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

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 years) who survived a first myocardial infarction and were exposed to clopidogrel treatment for at least a month, were enrolled in a multicentre registry and underwent 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.

Introduction

Acute and chronic clopidogrel treatment in combination with aspirin can prevent recurrent ischaemic events after an acute coronary syndrome or a percutaneous coronary intervention.¹ However, many patients on dual antiplatelet therapy still have thrombotic events. Attention has recently focused on the wide variability between individuals of response to clopidogrel,² with poor inhibition of the platelet P2Y₁₂ receptor in some patients.³ Persistent high platelet reactivity with clopidogrel treatment has also been associated with more frequent adverse events,4, 5 whereas a higher dose of clopidogrel or more potent drugs can help overcome such poor response and improve clinical outcome.6, 7, 8, 9, 10

High platelet reactivity with clopidogrel could be due to various reasons including polymorphism in the gene encoding the cytochrome P450 2C19 enzyme (CYP2C19), which contributes to the variability of platelet response to clopidogrel. Clopidogrel is a prodrug that has to be converted into an active metabolite that selectively and irreversibly binds to the P2Y₁₂ platelet membrane receptor.11, 12, 13 CYP2C19 is a key enzyme in this activation process,14, 15, 16 and the presence of the loss-of-function CYP2C19 681G>A polymorphism (also called *2) is associated with reduced clopidogrel responsiveness in healthy people and in patients with coronary artery disease.17, 18, 19, 20, 21 However, the direct relation with adverse clinical outcome has not been shown.²¹

Myocardial infarction in patients younger than 45 years is a rare but serious thrombotic event, which is often treated by percutaneous coronary intervention and stenting and needs optimum and extended antiplatelet therapy. We assessed the effect of the CYP2C19*2 loss-of-function polymorphism in a cohort of young (<45 years) patients who survived a first myocardial infarction and were treated chronically with clopidogrel.

With consideration of the early and extended treatment with clopidogrel for secondary prevention of these patients, we decided to assess the effect of CYP2C19*2 polymorphism on their long-term prognosis during clopidogrel exposure. Only patients who were exposed to clopidogrel were assessed in this pharmacogenetic investigation.