Association Between CYP2C19 Genotype and P2Y12 Reaction Units in Patients Receiving Clopidogrel After Acute Ischemic Stroke: A Prospective, Observational Study

BACKGROUND: Recurrent stroke accounts for substantial morbidity and mortality worldwide, with up to 25% of ischemic strokes occurring in patients with prior strokes. Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard for secondary prevention after minor acute ischemic stroke (AIS) or high-risk transient ischemic attack (TIA). However, clopidogrel efficacy is reduced in carriers of cytochrome P450 2C19 (CYP2C19) loss-of-function (LOF) alleles. Although genotype-guided DAPT has been shown to improve outcomes, the limited availability, high cost, and turnaround time of CYP2C19 genotyping constrain real-world use. P2Y12 reaction units (PRUs) measured by the VerifyNow P2Y12 assay represent a potentially accessible alternative, but their relevance in the cerebrovascular population remains unclear. OBJECTIVE: To investigate the viability of PRUs as a surrogate biomarker for clopidogrel resistance, we aimed to assess the association of PRUs with CYP2C19 genotype, which has been previously proven as predictive of clinical outcomes in patients receiving DAPT after AIS. METHODS: We conducted a prospective observational study of adults with non-cardioembolic minor AIS or high-risk TIA treated with 21 days of DAPT between December 2021 and May 2023. PRUs were measured ≥ 12 h after a clopidogrel loading dose. The primary outcome was the group difference in PRUs by CYP2C19 LOF carrier status. Secondary outcomes included associations between high platelet reactivity (PRU ≥ 208), CYP2C19 genotype, and 30-day stroke recurrence. RESULTS: Of the 35 patients included in the primary analysis, 17% were CYP2C19 LOF carriers. Mean PRUs were significantly higher in LOF carriers (265 vs. 161; p < 0.01), and high platelet reactivity was more frequent among carriers (83% vs. 21%; p < 0.01) compared with noncarriers, respectively. Twenty-seven patients completed 30-day follow-up; 26% reported recurrent stroke symptoms, but neither CYP2C19 LOF status nor high platelet reactivity was associated. Post hoc application of the ABCD-GENE score did not improve prediction of high platelet reactivity or clinical outcomes. CONCLUSIONS: PRUs appear to vary by CYP2C19 genotype in patients receiving DAPT after minor AIS or TIA, suggesting utility as a surrogate marker of clopidogrel nonresponse when genotyping is unavailable. However, PRUs were not associated with short-term clinical outcomes.