ARCA biopharma, Inc. announced that the paper entitled “Dose Limiting, Adverse Event Associated Bradycardia with ß-blocker Treatment of Atrial Fibrillation in the GENETIC-AF Trial” (William Abraham, et al) has been published in Heart Rhythm O2, a publication of the Hearth Rhythm Society. The paper details an analysis that examined the prevalence of bradycardia and its association with adverse events (AEs) and failure to achieve target dose in the GENETIC-AF Phase 2b clinical trial. In the genetically defined population of GENETIC-AF (all ADRB1 Arg389Arg genotype), the prevalence of clinically important bradycardia was lower for Gencaro compared to metoprolol, with an incidence of heart rate (HR) <50 beats/min of 0.24 episodes/patient per 6 months compared to 0.57 episodes/patient per 6 months for metoprolol succinate (P < .0001).   This translated to less dose reduction or limitation in the Gencaro group, with 75% of Gencaro subjects achieving target dose compared to 62% for metoprolol (P <0.0001) and 13 bradycardia adverse events in the metoprolol group compared to one for Gencaro (P = 0.001).

The 267-patient GENETIC-AF clinical trial tested the hypothesis that pharmacogenetic inhibitory targeting of the higher function, 389 arginine (ADRB1 Arg389) variant of the beta1-adrenergic receptor (beta1-AR) by Gencaro would be more effective in preventing AF than inhibition by metoprolol succinate, a beta blocker without differentiated effects for the ADRB1 Arg389Gly polymorphism. In order to assess the prevalence and importance of bradyarrhythmias in AF-prone HF patients treated with beta blockers and to investigate potential differences between agents with different pharmacologic properties, the paper's authors compared HRs, prevalence of bradycardia, bradycardia association with AEs, target dose attainment, and dose reductions between the second-generation beta blocker metoprolol and the fourth-generation compound Gencaro in the GENETIC-AF trial. Patients randomized to metoprolol (n = 125) or Gencaro (n = 131) entering 24-week efficacy follow-up and receiving study medication were evaluated.

Bradycardia was defined as an electrocardiogram (ECG) HR <60 beats per minute (bpm) and severe bradycardia <50 bpm. Additional analyses determined that mean HR in sinus rhythm (SR) was 62.6 ± 12.5 bpm for metoprolol and 68.3 ± 11.1 bpm for Gencaro (P < .0001), but in AF HRs were not different (87.5 bpm vs 89.7 bpm, respectively). Bradycardia episodes (HR <60 bpm) per patient for Gencaro vs metoprolol were 0.82 vs 2.08 (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.

On multivariate analysis of 21 candidate bradycardia predictors including presence of a device with pacing capability, Gencaro treatment was associated with the greater degree of prevention (Z odds ratio -4.24, P < .0001).