Precision antiplatelet therapy after percutaneous coronary intervention

摘要： 阿司匹林和P2 Y12受体抑制剂（氯吡格雷、普拉格雷或 替格瑞洛）是经皮冠状动脉介入治疗（PCI）后的标准治疗，以降低 动脉粥样硬化血栓形成事件。细胞色素P450（CYP）2C 19酶对氯吡格雷的代谢至关重要 （前药）转化为其非活性形式。大约30%的美国人携带CYP 2C 19 降低氯吡格雷生物活性和有效性的功能丧失（LOF）等位基因，而不是普拉格雷或 替格瑞洛，PCI后。我们已经证明了将CYP 2C 19基因分型纳入临床的可行性。 在CYP 2C 19 LOF患者中指导DAPT从氯吡格雷递增至普拉格雷或替格瑞洛的护理 等位基因，并且CYP 2C 19指导的升级策略降低了动脉粥样硬化血栓事件的风险。然而，在这方面， 关键患者特异性因素对基因型指导DAPT结局的影响（特别是非洲 祖先、影响氯吡格雷有效性的合并症和CYP 2C 19以外的基因型）尚未被 定义，但关键是要了解，以优化基因型指导的DAPT的临床影响。 此外，使用CYP 2C 19基因型来指导从多个剂量递减对临床结局的影响 在没有LOF等位基因的患者中，氯吡格雷的有效药物，由于 在急性冠状动脉综合征和PCI后更频繁地初始使用普拉格雷或替格瑞洛， 在一个多样化的，真实世界的临床环境中进行研究。我们的长期目标是优化精准医疗 改善PCI术后结局的DAPT策略。我们的总体目标是阐明影响 使用CYP 2C 19基因型指导的DAPT精准医学方法的结果。我们的假设是 多种临床和遗传因素共同影响CYP 2C 19 LOF等位基因的有效性和安全性- 在真实临床环境中PCI后DAPT的指导选择。我们建议通过以下方式来检验这一假设： 对6，000名接受PCI和临床CYP 2C 19基因检测的患者进行多中心观察性研究。 该登记研究将包括真实世界患者的不同人群，评估动脉粥样硬化血栓形成和出血 12个月内的结果，收集DNA样本进行额外的基因分型，进行血小板反应性测试， 患者的子集，并用于实现以下特定目标：（目的1）定义 非洲血统和其他患者特异性因素对CYP 2C 19基因型指导的DAPT临床结局的影响 在现实世界中PCI后;（AIM 2）评价CYP 2C 19基因型的安全性和有效性- 在真实环境中PCI后DAPT的指导性降级;（AIM 3）阐明遗传因素的影响 CYP 2C 19 LOF等位基因以外的变异对PCI后氯吡格雷的血小板反应性和临床结局的影响。 本研究将为个体化抗血小板治疗处方决策建立最佳策略 这可以改善结果，并可以切实应用于多样化的现实世界人群。

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.