Abstract WP331: CYP2C19 Genetic Variability, ADP Binding, and Clopidogrel Efficacy: Insights from a Comprehensive Stroke Center Retrospective Study on Patients with Acute Ischemic Stroke

Background: CYP2C19 is required to metabolize clopidogrel into its active form to inhibit adenosine diphosphate (ADP) platelet aggregation. Variability in patient response to clopidogrel is driven by CYP2C19 genetic polymorphisms. Abnormal metabolism has been shown to result in increased recurrent ischemic events. The purpose of this study was to examine CYP2C19 phenotypes and the impact on ADP aggregation in whole blood platelet aggregometry (WBPA) in acute stroke patients. Methods: We retrospectively reviewed electronic medical records of patients who presented to two academic Comprehensive Stroke Centers and discharged with acute ischemic stroke (AIS) or transient ischemic attack (TIA) from 1/1/2022 to 5/31/2025. Patients were included if they had AIS/TIA, WBPA, and CYP2C19 genotyping. WBPA had to be performed at least 6 hours after loading clopidogrel with 300 mg dose or >7 days of clopidogrel 75 mg daily. Nominal variables were examined with descriptives and frequencies. Non-parametric continuous variables were assessed by Kruskall-Wallis and Jonckheere-Terpstra was used to assess ADP aggregation by CYP2C19 phenotype. Results: We identified 115 patients (mean age 68.9±12.2 years, 68 male, 27.8% Hispanic) who met inclusion criteria. The frequency of CYP2C19 phenotype was 8 (7.0%) poor, 43 (37.4%) intermediate, 59 (51.3%) normal, and 5 (4.3%) ultrarapid metabolizers. There was no significant difference in age (p=0.38) or race (p=0.13) between phenotypes. CYP2C19 phenotypes was significantly associated with Hispanic ethnicity (p=0.001). There was no significant difference in ADP aggregation on WBPA between CYP2C19 phenotypes (p=0.58). The decision to change antiplatelet agents was significantly correlated with history of stroke (p=0.001); HTN (p=0.04); CAD (p=0.03); prior clopidogrel use (p<0.001); and ADP aggregation (p=0.02). Conclusion: In this study, CYP2C19 phenotype distribution was predominantly normal or intermeditate, with no significant association between phenotype and ADP aggregation on WBPA. CYP2C19 phenotype correlated with Hispanic ethnicity, suggesting population-level variability. Antiplatelet changes were significantly associated with clinical history (stroke, HTN, CAD, prior clopidogrel use) and ADP aggregation but not with phenotype. These findings underscore the need for larger studies to clarify genetic and clinical predictors of clopidogrel metabolism in stroke patients to better inform individualized antiplatelet therapy.