Trial DesignA 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
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.