Elsevier

American Heart Journal

Volume 199, May 2018, Pages 51-58
American Heart Journal

Trial Design
A genotype-directed comparative effectiveness trial of Bucindolol and metoprolol succinate for prevention of symptomatic atrial fibrillation/atrial flutter in patients with heart failure: Rationale and design of the GENETIC-AF trial

https://doi.org/10.1016/j.ahj.2017.12.001Get rights and content

Background

Few therapies are available for the safe and effective treatment of atrial fibrillation (AF) in patients with heart failure. Bucindolol is a non-selective beta-blocker with mild vasodilator activity previously found to have accentuated antiarrhythmic effects and increased efficacy for preventing heart failure events in patients homozygous for the major allele of the ADRB1 Arg389Gly polymorphism (ADRB1 Arg389Arg genotype). The safety and efficacy of bucindolol for the prevention of AF or atrial flutter (AFL) in these patients has not been proven in randomized trials.

Methods/design

The Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol Succinate for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure (GENETIC-AF) trial is a multicenter, randomized, double-blinded “seamless” phase 2B/3 trial of bucindolol hydrochloride versus metoprolol succinate, for the prevention of symptomatic AF/AFL in patients with reduced ejection fraction heart failure (HFrEF). Patients with pre-existing HFrEF and recent history of symptomatic AF are eligible for enrollment and genotype screening, and if they are ADRB1 Arg389Arg, eligible for randomization. A total of approximately 200 patients will comprise the phase 2B component and if pre-trial assumptions are met, 620 patients will be randomized at approximately 135 sites to form the Phase 3 population. The primary endpoint is the time to recurrence of symptomatic AF/AFL or mortality over a 24-week follow-up period, and the trial will continue until 330 primary endpoints have occurred.

Conclusions

GENETIC-AF is the first randomized trial of pharmacogenetic guided rhythm control, and will test the safety and efficacy of bucindolol compared with metoprolol succinate for the prevention of recurrent symptomatic AF/AFL in patients with HFrEF and an ADRB1 Arg389Arg genotype. (ClinicalTrials.gov NCT01970501).

Section snippets

Bucindolol and the BEST trial

Bucindolol hydrochloride has been extensively investigated for the treatment of symptomatic HFrEF. Several Phase 2 randomized studies demonstrated reductions in circulating norepinephrine, improved ventricular function, and improved quality of life with bucindolol in patients with HFrEF.8., 9., 10., 11., 12. Bucindolol was the first beta-blocker to be tested in a randomized trial for the reduction of all-cause mortality.8., 15. Despite its early start, several other trials with other agents

Endpoint assessment

The 24-week follow-up period begins on confirmation of SR in patients undergoing ECV, or 3 weeks after randomization in patients in SR at that time. Patients failing ECV are counted as AF/AFL events on Day 1 of follow-up. Ongoing surveillance is performed to assess the maintenance of SR, and to confirm the presence of symptomatic arrhythmias. During the 24-week Follow-up Period, heart rhythm will be assessed by 12-lead ECG at scheduled clinic visits (Figure 1). The full schedule of events is

Concurrent interventions

Other than HFrEF guideline-recommended beta-blockers, concurrent pharmacologic therapies for rhythm control in AF are prohibited within 1 week of randomization. Patients are excluded if they have had catheter ablation of AF or AFL within 30 days of randomization. If AF recurs during the study follow-up period, additional indicated rhythm control treatments may be added at the discretion of the investigator.

Statistical analyses

The primary efficacy analysis is time to symptomatic AF/AFL or mortality on the intention-to-treat (ITT) population with censoring at 24 weeks. Sample size calculation for the Phase 3 study population assumes a 60% event rate in the metoprolol succinate arm and a 25% risk reduction with bucindolol. Accrual of 330 primary events would yield 98% power at alpha = 0.05, and 90% for alpha = 0.01. Treatment effect will be stratified by (1) HF etiology (ischemic/non-ischemic); (2) LVEF (<35%/≥35%); (3)

Administrative organization

The administrative organization of the trial is given in an online Supplement (Figure S1).

Discussion

The prevalence of AF increases with HF severity, ranging from less than 5% in patients with NYHA class I to nearly 50% of patients NYHA class IV functional limitation.33 In patients with HF, development of AF leads to decreased quality of life (QOL) and worse cardiovascular outcomes, including increased risk of stroke, hospitalization, and death.3., 4., 34. Restoration of SR is associated with improved quality of life, decreased neurohormonal distress, and improved left ventricular dysfunction

Conclusions

The GENETIC-AF trial is the first pharmacogenetic rhythm control trial in AF, and utilizes a unique seamless Phase 2B/3 design. Given the rising burden and morbidity of AF and concomitant HFrEF the trial addresses an urgent clinical need, and may shed light on several controversies surrounding the mechanism of benefit of beta-blockade in patients with HFrEF complicated by AF. Bucindolol hydrochloride represents a promising therapy that may be both safer and more effective than alternative

Disclosure information

The GENETIC-AF trial is sponsored by ARCA Pharma. JPP receives funding for clinical research from ARCA biopharma, Boston Scientific, Gilead, Janssen Pharmaceuticals, Spectranetics, and St Jude Medical and serves as a consultant to Allergan, Amgen, GlaxoSmithKline, Johnson & Johnson, Medtronic, and Spectranetics. BAS reports research support from Boston Scientific, St Jude Medical, and BMS/Pfizer and serves as a consultant to BMS/Pfizer, Janssen Pharmaceuticals, and Biosense-Webster. SBW reports

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    RCT# NCT01970501

    W. H. Wilson Tang, MD served as guest editor for this article.

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