Reduced-Function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes Among Patients Treated With Clopidogrel Predominantly for PCI A Meta-analysis

Content Clopidogrel, one of the most commonly prescribed medications, is a prodrug requiring CYP450 biotransformation. Data suggest its pharmacologic effect varies based on CYP2C19 genotype, but there is uncertainty regarding the clinical risk imparted by specific genotypes. Objective To define the risk of major adverse cardiovascular outcomes among carriers of 1 (approximate to 26% prevalence in whites) and carriers of 2 (approximate to 2% prevalence in whites) reduced-function CYP2C19 genetic variants in patients treated with clopidogrel. Data Sources and Study Selection A literature search was conducted (January 2000-August 2010) in MEDLINE, Cochrane Database of Systematic Reviews, and EMBASE. Genetic studies were included in which clopidogrel was initiated in predominantly invasively managed patients in a manner consistent with the current guideline recommendations and in which clinical outcomes were ascertained. Data Extraction Investigators from 9 studies evaluating CYP2C19 genotype and clinical outcomes in patients treated with clopidogrel contributed the relevant hazard ratios (HRs) and 95% confidence intervals (CIs) for specific cardiovascular outcomes by genotype. Results Among 9685 patients (91.3% who underwent percutaneous coronary intervention and 54.5% who had an acute coronary syndrome), 863 experienced the composite end point of cardiovascular death, myocardial infarction, or stroke; and 84 patients had stent thrombosis among the 5894 evaluated for such. Overall, 71.5% were noncarriers, 26.3% had 1 reduced-function CYP2C19 allele, and 2.2% had 2 reduced-function CYP2C19 alleles. A significantly increased risk of the composite end point was evident in both carriers of 1 (HR, 1.55; 95% CI, 1.11-2.17; P=.01) and 2 (HR, 1.76; 95% CI, 1.24-2.50; P=.002) reduced-function CYP2C19 alleles, as compared with noncarriers. Similarly, there was a significantly increased risk of stent thrombosis in both carriers of 1 (HR, 2.67; 95% CI, 1.69-4.22; P<.0001) and 2 (HR, 3.97; 95% CI, 1.75-9.02; P=.001) CYP2C19 reduced-function alleles, as compared with noncarriers. Conclusion 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. JAMA. 2010; 304(16): 1821-1830