Bucindolol: A Pharmacogenomic Perspective on its Use in Chronic Heart Failure

Abstract

Bucindolol is a non-selective β-adrenergic receptor blocker with α-1 blocker properties and mild intrinsic sympatholytic activity. The Beta-Blocker Evaluation of Survival Trial (BEST), which is the largest clinical trial of bucindolol in patients with heart failure, was terminated prematurely and failed to show an overall mortality benefit. However, benefits on cardiac mortality and re-hospitalization rates were observed in the BEST trial. Bucindolol has not shown benefits in African Americans, those with significantly low ejection fraction and those in NYHA class IV heart failure. These observations could be due to the exaggerated sympatholytic response to bucindolol in these sub-groups that may be mediated by genetic polymorphisms or changes in gene regulation due to advanced heart failure. This paper provides a timely clinical update on the use of bucindolol in chronic heart failure.

Understanding the Importance of Race/Ethnicity in the Care of the Hypertensive Patient

“…In the Beta-Blocker Evaluation of Survival Trial (BEST) for heart failure, unlike in non-Blacks, no CVD mortality benefit was seen in Blacks with bucindolol [70]. Interestingly, GRK5-Leu41 polymorphism, consistent with non-responsive beta-adrenergic receptor signaling and less B-blocker benefits, is more common in Blacks, with a ∼35 % frequency in AfricanAmericans and ∼1-2 % in Whites [71].…”

Biomarker Applications in the Pharmaceutical Industry

“…Patients that carried a2C-adrenergic receptor gene polymorphisms (specifically a2C-Del carriers) responded differently to the drug yet had no evidence of a favorable survival benefit from treatment [80]. Other polymorphisms also seem to affect the pharmacodynamics of this drug [79]. Another example may be found in a recent study of perfinidone, which appears effective in only a subpopulation of patients with idiopathic pulmonary fibrosis, as determined by a combination of physiological measurements [105].…”

“…The use of selection biomarkers in late stage clinical trials has been recently reviewed [78], with the observation that this application could be further developed, as some of the more common tumors, such as prostate, have yet to be explored for biomarkers that may segment the patient population. Most certainly such molecular biomarker classification is not limited to cancer, an example being the treatment of chronic heart failure with the beta-blocker bucindolol, where an alpha2C-adrenergic receptor polymorphism alters the drugs norepinephrine-lowering effects and therapeutic response [79,80].…”

Cardiovascular Pharmacogenomics: Expectations and Practical Benefits

“…The interesting pharmacogenomics of bucindolol merit highlighting. Bucindolol is a nonselective β‐AR inhibitor with sympatholytic capability, weak α 1 ‐AR antagonism, 62 and inverse agonist activity in failing hearts expressing Arg389Arg β 1 ‐ARs 16 . The prognostic utility of bucindolol vs. placebo in New York Heart Association functional class III and IV HF patients with left‐ventricular ejection fraction ≤0.35 was assessed in the BEST RCT, which was terminated prematurely because bucindolol conferred no significant overall survival benefit 15 .…”

“…The prognostic utility of bucindolol vs. placebo in New York Heart Association functional class III and IV HF patients with left‐ventricular ejection fraction ≤0.35 was assessed in the BEST RCT, which was terminated prematurely because bucindolol conferred no significant overall survival benefit 15 . Subsequent subanalyses suggested that patients with New York Heart Association class IV symptoms, African Americans, and those with left‐ventricular ejection fraction <0.2 in particular derived no benefit from bucindolol 62 . Using combinatorial genotyping in the 1,040‐patient genetic substudy of BEST, a haplotype construct incorporating ADRB1 Arg389Gly and ADRA2C Ins322–325Del polymorphisms has been published 60 .…”