Background: Bucindolol is a β-blocker/mild vasodilator with the unique properties of sympatholysis and ADRB1 Arg389 inverse agonism and no intrinsic sympathomimetic activity in human heart. In the GENETIC-AF trial, similar results were observed for bucindolol and metoprolol succinate for the primary endpoint of time to first AF event in HF patients with the ADRB1 Arg389Arg genotype.
Objective: To examine the cumulative incidence of bradycardia in HF patients participating in the GENETIC-AF trial.
Methods: A total of 267 HF patients with symptomatic AF and the ADRB1 Arg389Arg genotype were randomized (1:1) to bucindolol or metoprolol and up-titrated prior to the start of efficacy follow-up. Analyses include all patients who entered efficacy follow-up or died (N=259). Bradycardia was determined by ventricular response rate (VRR) on ECG and confirmed by the investigator prior to unblinding. Incidence rates (IR; cumulative events/total patients) were generated for a composite endpoint of bradycardia on ECG or death. Comparisons between treatment groups were expressed by the IR Ratio (IRR; IR_BUC/IR_MET) and tested for significance using the Poisson regression test.
Results: Mean age was 66±10 years, left ventricular ejection fraction (LVEF) was 0.36 ± 0.10 (range: 0.12 to 0.55), and 73% had NYHA II/III symptoms at baseline. Patients had paroxysmal (49%) or persistent (51%) AF, and 44% underwent cardioversion to establish sinus rhythm prior to follow-up. The incidence of bradycardia was decreased by 55% (IRR=0.45; 95% CI: 0.34, 0.60; p < 0.001) in the bucindolol group (71 events) compared to the metoprolol group (151 events). Patients with bradycardia (N=71; mean VRR=50.4 bpm) had a 4-fold higher incidence of study drug dose reduction during efficacy follow-up (IRR=4.16; 95% CI: 2.15, 8.32; p < 0.001) compared to patients without bradycardia (N=188; mean VRR=77.0 bpm). Similar results favoring bucindolol were observed in a subgroup with AF and HF < 12 years who did not have AF >2 years prior to developing HF (N=190) and in a subgroup with LVEF values ≥ 0.40 (N=123).
Conclusion: In a pharmacogenetically-defined HF population at risk for AF, bucindolol was associated with a lower incidence of dose limiting bradycardia compared to metoprolol succinate.