For People Receiving Anticoagulant Therapy for Stroke, Antiplatelet Agents Increased Bleeding Risk and Offered No Clinical Benefit
Findings from the phase 4 ATIS-NVAF clinical trial (NCT03062319), published in JAMA Neurology, demonstrated that the addition of an antiplatelet agent to anticoagulant therapy provided no net clinical benefit for individuals with ischemic stroke or transient ischemic attack (TIA) and concurrent nonvalvular atrial fibrillation (NVAF) and atherosclerotic cardiovascular disease (ASCVD). The addition of an antiplatelet agent was instead shown to significantly increase bleeding risk.
The multicenter, open-label, randomized clinical trial included 316 individuals across 41 sites in Japan. Participants had experienced an ischemic stroke or TIA within 8 to 360 days of onset, had NVAF, and had at least 1 manifestation of ASCVD including carotid or intracranial artery stenosis, noncardioembolic stroke, ischemic heart disease, or peripheral artery disease. In the study, participants were randomized to receive either combination therapy with an anticoagulant plus an antiplatelet agent (n=159) or anticoagulant monotherapy (n=157). The primary end point was a composite of ischemic cardiovascular events and major bleeding within 2 years. The trial was terminated early after an interim analysis for futility.
Key findings included:
- The primary outcome occurred in 17.8% of participants the combination therapy group compared with 19.6% of those in the monotherapy group (hazard ratio [HR], .91; 95% CI, .53 to 1.55; P=.64)
- Ischemic cardiovascular events occurred in 11.1% and 14.2% of individuals in the combination and monotherapy groups, respectively (HR, .76; 95% CI, .39 to 1.48; P=.41)
- Major and clinically relevant nonmajor bleeding occurred significantly more often in those who received combination therapy (19.5%) compared with those who received monotherapy (8.6%) (HR, 2.42; 95% CI, 1.23 to 4.76; P=.008)
- Ischemic stroke rates were 9.2% in the combination group vs 13% in the monotherapy group (HR .67; 95% CI, .32 to 1.39; P=.28)
While combination therapy showed a trend toward reducing ischemic events, the findings suggest that anticoagulant monotherapy may be the safer option for secondary stroke prevention.
Source: Okazaki S, Tanaka K, Yazawa Y, et al. Optimal antithrombotics for ischemic stroke and concurrent atrial fibrillation and atherosclerosis: a randomized clinical trial. JAMA Neurol. Published online October 6, 2025. https://doi.org/10.1001/jamaneurol.2025.3662