GENETIC-AF: Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined Heart Failure Population.
OBJECTIVE: To compare the effectiveness of bucindolol and metoprolol succinate for the maintenance of sinus rhythm in a genetically defined heart failure (HF) population with atrial fibrillation (AF). BACKGROUND: Bucindolol is a beta-blocker whose unique pharmacologic properties provide greater benefit in HF patients with reduced ejection fraction (HFrEF) who have the beta1-adrenergic receptor (ADRB1) Arg389Arg genotype. METHODS: 267 HFrEF patients with a left ventricular ejection fraction (LVEF) < 0.50, symptomatic AF, and the ADRB1 Arg389Arg genotype were randomized 1:1 to bucindolol or metoprolol and up-titrated to target doses. The primary endpoint of AF/atrial flutter (AFL) or all-cause mortality (ACM) was evaluated by electrocardiogram (ECG) during a 24-week period. RESULTS: The hazard ratio (HR) for the primary endpoint was 1.01 (95% CI: 0.71, 1.42) but trends for bucindolol benefit were observed in several subgroups. Precision therapeutic phenotyping revealed that a differential response to bucindolol was associated with: 1) the interval of time from the initial diagnosis of HF and AF to randomization, and; 2) the onset of AF relative to initial HF diagnosis. In a cohort whose first HF and AF diagnoses were < 12 years prior to randomization, in which AF onset did not precede HF by more than 2 years (N=196) the HR was 0.54 (95% CI: 0.33, 0.87; p=0.011). CONCLUSION: Pharmacogenetic-guided bucindolol therapy did not reduce the recurrence of AF/AFL/ACM compared to metoprolol in HFrEF patients, but populations were identified that merit further investigation in future Phase 3 trials.
Piccini, JP; Abraham, WT; Dufton, C; Carroll, IA; Healey, JS; van Veldhuisen, DJ; Sauer, WH; Anand, IS; White, M; Wilton, SB; Aleong, R; Rienstra, M; Krueger, SK; Ayala-Paredes, F; Khaykin, Y; Merkely, B; Miloradović, V; Wranicz, JK; Ilkhanoff, L; Ziegler, PD; Davis, G; Emery, LL; Marshall, D; Kao, DP; Bristow, MR; Connolly, SJ; Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL for Prevention of Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure Trial Investigators,
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