Among patients with acute coronary syndromes (ACS) or atrial fibrillation (AF), the effect of clopidogrel as compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status, according to substudies of the CURE and the ACTIVE A trials presented this week at the European Society of Cardiology (ESC) congress in Stockholm, and simultaneously published online Aug. 29 in the New England Journal of Medicine.

Recent clinical data have found that in patients who are carriers of a loss-of-function CYP2C19 allele (including the *2 and *3 alleles), the conversion of clopidogrel (Plavix, Bristol-Myers Squibb/Plavix) to its active metabolite may be reduced, resulting in decreased inhibition of platelets, the authors wrote. As a result, the FDA has issued a black-box warning about the reduced effectiveness of clopidogrel in patients who are carriers of two loss-of-function alleles (or poor metabolizers), and has suggested that carriers of these alleles receive a higher dose of clopidogrel or an alternative antiplatelet agent.

Conversely, carriers of the ultrarapid enzyme activity allele *17 (so-called ultrametabolizers) reportedly have an increased platelet response to clopidogrel and an increased risk of bleeding (but not greater efficacy).

For this study, Guillaume Paré, MD, from the Population Health Research Institute at Hamilton Health Sciences in Hamilton, Ontario, and colleagues hypothesized that the benefits of clopidogrel as compared with placebo would be decreased in persons who carry a loss-of-function CYP2C19 allele and increased in carriers of the gain-of-function *17 allele.

To this end, the researchers examined the efficacy and safety of clopidogrel as compared with placebo according to genotype status among patients in two randomized trials: the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, in which patients with ACS were enrolled, and the ACTIVE A (AF Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) trial, in which patients with AF were enrolled.

The CURE study was a randomized, double-blind, placebo-controlled trial comparing clopidogrel (at a dose of 75 mg per day) with placebo—both in combination with aspirin—among 12,562 patients with ACS without ST-segment elevation. ACTIVE A was a randomized, double-blind trial comparing clopidogrel, at a dose of 75 mg per day, with placebo—both in combination with aspirin—for reducing the risk of stroke among patients with AF and at least one additional risk factor for stroke who were not eligible for warfarin therapy.

A total of 5,059 participants of self-reported European or Latin American ancestry were successfully genotyped, of whom 2,549 had been randomly assigned to clopidogrel and 2,510 to placebo, the authors wrote. Among these patients with ACS, clopidogrel as compared with placebo significantly reduced the rate of the primary efficacy outcome, irrespective of the genetically determined metabolizer phenotype.

Also, Paré and colleagues reported that the effect of clopidogrel in reducing the rate of the primary efficacy outcome was similar in patients who were heterozygous or homozygous for loss-of-function alleles and in those who were not carriers of the alleles (rate among carriers, 8 percent with clopidogrel vs. 11.6 percent with placebo; rate among noncarriers, 9.5 vs. 13 percent).

In contrast, they found that the gain-of-function carriers derived more benefit from clopidogrel treatment as compared with placebo than did noncarriers (rate of primary outcome among carriers, 7.7 vs. 13 percent; rate among noncarriers, 10 vs. 12.2 percent). The effect of clopidogrel on bleeding did not vary according to genotypic subgroups.

Among 1,156 genotyped patients with AF, there was no evidence of an interaction with respect to either efficacy or bleeding between the study treatment and the metabolizer phenotype, loss-of-function carrier status or gain-of-function carrier status, the authors wrote.

Based on their findings, Paré and colleagues concluded that CYP2C19 loss-of-function variants do not modify the efficacy and safety of clopidogrel. “Therefore, loss-of-function allele carrier status should not preclude the use of clopidogrel at currently recommended doses in patients with acute coronary syndromes whose condition is being managed conservatively,” they wrote.

Although similar results were observed in patients with AF, larger studies will be needed to definitively rule out a genetic effect of the loss-of-function alleles in this patient population, according to the authors.

Sanofi-Aventis and Bristol-Myers Squibb funded the CURE and ACTIVE A trials.