Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study

被引:741
作者
Collet, Jean-Philippe [1 ]
Hulot, Jean-Sebastien [2 ]
Pena, Anna [1 ]
Villard, Eric [2 ]
Esteve, Jean-Baptiste [1 ]
Silvain, Johanne [1 ]
Payot, Laurent [3 ]
Brugier, Delphine [1 ]
Cayla, Guillaume [1 ]
Beygui, Farzin [1 ]
Bensimon, Gilbert [2 ]
Funck-Brentano, Christian [2 ]
Montalescot, Gilles [1 ]
机构
[1] Univ Paris 06, Inst Cardiol, INSERM 856, Hop La Pitie Salpetriere, Paris, France
[2] Hop La Pitie Salpetriere AP HP, Serv Pharmacol, Unite Pharmacogenet, INSERM 621, Paris, France
[3] Hop Intercommunal Montreuil, Serv Cardiol, Montreuil, France
关键词
PERCUTANEOUS CORONARY INTERVENTION; OF-FUNCTION POLYMORPHISM; PLATELET ADP RECEPTOR; ANTIPLATELET THERAPY; RESPONSE VARIABILITY; DIABETES-MELLITUS; ACTIVE METABOLITE; LONG-TERM; REACTIVITY; CYP2C19;
D O I
10.1016/S0140-6736(08)61845-0
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background Clopidogrel and low-dose aspirin have become the mainstay oral antiplatelet regimen to prevent recurrent ischaemic events after acute coronary syndromes or stent placement. The frequent genetic functional variant 681. G>A (*2) of cytochrome P450 209 (CYP2C19) is an important contributor to the wide variability between individuals of the antiplatelet effect of clopidogrel. We assessed whether the CYP2C19*2 polymorphism affected long-term prognosis of patients who were chronically treated with clopidogrel. Methods Between April 1, 1996, and April 1, 2008, 259 young patients (aged <45 years) who survived a first myocardial infarction and were exposed to clopidogrel treatment for at least a month, were enrolled in a multicentre registry and underwent CYP2C19*2 determination. The primary endpoint was a composite of death, myocardial infarction, and urgent coronary revascularisation occurring during exposure to clopidogrel. Follow-up was every 6 months. The key secondary endpoint was stent thrombosis proven by angiography. Findings Median clopidogrel exposure time was 1. 07 years (IQR 0 . 28-3 . 0). Baseline characteristics were balanced between carriers (heterozygous *1/*2, n=64; homozygous *2/*2, n=9) and non-carriers (n=186) of CYP2C19*2 variant. The primary endpoint occurred more frequently in carriers than in non-carriers (15 vs 11 events; hazard ratio [HR] 3.69 [95% Cl 1.69-8.05], p=0-0005), as did stent thrombosis (eight vs four events; HR 6.02 [1.81-20.04], p=0.0009). The detrimental effect of the CYP2C19*2 genetic variant persisted from 6 months after clopidogrel initiation tip to the end of follow-up (HR 3.00 [1.27-7.10], p=0.009). After multivariable analysis, the CYP2C19*2 genetic variant was the only independent predictor of cardiovascular events (HR 4.04 [1.81-9.02], p=0.0006). Interpretation The CYP2C19*2 genetic variant is a major determinant of prognosis in young patients who are receiving clopidogrel treatment after myocardial infarction. Funding Delegation A la Recherche Clinique, Assistance Publique-Hopitaux de Paris.
引用
收藏
页码:309 / 317
页数:9
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