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Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population: The GENETIC-AF Trial.

Publication ,  Journal Article
Piccini, JP; Abraham, WT; Dufton, C; Carroll, IA; Healey, JS; van Veldhuisen, DJ; Sauer, WH; Anand, IS; White, M; Wilton, SB; Aleong, R ...
Published in: JACC Heart Fail
July 2019

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.

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Published In

JACC Heart Fail

DOI

EISSN

2213-1787

Publication Date

July 2019

Volume

7

Issue

7

Start / End Page

586 / 598

Location

United States

Related Subject Headings

  • Stroke Volume
  • Receptors, Adrenergic, beta-1
  • Proportional Hazards Models
  • Propanolamines
  • Precision Medicine
  • Pharmacogenomic Variants
  • Pharmacogenetics
  • Mortality
  • Middle Aged
  • Metoprolol
 

Citation

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Piccini, J. P., Abraham, W. T., Dufton, C., Carroll, I. A., Healey, J. S., van Veldhuisen, D. J., … GENETIC-AF Trial Investigators, . (2019). Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population: The GENETIC-AF Trial. JACC Heart Fail, 7(7), 586–598. https://doi.org/10.1016/j.jchf.2019.04.004
Piccini, Jonathan P., William T. Abraham, Christopher Dufton, Ian A. Carroll, Jeff S. Healey, Dirk J. van Veldhuisen, William H. Sauer, et al. “Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population: The GENETIC-AF Trial.JACC Heart Fail 7, no. 7 (July 2019): 586–98. https://doi.org/10.1016/j.jchf.2019.04.004.
Piccini JP, Abraham WT, Dufton C, Carroll IA, Healey JS, van Veldhuisen DJ, et al. Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population: The GENETIC-AF Trial. JACC Heart Fail. 2019 Jul;7(7):586–98.
Piccini, Jonathan P., et al. “Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population: The GENETIC-AF Trial.JACC Heart Fail, vol. 7, no. 7, July 2019, pp. 586–98. Pubmed, doi:10.1016/j.jchf.2019.04.004.
Piccini JP, Abraham WT, Dufton C, Carroll IA, Healey JS, van Veldhuisen DJ, Sauer WH, Anand IS, White M, Wilton SB, Aleong R, Rienstra M, Krueger SK, Ayala-Paredes F, Khaykin Y, Merkely B, Miloradović V, Wranicz JK, Ilkhanoff L, Ziegler PD, Davis G, Emery LL, Marshall D, Kao DP, Bristow MR, Connolly SJ, GENETIC-AF Trial Investigators. Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population: The GENETIC-AF Trial. JACC Heart Fail. 2019 Jul;7(7):586–598.
Journal cover image

Published In

JACC Heart Fail

DOI

EISSN

2213-1787

Publication Date

July 2019

Volume

7

Issue

7

Start / End Page

586 / 598

Location

United States

Related Subject Headings

  • Stroke Volume
  • Receptors, Adrenergic, beta-1
  • Proportional Hazards Models
  • Propanolamines
  • Precision Medicine
  • Pharmacogenomic Variants
  • Pharmacogenetics
  • Mortality
  • Middle Aged
  • Metoprolol