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Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population: The GENETIC-AF Trial

Jonathan P Piccini1, William T Abraham2, Christopher Dufton3

  • 1Duke Clinical Research Institute and Duke University Medical Center, Durham, North Carolina.

JACC. Heart Failure
|May 3, 2019
PubMed

Insights

Bucindolol did not outperform metoprolol succinate in maintaining sinus rhythm for heart failure patients with atrial fibrillation. However, specific patient subgroups showed potential benefits, warranting further research.

Area of Science:

  • Cardiology
  • Pharmacogenomics
  • Heart Failure Research

Background:

  • Bucindolol, a beta-blocker, demonstrates unique pharmacologic properties beneficial for heart failure with reduced ejection fraction (HFrEF) patients carrying the beta1-adrenergic receptor (ADRB1) Arg389Arg genotype.
  • Genetic variations, specifically the ADRB1 Arg389Arg genotype, influence patient response to beta-blocker therapy in heart failure.

Purpose of the Study:

  • To compare the efficacy of bucindolol versus metoprolol succinate in maintaining sinus rhythm among a genetically defined population of heart failure (HF) patients experiencing atrial fibrillation (AF).
  • To investigate the role of pharmacogenetics in tailoring beta-blocker therapy for HF patients with AF.

Main Methods:

  • A randomized controlled trial involving 267 HFrEF patients (left ventricular ejection fraction <0.50) with symptomatic AF and the ADRB1 Arg389Arg genotype.
  • Patients were randomized 1:1 to receive either bucindolol or metoprolol, with doses titrated to target levels.
  • The primary endpoint, assessed via electrocardiogram (ECG) over 24 weeks, included the recurrence of AF/atrial flutter (AFL) or all-cause mortality (ACM).

Main Results:

  • The overall hazard ratio (HR) for the primary endpoint did not show a significant difference between bucindolol and metoprolol (HR: 1.01, 95% CI: 0.71 to 1.42).
  • Precision therapeutic phenotyping identified subgroups with differential responses to bucindolol, particularly those diagnosed with AF and HF less than 12 years prior to randomization, and with AF onset not preceding HF by more than 2 years (HR: 0.54, 95% CI: 0.33 to 0.87).
  • Trends suggesting bucindolol benefit were observed in specific patient subgroups.

Conclusions:

  • Pharmacogenetically guided bucindolol therapy was not superior to metoprolol in preventing AF/AFL recurrence or ACM in HFrEF patients.
  • Specific patient populations exhibiting particular timing of AF and HF diagnoses showed potential for bucindolol efficacy, meriting further investigation in future Phase 3 trials.
Abstract

Keywords:
atrial fibrillationbeta-blockerbucindololheart failurepharmacogeneticsprecision medicine

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