Cytochrome P450 2C19 Polymorphism in Young Patients Treated With Clopidogrel After Myocardial Infarction: A Cohort Study

Lancet. 2009 Jan 24;373(9660):309-17. doi: 10.1016/S0140-6736(08)61845-0. Epub 2008 Dec 26.

Abstract

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Angioplasty, Balloon, Coronary
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / physiology
  • Clopidogrel
  • Cytochrome P-450 CYP2C19
  • Endpoint Determination
  • Female
  • Follow-Up Studies
  • Genotype
  • Humans
  • Male
  • Myocardial Infarction / prevention & control*
  • Myocardial Infarction / therapy
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Polymorphism, Genetic*
  • Proportional Hazards Models
  • Risk Factors
  • Secondary Prevention
  • Stents
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / therapeutic use

Substances

  • Platelet Aggregation Inhibitors
  • Clopidogrel
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Ticlopidine