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

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.