细胞色素 2C19*17 等位基因变异、血小板聚集、出血事件和氯吡格雷治疗的冠状动脉支架置入患者的支架血栓形成。

Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement.

机构信息

Deutsches Herzzentrum München, Lazarettstrasse 36, 80636 München, Germany.

出版信息

Circulation. 2010 Feb 2;121(4):512-8. doi: 10.1161/CIRCULATIONAHA.109.885194. Epub 2010 Jan 18.

DOI:10.1161/CIRCULATIONAHA.109.885194

PMID:20083681

Abstract

BACKGROUND

The cytochrome P450 (CYP) 2C19 isoenzyme plays an important role in clopidogrel metabolization. A recently explored CYP2C1917 allelic variant has been linked to increased transcriptional activity, resulting in extensive metabolization of CYP2C19 substrates, which may lead to an enhanced platelet response to clopidogrel treatment. The aim of this study was to assess the impact of CYP2C1917 on ADP-induced platelet aggregation, the risk of bleeding, and stent thrombosis in clopidogrel-treated patients undergoing percutaneous coronary intervention.

METHODS AND RESULTS

The study population included 1524 patients undergoing percutaneous coronary intervention after pretreatment with 600 mg clopidogrel. Genotypes were determined with a TaqMan assay. ADP-induced platelet aggregation was assessed on a Multiplate analyzer. The primary clinical safety end point was the 30-day incidence of bleeding defined according to Thrombolysis in Myocardial Infarction criteria, and the primary clinical efficacy end point was the 30-day incidence of stent thrombosis. For both heterozygous (*wt/*17; n=546) and homozygous (17/17; n=76) allele carriers, significantly lower ADP-induced platelet aggregation values were found compared with wild-type homozygotes (wt/wt; n=902; P=0.039 and P=0.008, respectively). CYP2C1917 allele carriage was significantly associated with an increased risk of bleeding; the highest risk was observed for CYP2C1917 homozygous patients (P=0.01, chi(2) test for trend). Multivariate analysis confirmed the independent association of CYP2C1917 allele carriage with platelet aggregation values (P<0.001) and the occurrence of bleeding (P=0.006). No significant influence of CYP2C1917 on the occurrence of stent thrombosis was found (P=0.79).

CONCLUSIONS

CYP2C19*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding.

摘要

背景

细胞色素 P450（CYP）2C19 同工酶在氯吡格雷代谢中起着重要作用。最近探索的 CYP2C1917 等位基因变异与转录活性增加有关，导致 CYP2C19 底物的广泛代谢，这可能导致氯吡格雷治疗的血小板反应增强。本研究旨在评估 CYP2C1917 对接受经皮冠状动脉介入治疗的氯吡格雷治疗患者的 ADP 诱导的血小板聚集、出血风险和支架血栓形成的影响。

方法和结果

该研究人群包括 1524 例接受 600mg 氯吡格雷预处理后行经皮冠状动脉介入治疗的患者。采用 TaqMan 法测定基因型。用 Multiplate 分析仪评估 ADP 诱导的血小板聚集。主要临床安全性终点是根据血栓溶解心肌梗死标准定义的 30 天出血发生率，主要临床疗效终点是 30 天支架血栓形成发生率。与野生型纯合子（*wt/*wt；n=902）相比，杂合子（wt/17；n=546）和纯合子（17/17；n=76）携带者的 ADP 诱导的血小板聚集值明显降低（P=0.039 和 P=0.008）。CYP2C1917 等位基因携带与出血风险增加显著相关；CYP2C1917 纯合子患者的风险最高（P=0.01，卡方趋势检验）。多变量分析证实 CYP2C1917 等位基因携带与血小板聚集值（P<0.001）和出血发生（P=0.006）独立相关。未发现 CYP2C1917 对支架血栓形成发生的显著影响（P=0.79）。