Association of Reduced-Function CYP2C19 Alleles and Adverse Outcomes in Patients Treated with Clopidogrel

In patients presenting with an acute coronary syndrome (ACS), particularly those who are candidates for percutaneous coronary intervention (PCI), clopidogrel has been shown to reduce cardiovascular events. Clopidogrel acts by blocking the P2Y12 adenosine diphosphate receptor on platelets. Clopidogrel is a prodrug requiring biotransformation to generate its active metabolite, creating variability in the pharmacodynamic response to the drug. Cytochrome P450 (CYP) isoenzymes, specifically CYP2C19, play a key role in metabolism of clopidogrel. Carriers of reduced-function genetic variants in the CYP2C19 gene have lower active clopidogrel metabolite levels and diminished platelet inhibition. The US Food and Drug Administration announced a boxed warning on clopidogrel stating that the drug has a diminished effect based on an individual’s CYP2C19 genotype (those who harbor 2 reduced-function CYP2C19 alleles). However, according to researchers, there is no consensus whether the diminished pharmacologic response translates into worse outcomes and whether the possible increased risk is present with 1 reduced-function CYP2C19 allele (present in ~26% of the white population) as well as with 2 (present in ~2% of the white population). To define the risk of major adverse cardiovascular outcomes among carriers of 1 and carriers of 2 reduced-function CYP2C19 genetic variants in patients treated with clopidogrel, researchers recently conducted a meta-analysis of a literature search in MEDLINE, Cochrane Database of Systemic Reviews, and EMBASE. They reported results of the search in the Journal of the American Medical Association [2010;304(16):1821-1830]. The search was conducted from January 2000 through August 2010, using the terms lopidogrel and CYP2C19. The meta-analysis included cohort studies and clinical trials in which clopidogrel was initiated in predominantly invasively managed patients. If the studies did not include measurements of clinical outcomes, they were excluded from the analysis. Thirty-one studies were screened for inclusion. Of those, 22 were subsequently excluded because the data were incomplete, data could not be extracted from the information in the main manuscript, or the studies included patients from different clinical populations (in whom clopidogrel was not guideline indicated or who were predominantly conservatively managed). Of the remaining 9 studies, all investigators agreed to provide study-level data and participate in a collaborative meta-analysis. The studies represented 9685 patients. Average participant age was 64.2 years, 74.4% (n=7204) were men, 91.3% (n=5278) underwent PCI, and 54.5% (n=5278) had an ACS. Nearly three quarters of the patients (71.5%, n=6923) had no CYP2C19 reduced-function alleles, 26.3% (n=2544) had 1 reduced-function CYP2C19 allele, and 2.2% (n=218) had 2 reduced-function CYP2C19 alleles. Baseline characteristics were similar across genotypes. Stent thrombosis was an end point in 6 studies, creating a population of 5894 patients with stents in the stent thrombosis analyses. In this subset, 71.6% (n=4220) did not have CYP2C19 reduced-function alleles, 26.0% (n=1535) with 1 reduced-function CYP2C19 allele, and 2.4% (n=139) with 2 reduced-function CYP2C19 alleles. Of the 9685 patients, 863 experienced the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke. Carriers of 1 or 2 reduced-function CYP2C19 alleles had a significantly increased risk of the composite end point (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.16; P=.006). Analyses for individual end points found that 272 patients died of a cardiovascular-related cause, 575 had a nonfatal myocardial infarction, and 68 had a nonfatal stroke. All components of the composite end point had a directionally consistent risk associated with the presence of 1 or 2 reduced-function CYP2C19 alleles. The HR for cardiovascular death was 1.84 (95% CI, 1.03-3.28; P=.041). For nonfatal myocardial infarction, the HR was 1.45 (95% CI, 1.09-1.92; P=.01), and for nonfatal stroke, the HR was 1.73 (95% CI, 0.68-4.38; P=.25). Of those evaluated for stent thrombosis, that end point occurred in 84 of 5894 patients. The risk of stent thrombosis was significantly increased in carriers of 1 reduced-function CYP2C19 allele (HR, 2.67; 95% CI, 1.69-4.22; P<.0001) and in carriers of 2 reduced-function CYP2C19 alleles (HR, 3.97; 95% CI, 1.75-9.02; P=.001), versus noncarriers. In conclusion, the researchers stated that “among patients treated with clopidogrel for percutaneous coronary intervention, carriage of even 1 reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.”