolol and obviation mortality reduction by bucindolol. These data suggest that 1) in the entire cohort bucindolol has a highly statistically significant (p <0.001 by log rank) favorable effect on the CMM; 2) both the β1 389 Arg/Arg and α2c Wt/Wt subgroups have favorable responses to bucindolol relative to their respective cognate polymorphism carrier-state subgroups; 3) the combination of β1 389 Arg/Arg and α2c Wt/Wt constitutes a “hyper-response” diplotype, and 4) β1 389 Gly carrier, α2c Del carrier or the combination diplotype are less favorable response genotypes. We conclude that for lowering heart-failure-related morbidity and mortality, pharmacogenetic targeting may be useful in selection of patients treated with bucindolol.