Abstract
BackgroundCYP2C19*2 polymorphism is related to metabolizer phenotypes resulting in reduced effectiveness in converting the antiplatelet drug clopidogrel to active drug. An association of the genotype itself with adverse outcomes is discussed. We investigated the prognostic value of carriage of the CYP2C19*2 allele in a high risk group of patients with prevalent coronary heart disease (CHD) at baseline during long-term follow-up under conditions of routine clinical care.MethodsIn n=1050 patients with stable CHD at baseline genotyping of CYP2C19 allele *2 (rs4244285; 681G>A) was performed. The Cox-proportional hazards model was employed to investigate the association of CYPC19*2 allele status with cardiovascular disease (CVD) events during eight year follow-up. The analysis was also performed in patients who did not take clopidogrel or ticlopidin.ResultsOnly the very few patients homozygous for a loss-of-function variant of CYP2C19, allele *2 (2.6%), had a statistically significantly higher incidence rate for secondary CVD events during long-term follow-up than wild-type carriers (50.8 versus 21.5 per 1000 patients years; rate for heterozygous carries 17.2 per 1000 patient years). The hazard ratio after adjustment for covariates compared to the wild-type carriers was 2.59 (95% confidence interval (CI) 1.27-5.28) and 0.80 (95% CI 0.52-1.23) for homozygous and heterozygous allele carriers, respectively.ConclusionsIn this medium-size group of patients with stable CHD homozygous carriers of the loss-of-function allele CYP2C19*2 were at increased risk for subsequent CVD events during 8 year follow-up independent of other risk factors. As only few patients carried the homozygous loss-of-function variant and we found overall no evidence for improved clinical utility, a benefit of genotyping in this patient population seems unlikely.
Highlights
Cytochrome P450 (CYP2C19)*2 polymorphism is related to metabolizer phenotypes resulting in reduced effectiveness in converting the antiplatelet drug clopidogrel to active drug
A collaborative meta-analysis conducted by Mega et al [6] including patients with acute coronary heart disease (CHD) and treated with clopidogrel showed that carriage of even one reduced-function CYP2C19 allele was associated with a significantly increased risk of adverse cardiovascular events
We investigated the prognostic value of carriage of the CYP2C19*2 allele in a high risk group of patients with prevalent CHD at baseline during long-term follow-up of eight years under conditions of routine clinical care and considering other concurrent risk factors
Summary
CYP2C19*2 polymorphism is related to metabolizer phenotypes resulting in reduced effectiveness in converting the antiplatelet drug clopidogrel to active drug. Pare and colleagues presented data from two large randomized controlled trials showing no association between increased cardiovascular risk and CYP2C19 loss of function variants [5] The latter may have been caused by the comparison of loss-of-function allele carriers taking clopidogrel with those taking placebo, which showed that carriers taking clopidogrel still had improved outcomes compared to placebo. A collaborative meta-analysis conducted by Mega et al [6] including patients with acute coronary heart disease (CHD) and treated with clopidogrel showed that carriage of even one reduced-function CYP2C19 allele was associated with a significantly increased risk of adverse cardiovascular events
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