Dual Antiplatelet Therapy in Stroke Without Stenotic Atherosclerosis: A Meta-Analysis with Trial Sequential Analysis

BACKGROUND AND AIM: Individuals without stenotic large-artery atherosclerosis (LAA) are an important subgroup of the patients who suffer transient ischemic attack (TIA) or ischemic stroke (IS), and they are commonly treated with dual antiplatelet therapy (DAPT). Stenotic LAA is a marker of higher vascular risk, and current guideline-defining trials did not prospectively evaluate if negative LAA status modifies the effect of DAPT. Moreover, platelet activation may not contribute as much towards future stroke risk after excluding stenotic LAA, leaving uncertainty regarding the applicability of this treatment amongst populations without this marker. We aimed to evaluate the efficacy and safety of DAPT compared with monotherapy for patients who suffered a TIA or IS without stenosis of 50% or more on vessel imaging. METHODS: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from inception to November 2025 for publications in English. We included randomized controlled trials comparing short-term (up to 90 days) DAPT to single antiplatelet therapy after a TIA or IS with outcome data available for the groups without 50% or more stenosis on vessel imaging. Data was pooled using random-effects for non-rare outcomes and Bayesian models for rare outcomes. The primary outcome was a new ischemic or hemorrhagic stroke. We also analyzed ischemic and hemorrhagic stroke individually, moderate and severe bleeding, any bleeding, all-cause death, functionality and a composite vascular outcome. RESULTS: 8 publications met the eligibility criteria. DAPT was associated with a reduction in new stroke, with a relative risk of 0.80 (95% CI 0.65 to 0.98; p = 0.04, I² = 25.5%). Trial sequential analysis showed a substantial risk of type I error, and a sensitivity analysis restricted to studies that included only high-risk TIA or mild IS found no significant benefit. There was an increase in moderate and severe bleeding (odds ratio of 2.70, 95% Bayesian Credible Interval 1.28 to 4.85) and no differences in functionality and mortality. Heterogeneity in trial methodology and populations may limit interpretation of our findings, but sensitivity analyses evaluating the impacts of DAPT duration and region of trial conduction on new stroke did not show significant effects, although they are hindered by the small number of studies. CONCLUSION: In patients with TIA or IS with a negative assessment of stenotic atherosclerosis on any vessel imaging, the benefit of DAPT is unclear, particularly for individuals with high-risk TIA and mild IS, while there is an increased risk of bleeding. Further trials are required to clarify if DAPT is truly beneficial for these patients.