Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study

Original Text

Jean-Philippe Collet MD a, Jean-Sébastien Hulot MD b, Anna Pena PhD a, Eric Villard PhD b, Jean-Baptiste Esteve MD a, Johanne Silvain MD a, Laurent Payot MD c, Delphine Brugier PhD a, Guillaume Cayla MD a, Farzin Beygui MD a, Gilbert Bensimon MD b, Prof Christian Funck-Brentano MD b, Prof Gilles Montalescot MD a

Summary

Background

Clopidogrel and low-dose aspirin have become the mainstay oral antiplatelet regimen to prevent recurrent ischaemic events after acute coronary syndromes or stent placement. The frequent genetic functional variant 681 G>A (*2) of cytochrome P450 2C19 (CYP2C19) is an important contributor to the wide variability between individuals of the antiplatelet effect of clopidogrel. We assessed whether the CYP2C19*2 polymorphism affected long-term prognosis of patients who were chronically treated with clopidogrel.

Methods

Between April 1, 1996, and April 1, 2008, 259 young patients (aged <45>CYP2C19*2 determination. The primary endpoint was a composite of death, myocardial infarction, and urgent coronary revascularisation occurring during exposure to clopidogrel. Follow-up was every 6 months. The key secondary endpoint was stent thrombosis proven by angiography.

Findings

Median clopidogrel exposure time was 1·07 years (IQR 0·28—3·0). Baseline characteristics were balanced between carriers (heterozygous *1/*2, n=64; homozygous *2/*2, n=9) and non-carriers (n=186) of CYP2C19*2 variant. The primary endpoint occurred more frequently in carriers than in non-carriers (15 vs 11 events; hazard ratio [HR] 3·69 [95% CI 1·69—8·05], p=0·0005), as did stent thrombosis (eight vs four events; HR 6·02 [1·81—20·04], p=0·0009). The detrimental effect of the CYP2C19*2 genetic variant persisted from 6 months after clopidogrel initiation up to the end of follow-up (HR 3·00 [1·27—7·10], p=0·009). After multivariable analysis, the CYP2C19*2 genetic variant was the only independent predictor of cardiovascular events (HR 4·04 [1·81—9·02], p=0·0006).

Interpretation

The CYP2C19*2 genetic variant is a major determinant of prognosis in young patients who are receiving clopidogrel treatment after myocardial infarction.

Funding

Délégation à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris.