Does the Burden of CSVD Modify the Efficacy of Dual Antiplatelet Therapy?: A Post Hoc Analysis of the INSPIRES Trial

BACKGROUND: The prevalence of cerebral small vessel disease (CSVD) imaging markers is high, yet their influence on stroke prognosis remains unclear. This study aimed to estimate the effects of CSVD on the efficacy and safety of clopidogrel+aspirin versus aspirin among patients with minor stroke or high-risk transient ischemic attack. METHODS: This was a post hoc subgroup analysis of the INSPIRES trial (Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis), which was a double-blind, placebo-controlled, 2×2 factorial, and randomized clinical trial conducted at 222 centers in China from September 2018 to October 2022. Patients were classified into CSVD score 0 to 2 and CSVD score ≥3 groups based on a modified CSVD burden score without microbleeds. The primary efficacy and safety outcomes were stroke recurrence and moderate-to-severe bleeding risk within 90-day follow-up. We used Cox proportional hazards models to test the treatment-by-CSVD group interaction for stroke and bleeding risk. RESULTS: A total of 5126 patients (median age, 65 [57–71] years; 3915 [64.2%] males) were enrolled and 2131 (41.57%) had a modified CSVD score ≥3. Patients with CSVD score ≥3 had numerically higher stroke recurrence rate (9.10% versus 8.05%) and lower risk of moderate-to-severe bleeding (0.56% versus 0.80%) than those with CSVD score 0 to 2 within 90 days. Clopidogrel+aspirin versus aspirin reduced stroke recurrence to a similar relative degree in both CSVD score 0 to 2 (adjusted hazard ratio, 0.78 [95% CI, 0.61–1.01]; P =0.06) and CSVD score ≥3 groups (adjusted hazard ratio, 0.82 [95% CI, 0.62–1.09]; P =0.12) with no evidence of statistical interaction ( P =0.84). Clopidogrel+aspirin versus aspirin increased bleeding risk to a similar relative degree in both CSVD score 0 to 2 (adjusted hazard ratio, 2.83 [95% CI, 1.52–5.27]; P =0.03) and CSVD score ≥3 groups (adjusted hazard ratio, 2.13 [95% CI, 1.08–4.19]; P =0.22) with no statistical interaction ( P =0.68). CONCLUSIONS: In this post hoc subgroup analysis, no significant interaction effect was observed between the antiplatelet treatment and the modified CSVD score, suggesting that clopidogrel+aspirin may not provide a significantly different benefit-risk profile across patients with CSVD score 0 to 2 versus CSVD score ≥3. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03635749.