Abstract 901: Effects of Bucindolol on Cardiovascular Mortality and Morbidity are Determined by the Beta-1 389 Arg/Gly Receptor Polymorphism
Introduction: Bucindolol is a nonselective beta-adrenergic blocker with potent sympatholytic properties. The Beta-blocker Evaluation of Survival Trial (BEST) reported that the administration of bucindolol resulted in a nonsignificant decrease in total mortality (HR = 0.89 (0.78, 1.02), unadjusted p=0.10) in patients with advanced, NYHA Class III-IV heart failure (HF). Recent observations from that trial also reported that the amino acid arginine (Arg/Arg) or glycine (any Gly) in position 389 of the beta-1 receptor plays a significant role on the clinical response to bucindolol. The impact of bucindolol on cardiovascular mortality and morbidity (cardiovascular hospitalizations) has been incompletely investigated, because hospitalizations had been evaluated from case report forms (CRFs) only, and never adjudicated by the endpoints committee (EPC).
Methods: The BEST data base consists of 2708 patients with a mean follow-up of 2.0 years. Cardiovascular (CV) mortality and hospitalizations have now been evaluated by EPC, which further subclassified total hospitalizations into cardiovascular (CV) and those due to worsening heart failure (HF). The impacts of Arg or Gly encoded at amino acid position 389 on endpoints were further investigated in the 1040 patient substudy.
Results: Time to event results for adjudicated CV endpoints are presented below.
Conclusions: Chronic administration of bucindolol results in a significant reduction in cardiovascular hospitalizations and mortality. Effects on either are strikingly beta-1 389 Arg/Gly specific, with the higher functioning, Arg/Arg version of the receptor associated with large treatment effects and Gly carriers exhibiting little or no evidence of efficacy. Genetic targeting of the β1-ΑR 389 polymorphism may improve the clinical responses to bucindolol for CV mortality and morbidity.