Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis.
Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis.
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DOI：
10.1016/s0140-6736(10)61273-1
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发表时间：
2010-10-16
期刊：
影响因子：
168.9
通讯作者：
Sabatine, Marc S.
中科院分区：
文献类型：
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作者：
Mega, Jessica L.;Close, Sandra L.;Wiviott, Stephen D.;Shen, Lei;Walker, Joseph R.;Simon, Tabassome;Antman, Elliott M.;Braunwald, Eugene;Sabatine, Marc S.
噻吩并吡啶氯吡格雷是全球最常用的处方药之一。氯吡格雷和第三代噻吩并吡啶普拉格雷均通过P-糖蛋白（由ABCB 1编码，也称为MDR 1）外排。体外和临床研究表明，ABCB 1多态性，特别是C3435 T，可能与药物代谢和疗效的改变有关。我们在TRITON-TIMI中对2，932例接受氯吡格雷或普拉格雷治疗的急性冠状动脉综合征（ACS）患者进行了基因分型，并对321例健康个体进行了氯吡格雷或普拉格雷的药理学反应测定。在接受氯吡格雷治疗的ACS患者中，ABCB 1 C3435 T基因型与心血管死亡、MI或卒中的主要终点风险显著相关（P=0.0064）。与CT /CC个体相比，TT纯合子（人群的804/2，932 [27%]）的主要终点风险增加72%（52/414 [12.9%] vs. 80/1，057 [7.8%]，HR 1.72，95% CI 1.22-2.44，P=0.002）。ABCB 1 C3435 T和CYP 2C 19基因型是主要终点的显著独立预测因子，47%的受试者在研究中未发现ABCB 1基因型。在CYP 2C 19功能降低等位基因携带者、ABCB 1 3435 TT纯合子或两者均携带者人群中，有681/1454例患者的心血管死亡、MI或卒中风险显著增加（HR 1.97，95% CI 1.38-2.82，P=0.0002）。在健康受试者中，3435名TT纯合子使用氯吡格雷后血小板聚集率降低7.3个绝对百分点（即，血小板抑制较少）与CT/CC个体相比（P=0.0127）。在接受普拉格雷治疗的ACS或健康个体中，ABCB 1基因型与临床或药理学结局无显著相关性。ABCB 1 3435 TT基因型个体的血小板抑制作用较低，在氯吡格雷治疗的背景下，复发性缺血事件的风险显著增加。考虑到ABCB 1和CYP 2C 19，近一半的人群携带与服用标准剂量氯吡格雷时主要不良心血管事件风险增加相关的基因型。
The thienopyridine clopidogrel is one of the most commonly prescribed drugs worldwide. Both clopidogrel and the third-generation thienopyridine prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1, also known as MDR1). In vitro and clinical studies suggest that ABCB1 polymorphisms, particularly C3435T, may be associated with altered drug metabolism and efficacy. We genotyped 2,932 patients with an acute coronary syndrome (ACS) in TRITON-TIMI 38 treated with clopidogrel or prasugrel and 321 healthy individuals in whom we measured the pharmacologic response to clopidogrel or prasugrel. Among ACS patients treated with clopidogrel, ABCB1 C3435T genotype was significantly associated with risk for the primary endpoint of cardiovascular death, MI, or stroke (P=0.0064). TT homozygotes (804/2,932 [27%] of the population) had a 72% increased risk of the primary endpoint as compared with CT /CC individuals (52/414 [12.9%] vs. 80/1,057 [7.8%], HR 1.72, 95% CI 1.22–2.44, P=0.002). ABCB1 C3435T and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and the 47% (681/1454) of the population who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at significantly increased risk of cardiovascular death, MI, or stroke (HR 1.97, 95% CI 1.38–2.82, P=0.0002). In healthy subjects, 3435 TT homozygotes had a reduction in platelet aggregation with clopidogrel that was 7.3 absolute percentage points lower (i.e., less platelet inhibition) vs. CT/CC individuals (P=0.0127). ABCB1 genotypes were not significantly associated with clinical or pharmacologic outcomes among ACS or healthy individuals treated with prasugrel. Individuals with the ABCB1 3435 TT genotype have less platelet inhibition and are at significantly increased risk of recurrent ischemic events in the setting of clopidogrel treatment. Taking into account both ABCB1 and CYP2C19, nearly half of the population carries a genotype associated with an increased risk for major adverse cardiovascular events while on standard doses of clopidogrel.