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

Abstract

Objectives: The purpose of this study was to compare the effectiveness of bucindolol with that of 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: A total of 267 HFrEF patients with a left ventricular ejection fraction (LVEF) <0.50, symptomatic AF, and the ADRB1 Arg389Arg genotype were randomized 1:1 to receive bucindolol or metoprolol therapy and were up-titrated to target doses. The primary endpoint of AF or 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% confidence interval [CI]: 0.71 to 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 the interval of time from the initial diagnoses of AF and HF to randomization and with the onset of AF relative to that of the initial HF diagnosis. In a cohort whose first AF and HF 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 to 0.87; p = 0.011).

Conclusions: Pharmacogenetically guided bucindolol therapy did not reduce the recurrence of AF/AFL or ACM compared to that of metoprolol therapy in HFrEF patients, but populations were identified who merited further investigation in future phase 3 trials.

Keywords: atrial fibrillation; beta-blocker; bucindolol; heart failure; pharmacogenetics; precision medicine.

CENTRAL ILLUSTRATION. Treatment Effect by Duration and Relative Onset of AF and HF prior to Randomization

A. 3-dimensional plot of HF DxT (x-axis) and AF DxT (y-axis) versus treatment effect (z-axis). B. 3-dimensional plot of AF onset prior to HF (x-axis) and HF onset prior to AF (y-axis) versus treatment effect (z-axis). Hazard ratio is for time to AF/AFL/ACM endpoint. HF DxT=time from initial HF diagnosis to randomization. AF DxT=time from initial AF diagnosis to randomization. DTRI (Diagnosis to Randomization Index) = HF DxT − AF DxT. AF onset prior to HF = absolute value of DTRI lower bound. HF onset prior to AF = DTRI upper bound.

FIGURE 1. Consort Diagram

Proportion of patients with the ADRB1 Arg389Arg genotype was consistent with previous findings (–11)

FIGURE 2. Time to First AF/AFL/ACM Event

Cox proportional hazards model adjusted for the four randomization strata. Non-stratified hazard ratio = 0.96 (95% CI: 0.69, 1.33). Stratified analysis including adjustment for previous use of class III anti-arrhythmic drugs (yes/no): HR = 0.92 (95% CI: 0.63, 1.33).

FIGURE 3. Time to First Event of AF/AFL/ACM in the Device Substudy

A. Device-based detection. B. ECG-based detection. For device-based detection an AF/AFL event was defined as AF burden ≥ 6 hours per day. Non-stratified Cox proportional hazards model.

FIGURE 4. Time to First Event of AF/AFL/ACM in the DxT12/DTRI-2 Cohort

A. ECG-based detection in the entire cohort. B. Device-based detection in the substudy cohort. For device-based detection an AF/AFL event=AF burden ≥6 hours per day. HR=hazard ratio. FU=follow-up.