细胞色素 2C19 多态性携带与高维持剂量（150mg/天）氯吡格雷治疗后高血小板反应风险相关：根据基因多态性的双重剂量氯吡格雷加速血小板抑制（ACCEL-DOUBLE）研究结果。
Carriage of cytochrome 2C19 polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance-dose clopidogrel of 150 mg/day: results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) study.
机构信息
Division of Cardiology, Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Korea.
出版信息
JACC Cardiovasc Interv. 2010 Jul;3(7):731-41. doi: 10.1016/j.jcin.2010.05.007.
OBJECTIVES
This study sought to determine the impact of gene polymorphisms on platelet reactivity (PR) after clopidogrel 150 mg/day in patients treated with percutaneous coronary intervention (PCI).
BACKGROUND
Although high maintenance-dose (MD) clopidogrel reduces PR, it is unknown whether gene polymorphisms are related with the risk of high post-treatment PR (HPPR) after high-MD clopidogrel.
METHODS
We included mostly patients receiving high-MD clopidogrel after PCI from previously registered Gyeongsang National University Hospital data. A total of 126 PCI-treated patients receiving high-MD clopidogrel were enrolled. Platelet reactivity was assessed with conventional aggregometry and VerifyNow (Accumetrics Inc., San Diego, California) after receiving clopidogrel 150 mg/day for at least 1 month. CYP3A5, CYP2C19, and ABCB1 genotyping was performed. We defined HPPR as 5 micromol/l adenosine diphosphate (ADP)-induced maximal PR (PR(max)) >50%.
RESULTS
CYP3A5 and ABCB1 polymorphisms did not influence PR. Carriers of CYP2C19 variant (*2 or *3) (n = 80) had significantly higher 5 and 20 micromol/l ADP-induced PR(max) than did noncarriers (n = 46) (40.7 +/- 16.8% vs. 30.3 +/- 12.6%, p < 0.001; 54.2 +/- 16.2% vs. 40.5 +/- 15.8%, p < 0.001, respectively). Late PR and VerifyNow results indicated consistently greater measures in carriers versus noncarriers of CYP2C19 variant. All platelet measures proportionally increased according to the number of CYP2C19 variant alleles. Twenty-seven (21.4%) patients met the criteria for HPPR. Prevalence of HPPR was 8.7%, 21.7%, and 50.0% in carriers of 0, 1, and 2 CYP2C19 variant alleles, respectively (p < 0.001). By multivariate analysis, carriage of CYP2C19 variant was a significant predictor of HPPR (odds ratio: 5.525, 95% confidence interval: 1.333 to 23.256, p = 0.018).
CONCLUSIONS
Among PCI-treated patients receiving high-MD clopidogrel, carriage of CYP2C19 variant relates to increased PR and predicts risk of HPPR. (Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction [AMI] Patients According to CYP2C19 Polymorphism [ACCELAMI2C19]; NCT00915733; and Comparison of Platelet Inhibition With Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel According to Hepatic Cytochrome 2C19 Allele (CYP2C19) Polymorphism [ACCEL2C19]; NCT00891670).
目的
本研究旨在探讨基因多态性对接受经皮冠状动脉介入治疗（PCI）的患者使用氯吡格雷 150mg/日后血小板反应性（PR）的影响。
背景
尽管高维持剂量（MD）氯吡格雷可降低 PR，但尚不清楚基因多态性是否与高 MD 氯吡格雷治疗后高治疗后 PR（HPPR）的风险相关。
方法
我们纳入了大多数来自先前注册的庆尚国立大学医院数据的 PCI 术后接受高 MD 氯吡格雷治疗的患者。共纳入了 126 例接受高 MD 氯吡格雷治疗的 PCI 术后患者。在接受氯吡格雷 150mg/日治疗至少 1 个月后，使用常规聚集仪和 VerifyNow（Accumetrics Inc.，加利福尼亚州圣地亚哥）评估血小板反应性。进行 CYP3A5、CYP2C19 和 ABCB1 基因分型。我们将 HPPR 定义为 5μmol/L 二磷酸腺苷（ADP）诱导的最大 PR（PR(max))＞50%。
结果
CYP3A5 和 ABCB1 多态性不影响 PR。CYP2C19 变异体（*2 或 *3）携带者（n=80）的 5 和 20μmol/L ADP 诱导的 PR(max)明显高于非携带者（n=46）（40.7±16.8%比 30.3±12.6%，p＜0.001；54.2±16.2%比 40.5±15.8%，p＜0.001）。迟发性 PR 和 VerifyNow 结果表明，CYP2C19 变异体携带者的测量值始终更大。根据 CYP2C19 变异体等位基因的数量，所有血小板测量值呈比例增加。27（21.4%）例患者符合 HPPR 标准。CYP2C19 变异体携带者的 HPPR 发生率分别为 0、1 和 2 个 CYP2C19 变异等位基因携带者的 8.7%、21.7%和 50.0%（p＜0.001）。多变量分析显示，CYP2C19 变异体携带是 HPPR 的显著预测因子（优势比：5.525，95%置信区间：1.333 至 23.256，p=0.018）。
结论
在接受高 MD 氯吡格雷治疗的 PCI 术后患者中，CYP2C19 变异体携带与 PR 增加相关，并预测 HPPR 的风险。（急性心肌梗死患者根据 CYP2C19 多态性使用西洛他唑与高维持剂量氯吡格雷的辅助作用 [ACCELAMI2C19]；NCT00915733；根据肝细胞色素 2C19 等位基因（CYP2C19）多态性比较西洛他唑与高维持剂量氯吡格雷对血小板抑制作用的研究 [ACCEL2C19]；NCT00891670）。
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