Apixaban for Patients with Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial

Abstract

Background: There is no randomized data evaluating the safety or efficacy of apixaban for stroke prevention in patients with end-stage kidney disease (ESKD) on hemodialysis and with atrial fibrillation (AF).

Methods: The RENAL-AF trial was a prospective, randomized, open-label, blinded-outcome evaluation (PROBE) of apixaban versus warfarin in patients receiving hemodialysis with AF and CHA ₂ DS ₂ -VASc score ≥2. Patients were randomized 1:1 to apixaban 5mg twice daily (2.5mg twice daily with age ≥80 years and/or weight ≤60kg) or dose-adjusted warfarin. The primary outcome was time to major or clinically relevant non-major bleeding. Secondary outcomes included stroke, mortality, and apixaban pharmacokinetics. Pharmacokinetic sampling was day 1, day 3, and month 1.

Results: From January 2017 through January 2019, 154 patients were randomized to apixaban (n=82) or warfarin (n=72). The trial stopped prematurely due to enrollment challenges. Time in therapeutic range (INR 2.0-3.0) for warfarin-treated patients was 44% (interquartile range; 23-59%). The 1-year rates for major or clinically relevant non-major bleeding were 32% and 26% in apixaban and warfarin groups, respectively (HR 1.20, 95% CI 0.63-2.30), while 1-year rates for stroke or systemic embolism were 3.0% and 3.3% in apixaban and warfarin groups, respectively. Death was the most common major event in the apixaban (21 patients [26%]) and warfarin (13 patients [18%]) arms. The pharmacokinetic substudy enrolled the target 50 patients. Median steady state 12-hour area under the curve (AUC0-12) was 2,475 ng-h/mL (10 ^th -90 ^th percentiles 1,342-3,285) for 5mg apixaban twice daily and 1,269 ng-h/mL (10 ^th -90 ^th percentiles 615-1,946) for 2.5mg apixaban twice daily. There was substantial overlap between minimum apixaban blood concentration, 12-hour AUC0-12, and maximum apixaban blood concentration for patients with and without a major or clinically relevant non-major bleeding events.

Conclusions: There was inadequate power to draw any conclusion regarding rates of major or clinically relevant non-major bleeding comparing apixaban and warfarin in patients with AF and ESKD on hemodialysis. Clinically relevant bleeding events were approximately 10-fold more frequent than stroke or systemic embolism among this population on anticoagulation, highlighting the need for future randomized studies evaluating the risks versus benefits of anticoagulation among patients with AF and ESKD on hemodialysis.