Carrying just one reduced-function CYP2C19 allele conveys a poor response to clopidogrel in patients undergoing percutaneous coronary intervention, significantly raising the risk of adverse cardiovascular events, especially stent thrombosis, according to a meta-analysis reported in the Oct. 27 issue of JAMA.
“CYP2C19 genetic information identifies approximately 30% of the population who may be less likely to be protected from recurrent ischemic events after PCI despite treatment with standard doses of clopidogrel,” said Dr. Jessica L. Mega of Brigham and Women’s Hospital, Boston, and her associates.
Certain variants of the CYP2C19 gene, which encodes for cytochrome P450 isoenzymes, are known to diminish the platelet inhibition effect of clopidogrel. However, “there is not consensus as to whether the diminished pharmacologic response translates into worse clinical outcomes and whether the proposed increased risk of adverse cardiovascular outcomes requires two reduced-function CYP2C19 alleles (present in approximately 2% of the white population) or can be seen with just one (present in approximately 26% of the white population),” Dr. Mega and her colleagues said.
To examine the association between CYP2C19 genotype and clinical outcomes, the researchers performed a collaborative meta-analysis with investigators in nine cohort studies and clinical trials of the issue. Authors of each study provided data on 9,685 subjects’ genotypic status and on overall outcomes. More than 91% of the study subjects received clopidogrel because they were undergoing PCI, and the remainder did so for the treatment of acute coronary syndromes.
A total of 72% of the subjects had no reduced-function CYP2C19 alleles, 26% had one reduced-function allele, and 2% had two reduced-function alleles.
Overall, 863 of the 9,685 study subjects developed the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke. Carriers of either one or two reduced-function alleles were significantly more likely to achieve this end point than were noncarriers (hazard ratio, 1.57). More specifically, carriers of two reduced-function alleles had a significantly higher risk for the composite end point (HR 1.76) than did those with one such allele (HR 1.55), compared with noncarriers.
Regarding the individual components of the composite end point, carriers of one or two reduced-function CYP2C19 alleles had hazard ratios of 1.84 for cardiovascular death, 1.45 for nonfatal MI, and 1.73 for stroke, compared with noncarriers.
A particularly strong association was seen between the genotype and stent thrombosis. In the subset of 5,894 patients who received stents during PCI, 84 developed stent thrombosis, predominantly in the early postoperative period. Compared with noncarriers, carriers of one reduced-function allele had a hazard ratio of 2.67 and carriers of two reduced-function alleles had a hazard ratio of 3.97 for stent thrombosis.
“Even partial reductions in the antiplatelet effect of clopidogrel could translate into a several-fold increase in the risk of major adverse cardiovascular outcomes,” Dr. Mega and her associates said (JAMA 2010;304:1821-30).
The findings of this meta-analysis support the theory that reduced-function variants of the CYP2C19 gene exert their blunting effect on clopidogrel by reducing bioactivation of the drug into its active metabolite.
“Tests are available to identify a patient’s CYP2C19 genotype. Although these tests are not widely used at this time, some physicians have started to use a strategy of CYP2C19 genotyping among participants initiating treatment with clopidogrel. Moving forward, point-of-care genotyping will likely [become] available, and this technology could further ease the implementation of CYP2C19 testing for interested clinicians and patients,” they added.
This study was funded in part by the National Institutes of Health. Dr. Mega reported ties to Bayer Healthcare, Bristol-Myers Squibb and Sanofi-Aventis (comakers of Plavix), Daiichi Sankyo, Eli Lilly & Co., Johnson & Johnson, Accumetrics Inc., Nanosphere Inc., AstraZeneca, and Novartis. Her associates reported numerous ties to drug and device manufacturers.