Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Oct 6:e253662.
doi: 10.1001/jamaneurol.2025.3662. Online ahead of print.

Optimal Antithrombotics for Ischemic Stroke and Concurrent Atrial Fibrillation and Atherosclerosis: A Randomized Clinical Trial

Shuhei Okazaki  1   2 , Kanta Tanaka  3   4 , Yukako Yazawa  5 , Ryosuke Doijiri  6 , Masatoshi Koga  4 , Masafumi Ihara  7 , Shiro Yamamoto  8 , Kenji Kamiyama  9 , Yuko Honda  10 , Kazutaka Uchida  11 , Takeshi Yoshimoto  12 , Koko Asakura  13 , Katsuhiro Omae  13 , Kenta Tanaka  13 , Hirotada Maeda  13 , Haruko Yamamoto  13 , Teruyuki Hirano  10 , Kazunori Toyoda  4 , Yasuyuki Iguchi  14 , Teruo Noguchi  15 , Yasushi Okada  16 , Kazuo Kitagawa  17 , Nobuyuki Sakai  18   19 , Hiroshi Yamagami  1   20 ; ATIS-NVAF Trial Investigators
Collaborators, Affiliations

Optimal Antithrombotics for Ischemic Stroke and Concurrent Atrial Fibrillation and Atherosclerosis: A Randomized Clinical Trial

Shuhei Okazaki et al. JAMA Neurol. .

Abstract

Importance: Patients with ischemic stroke and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease are at an elevated risk of recurrent ischemic events. Although combined anticoagulant and antiplatelet therapy may reduce ischemic risk, it also increases bleeding, and the optimal antithrombotic strategy remains uncertain.

Objective: To determine whether adding an antiplatelet agent to anticoagulant therapy influences the net clinical benefit in patients with ischemic stroke or transient ischemic attack and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease.

Design, setting, and participants: This multicenter, open-label randomized clinical trial was conducted at 41 sites across Japan from November 2016 to March 2025. Eligible patients had an ischemic stroke or transient ischemic attack within 8 to 360 days of onset, nonvalvular atrial fibrillation, and at least 1 manifestation of atherosclerotic cardiovascular disease (carotid or intracranial artery stenosis, noncardioembolic stroke, ischemic heart disease, or peripheral artery disease). Data were analyzed from April 16, 2024, to October 14, 2024.

Interventions: Patients were randomized to receive combination therapy (anticoagulant plus antiplatelet) or anticoagulant monotherapy.

Main outcomes and measures: The primary outcome was a composite of ischemic cardiovascular events and major bleeding within 2 years. Secondary outcomes included ischemic cardiovascular events; safety outcomes included major and clinically relevant nonmajor bleeding.

Results: In total, 316 patients were randomized to combination therapy (n = 159) or monotherapy (n = 157) (mean [SD] age, 77.2 [7.4] years; 90 female patients [28.5%]). The trial was terminated on July 18, 2023, after an interim analysis for futility. The cumulative incidence of the primary outcome was 17.8% in the combination therapy group and 19.6% in the monotherapy group (hazard ratio [HR], 0.91; 95% CI, 0.53-1.55; P = .64). Ischemic cardiovascular events occurred in 11.1% and 14.2% (HR, 0.76; 95% CI, 0.39-1.48; P = .41), and major and clinically relevant nonmajor bleeding occurred in 19.5% and 8.6% (HR, 2.42; 95% CI, 1.23-4.76; P = .008) of combination therapy and monotherapy groups, respectively.

Conclusions and relevance: In this randomized clinical trial, in patients with ischemic stroke or transient ischemic attack and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease, adding an antiplatelet agent to anticoagulant therapy provided no net clinical benefit over anticoagulant monotherapy, with higher bleeding risk.

Trial registration: ClinicalTrials.gov Identifier: NCT03062319.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Koga reported lecture fees from Bayer Yakuhin, Boehringer Ingelheim, and Daiichi Sankyo and research funding from Boehringer Ingelheim and Daiichi Sankyo outside the submitted work. Dr Uchida reported lecture fees from Daiichi Sankyo, Johnson & Johnson, Kaneka, Medtronic, Stryker, and Tokai Medical Products outside the submitted work. Dr Toyoda reported personal fees from Daiichi Sankyo and Janssen outside the submitted work. Dr Iguchi reported personal fees from Chugai Pharmaceutical, CSL Behring, Eisai, JB, Novartis, Pfizer, and Sumitomo Dainippon and grants from Daiichi Sankyo, Medical Concierge Co, Mitsubishi-Tanabe, NAGATANIEN, Otsuka, and Shionogi outside the submitted work. Dr Kitagawa reported lecture fees from Daiichi Sankyo, Eisai, Kowa, Kyowa Kirin Pharmaceuticals, and Otsuka Pharmaceuticals outside the submitted work. Dr Sakai reported personal fees from Asahi Intecc, Kaneka, Medtronic, Stryker, and Terumo outside the submitted work. Dr Yamagami reported grants from Bristol Myers Squibb during the conduct of the study; lecture fees from Abbott Medical Japan, Boston Scientific Japan, Bristol Myers Squibb, Daiichi Sankyo, Medtronic, Otsuka Pharmaceutical, and Stryker outside the submitted work. No other disclosures were reported.

Comment in

  • doi: 10.1001/jamaneurol.2025.3534

References

    1. Huxley RR, Lopez FL, Folsom AR, et al. Absolute and attributable risks of atrial fibrillation in relation to optimal and borderline risk factors: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2011;123(14):1501-1508. doi: 10.1161/CIRCULATIONAHA.110.009035 - DOI - PMC - PubMed
    1. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke. 2021;52(7):e364-e467. doi: 10.1161/STR.0000000000000375 - DOI - PubMed
    1. Klijn CJM, Paciaroni M, Berge E, et al. Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation: a European Stroke Organisation guideline. Eur Stroke J. 2019;4(3):198-223. doi: 10.1177/2396987319841187 - DOI - PMC - PubMed
    1. Dawson J, Béjot Y, Christensen LM, et al. European Stroke Organisation (ESO) guideline on pharmacological interventions for long-term secondary prevention after ischaemic stroke or transient ischaemic attack. Eur Stroke J. 2022;7(3):I-II. doi: 10.1177/23969873221100032 - DOI - PMC - PubMed
    1. Miyamoto S, Ogasawara K, Kuroda S, et al. ; Committee for Stroke Guideline 2021, the Japan Stroke Society . Japan Stroke Society guideline 2021 for the treatment of stroke. Int J Stroke. 2022;17(9):1039-1049. doi: 10.1177/17474930221090347 - DOI - PMC - PubMed

Associated data