Effects of CYP2C19 Genotype on Outcomes of Clopidogrel Treatment
Effects of CYP2C19 Genotype on Outcomes of Clopidogrel Treatment
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DOI：
10.1056/nejmoa1008410
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发表时间：
2010-10-28
影响因子：
158.5
通讯作者：
Eikelboom, John W.
中科院分区：
文献类型：
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作者：
Pare, Guillaume;Mehta, Shamir R.;Eikelboom, John W.
研究背景已经表明，在那些携带有与氯吡格雷向其活性代谢物转化减少相关的功能丧失型CYP 2C 19等位基因的人中，氯吡格雷在降低心血管事件发生率方面可能效果较差。降低急性冠脉综合征患者和房颤患者的心血管事件发生率（主要疗效结局）。对患者进行了三种单核苷酸多态性（（星星）2、（星星）3、（星星）17）的基因分型，这些多态性定义了CYP 2C 19的主要等位基因。在5059例基因分型的急性冠状动脉综合征患者中，与安慰剂相比，氯吡格雷显著降低了主要疗效结局的发生率，而与基因决定的代谢者表型无关（异质性P = 0.12）。氯吡格雷在降低功能丧失等位基因杂合或纯合患者和非等位基因携带者的主要疗效结局发生率方面的作用相似（携带者中的发生率，氯吡格雷组为8.0%，安慰剂组为11.6%;氯吡格雷组的风险比为0.69; 95%置信区间[CI]为0.49至0.98;非携带者的患病率为9.5% vs. 13.0%;风险比为0.72; 95%CI为0.59 - 0.87）。相反，与安慰剂相比，功能获得性携带者从氯吡格雷治疗中获得的益处多于非携带者（携带者中主要结局发生率，7.7% vs. 13.0%;风险比，0.55; 95%CI，0.42 - 0.73;非携带者中主要结局发生率，10.0% vs. 12.2%;风险比，0.85; 95%CI，0.68 - 1.05;相互作用P = 0.02）。氯吡格雷对出血的影响不因基因型亚组而异。在1156名基因型房颤患者中，没有证据表明研究治疗与代谢者表型、功能丧失携带者状态或功能获得携带者状态之间在疗效或出血方面存在相互作用。结论在急性冠状动脉综合征或房颤患者中，氯吡格雷与安慰剂相比的效果是一致的，无论CYP 2C 19功能丧失携带者状态如何。
BACKGROUNDIt has been suggested that clopidogrel may be less effective in reducing the rate of cardiovascular events among persons who are carriers of loss-of-function CYP2C19 alleles that are associated with reduced conversion of clopidogrel to its active metabolite.METHODSWe genotyped patients from two large, randomized trials that showed that clopidogrel, as compared with placebo, reduced the rate of cardiovascular events (the primary efficacy outcome) among patients with acute coronary syndromes and among patients with atrial fibrillation. Patients were genotyped for three single-nucleotide polymorphisms ((star)2, (star)3, (star)17) that define the major CYP2C19 alleles.RESULTSAmong 5059 genotyped patients with acute coronary syndromes, clopidogrel as compared with placebo significantly reduced the rate of the primary efficacy outcome, irrespective of the genetically determined metabolizer phenotype (P = 0.12 for heterogeneity). The effect of clopidogrel in reducing the rate of the primary efficacy outcome was similar in patients who were heterozygous or homozygous for loss-of-function alleles and in those who were not carriers of the alleles (rate among carriers, 8.0% with clopidogrel vs. 11.6% with placebo; hazard ratio with clopidogrel, 0.69; 95% confidence interval [CI], 0.49 to 0.98; rate among noncarriers, 9.5% vs. 13.0%; hazard ratio, 0.72; 95% CI, 0.59 to 0.87). In contrast, gain-of-function carriers derived more benefit from clopidogrel treatment as compared with placebo than did noncarriers (rate of primary outcome among carriers, 7.7% vs. 13.0%; hazard ratio, 0.55; 95% CI, 0.42 to 0.73; rate among noncarriers, 10.0% vs. 12.2%; hazard ratio, 0.85; 95% CI, 0.68 to 1.05; P = 0.02 for interaction). The effect of clopidogrel on bleeding did not vary according to genotypic subgroups. Among 1156 genotyped patients with atrial fibrillation, there was no evidence of an interaction with respect to either efficacy or bleeding between the study treatment and the metabolizer phenotype, loss-of-function carrier status, or gain-of-function carrier status.CONCLUSIONSAmong patients with acute coronary syndromes or atrial fibrillation, the effect of clopidogrel as compared with placebo is consistent, irrespective of CYP2C19 loss-of- function carrier status.