• Myocardial Infarction
• Cardiology Genomics
• Arrhythmias

Genetic variations that are related to clopidogrel metabolism did not diminish clopidogrel efficacy in patients with acute coronary syndromes (ACS) or atrial fibrillation (AF), according to new data from two clinical trials. Guillaume Paré, MD, MSc, McMaster University, Hamilton, Ontario, Canada, presented new findings from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) trials.

The CYP2C19 gene is associated with the conversion of clopidogrel to its active metabolite. Variations in this gene include the loss-of-function CYP2C19 alleles (CYPC19*2 and CYPC19*3), which slow this conversion, and the gain-of-function CYP2C19 allele (CYPC19*17), which facilitates the metabolism of clopidogrel to its active form. To examine the influence of genetic variations on platelet response, Prof. Paré and colleagues evaluated safety and efficacy outcomes among patients who were enrolled in the CURE (n=5059) and ACTIVE (n=1156) trials according to CYP2C19 genotype (*2, *3, or *17).

In the CURE trial, there was no interaction between loss-of-function CYP2C19 alleles and the efficacy of clopidogrel relative to placebo (p=0.12). Clopidogrel provided a similar magnitude of protection against the primary endpoint compared with placebo in carriers of a loss-of-function allele (8.0% vs 11.6%; HR, 0.69; 95% CI, 0.49 to 0.98) and in those who did not carry a loss-of-function allele (9.5% vs 13.0%; HR, 0.72; 95% CI, 0.59 to 0.87).

By comparison, patients who were carriers of the CYP2C19 gain-of-function allele derived a greater benefit from clopidogrel than noncarriers (p=0.02) in the CURE trial. Clopidogrel significantly reduced the risk of the primary outcome versus placebo among gain-of-function allele carriers (7.7% vs 13.0%; HR, 0.55; 95% CI, 0.42 to 0.73) but not among noncarriers of the CYP2C19 gain-of-function allele (10.0% vs 12.2%; HR, 0.85; 95% CI, 0.68 to 1.05).

In the ACTIVE A trial, no differences in clopidogrel efficacy were observed between carriers and noncarriers of CYP2C19 loss-of-function alleles (p=0.87) or between carriers and noncarriers of the gain-of-function CYP2C19 allele (p=0.34). In both the CURE and ACTIVE A trials, bleeding risk among clopidogrel-treated patients did not vary according to CYP2C19 genotype.

In addition to ACTIVE A, future larger studies will be needed to rule out an adverse effect of CYP2C19 loss-of-function alleles on clopidogrel efficacy in patients with AF. However, the CURE trial provided strong data that support the continued use of clopidogrel in patients with ACS, regardless of CYP219 genotype status. In particular, conservatively managed ACS patients who carry the CYP2C19 loss-of-function allele should not be restricted from using clopidogrel at currently recommended doses, Prof. Paré concluded. Further studies will be needed to define the clinical role, if any, of the gain-of-function allele.

• © 2010 MD Conference Express