Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis

Abstract

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 (≈ 26% prevalence in whites) and carriers of 2 (≈ 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.

Figures

Figure 1. Cardiovascular Death, Myocardial Infarction, or Ischemic Stroke by CYP2C19 Genotype

Among patients treated with clopidogrel, hazard ratios are reported for cardiovascular death, myocardial infarction, or ischemic stroke among carriers of one or two (Panel A), one (Panel B), or two (Panel C) CYP2C19 reduced-function alleles versus non-carriers. Squares with horizontal lines represent the hazard ratio and corresponding 95% confidence intervals, and the size of each square reflects the statistical weight of the study in the meta-analysis. The diamond represents the 95% confidence for the overall hazard ratio. The number of events and the number of individuals at risk for events is presented for each study. In Panel C, studies that had no adverse cardiovascular events among carriers of two reduced-function CYP2C19 alleles could not be included in the analysis. A. Carriers of One or Two CYP2C19 Reduced-Function Alleles versus Non-Carriers B. Carriers of One CYP2C19 Reduced-Function Alleles versus Non-Carriers C. Carriers of Two CYP2C19 Reduced-Function Alleles versus Non-Carriers

Figure 2. Stent Thrombosis by CYP2C19 Genotype

Among patients treated with clopidogrel, hazard ratios are reported for stent thrombosis among carriers of one or two (Panel A), one (Panel B), or two (Panel C) CYP2C19 reduced-function alleles versus non-carriers. Squares with horizontal lines represent the hazard ratio and corresponding 95% confidence intervals, and the size of each square reflects the statistical weight of the study in the meta-analysis. The diamond represents the 95% confidence for the overall hazard ratio. The number of events and the number of individuals at risk for events is presented for each study. In Panel C, studies that had no stent thrombosis events among carriers of two reduced-function CYP2C19 alleles could not be included in the analysis. A. Carriers of One or Two CYP2C19 Reduced-Function Alleles versus Non-Carriers B. Carriers of One CYP2C19 Reduced-Function Alleles versus Non-Carriers C. Carriers of Two CYP2C19 Reduced-Function Alleles versus Non-Carriers

Figure 3. Timing of Events for Cardiovascular Death, Myocardial Infarction, or Ischemic Stroke and Stent Thrombosis

Among patients treated with clopidogrel, hazard ratios are reported for cardiovascular death, myocardial infarction, or ischemic stroke and for stent thrombosis among carriers of one or two CYP2C19 reduced-function alleles versus non-carriers. Diamonds with horizontal lines represent the hazard ratio and corresponding 95% confidence intervals across the different timepoints. Nine studies contributed to the endpoint of cardiovascular death, myocardial infarction, or stroke from 0 to 30 days, and six studies from 31 days to end of follow-up. Analogously, six studies contributed to the endpoint of stent thrombosis from 0 to 30 days, and three studies from 31 days to end of follow-up. The number of events and the number of individuals at risk for events is presented for each study. In the analysis, a patient could have had a non-fatal event during 0 to 30 days and a subsequent event after day 30.