Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis.
OBJECTIVE
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.


BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Hulot
Jean-Sébastien
JS
Service de Pharmacologie, Unité de Pharmacogénétique, INSERM UMRS 956, Hôpital Pitié-Salpêtrière, Paris, France.
Collet
Jean-Philippe
JP
Silvain
Johanne
J
Pena
Ana
A
Bellemain-Appaix
Anne
A
Barthélémy
Olivier
O
Cayla
Guillaume
G
Beygui
Farzin
F
Montalescot
Gilles
G
D000483:Alleles; D000077144:Clopidogrel; D003328:Coronary Thrombosis / Q000209:etiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D006801:Humans; D017202:Myocardial Ischemia / Q000139:chemically induced* / Q000401:mortality; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage*; D012307:Risk Factors; D012680:Sensitivity and Specificity; D015607:Stents; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; D013988:Ticlopidine