CYP2C19 Genotype and Efficacy of Clopidogrel Initiated Between 24 to 72 Hours for Ischemic Stroke

BACKGROUND: The aim of this study was to investigate the clinical outcomes of clopidogrel-aspirin therapy initiated between 24 and 72 hours from the symptom onset among patients with minor stroke or transient ischemic attack stratified by CYP2C19 loss-of-function allele status. METHODS: This was a prespecified secondary analysis of the INSPIRES trial (Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis), which was a randomized clinical trial conducted across 222 centers in China from September 2018 to October 2022. Two loss-of-function alleles ( CYP2C19*2 , CYP2C19*3 ) and 1 gain-of-function allele ( CYP2C19*17 ) were genotyped in the INSPIRES study. Patients with CYP2C19 loss-of-function allele carriers were patients with either CYP2C19*2 or CYP2C19*3 . All participants were randomized to receive clopidogrel-aspirin or aspirin treatment, and those started treatment between 24 and 72 hours from the symptom onset were included in this study. The primary efficacy outcome was new stroke within 90 days. The primary safety outcome was moderate-to-severe bleeding. Cox proportional hazards models were performed to estimate the interaction between treatment assignment and CYP2C19 loss-of-function allele status for the primary outcomes. RESULTS: Among 5003 patients, 2911 (58.2%) patients were loss-of-function carriers, and 2092 (41.8%) patients were noncarriers. Relative to aspirin alone, clopidogrel-aspirin reduced the rate of new stroke in the noncarriers (hazard ratio, 0.67 95% CI, 0.49–0.91; P =0.01) but not in the carriers (hazard ratio, 0.96 95% CI, 0.73–1.25, P =0.74; P =0.09 for interaction). For the safety outcome, moderate-to-severe bleeding did not vary significantly between the carriers (hazard ratio, 1.83 95% CI, 0.68–4.95; P =0.23) and noncarriers (hazard ratio, 2.07 95% CI, 0.62–6.88, P =0.23; P =0.88 for interaction). CONCLUSIONS: Clopidogrel-aspirin treatment presented a priority to aspirin in reducing the risk of new stroke in CYP2C1 9 loss-of-function noncarriers when administered between 24 and 72 hours after stroke onset. These findings supported the necessity of CYP2C19 genotyping in the choice of antiplatelet therapy with an extended treatment window to 72 hours. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03635749.