Precision antiplatelet therapy after percutaneous coronary intervention

经皮冠状动脉介入治疗后精准抗血小板治疗

• 批准号: 10413897
• 负责人: Larisa Humma Cavallari
• 金额: $ 72.2万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413897
• 关键词: Acute; Address; Adoption; African American; African American population; African ancestry; Alleles; Aspirin; Blood Platelets; CYP2C19 gene; Chronic; Clinical; Clinical Practice Guideline; Cytochrome P450; DNA; Data; Effectiveness; Enzymes; European; Event; Genetic; Genotype; Goals; Hemorrhage; Investigation; Medical Genetics; Metabolism; Observational Study; Outcome; Participant; Pathway interactions; Patient Self-Report; Patient risk; Patient-Focused Outcomes; Patients; Pharmacodynamics; Pharmacology; Population; Population Heterogeneity; Prevalence; Prodrugs; Race; Randomized Controlled Trials; Registries; Research Project Grants; Risk; Risk Factors; Safety; Sampling; Testing; acute coronary syndrome; adherence rate; base; cardiovascular risk factor; clinical care; clinical practice; clinically relevant; clopidogrel; comorbidity; cost; genetic panel test; genetic testing; genetic variant; genotyped patients; high risk; improved outcome; inhibitor; interpatient variability; loss of function; novel; patient subsets; percutaneous coronary intervention; personalized strategies; platelet function; precision medicine; preference; prevent; racial diversity; receptor; response; safety and feasibility; standard of care

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.

抽象的： 与阿司匹林和P2Y12受体抑制剂（氯吡格雷，prasugrel或 ticagrelor）是经皮冠状动脉干预（PCI）后的护理标准 动脉粥样硬化事件。细胞色素P450（CYP）2C19酶对于氯吡格雷代谢至关重要 （前药）的药理活性形式。大约30％的美国人口携带CYP2C19 功能丧失（LOF）等位基因可降低氯吡格雷的生物活化和有效性，而不是prasugrel或prasugrel或 ticagrelor，之后。我们已经证明了将CYP2C19基因分型纳入临床的可行性 注意将DAPT从氯吡格雷升级为prasugrel或ticagrelor在患有CYP2C19 LOF的患者中 等位基因，并且CYP2C19指导的升级策略降低了动脉粥样硬化事件的风险。然而， 关键患者特异性因素对基因型引导DAPT结果的影响（尤其是非洲人 祖先，影响氯吡格雷有效性的合并症以及CYP2C19以外的基因型） 定义但要理解至关重要，以优化基因型引导DAPT的临床影响。 此外，对使用CYP2C19基因型的临床结果的影响指导了更多 在没有LOF等位基因的患者中对氯吡格雷的有效药物，由于 急性冠状动脉综合征和PCI后，更频繁地使用Prasugrel或Ticagrelor的初始使用尚未 在多样化的现实世界临床环境中进行了研究。我们的长期目标是优化精密医学 DAPT策略改善了PCI后结果。我们的总体目的是阐明影响的关键因素 CYP2C19基因型引导的精确医学方法DAPT的结果。我们的假设是 多种临床和遗传因素共同有助于CYP2C19 LOF等位基因的有效性和安全性 在现实世界中，PCI之后的DAPT进行了指导选择。我们建议通过 对6,000例PCI和临床CYP2C19基因检测患者进行了多中心的观察性研究。 该注册表将包括各种各样的现实世界患者，评估动脉粥样硬化和出血 结果超过12个月，收集DNA样品以进行其他基因分型，进行血小板反应性测试 一部分患者，并用于完成以下特定目的：（目标1）定义 CYP2C19基因型引导DAPT的非洲血统和其他针对临床结果的患者特异性因素 在现实世界中遵循PCI； （AIM 2）评估CYP2C19基因型的安全性和有效性 在现实环境中PCI后DAPT的指导下降； （AIM 3）阐明遗传的影响 CYP2C19 LOF等位基因以外的变体在PCI后与氯吡格雷的血小板反应性和临床结果。 这项调查将为个性化的抗血小板治疗规定决定建立最佳策略 这可以改善结果，并且可以在多样化的现实世界中可行地应用。