Background and Purpose:Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT.Methods:Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death.Results:Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09–1.21]; P=0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32–1.34]; P=0.25) among noncarriers. There was no significant interaction by genotype for major ischemia (P=0.36) or stroke (P=0.33).Conclusions:This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%.Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

中文翻译：

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POINT 试验中基于 CYP2C19 等位基因状态的氯吡格雷预防中风的疗效。

背景和目的：氯吡格雷是一种抗血小板药物，通过CYP2C19酶代谢成活性形式。CHANCE 试验（氯吡格雷用于急性非致残性脑血管事件的高危患者）发现CYP2C19的功能丧失等位基因状态之间存在显着的相互作用基因以及阿司匹林和氯吡格雷双重抗血小板治疗对急性短暂性脑缺血发作/轻微卒中后早期复发卒中发生率的影响。POINT（新 TIA 和轻微缺血性卒中试验中的血小板导向抑制试验）在设计上与 CHANCE 相似，但主要在北美和欧洲进行，表明与单用阿司匹林相比，双重抗血小板治疗可减少早期复发性卒中。这项子研究旨在评估功能丧失CYP2C19等位基因与 POINT 治疗组结果之间的潜在相互作用。方法：在 10 个国家的 269 个地点纳入 POINT 患者，134 个地点参与了该子研究。对CYP2C19的 DNA 样本进行基因分型*2、*3 和 *17 等位基因，分类为功能丧失等位基因的携带者或非携带者。主要缺血包括缺血性中风、心肌梗死或缺血性血管死亡。结果：932 名患者提供了可分析的 DNA。在功能丧失等位基因携带者中，阿司匹林组的严重缺血率为 6.7%，而双重抗血小板治疗组为 2.3%（风险比，0.33 [95% CI，0.09-1.21]；P = 0.09）。在非携带者中，阿司匹林组的严重缺血发生率为 5.6%，而双重抗血小板治疗组为 3.7%（风险比，0.65 [95% CI，0.32-1.34]；P = 0.25）。严重缺血（P = 0.36）或中风（P=0.33)。结论：POINT 的这项子研究发现治疗组与CYP2C19功能丧失携带者状态和结果没有显着的相互作用。未能证实 CHANCE 试验的结果可能是因为所测试的功能丧失等位基因在这种情况下在临床上并不重要，或者因为 2 项试验在种族/民族组成方面存在差异。此外，两项试验之间的差异可能是偶然的，因为我们的统计能力被限制在 50%。注册：URL：https://www.clinicaltrials.gov。唯一标识符：NCT00991029。