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： 使用阿司匹林和 P2Y12 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）后的标准治疗方法，可降低以下风险： 动脉粥样硬化血栓事件。细胞色素 P450 (CYP)2C19 酶对于氯吡格雷的代谢至关重要 （前药）为其药理活性形式。大约 30% 的美国人携带 CYP2C19 功能丧失 (LOF) 等位基因会降低氯吡格雷的生物活性和有效性，但不会降低普拉格雷或 替格瑞洛，PCI 后。我们已经证明了将 CYP2C19 基因分型纳入临床的可行性 指导 CYP2C19 LOF 患者的 DAPT 从氯吡格雷升级为普拉格雷或替格瑞洛的护理 等位基因，CYP2C19 引导的升级策略降低了动脉粥样硬化血栓事件的风险。然而， 关键患者特异性因素对基因型引导 DAPT 结局的影响（尤其是非洲 血统、影响氯吡格雷有效性的合并症以及 CYP2C19 以外的基因型）尚未得到证实 已定义，但为了优化基因型引导的 DAPT 的临床影响，理解这一点至关重要。 此外，使用 CYP2C19 基因型指导降级对临床结果的影响 对于不带 LOF 等位基因的患者，氯吡格雷是有效的药物，由于以下原因，氯吡格雷已变得高度临床相关： 急性冠脉综合征和 PCI 后更频繁地首次使用普拉格雷或替格瑞洛，但尚未发现 在多样化的真实临床环境中进行了研究。我们的长期目标是优化精准医疗 改善 PCI 后结果的 DAPT 策略。我们的总体目标是阐明影响的关键因素 CYP2C19 基因型引导的精准医学方法进行 DAPT 的结果。我们的假设是 多种临床和遗传因素共同影响 CYP2C19 LOF 等位基因的有效性和安全性 在真实临床环境中指导 PCI 后 DAPT 的选择。我们建议通过以下方式检验这一假设 对 6,000 名 PCI 患者和临床 CYP2C19 基因检测进行了多中心观察性研究。 该登记系统将包括现实世界患者的不同群体，评估动脉粥样硬化血栓和出血 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 患者子集，并用于实现以下特定目标：（目标 1）定义 非洲血统和其他患者特异性因素对 CYP2C19 基因型引导 DAPT 临床结果的影响 在现实环境中遵循 PCI； (AIM 2)评估CYP2C19基因型的安全性和有效性- 在现实环境中 PCI 后引导 DAPT 降级； （目标 3）阐明遗传因素的影响 CYP2C19 LOF 等位基因以外的变异对 PCI 后血小板反应性和氯吡格雷临床结果的影响。 这项研究将为个体化抗血小板治疗处方决策建立最佳策略 可以改善结果，并且可以切实应用于多样化的现实世界人群。