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

  • Heart Rhythm O2. 2021 Nov 14;3(1):40-49. doi: 10.1016/j.hroo.2021.11.005.
William T Abraham  1 ,  Jonathan P Piccini  2 ,  Christopher Dufton  3 ,  Ian A Carroll  3 ,  Jeffrey S Healey  4 ,  Christopher M O'Connor  5 ,  Debra Marshall  3 ,  Ryan Aleong  6 ,  Dirk J van Veldhuisen  7 ,  Michiel Rienstra  7 ,  Stephen B Wilton  8 ,  Michel White  9 ,  William H Sauer  10 ,  Inder S Anand  11 ,  Sophia P Huebler  3 ,  Stuart J Connolly  4 ,  Michael R Bristow  3  6
Affiliations
  • 1. Ohio State University Medical Center, Columbus, Ohio.
  • 2. Duke Clinical Research Institute and Duke University Medical Center, Durham, North Carolina.
  • 3. ARCA biopharma, Inc, Westminster, Colorado.
  • 4. Population Health Research Institute, McMaster University, Hamilton, California.
  • 5. Inova Heart and Vascular Institute, Fairfax, Virginia.
  • 6. University of Colorado Anschutz Medical Campus Division of Cardiology, Aurora, Colorado.
  • 7. University of Groningen, University Medical Center, Groningen, the Netherlands.
  • 8. Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada.
  • 9. Montreal Heart Institute, Montreal, Canada.
  • 10. Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • 11. University of Minnesota, Minneapolis, Minnesota.
PMID: 35243434 DOI: 10.1016/j.hroo.2021.11.005
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 (Zodds 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.
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