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Pare, Guillaume (Canada)
see Discussant report
List of Authors: Guillaume Pare, Shamir R. Mehta, Salim Yusuf, Sonia S. Anand, Stuart J. Connolly, Jack Hirsh, Katy Simonsen, Deepak L. Bhatt, Keith A.A. Fox, John W. Eikelboom
Aims: It has been suggested that clopidogrel may be ineffective in preventing cardiovascular (CV) events in individuals who are carriers of loss-of-function CYP2C19 alleles that are associated with reduced conversion of clopidogrel to its active metabolite. Methods and results: Patients from two large randomized trials that demonstrated benefits of clopidogrel versus placebo in preventing CV events in acute coronary syndromes (ACS) and atrial fibrillation (AF) were genotyped for three single nucleotide polymorphisms (*2, *3, *17) that define the major CYP2C19 alleles. In 5059 ACS patients from the CURE trial, clopidogrel compared with placebo significantly reduced the primary efficacy outcome, irrespective of genetically determined metabolizer phenotype (P= 0.12 for heterogeneity). Patients heterozygous or homozygous for loss-of-function alleles derived a similar protection against CV events from clopidogrel versus placebo (8.0% vs 11.6%, HR=0.69, 95%CI 0.49-0.98) as compared with noncarriers (9.5% vs 13.0%, HR=0.72, 95%CI 0.59- 0.87). By contrast, gain-of-function carriers derived increased benefit (interaction P=0.02) from clopidogrel treatment (7.7% vs 13.0%, HR=0.55, 95% CI 0.42- 0.73) as compared with noncarriers (10.0% vs 12.2%, HR=0.85, 95%CI 0.68-1.05). The effect of clopidogrel on bleeding did not vary by genotypic subgroups. In 1156 AF patients from the ACTIVE trial, there was no evidence of interaction either on efficacy or bleeding between treatment and metabolizer phenotype, loss-of-function carrier status or gain-of-function carrier status. Conclusion: The effect of clopidogrel compared with placebo in patients with ACS or AF is consistently observed irrespective of CYP2C19 genotype. The increased benefit of clopidogrel observed in ACS gain-of-function allele carriers requires confirmation.
Califf, Robert M (United States of America)
see Presenter abstract
The presentation by Pare reports the results of an analysis of 2 clinical trials in which clopidogrel was compared with placebo on top of standard of care. The question addressed was whether the CYP2C19 allele status affected either the underlying event rate or the treatment difference between clopidogrel treatment and placebo. The CURE Trial evaluated clopidogrel treatment in the setting of acute coronary syndromes while the ACTIVE Trial evaluated clopidogrel treatment in patients with atrial fibrillation who were not candidates for warfarin treatment. The authors conducted a sophisticated analysis that evaluated 2 loss of function alleles and 1 gain of function allele. The primary finding was that there was no relationship between allele status and placebo event rates, and for the most part, no relationship to treatment effect. Clopidogrel was effective in preventing ischemic events and caused more bleeding than placebo, regardless of allele status in CURE. Clopidogrel was effective in preventing vascular events and caused more bleeding than placebo regardless of allele status in ACTIVE. Of 15 tests for interaction looking for differential treatment effect, only 2 came out marginally significant: the gain of function carrier state was found to be associated with a greater treatment effect in CURE with p values of .016 and .029 for the 2 key composite endpoints for CV ischemic events. Overall, the study points out that simple interpretations of pharmacogenetics are likely to be overly enthusiastic. When only 2/15 interaction tests are significant, one must question the validity of the finding. Prospective clinical trials are needed that have adequate power and include first rate clinical characterization, platelet function measurements and genetics.
709011 - 709012
Clinical Trial Update I
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