Abstract Body: Background
The ABCD-GENE score, incorporating age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genotypes, is a validated risk score that integrates clinical risk factors with genetic information to predict clopidogrel response. However, to enhance the accuracy of risk identification, it is essential to assess the individual impact of each clinical risk factor. Notably, diabetes has been linked to the modulation of clopidogrel’s antiplatelet efficacy by CYP2C19 genotypes. Therefore, excluding the confounding effect of diabetes may refine the precision of identifying at-risk patients by isolating the interaction between CYP2C19 genotypes and clinical outcomes.

Method
This study is a post-hoc analysis of the PLATELET trial (A Multicenter Prospective Observational Study to Evaluate the Effect of Clopidogrel on the Prevention of Major Vascular Events According to the Genotype of Cytochrome P450 2C19 in Ischemic Stroke Patients, NCT04072705). Patients were stratified based on CYP2C19 genotyping into carriers and non-carriers of the loss-of-function CYP2C19 allele. Clopidogrel therapy was continued throughout the study period. The primary efficacy endpoint was the incidence of cardiovascular events (including ischemic or hemorrhagic stroke, myocardial infarction, or cardiovascular death) within six months following an ischemic stroke in carriers versus non-carriers of the loss-of-function CYP2C19 allele. The primary safety endpoints were all-cause mortality and the incidence of major bleeding events.

Results
Out of the 2,925 patients enrolled in the PLATELET trial across 37 clinical sites, 2,001 non-diabetic patients were included in this analysis. The mean age of the participants was 64.4 years, with 65.0% being male. Among these patients, 61.5% were identified as carriers and 38.5% as non-carriers of the loss-of-function CYP2C19 allele. The primary efficacy outcome occurred more frequently in carriers than in non-carriers (2.5% [31 of 1,230] vs 1.2% [9 of 771], log-rank p-value = 0.038). There were no significant differences between the two groups in terms of major bleeding or all-cause mortality (p = 0.760 and p = 0.667, respectively).

Conclusions
In non-diabetic patients with acute ischemic stroke treated with clopidogrel, those carrying the loss-of-function CYP2C19 genotype exhibited a higher risk of cardiovascular events compared to non-carriers.