A Phase II, double‐blind, randomized, parallel group, dose‐finding study of the safety and tolerability of darexaban compared with warfarin in patients with non‐valvular atrial fibrillation: the oral factor Xa inhibitor for prophylaxis of stroke in atrial fibrillation study 2 (OPAL‐2)

Abstract

Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa. To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF). In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15mg bid, 30mg qd, 30mg bid, 60mg qd, 60mg bid or 120mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability. A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28weeks (interquartile range, 24-36). At daily doses of 30-60mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity. In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered.