Cytochrome P450 2C19 Genotypes and Clopidogrel in Patients With Ischemic Stroke: A Nonrandomized Clinical Trial

Abstract

Importance: Cytochrome P450 2C19 (CYP2C19) genotypes influence the antiplatelet effectiveness of clopidogrel by affecting its conversion to its active metabolite. However, evidence from prospective trials regarding the effects of CYP2C19 genotypes on the role of clopidogrel preventing cardiovascular events among patients with acute ischemic stroke remains limited.

Objective: To investigate the association of the CYP2C19 genotypes with the clinical prognosis of patients with acute ischemic stroke treated with clopidogrel.

Design, setting, and participants: A prospective, nonrandomized clinical trial was conducted from September 1, 2019, to January 27, 2023, at 37 clinical sites in South Korea. Patients who received clopidogrel within 72 hours of experiencing an acute ischemic stroke were included.

Interventions: Patients were classified using CYP2C19 genotyping into carrier and noncarrier of CYP2C19 loss-of-function (LOF) allele. Clopidogrel treatment was maintained throughout the study period.

Main outcomes and measures: The primary outcome was the difference in the risk of cardiovascular events (including ischemic or hemorrhagic stroke, myocardial infarction, or cardiovascular death) within 6 months after an ischemic stroke between patients who were carriers or noncarriers of the CYP2C19 LOF allele. The primary safety outcomes were the differences in all-cause mortality and the occurrence of major bleeding. Intention-to-treat analysis was performed.

Results: Overall, 2925 patients were enrolled in the PLATELET trial. The mean (SD) age of the participants was 65.3 (12.4) years, and 1928 (66.3%) were men. Among these patients, 15 were excluded. Of the remaining 2910 patients, 61.3% were classified as poor or intermediate metabolizers and 38.7% as extensive metabolizers. The primary outcome occurred more frequently in carriers of the LOF CYP2C19 allele than in noncarriers (2.7% [49 of 1785] vs 1.6% [18 of 1125]; log-rank P = .048). No significant differences were observed between CYP2C19 LOF allele carriers and noncarriers regarding the occurrence of major bleeding (0.6% [11 of 1785] vs 0.8% [9 of 1125]; P = .56) and all-cause mortality (0.3% [5] vs 0.1% [1]; P = .27).

Conclusions and relevance: In this prospective nonrandomized clinical trial, carriers of the CYP2C19 LOF allele genotype exhibited a higher likelihood of experiencing cardiovascular events.

Trial registration: ClinicalTrials.gov Identifier: NCT04072705.