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

Introduction The efficacy and safety of the oral factor Xa inhibitor edoxaban compared to warfarin stratified by CHA(2)DS(2)VASc 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 CHA(2)DS(2)VASc 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 CHA(2)DS(2)VASc 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 CHA(2)DS(2)VASc score increased. The hazard ratios per unit increase of CHA(2)DS(2)VASc 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 CHA(2)DS(2)VASc scores, whereas edoxaban trough concentration, exogenous anti-FXa activity and %inhibition of endogenous FXa were higher at increasing CHA(2)DS(2)VASc scores. Edoxaban reduced SSE, MB, intracranial hemorrhage, and cardiovascular mortality vs warfarin to a similar degree across the range of CHA(2)DS(2)VASc 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 CHA(2)DS(2)VASc scores.Conclusion The benefit and safety of edoxaban versus warfarin is maintained across CHA(2)DS(2)VASc scores. While the relative risk reductions remain similar, edoxaban provides incrementally larger absolute reductions in outcomes over warfarin in patients with higher CHA(2)DS(2)VASc scores.