Rivaroxaban Underdose for Atrial Fibrillation with Stable Coronary Disease: The AFIRE Trial Findings

Abstract

Background: Rivaroxaban monotherapy was noninferior to combination therapy (rivaroxaban plus antiplatelet therapy) in efficacy but superior in safety in the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial. Among 2,215 patients with atrial fibrillation (AF) and stable coronary artery disease (CAD), 1,378 had baseline creatinine clearance (CrCl) ≥50 mL/min and received 10 (underdose) or 15 mg/d (standard-dose) rivaroxaban. We aimed to assess the effects of rivaroxaban underdose on clinical outcomes.

Methods: We assessed efficacy endpoint (a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and death from any cause) and major bleeding in the subgroup of patients with preserved renal function in the AFIRE trial.

Results: Age ≥75 years, female sex, lower CrCl, heart failure, and percutaneous coronary intervention history were associated with the underdose prescription. The underdose group had a similar incidence of the efficacy endpoint (3.62 vs. 3.51% per patient-year; p = 0.871) and significantly lower incidence of major bleeding (0.82 vs. 2.17% per patient-year; p = 0.022) than the standard-dose group. In patients receiving monotherapy, the incidences of efficacy endpoint and major bleeding were similar between the groups, whereas in those receiving combination therapy, the incidence of major bleeding was significantly lower in the underdose group than that in the standard-dose group.

Conclusion: In patients with AF, stable CAD, and preserved renal function, rivaroxaban underdose was associated with similar rates of thrombotic events but a lower incidence of hemorrhagic events than the standard dose.

Clinical trial registration: AFIRE UMIN Clinical Trials Registry (https://www.umin.ac.jp/ctr/), number UMIN000016612, and ClinicalTrials.gov, number NCT02642419.

Conflict of interest statement

H.A. reports personal fees from Takeda Pharmaceutical, Terumo, Abbott, Otsuka Pharmaceutical, and Bayer Yakuhin. J.Y. reports grants and personal fees from Abbott and Terumo, grants from Boston Scientific and Medtronic, and personal fees from Bristol Myers Squibb and Daiichi-Sankyo. S.Y. reports grants from Takeda Pharmaceutical, Abbott, and Boston Scientific, and personal fees from Daiichi-Sankyo and Bristol Myers Squibb. K.K. reports grants from Grants-in-Aid for Scientific Research (20K08451) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and grants and personal fees from Bayer Yakuhin and Daiichi-Sankyo. T.M. reports grants from the Japan Cardiovascular Research Foundation and personal fees from Nippon Boehringer Ingelheim, Daiichi-Sankyo, AstraZeneca, and Bayer Yakuhin. M.A. reports grants from the Japan Agency for Medical Research and Development (AMED), personal fees from Bristol Myers Squibb and Nippon Boehringer Ingelheim, and grants and personal fees from Bayer Yakuhin and Daiichi-Sankyo. J.A. reports personal fees from Bayer Yakuhin and Sanofi and grants and personal fees from Daiichi-Sankyo. M.N. reports grants and personal fees from Bayer Yakuhin, Daiichi-Sankyo, and Sanofi, and personal fees from Bristol Myers Squibb and Nippon Boehringer Ingelheim. K.M. reports personal fees from Amgen Astellas BioPharma, Astellas Pharma, MSD, Bayer Yakuhin, Sanofi, Takeda Pharmaceutical, Daiichi-Sankyo, Nippon Boehringer Ingelheim, and Bristol Myers Squibb. N.H. reports grants and personal fees from Bayer Yakuhin, grants from Nippon Boehringer Ingelheim, and personal fees from Bristol Myers Squibb. Kimura reports grants from the Japan Cardiovascular Research Foundation, grants and personal fees from Bayer Yakuhin, Daiichi-Sankyo, Sanofi, MSD, and AstraZeneca, and personal fees from Bristol Myers Squibb and Nippon Boehringer Ingelheim. A.H. reports grants and personal fees from Boston Scientific Japan, Otsuka Pharmaceutical, Sanofi, Astellas Pharma, Bristol Myers Squibb, Daiichi-Sankyo, and Bayer Yakuhin, grants from Fukuda Denshi, Abbott Japan, Japan Lifeline, Takeda Pharmaceutical, and Sumitomo Dainippon Pharma, and personal fees from Toa Eiyo, Nippon Boehringer Ingelheim, Amgen Astellas BioPharma, and AstraZeneca. H.O. reports personal fees from Towa Pharmaceutical, Bristol Myers Squibb, Pfizer, Toa Eiyo, Bayer Yakuhin, and Novartis Pharma. The other authors declare that there are no conflicts of interest for this study.

The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Figures

Fig. 1

Flow chart. We included 1,378 patients from the AFIRE trial who had baseline creatinine clearance of ≥50 mL/min and categorized them into two groups based on the administered dose of rivaroxaban: 10 mg/d (the underdose group,n = 356 [25.8%]) and 15 mg/d (the standard-dose group,n = 1,022 [74.2%]). CrCl, creatinine clearance.

Fig. 2

Primary efficacy and safety endpoints. Cumulative incidences of (A) the primary efficacy endpoint, which included stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause, and (B) the primary safety endpoint, which included major bleeding. Incidence rates per patient-year are provided in parentheses. CI, confidence interval; HR, hazard ratio.

Fig. 3

Primary and secondary efficacy and safety endpoints. Hazard ratios for the primary and secondary endpoints per initial dose of rivaroxaban. CI, confidence interval; HR, hazard ratio.

Fig. 4

Primary efficacy and safety endpoints according to the treatment group and dose of rivaroxaban. Cumulative incidences of (A) the primary efficacy endpoint, which included stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause, and (B) the primary safety endpoint, which included major bleeding. The doses of rivaroxaban and the treatment group (monotherapy [solid line] or combination therapy [dotted line]) were assigned during the AFIRE trial. CI, confidence interval; HR, hazard ratio.