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Increased major bleeding incidence in atrial fibrillation patients with apixaban: a review of Japanese post-marketing surveillance studies of direct oral anticoagulants

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Abstract

Large-scaled post-marketing surveillance studies (PMSSs) of 4 direct oral anticoagulants (DOACs) for stroke prevention in non-valvular atrial fibrillation (AF) were conducted since 2011 in Japan, and the results of the last one have recently been published. Each reported a more than acceptable ischemic stroke prevention. The major bleeding rates were also acceptably low and comparable to each other in the PMSSs of dabigatran (J-dabigatran), rivaroxaban (XAPASS), and edoxaban (ETNA-AF-Japan). However, the incidence in PMSS of apixaban (STANDARD) was more than double the others. This finding appeared to contradict the globally accepted theory that apixaban is less likely than other DOACs to cause bleeding events. Possible responsible mechanisms included (1) the age and kidney function, (2) concomitant antiplatelet therapy, (3) drug actions, (4) follow-up duration, and (5) dose reduction criteria. Similarities in the clinical background shared by the 4 different PMSSs’ participants and knowledge from previous studies did not support a dominant contribution of any of those former 4 factors to the increased major bleeding incidence in STANDARD. A possibility of the 5th factor was then examined. An estimated calculation we created showed that apixaban’s dose reduction criteria was strict enough to considerably reduce the opportunity for participants to take its reduced rather than standard dose. We then successfully simulated how the “strict” dose reduction criteria would have increased the bleeding event rates under DOAC therapy. The discussion in this review may therefore raise a question about the validity of the current dose reduction criteria of apixaban for Japanese AF patients.

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Authors and Affiliations

  1. Department of Cardiology, Cardiovascular Center, National Hospital Organization Higashihiroshima Medical Center, 513 Jike, Saijo-cho, 739-0041, Higashihiroshima, Japan

    Akinori Sairaku

  2. Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan

    Akinori Sairaku & Yukiko Nakano

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  1. Akinori Sairaku
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Both authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Akinori Sairaku. The first draft of the manuscript was written by Akinori Sairaku, and both authors commented on previous versions of the manuscript. Both authors read and approved the final manuscript.

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Correspondence to Akinori Sairaku.

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Key points

• Compared to post-marketing surveillance studies (PMSSs) of dabigatran, rivaroxaban, and edoxaban for stroke prevention in Japanese atrial fibrillation patients, a twofold higher major bleeding incidence was noted in that of apixaban (STANDARD study).

• A simulation of the influence of tightening the dose reduction criteria on the bleeding event rate suggested that apixaban’s strict dose reduction criteria possibly contributed to the increased major bleeding incidence in the STANDARD study.

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Sairaku, A., Nakano, Y. Increased major bleeding incidence in atrial fibrillation patients with apixaban: a review of Japanese post-marketing surveillance studies of direct oral anticoagulants. Eur J Clin Pharmacol 79, 579–588 (2023). https://doi.org/10.1007/s00228-023-03471-x

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