Cardiovascular Risk in Clopidogrel-Treated Patients According to Cytochrome P450 2C192 Loss-of-Function Allele or Proton Pump Inhibitor Coadministration: A Systematic Meta-Analysis

• Published in: Journal of the American College of Cardiology Vol. 56; no. 2; pp. 134 - 143
• Main Authors: HULOT, Jean-Sébastien, COLLET, Jean-Philippe, SILVAIN, Johanne, PENA, Ana, BELLEMAIN-APPAIX, Anne, BARTHELEMY, Olivier, CAYLA, Guillaume, BEYGUI, Farzin, MONTALESCOT, Gilles
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier 06.07.2010; Elsevier Limited
• Subjects: Alleles; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology; Cardiology. Vascular system; Cardiovascular disease; Confidence intervals; Coronary Thrombosis - etiology; Coronary vessels; Cytochrome P-450 Enzyme System - genetics; Drug therapy; Heart attacks; Humans; Medical sciences; Meta-analysis; Metabolites; Mortality; Myocardial Ischemia - chemically induced; Myocardial Ischemia - mortality; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - adverse effects; Proton Pump Inhibitors - administration & dosage; Risk Factors; Sensitivity and Specificity; Stents; Stroke; Studies; Ticlopidine - administration & dosage; Ticlopidine - adverse effects; Ticlopidine - analogs & derivatives; Human; Cytochrome P450; Loss; Patient; Cardiovascular disease; Antiplatelet agent; Proton pump inhibitor; Vascular disease; Allele; Treatment; Analysis; Atherosclerosis; Risk factor; Clopidogrel; Circulatory system; Cardiology
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2009.12.071

The aim of this study was to assess the association between the loss-of-function cytochrome P450 2C19 (CYP2C19)*2 variant (10 studies, 11,959 patients) or the use of proton pump inhibitors (PPIs) (13 studies, 48,674 patients) and ischemic outcomes (major adverse cardiovascular events [MACE]) in patients treated with clopidogrel. In clopidogrel-treated patients, increased cardiovascular risk has been identified with the loss-of-function CYP2C19*2 allele or the use of PPIs, some of them CYP2C19 inhibitors. To further estimate the effect of a reduction in activity of this enzyme, the authors performed a meta-analysis of the studies available. The meta-analysis was performed on 23 studies using the odds ratio (OR) as the parameter of efficacy, with a fixed-effect model. The end points were MACE, mortality, or stent thrombosis. Of the 11,959 patients, carriers of the loss-of-function CYP2C19*2 allele (28% [n = 3,418]) displayed a 30% increase in the risk for MACE compared with noncarriers (9.7% vs. 7.8%; OR: 1.29; 95% confidence interval [CI]: 1.12 to 1.49; p < 0.001). This single gene variant (CYP2C19*2) was also associated with an excess of mortality (1.8% vs. 1.0%; OR: 1.79; 95% CI: 1.10 to 2.91; p = 0.019; n = 6,225) and of stent thrombosis (2.9% vs. 0.9%; OR: 3.45; 95% CI: 2.14 to 5.57; p < 0.001; n = 4,905). This increased risk was apparent in both heterozygotes and homozygotes and was independent of the baseline cardiovascular risk. PPI users (42% [n = 19,614]) displayed increased risk for MACE (21.8% vs. 16.7%; OR: 1.41; 95% CI: 1.34 to 1.48; p < 0.001) and mortality (12.7% vs. 7.4%; OR: 1.18; 95% CI: 1.07 to 1.30; p < 0.001; n = 23,977) compared with nonusers. The impact of PPI use was, however, significantly influenced by baseline cardiovascular risk, being significant only in high-risk patients. In this global meta-analysis, reduced CYP2C19 function appears to expose clopidogrel-treated patients to excess cardiovascular risk and mortality. Conflicting results among studies may be explained by differences in types and/or levels of risk of patients.