Dose-limiting, adverse event-associated bradycardia with β-blocker treatment of atrial fibrillation in the GENETIC-AF trial

Abstract

Background: Heart failure (HF) patients with atrial fibrillation (AF) often have conduction system disorders, which may be worsened by β-blocker therapy.

Objective: In a post hoc analysis we examined the prevalence of bradycardia and its association with adverse events (AEs) and failure to achieve target dose in the GENETIC-AF trial.

Methods: Patients randomized to metoprolol (n = 125) or bucindolol (n = 131) entering 24-week efficacy follow-up and receiving study medication were evaluated. Bradycardia was defined as an electrocardiogram (ECG) heart rate (HR) <60 beats per minute (bpm) and severe bradycardia <50 bpm.

Results: Mean HR in sinus rhythm (SR) was 62.6 ± 12.5 bpm for metoprolol and 68.3 ± 11.1 bpm for bucindolol (P < .0001), but in AF HRs were not different (87.5 bpm vs 89.7 bpm, respectively). Episodes per patient for bucindolol vs metoprolol were 0.82 vs 2.08 (P < .001) for bradycardia and 0.24 vs 0.57 for severe bradycardia (P < .001), with 98.9% of the episodes occurring in SR. Patients experiencing bradycardia had a 4.15-fold higher prevalence of study medication dose reduction (P <.0001) compared to patients without bradycardia. Fewer patients receiving metoprolol were at target dose (61.7% vs 74.9% for bucindolol, P < .0001) at ECG recordings, and bradycardia AEs were more prevalent in the metoprolol group (13 vs 1 for bucindolol, P = .001). On multivariate analysis of 21 candidate bradycardia predictors including presence of a device with pacing capability, bucindolol treatment was associated with the greatest degree of prevention (Z_{odds ratio} -4.24, P < .0001).

Conclusion: In AF-prone HF patients bradycardia may limit the effectiveness of β blockers, and this property is agent-dependent.

Keywords: Atrial fibrillation; Beta blockers; Bradyarrhythmias; Heart failure; Pharmacogenetics.

Figure 1

Flow diagram of patients (Ns) with at least 1 electrocardiogram episode with a heart rate <60 beats/min (bradycardia) or <50 beats/min (severe bradycardia). AE = adverse event; F/U = follow-up; HR = heart rate.

Figure 2

Heart rates at scheduled electrocardiogram (ECG) monitoring visits. A: Sinus rhythm (SR) scheduled ECGs in patients at each protocol-defined time point (∗2 patients who were in SR during screening and at the start of efficacy follow-up had no ECG recorded at randomization). B: Atrial fibrillation/flutter (AF/AFL) scheduled ECGs in patients at each time point (94% AF and 6% AFL). Neither SR nor AF/AFL heart rates exhibited significant departures from a normal distribution. B = bucindolol; M = metoprolol; Rnd = randomization; VRR = ventricular rate regulation.

Figure 3

Patients experiencing or achieving: A: bradycardia adverse events (AEs); B: combined endpoint of a bradycardia AE or never reaching target dose (4 patients in the metoprolol group had a bradycardia AE AND failed to reach target); C: target dose at any time; D: at target dose at the time of an ECG recording (scheduled or unscheduled). The mean doses for all patients in the % achieving target dose plot (C) were 169 ± 57 mg/d for metoprolol and 163 ± 59 mg/d for bucindolol, where target doses were 200 mg/d and 187 mg/d, respectively.

Figure 4

Forest plot of candidate predictors of bradycardia (heart rate <60), multivariate analysis with standardized odds ratios. AF = atrial fibrillation; BP = blood pressure; DxT = time from initial diagnosis to randomization; ECV = electrically cardioverted; HF = heart failure; LVEF = left ventricular ejection fraction.