CYP2C19 Loss-of-Function Associated with First-Time Ischemic Stroke in Non-surgical Asymptomatic Carotid Artery Stenosis During Clopidogrel Therapy

This study measures effect of CYP2C19 genotype on ischemic stroke risk during clopidogrel therapy for asymptomatic, extracranial carotid stenosis patients. Using deidentified electronic health records, patients were selected for retrospective cohort using administrative code for carotid stenosis, availability of CYP2C19 genotype result, clopidogrel exposure, and established patient care. Patients with intracranial atherosclerosis, aneurysm, arteriovenous malformation, prior ischemic stroke, or observation time <1 month were excluded. Dual antiplatelet therapy patients were included. Patients with carotid endarterectomy or stenting were analyzed in a separate subgroup. Time-to-event analysis using Cox regression was conducted to model ischemic stroke events based on CYP2C19 loss-of-function allele and adjusted with the most predictive covariates from univariate analysis. Covariates included age, gender, race, length of aspirin, length of concurrent antiplatelet/anticoagulant treatment, diabetes, coagulopathy, hypertension, heart disease, atrial fibrillation, and lipid disorder. A total of 1110 patients met selection criteria for medical therapy cohort (median age 68 [interquartile range (IQR) 60–75] years, 64.9% male, 91.9% Caucasian). Median study period was 2.8 [0.8–5.3] years. A total of 47 patients (4.2%) had an ischemic stroke event during study period. CYP2C19 loss-of-function allele was strongly associated with ischemic stroke events (one allele: HR 2.3, 95% CI 1.1–4.7, p=0.020; two alleles: HR 10.2, 95% CI 2.8–36.8, p<0.001) after adjustment. For asymptomatic carotid stenosis patients receiving clopidogrel to prevent ischemic stroke, CYP2C19 loss-of-function allele is associated with 2- to 10-fold increased risk of ischemic stroke. CYP2C19 genotype may be considered when selecting antiplatelet therapy for stroke prophylaxis in non-procedural, asymptomatic carotid stenosis.