Author + information
- Received February 15, 2019
- Revision received April 17, 2019
- Accepted April 17, 2019
- Published online April 29, 2019.
- Jonathan P. Piccini, MD, MHS, FACC1,∗ (, )
- William T. Abraham, MD, FACC2,
- Christopher Dufton, PhD3,
- Ian A. Carroll, PhD3,
- Jeff S. Healey, MD, FHRS4,
- Dirk J. van Veldhuisen, MD, PhD, FACC5,
- William H. Sauer, MD, FHRS, FACC6,
- Inder S. Anand, MD, PhD, FACC7,
- Michel White, MD8,
- Stephen B. Wilton, MD, MSc9,
- Ryan Aleong, MD, FHRS, FACC6,
- Michiel Rienstra, MD, PhD5,
- Steven K. Krueger, MD10,
- Felix Ayala-Paredes, MD11,
- Yaariv Khaykin, MD12,
- Bela Merkely, MD, PhD, FESC, FACC13,
- Vladimir Miloradović, MD14,
- Jerzy K. Wranicz, MD, PhD15,
- Leonard Ilkhanoff, MD, MS, FHRS, FACC16,
- Paul D. Ziegler, MS17,
- Gordon Davis, MSPH3,
- Laura L. Emery, MSPH3,
- Debra Marshall, MD, FACC3,
- David P. Kao, MD6,
- Michael R. Bristow, MD, PhD, FACC3,6,
- Stuart J. Connolly, MD4,
- on behalf of the Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL for Prevention of Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure Trial Investigators
- 1Duke Clinical Research Institute and Duke University Medical Center
- 2Ohio State University Medical Center
- 3ARCA biopharma, Inc.
- 4Population Health Research Institute, McMaster University
- 5University of Groningen, University Medical Center Groningen, The Netherlands
- 6University of Colorado
- 7US Department of Veterans Affairs
- 8Montreal Heart Institute
- 9Libin Cardiovascular Institute of Alberta, University of Calgary
- 10Bryan Heart Institute
- 11Centre Hospitalier Universitaire de Sherbrooke
- 12Southlake Regional Health Centre
- 13Heart and Vascular Center of the Semmelweis University, Budapest
- 14University of Kragujevac and Clinical Center Kragujevac, Serbia
- 15Medical University of Lodz, Poland
- 16Inova Heart and Vascular Institute
- 17Medtronic, PLC
- ↵∗Corresponding Author: Jonathan P. Piccini, MD, MHS, FACC Duke University Duke Clinical Research Institute PO Box 17969 Durham, NC 27710 United States 919-564-9666 919-668-7057 (fax).
Objective To compare the effectiveness of bucindolol and 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 267 HFrEF patients with a left ventricular ejection fraction (LVEF) < 0.50, symptomatic AF, and the ADRB1 Arg389Arg genotype were randomized 1:1 to bucindolol or metoprolol and up-titrated to target doses. The primary endpoint of AF/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% CI: 0.71, 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: 1) the interval of time from the initial diagnosis of HF and AF to randomization, and; 2) the onset of AF relative to initial HF diagnosis. In a cohort whose first HF and AF 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, 0.87; p=0.011).
Conclusion Pharmacogenetic-guided bucindolol therapy did not reduce the recurrence of AF/AFL/ACM compared to metoprolol in HFrEF patients, but populations were identified that merit further investigation in future Phase 3 trials.
Funding: ARCA biopharma
GENETIC-AF was sponsored by ARCA biopharma. JPP receives research funding from ARCA, Boston Scientific, Gilead, Janssen Pharmaceuticals, Spectranetics, and St Jude Medical and serves as consultant to Allergan, Amgen, GlaxoSmithKline, Johnson & Johnson, Medtronic, and Spectranetics. SBW reports research support from Medtronic, Abbott, and Boston Scientific and serves as consultant to ARCA. WTA receives consulting fees from ARCA. PDZ is an employee of Medtronic. MRB is an officer and director of ARCA. CD, DAM, IAC, LLE and GWD are employees of ARCA.
- Received February 15, 2019.
- Revision received April 17, 2019.
- Accepted April 17, 2019.
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