Outcomes associated with under-dosing of rivaroxaban for management of non-valvular atrial fibrillation in real-world Japanese clinical settings

Takanori Ikeda, Satoshi Ogawa, Takanari Kitazono, Jyoji Nakagawara, Kazuo Minematsu, Susumu Miyamoto, Yuji Murakawa, Sanghun Iwashiro, Yoko Kidani, Yutaka Okayama, Toshiyuki Sunaya, Shoichiro Sato, Satoshi Yamanaka, Takanori Ikeda, Satoshi Ogawa, Takanari Kitazono, Jyoji Nakagawara, Kazuo Minematsu, Susumu Miyamoto, Yuji Murakawa, Sanghun Iwashiro, Yoko Kidani, Yutaka Okayama, Toshiyuki Sunaya, Shoichiro Sato, Satoshi Yamanaka

Abstract

The approved dose of oral anticoagulant rivaroxaban for patients with non-valvular atrial fibrillation (NVAF) in Japan is 15 mg once daily (od) in patients whose creatinine clearance is ≥ 50 mL/min, but recent real-world studies have demonstrated that these patients often received less than the recommended dose due to bleeding concerns. The effect of under-dosing on safety and effectiveness outcomes remains unclear. We used 1-year follow-up data from the XAPASS, a real-world Japanese prospective, single-arm, observational study. Of the 11,308 patients, 6521 patients who completed a 1-year follow-up and had a creatinine clearance ≥ 50 mL/min were included in this sub-analysis. Primary endpoints were any bleeding and a composite of stroke/non-central nervous system systemic embolism (non-CNS SE)/myocardial infarction (MI). Among the 6521 patients, 4185 (64.2%; mean CHADS2 score: 1.8) received the 15 mg od (recommended dose), whereas 2336 (35.8%; mean CHADS2 score: 2.3) received 10 mg od (under-dose). After adjusting for patient characteristics by propensity scoring and inverse probability of treatment weighting, incidence rates of major bleeding were comparable between under-dosed patients and patients who received the recommended dose (1.34 vs. 1.63 events/100 patient-years, p = 0.197), although the incidence rates of stroke/non-CNS SE/MI were higher in under-dosed patients than in those who received the recommended dose (2.15 vs. 1.48 events/100 patient-years, p = 0.009). In Japanese clinical practice, some NVAF patients receive rivaroxaban doses inconsistent with the recommendation. Considering the total clinical benefit, the recommended dose may be preferable in terms of balance of safety and effectiveness.Clinicaltrials.gov NCT01582737.

Keywords: Anticoagulants; Atrial fibrillation; Rivaroxaban; Stroke prevention; Underdosing.

Conflict of interest statement

TI, SO, TK, JN, KM, SM and YM were advisory board members for Bayer Yakuhin, Ltd. TI received research grants from Daiichi Sankyo, Bristol-Myers Squibb, Medtronic Japan, St. Jude Medical and Bayer Yakuhin, Ltd., and honoraria from Daiichi Sankyo, Ono, Bayer Yakuhin, Ltd., Bristol-Myers Squibb and Pfizer and TI was an advisory board member for Bristol-Myers Squibb. TK received a research grant from Bayer Yakuhin, Ltd. JN received a research grant from Nihon Medi-Physics. KM received honoraria from Bayer Yakuhin, Ltd., Otsuka, Boehringer-Ingelheim, AstraZeneca, Pfizer, Mitsubishi-Tanabe, Japan Stryker, Kowa, Nihon Medi-Physics, BMS, Sawai, Sumitomo Dainippon, Dai-ichi Sankyo, Astellas and Nippon Chemiphar, and KM was an advisory board member for CSL Behring and Medico’s Hirata. SM received research grants from Takeda, CSL Behring, Meiji, MSD, Astellas, Eisai, Otsuka, Carl Zeiss Meditec, Philips Electronics Japan, Sanofi, Siemens Healthcare, Daiichi Sankyo, Mitsubishi-Tanabe, Chugai, Nihon Medi-Physics, Pfizer, Bristol-Myers Squibb, Brainlab, Mizuho and Medtronic. YM received research grants from Bayer Yakuhin, Ltd., Daiichi Sankyo and Boehringer-Ingelheim and honoraria from Bayer Yakuhin, Ltd., Daiichi Sankyo, Boehringer-Ingelheim and Bristol-Myers Squibb. SI, YK, YO, TS, SS and SY are employees of Bayer Yakuhin, Ltd.

Figures

Fig. 1
Fig. 1
Cumulative rates of a any bleeding, b major bleeding, and c stroke/non-CNS SE/MI in patients who received the recommended dose of rivaroxaban [15 mg once daily (od)] versus patients who received under-dose rivaroxaban (10 mg od). CI confidence interval, HR hazard ratio, non-CNS SE non-central nervous system systemic embolism, MI myocardial infarction
Fig. 2
Fig. 2
The reasons for prescribing under-dose rivaroxaban from surveillance sheets (overlapping exists)

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