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Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease

Satoshi Yasuda, M.D., Ph.D.,
Koichi Kaikita, M.D., Ph.D.,
Masaharu Akao, M.D., Ph.D.,
Junya Ako, M.D., Ph.D.,
Tetsuya Matoba, M.D., Ph.D.,
Masato Nakamura, M.D., Ph.D.,
Katsumi Miyauchi, M.D., Ph.D.,
Nobuhisa Hagiwara, M.D., Ph.D.,
Kazuo Kimura, M.D., Ph.D.,
Atsushi Hirayama, M.D., Ph.D.,
Kunihiko Matsui, M.D., M.P.H.,
and Hisao Ogawa, M.D., Ph.D.
for the AFIRE Investigators^*

Abstract

Background

There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease.

Methods

In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non–vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority.

Results

The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P<0.001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01 for superiority).

Conclusions

As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease. (Funded by the Japan Cardiovascular Research Foundation; AFIRE UMIN Clinical Trials Registry number, UMIN000016612; and ClinicalTrials.gov number, NCT02642419.)

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Funding and Disclosures

Supported by the Japan Cardiovascular Research Foundation through a contract with Bayer Yakuhin.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Dr. Yasuda reports receiving grant support from Takeda and Abbott and lecture fees from Daiichi Sankyo and Bristol-Myers Squibb; Dr. Kaikita, receiving grant support from Bayer Yakuhin, Daiichi Sankyo, Novartis Pharma, and SBI Pharma; Dr. Akao, receiving lecture fees from Bristol-Myers Squibb and Nippon Boehringer Ingelheim and grant support and lecture fees from Bayer Yakuhin and Daiichi Sankyo; Dr. Ako, receiving lecture fees from Bayer Yakuhin and Sanofi and grant support and lecture fees from Daiichi Sankyo; Dr. Matoba, receiving lecture fees from Nippon Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca, and Bayer Yakuhin; Dr. Nakamura, receiving grant support and honoraria from Bayer Yakuhin, Daiichi Sankyo, Sanofi, and Nippon Boehringer Ingelheim and honoraria from Bristol-Myers Squibb; Dr. Miyauchi, receiving lecture fees from Amgen Astellas BioPharma, Astellas Pharma, Merck Sharp & Dohme, Bayer Yakuhin, Sanofi, Takeda, Daiichi Sankyo, Nippon Boehringer Ingelheim, and Bristol-Myers Squibb; Dr. Hagiwara, receiving grant support and lecture fees from Bayer Yakuhin and Nippon Boehringer Ingelheim, lecture fees from Bristol-Myers Squibb, and grant support from Daiichi Sankyo and Pfizer Japan; Dr. Kimura, receiving lecture fees from Bristol-Myers Squibb and Nippon Boehringer Ingelheim, grant support, lecture fees, and advisory fees from Bayer Yakuhin, and grant support and lecture fees from Daiichi Sankyo and Sanofi; Dr. Hirayama, receiving lecture fees from Sanofi, Astellas Pharma, Sumitomo Dainippon Pharma, AstraZeneca, Nippon Boehringer Ingelheim, and Amgen Astellas BioPharma, grant support and lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, and Bayer Yakuhin, lecture and consulting fees from Toa Eiyo, grant support from Pfizer Japan, serving as an endowed chair for Boston Scientific Japan, Hokushin Medical, Abbott Japan, Active Medical, Fukuda Denshi, Medtronic Japan, Japan Lifeline, and Kurihara Medical Instrument, and receiving lecture fees and serving as an endowed chair for Otsuka Pharma; and Dr. Ogawa, receiving lecture fees from Towa Pharmaceutical and honoraria from Novartis Pharma. No other potential conflict of interest relevant to this article was reported.

This article was published on September 2, 2019, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank Cindy Jenner of Chameleon Communications International for providing editorial assistance with an earlier version of the manuscript and the staff members of Mebix for their assistance in the management of data collection, storage, and analysis.

Author Affiliations

From the National Cerebral and Cardiovascular Center, Suita (S.Y., H.O.), the Department of Cardiology, Osaka Police Hospital, Osaka (A.H.), the Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University (K. Kaikita), and the Department of General Medicine, Kumamoto University Hospital (K. Matsui), Kumamoto, the Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto (M.A.), the Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara (J.A.), the Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka (T.M.), the Division of Cardiovascular Medicine, Toho University Ohashi Medical Center (M.N.), the Department of Cardiology, Juntendo University School of Medicine (K. Miyauchi), and the Department of Cardiology, Tokyo Women’s Medical University (N.H.), Tokyo, and the Cardiovascular Center, Yokohama City University Medical Center, Yokohama (K. Kimura) — all in Japan.

Address reprint requests to Dr. Yasuda at the Japan Cardiovascular Research Foundation, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 565-8565, Japan, or at [email protected].

A full list of the AFIRE investigators and committee members is provided in the Supplementary Appendix, available at NEJM.org.

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