Edoxaban versus warfarin in patients with atrial fibrillation in relation to the risk of stroke: A secondary analysis of the ENGAGE AF-TIMI 48 study

Abstract

Introduction: The efficacy and safety of the oral factor Xa inhibitor edoxaban compared to warfarin stratified by CHA₂DS₂VASc scores have not been described.

Methods: The ENGAGE AF-TIMI 48 trial randomized patients with atrial fibrillation to once-daily edoxaban or warfarin. We classified patients based on CHA₂DS₂VASc score and compared pharmacokinetics (edoxaban concentration), pharmacodynamics (anti-factor Xa [FXa] with edoxaban, time-in-therapeutic range for warfarin), efficacy (stroke or systemic embolism [SSE]), safety (major bleeding [MB], intracranial hemorrhage), and cardiovascular mortality, for the approved edoxaban regimen vs warfarin.

Results: The distribution CHA₂DS₂VASc score were:≤3, N = 4159 (29.6%); 4, N = 4066 (28.9%); 5, N = 3165 (22.5%); and ≥6, N = 2681 (19.1%). Increasing rates of SSE (1.05 to 2.99%/year) and MB (2.27 to 4.66%/year) were observed in the warfarin arm as the CHA₂DS₂VASc score increased. The hazard ratios per unit increase of CHA₂DS₂VASc score were 1.29 (1.21-1.38) and 1.26 (1.17-1.36) for SSE, and 1.20 (1.13-1.27) and 1.19 (1.12-1.27) for MB, with warfarin and edoxaban, respectively. Time-in-therapeutic range in warfarin-treated patients was similar and high (median 68%-69%) across CHA₂DS₂VASc scores, whereas edoxaban trough concentration, exogenous anti-FXa activity and %inhibition of endogenous FXa were higher at increasing CHA₂DS₂VASc scores. Edoxaban reduced SSE, MB, intracranial hemorrhage, and cardiovascular mortality vs warfarin to a similar degree across the range of CHA₂DS₂VASc scores (P-int = 0.90, 0.96, 0.21, and 0.37, respectively). Because of higher event rates the number of events prevented with edoxaban tended to be greater in patients with higher CHA₂DS₂VASc scores.

Conclusion: The benefit and safety of edoxaban versus warfarin is maintained across CHA₂DS₂VASc scores. While the relative risk reductions remain similar, edoxaban provides incrementally larger absolute reductions in outcomes over warfarin in patients with higher CHA₂DS₂VASc scores.