F2R Polymorphisms and Efficacy of Clopidogrel Initiated Within 72 Hours for Ischemic Stroke

BACKGROUND: The aim of this study was to investigate the association between PAR-1 (protease-activated receptor-1) gene F2R polymorphisms and the efficacy of clopidogrel therapy initiated within a time window extended to 72 hours for mild ischemic stroke or transient ischemic attack with intracranial or extracranial atherosclerosis. METHODS: This was a secondary analysis of the INSPIRES trial (Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis), a randomized clinical trial conducted at 222 centers across China between September 2018 and October 2022. Four single-nucleotide polymorphisms ( F2R [IVSn-14 A/T, rs168753], CYP2C19*2 [681G>A, rs4244285], CYP2C19*3 [636G>A, rs4986893], and CYP2C19*17 [−806C>T, rs12248560]) were genotyped among 5791 patients treated with clopidogrel plus aspirin (n=2894) or aspirin alone (n=2897). The primary efficacy outcome was new stroke, and the safety outcome was moderate-to-severe bleeding within 90 days. Cox proportional hazards models were used to estimate the interaction between treatment assignment and F2R polymorphisms for the primary outcomes. RESULTS: Among 5791 patients, 1698 (29.3%) were AA homozygotes, and 4093 (70.7%) were the T-allele carriers (AT/TT) for F2R IVSn-14 polymorphisms. Compared with aspirin alone, clopidogrel-aspirin reduced the rate of new stroke in patients with AT/TT genotype (7.1% versus 9.2%; hazard ratio [HR], 0.77 [95% CI, 0.62–0.95]; P =0.02) but not in carriers of the AA genotype (7.7% versus 8.1%; HR, 0.95 [95% CI, 0.67–1.33]; P =0.75; P =0.30 for interaction). For the safety outcome, the risk of moderate-to-severe bleeding between the clopidogrel plus aspirin group and aspirin group was not significant in patients with AT/TT genotype (HR, 1.91 [95% CI, 0.85–4.29]; P =0.12) or AA genotype (HR, 1.97 [95% CI, 0.59–6.55]; P =0.27; P =0.97 for interaction). Moreover, the presence of CYP2C19 loss-of-function allele carrier status did not alter the effect of the F2R polymorphisms on clinical outcomes, although a marginally reduced risk of stroke with clopidogrel-aspirin versus aspirin alone was observed only among carriers of at least 1 F2R IVSn-14 T allele without CYP2C19 loss-of-function allele (HR, 0.73 [95% CI, 0.52–1.01]; P =0.06). CONCLUSIONS: With the treatment initiated within a time window extended to 72 hours after mild ischemic stroke or transient ischemic attack onset, we found that clopidogrel plus aspirin may reduce the occurrence of new stroke specifically in F2R IVSn-14 T-allele carriers. This finding suggests that the clopidogrel-aspirin treatment may appear more beneficial among carriers of the F2R IVSn-14 T allele. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03635749.