Division of Cardiology, Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Korea.
Circ Cardiovasc Interv. 2011 Dec 1;4(6):585-94. doi: 10.1161/CIRCINTERVENTIONS.111.962555. Epub 2011 Nov 1.
As compared with whites, East Asians more often carry the cytochrome P450 (CYP) 2C19 loss-of-function (LOF) allele with the CYP2C19*3 variant. The influence of the CYP2C19 LOF alleles (*2 and *3) on clopidogrel response and clinical outcomes in East Asians with acute myocardial infarction (AMI) has not been reported. We sought to evaluate the effect of the CYP2C19 variants on clopidogrel pharmacodynamics and long-term prognosis in these patients.
Patients who survived an AMI (n=266) were enrolled in a single-center registry. Predischarge platelet reactivity was assessed with light transmittance aggregometry and the VerifyNow P2Y12 assay; the CYP2C19*2, *3, *17 and ABCB1 3435C>T variants were determined. The primary clinical end point was the composite of cardiovascular death, nonfatal MI, and ischemic stroke. The median exposure to clopidogrel was 21 months (interquartile range, 13-29). The ABCB1 3435C>T was not related to clopidogrel response or cardiovascular events. Carriage of the CYP2C19 LOF variant allele was relatively high (60.9%, n=162; *2/*17=2, *3/*17=1, *1/*2=96, *1/*3=29, *2/*2=20, and *2/3=14). Platelet reactivity increased proportionally according to the number of the CYP2C19 LOF alleles. In a multivariate regression analysis, the risk of high on-treatment platelet reactivity (HPR) increased depending on the number of CYP2C19 LOF allele [1 LOF allele; odds ratio (OR), 1.8; 95% confidence interval (CI), 0.8 to 4.2, P=0.152; and 2 LOF alleles; OR, 2.8; 95% CI, 1.2 to 6.5; P=0.016]; platelet reactivity and the rate of HPR did not differ between the CYP2C192 versus 3 allele carriage. In addition, cardiovascular event occurrence increased according to the number of the CYP2C19 LOF allele; compared with noncarriers, carriers of 1 [hazard ratio (HR), 3.1; 95% CI, 0.8 to 11.6; P=0.089] and 2 CYP2C19 LOF allele(s) (HR, 10.1; 95% CI, 1.8-58.8; P=0.008) were associated with clinical end point. The clinical impact of the CYP2C192 versus *3 allele carriage also did not differ.
Among East Asian patients who survived an AMI, the CYP2C19 LOF allele carriage appears to affect clopidogrel pharmacodynamics and cardiovascular events according to the number of the CYP2C19 LOF allele; the influence of the CYP2C19*2 and *3 alleles on clopidogrel response and long-term outcomes does not differ.
与白人相比，东亚人更常携带细胞色素 P450（CYP）2C19 失活（LOF）等位基因，即 CYP2C19*3 变异。CYP2C19 LOF 等位基因（*2 和 *3）对东亚急性心肌梗死（AMI）患者氯吡格雷反应和临床结局的影响尚未报道。我们旨在评估 CYP2C19 变异对这些患者氯吡格雷药代动力学和长期预后的影响。
我们在一项单中心注册研究中纳入了存活 AMI 的患者（n=266）。使用光透射聚集法和 VerifyNow P2Y12 测定法评估出院前血小板反应性；确定 CYP2C19*2、*3、*17 和 ABCB1 3435C>T 变异。主要临床终点为心血管死亡、非致死性心肌梗死和缺血性卒中的复合终点。氯吡格雷中位暴露时间为 21 个月（四分位距，13-29）。ABCB1 3435C>T 与氯吡格雷反应或心血管事件无关。CYP2C19 LOF 变异等位基因的携带率相对较高（60.9%，n=162；*2/*17=2，*3/*17=1，*1/*2=96，*1/*3=29，*2/*2=20，*2/3=14）。血小板反应性随 CYP2C19 LOF 等位基因数量呈比例增加。在多变量回归分析中，高治疗期血小板反应性（HPR）的风险取决于 CYP2C19 LOF 等位基因的数量[1 个 LOF 等位基因；比值比（OR），1.8；95%置信区间（CI），0.8 至 4.2，P=0.152；和 2 个 LOF 等位基因；OR，2.8；95%CI，1.2 至 6.5；P=0.016]；CYP2C192 与 3 等位基因携带的血小板反应性和 HPR 率无差异。此外，心血管事件的发生随 CYP2C19 LOF 等位基因数量的增加而增加；与非携带者相比，携带 1 个 [风险比（HR），3.1；95%CI，0.8 至 11.6；P=0.089]和 2 个 CYP2C19 LOF 等位基因（HR，10.1；95%CI，1.8-58.8；P=0.008）与临床终点相关。CYP2C192 与 *3 等位基因携带对氯吡格雷反应和长期结局的影响也没有差异。
在存活 AMI 的东亚患者中，CYP2C19 LOF 等位基因携带似乎根据 CYP2C19 LOF 等位基因的数量影响氯吡格雷的药代动力学和心血管事件；CYP2C19*2 和 *3 等位基因对氯吡格雷反应和长期结局的影响没有差异。
