CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(09): 1584-1593
DOI: 10.1055/s-0042-1744543
Stroke, Systemic or Venous Thromboembolism

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

Hiroyuki Arashi
1   Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan
Junichi Yamaguchi
1   Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan
Nobuhisa Hagiwara
1   Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan
Satoshi Yasuda
2   Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
3   National Cerebral and Cardiovascular Center, Osaka, Japan
Koichi Kaikita
4   Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
5   Division of Cardiovascular Medicine and Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Masaharu Akao
6   Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
Junya Ako
7   Department of Cardiovascular Medicine, Kitasato University School of Medicine, Kanagawa, Japan
Tetsuya Matoba
8   Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
Masato Nakamura
9   Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan
Katsumi Miyauchi
10   Department of Cardiovascular Medicine, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan
Kazuo Kimura
11   Cardiovascular Center, Yokohama City University Medical Center, Kanagawa, Japan
Atsushi Hirayama
12   Department of Cardiology, Osaka Police Hospital, Osaka, Japan
Kunihiko Matsui
13   Department of General Medicine and Primary Care, Kumamoto University Hospital, Kumamoto, Japan
Hisao Ogawa
14   Kumamoto University, Kumamoto, Japan
on behalf of the AFIRE investigators › Author Affiliations
Funding This work was supported by the Japan Cardiovascular Research Foundation based on a contract with Bayer Yakuhin, Ltd. The study sponsors had no role in the trial design, collection, or analysis of the data, interpretation of the trial results, or writing of the manuscript.


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 (, number UMIN000016612, and, number NCT02642419.

Supplementary Material

Publication History

Received: 14 October 2021

Accepted: 10 February 2022

Article published online:
13 June 2022

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