Author + information
- Received February 15, 2019
- Revision received April 17, 2019
- Accepted April 17, 2019
- Published online June 24, 2019.
- Jonathan P. Piccini, MD, MHSa,∗ (, )
- William T. Abraham, MDb,
- Christopher Dufton, PhDc,
- Ian A. Carroll, PhDc,
- Jeff S. Healey, MDd,
- Dirk J. van Veldhuisen, MD, PhDe,
- William H. Sauer, MDf,
- Inder S. Anand, MD, PhDg,
- Michel White, MDh,
- Stephen B. Wilton, MD, MSci,
- Ryan Aleong, MDf,
- Michiel Rienstra, MD, PhDe,
- Steven K. Krueger, MDj,
- Felix Ayala-Paredes, MDk,
- Yaariv Khaykin, MDl,
- Bela Merkely, MD, PhDm,
- Vladimir Miloradović, MDn,
- Jerzy K. Wranicz, MD, PhDo,
- Leonard Ilkhanoff, MD, MSp,
- Paul D. Ziegler, MSq,
- Gordon Davis, MSPHc,
- Laura L. Emery, MSPHc,
- Debra Marshall, MDc,
- David P. Kao, MDf,
- Michael R. Bristow, MD, PhDc,f,
- Stuart J. Connolly, MDd,
- for the GENETIC-AF Trial Investigators
- aDuke Clinical Research Institute and Duke University Medical Center, Durham, North Carolina
- bOhio State University Medical Center, Columbus, Ohio
- cARCA Biopharma, Inc., Westminster, Colorado
- dPopulation Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- eUniversity of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- fUniversity of Colorado, Boulder, Colorado
- gU.S. Department of Veterans Affairs, Washington, DC
- hMontreal Heart Institute, Montreal, Quebec, Canada
- iLibin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada
- jBryan Heart Institute, Columbus, Nebraska
- kCentre Hospitalier Universitaire de Sherbrooke, Quebec, Canada
- lSouthlake Regional Health Centre, Newmarket, Ontario, Canada
- mHeart and Vascular Center of the Semmelweis University, Budapest, Hungary
- nUniversity of Kragujevac and Clinical Center Kragujevac, Kragujevac, Serbia
- oMedical University of Lodz, Lodz, Poland
- pInova Heart and Vascular Institute, Falls Church, Virginia
- qMedtronic, Mounds View, Minnesota
- ↵∗Address for correspondence:
Dr. Jonathan P. Piccini, Duke University Duke Clinical Research Institute, PO Box 17969, Durham, North Carolina 27710.
Objectives The purpose of this study was to compare the effectiveness of bucindolol with that of 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 A total of 267 HFrEF patients with a left ventricular ejection fraction (LVEF) <0.50, symptomatic AF, and the ADRB1 Arg389Arg genotype were randomized 1:1 to receive bucindolol or metoprolol therapy and were up-titrated to target doses. The primary endpoint of AF or 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% confidence interval [CI]: 0.71 to 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 the interval of time from the initial diagnoses of AF and HF to randomization and with the onset of AF relative to that of the initial HF diagnosis. In a cohort whose first AF and HF 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 to 0.87; p = 0.011).
Conclusions Pharmacogenetically guided bucindolol therapy did not reduce the recurrence of AF/AFL or ACM compared to that of metoprolol therapy in HFrEF patients, but populations were identified who merited further investigation in future phase 3 trials.
The GENETIC-AF study was supported by ARCA Biopharma. Dr. Piccini has received research funding from ARCA Biopharma, Boston Scientific, Gilead, Janssen Pharmaceuticals, Spectranetics, and St. Jude Medical; and is a consultant for Allergan, Amgen, GlaxoSmithKline, Johnson and Johnson, Medtronic, and Spectranetics. Dr. Healey has received research support from Medtronic, Boston Scientific, and ARCA Biopharma. Dr. Wilton has received research support from Medtronic, Abbott, and Boston Scientific; and is a consultant for ARCA. Dr. van Veldhuisen is a compensated member of the ARCA Biopharma Board. Drs. Abraham, Aleong, White, and Connolly are consultants for ARCA Biopharma. Dr. Krueger is a member of the speaker bureaus of Boehringer Ingelheim, Amgen, Pfizer, and Amarin. Dr. Ilkhanoff is a speaker for Janssen. Dr. Ziegler is an employee of Medtronic. Drs. Dufton, Davis, Carroll, Emery, Marshall, and Bristow are employees of ARCA Biopharma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received February 15, 2019.
- Revision received April 17, 2019.
- Accepted April 17, 2019.
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