Asymptomatic Intracranial Hemorrhage Among Japanese Patients Taking Edoxaban for Non-Valvular Atrial Fibrillation.

Edoxaban (the free base of DU-176b) is an oral, selective, reversible, direct factor Xa inhibitor in clinical development for the prevention of stroke in patients with non-valvular atrial fibrillation (AF). There is evidence that asymptomatic intracranial hemorrhage (ICH) may be a risk factor for symptomatic ICH in anticoagulated patients. A phase IIb study in Japanese AF patients compared the incidence of asymptomatic ICH with edoxaban and warfarin use.

This was a multicenter, randomized, dose comparison study. Patients aged ≥20 years with CHADS₂ score ≥1 were randomly assigned to receive 1 of 3 doses of edoxaban (30 mg, 45 mg, or 60 mg QD) or open-label warfarin dose-adjusted to a target international normalized ratio (INR) of 2.0 to 3.0 inclusive for patients aged <70 years and 1.6 to 2.6 inclusive for patients aged ≥70 years, for 12 weeks. The primary objective of the study was to assess the incidence of all bleeding events (major, clinically relevant non-major and minor bleeds) including asymptomatic ICH. Asymptomatic ICH was defined as newly detected hemorrhage on brain image (CT or MRI) by assessing pre- and post-treatment brain images and was obtained from all enrolled patients. All images were assessed by an Asymptomatic ICH Committee that was blinded to treatment assignment.

There were no clinically relevant differences in patient demographics and baseline characteristics between treatment groups. Overall, the time within the target INR range was 83% and 73% for patients aged ≥70 years and aged <70 years, respectively. The incidence of all bleeding events increased with increasing doses of edoxaban, but there were no statistically significant differences among the 3 edoxaban groups. The mean (95% confidence interval) incidences of all bleeding for edoxaban 30 mg, 45 mg, and 60 mg, and warfarin were 18.5% (12.7, 26.0), 22.4% (16.2, 30.2), 27.7% (20.7, 35.9), and 20.0% (13.9, 27.9), respectively. Of the total 536 patients enrolled, 17 patients did not fulfill the assessment criteria for asymptomatic ICH. Of the 17 patients, 1 patient in the edoxaban 60-mg group had symptomatic ICH. The remaining 519 (391 edoxaban, 128 warfarin) patients were evaluated for asymptomatic ICH. A total of 431 patients underwent CT (329 edoxaban, 102 warfarin), 81 patients underwent MRI (57 edoxaban, 24 warfarin), and 7 patients underwent CT/MRI (5 edoxaban, 2 warfarin). There were no asymptomatic ICH events in any treatment group. Conclusions: In this study of 3 fixed doses of edoxaban compared with well-controlled warfarin, edoxaban was safe and asymptomatic ICH was not detected.

Yasaka:Nippon Boehringer lngelheim Co., Ltd.: Consultancy; Pfizer Japan Inc.: Consultancy; Daiichi Sankyo Co., LTD.: Consultancy. Kawai:Toyama Chemical: Consultancy; DaiichiSankyo: Consultancy. Yamaguchi:Mitsubishi Tanabe Pharma: Consultancy; Otsuka Pharmaceutical: Consultancy. Uchiyama:Bayer Yakuhin, LTD. : Consultancy; Nippon Boehringer lngelheim Co., Ltd.: Consultancy; Astellas Pharma Inc.: Consultancy. Ogawa:TEIJIN PHARMA LIMITED: Consultancy; Pfizer Japan Inc.: Consultancy; Bayer Yakuhin, LTD.: Consultancy; Astellas Pharma : Share Holder; Sanofi-aventis : Paid Instructor. Koretsune:Daiichi Sankyo: Consultancy, National Lead Investigator. Yamashita:Novartis: Consultancy; DaiichiSankyo: Consultancy, National Lead Investigator; Otsuka Pharmaceutical: Paid Instructor; Sanofi-aventis: Paid Instructor; TEIJIN PHARMA: Paid Instructor.