Precision antiplatelet therapy after percutaneous coronary intervention

摘要： 阿司匹林和P2Y12受体抑制剂(氯吡格雷、普拉格雷或 替卡格雷)是经皮冠状动脉介入治疗(PCI)后的标准护理，以降低 动脉粥样硬化血栓事件。细胞色素P450(CYP)2C19酶是氯吡格雷代谢所必需的 (一种前药)使其具有药理活性。大约30%的美国人携带CYP2C19 降低氯吡格雷的生物活性和有效性的功能丧失(LOF)等位基因，但不包括普拉格雷或 替卡格雷，后经皮冠状动脉介入治疗。我们已经证明了将CYP2C19基因分型应用于临床的可行性。 注意引导CYP2C19 LOF患者的DAPT从氯吡格雷升级为普拉格雷或替卡格雷 等位基因，并且CYP2C19引导的升级策略降低了动脉粥样硬化血栓形成事件的风险。然而， 关键患者特有因素对基因导引DAPT(尤其是非洲人)结果的影响 血统、影响氯吡格雷有效性的合并症，以及超过CYP2C19的基因类型)尚未 为了优化基因导引的DAPT的临床影响，明确但了解是至关重要的。 此外，使用CYP2C19基因来指导更多患者的降级对临床结果的影响 在没有LOF等位基因的患者中使用氯吡格雷的有效药物，这已成为高度临床相关的原因 急性冠脉综合征和经皮冠状动脉介入治疗后更频繁的首次使用普拉格雷或替卡格雷 在不同的、真实的临床环境中进行了调查。我们的长期目标是优化精准医疗 DAPT策略，可改善介入治疗后的结果。我们的总体目标是阐明影响 用CYP2C19基因导引的精确医学方法治疗DAPT的结果。我们的假设是 多种临床和遗传因素共同作用于CYP2C19 LOF等位基因的有效性和安全性。 在真实的临床环境中指导选择经皮冠状动脉介入治疗后的DAPT。我们建议通过以下方式来检验这一假设 对6,000名接受冠状动脉介入治疗的患者进行了一项多中心的观察性研究，并对其进行了临床CYP2C19基因检测。 这项登记将包括不同人群的真实世界患者，评估动脉粥样硬化血栓形成和出血。 结果超过12个月，收集DNA样本进行额外的基因分型，在 患者的子集，并用于实现以下特定目标：(目标1)确定 非洲血统和其他患者特有因素对CYP2C19基因导引的DAPT临床结局的影响 在真实世界环境下进行经皮冠状动脉介入治疗；(目的2)评估CYP2C19基因- 在现实环境中引导冠状动脉介入术后DAPT的降级；(目标3)阐明遗传因素的影响(S) 超过CYP2C19 LOF等位基因的变异对氯吡格雷介入治疗后的血小板反应性和临床结果的影响。 这项研究将建立个性化抗血小板治疗处方决策的最佳策略 这改善了结果，并可以可行地应用于多样化的现实世界人口。

ABSTRACT: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is the standard of care after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. The cytochrome P450 (CYP)2C19 enzyme is essential for metabolism of clopidogrel (a prodrug) to its pharmacologically active form. Approximately 30% of the U.S. population carries a CYP2C19 loss-of-function (LOF) allele that reduces the bioactivation and effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have demonstrated the feasibility of incorporating CYP2C19 genotyping into clinical care to guide escalation of DAPT from clopidogrel to prasugrel or ticagrelor in patients with a CYP2C19 LOF allele, and that a CYP2C19-guided escalation strategy reduced the risk for atherothrombotic events. However, the influence of key patient-specific factors on outcomes with genotype-guided DAPT (notably African ancestry, comorbidities that impact clopidogrel effectiveness, and genotypes beyond CYP2C19) has not been defined but is critical to understand in order to optimize the clinical impact of genotype-guided DAPT. Moreover, the impact on clinical outcomes of using CYP2C19 genotype to guide de-escalation from more potent agents to clopidogrel in patients without a LOF allele, which has become highly clinically relevant due to more frequent initial use of prasugrel or ticagrelor after acute coronary syndrome and PCI, has not been investigated in a diverse, real-world clinical setting. Our long-term goal is to optimize a precision medicine DAPT strategy that improves outcomes post-PCI. Our overall aim is to elucidate the key factors that influence outcomes with a CYP2C19 genotype-guided precision medicine approach to DAPT. Our hypothesis is that multiple clinical and genetic factors jointly contribute to the effectiveness and safety of CYP2C19 LOF allele- guided selection of DAPT after PCI in a real-world clinical setting. We propose to test this hypothesis by conducting a multi-center, observational study of 6,000 patients with PCI and clinical CYP2C19 genetic testing. This registry will include a diverse population of real-world patients, assess atherothrombotic and bleeding outcomes over 12 months, collect DNA samples for additional genotyping, conduct platelet reactivity testing in a subset of patients, and be used to accomplish the following specific aims: (AIM 1) define the influence of African ancestry and other patient-specific factors on clinical outcomes with CYP2C19 genotype-guided DAPT following PCI in a real-world setting; (AIM 2) evaluate the safety and effectiveness of CYP2C19 genotype- guided de-escalation of DAPT following PCI in a real-world setting; (AIM 3) elucidate the effect(s) of genetic variants beyond CYP2C19 LOF alleles on platelet reactivity and clinical outcomes with clopidogrel after PCI. This investigation will establish optimal strategies for individualized antiplatelet therapy prescribing decisions that improve outcomes and can be feasibly applied in a diverse, real-world population.