Bucindolol Decreases Atrial Fibrillation Burden in Patients With Heart Failure and the
ADRB1
Arg389Arg Genotype
Authors: Piccini Jonathan P. , Dufton Christopher , Carroll Ian A. , Healey Jeff S. , Abraham William T. , Khaykin Yaariv , Aleong Ryan , Krueger Steven K. , Sauer William H. , Wilton Stephen B. , Rienstra Michiel , van Veldhuisen Dirk J. , Anand Inder S. , White Michel , Camm A. John , Ziegler Paul D. , Marshall Debra , Bristow Michael R. , Connolly Stuart J. , Ayala-Paredes F , Bakbak A , Bernier ML , Birnie DH , Coutu B , Crystal E , Deyell MW , Dyrda KM , Hartleib MC , Laksman ZW , Leong-Sit P , Morillo CA , Pandey AS , Philippon F , Vizel S , Andréka P , Csanadi Z , Duray GZ , Forster T , Kerkovits G , Merkely B , Nagy AC , Simor T , Czarnecka D , Kasprzak JD , Musial WJ , Raczak G , Szachniewicz J , Wranicz JK , Apostolović S , Hinić S , Miloradović V , Simić D , Milhous GJ , Oomen A , Romer TJ , van Vijk LM , Adamson PB , Allred JD , Amjadi N , Bahu MM , Bank AJ , Berman AE , Bernabei MA , Bhagwat RS , Borgatta L , Buda AJ , Cole RT , Collier JL , Compton SJ , Costantini O , Costanzo MR , Dauber IM , Donahue MP , Dor I , Egnacyzk GF , Eichhorn EJ , Eiswirth CC , Emani S , Ewald GA , Forde-McLean RC , Gelernt MD , Haines DE , Henrikson CA , Herre JM , Herweg B , Ilkhanoff L , Jackson LR , Lala A , Lo R , London B , Lowes BD , Mackall JA , Malhotra V , McGrew FA , Murali S , Natale A , Nilsson KR , Okolo J , Perez MV , Phang RS , Ranjan R , Rashtian MY , Ross MJ , Samii SM , Shinn T , Shoemaker MB , Strickberger SA , Tholakanahalli VN , Tzur A , Wang PJ , Younis LT 
Published: July 2021

Background:

Bucindolol is a genetically targeted β-blocker/mild vasodilator with the unique pharmacological properties of sympatholysis and
ADRB1
Arg389 receptor inverse agonism. In the GENETIC-AF trial (Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL for the Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients With Heart Failure) conducted in a genetically defined heart failure population at high risk for recurrent atrial fibrillation (AF), similar results were observed for bucindolol and metoprolol succinate for the primary end point of time to first AF event; however, AF burden and other rhythm control measures were not analyzed.

Methods:
The prevalence of ECGs in normal sinus rhythm, AF interventions for rhythm control (cardioversion, ablation, and antiarrhythmic drugs) and biomarkers were evaluated in the overall population entering efficacy follow-up (N=257). AF burden was evaluated for 24 weeks in the device substudy (N=67).

Results:

In 257 patients with heart failure, the mean age was 65.6±10.0 years, 18% were female, mean left ventricular ejection fraction was 36%, and 51% had persistent AF. Cumulative 24-week AF burden was 24.4% (95% CI, 18.5–30.2) for bucindolol and 36.7% (95% CI, 30.0–43.5) for metoprolol (33% reduction,
P
<0.001). Daily AF burden at the end of follow-up was 15.1% (95% CI, 3.2–27.0) for bucindolol and 34.7% (95% CI, 17.9–51.2) for metoprolol (55% reduction,
P
<0.001). For the metoprolol and bucindolol respective groups, the prevalence of ECGs in normal sinus rhythm was 4.20 and 3.03 events per patient (39% increase in the bucindolol group,
P
<0.001), while the rate of AF interventions was 0.56 and 0.82 events per patient (32% reduction for bucindolol,
P
=0.011). Reductions in plasma norepinephrine (
P
=0.038) and NT-proBNP (N-terminal pro B-type natriuretic peptide;
P
=0.009) were also observed with bucindolol compared with metoprolol.

Conclusions:

Compared with metoprolol, bucindolol reduced AF burden, improved maintenance of sinus rhythm, and lowered the need for additional rhythm control interventions in patients with heart failure and the
ADRB1
Arg389Arg genotype.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01970501.