Cytochrome P-450 Polymorphisms and Response to Clopidogrel.

被引:1883
作者
Mega, Jessica L. [1 ,2 ]
Close, Sandra L. [3 ]
Wiviott, Stephen D. [1 ,2 ]
Shen, Lei [3 ]
Hockett, Richard D. [3 ]
Brandt, John T. [3 ]
Walker, Joseph R. [4 ]
Antman, Elliott M. [1 ,2 ]
Macias, William [3 ]
Braunwald, Eugene [1 ,2 ]
Sabatine, Marc S. [1 ,2 ]
机构
[1] Brigham & Womens Hosp, Div Cardiovasc, Thrombolysis Myocardial Infarct Study Grp, Dept Med, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Boston, MA 02115 USA
[3] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA
[4] Daiichi Sankyo Pharma Dev, Edison, NJ USA
关键词
PERCUTANEOUS CORONARY INTERVENTION; PLATELET INHIBITION; INDIVIDUAL RESPONSIVENESS; ATHEROTHROMBOTIC EVENTS; STENT THROMBOSIS; INCREASED RISK; PRASUGREL; PHARMACOKINETICS; PHARMACODYNAMICS; VARIABILITY;
D O I
10.1056/NEJMoa0809171
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function. Methods: We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38. Results: In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P<0.001). Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9 percentage points less than that seen in noncarriers (P<0.001). Among clopidogrel-treated subjects in TRITON-TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval [CI], 1.07 to 2.19; P=0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P=0.02). Conclusions: Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers. N Engl J Med 2009;360:354-62.
引用
收藏
页码:354 / 362
页数:9
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