Antiplatelet Therapy: Platelet Inhibition, Polymorphisms, and Protein Biomarkers

抗血小板治疗：血小板抑制、多态性和蛋白质生物标志物

• 批准号: 8110518
• 负责人: MARC S SABATINE
• 金额: $ 44.58万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110518
• 关键词: ABCB1 gene; Acute; Adenosine Diphosphate; Ancillary Study; Aspirin; Biological Assay; Biological Markers; Blood Platelets; Blood specimen; CYP2C19 gene; CYP3A4 gene; Carboxylic Ester Hydrolases; Cardiovascular system; Cessation of life; Chronic; Clinical; Clinical Trials; Coronary; Data; Double-Blind Method; Drug Interactions; Enrollment; Enzymes; Equilibrium; Event; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Guidelines; Health; Hemorrhage; Incidence; Individual; Intestines; Measures; Metabolic; Metabolism; Myocardial Infarction; Observational Study; Outcome; P-Glycoprotein; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphorylation; Platelet Activation; Procedures; Prodrugs; Proteins; Randomized; Resources; Risk; Staging; Stents; Stroke; Testing; Thrombosis; Time; United States; Validation; Work; absorption; atherothrombosis; carboxylesterase; clopidogrel; cohort; efflux pump; genetic variant; improved; insight; percutaneous coronary intervention; randomized trial; receptor; response; thienopyridine; treatment planning; vasodilator-stimulated phosphoprotein

DESCRIPTION (provided by applicant): The overall goal of this proposal is to measure platelet function, genotypes, and circulating protein biomarkers in subjects enrolled in a clinical trial of prolonged dual antiplatelet therapy (aspirin and a thienopyridine) after percutaneous coronary intervention (PCI) and correlate these measures with clinical outcomes, including death, myocardial infarction, stroke, stent thrombosis, and bleeding, in order to improve our ability to risk stratify patients and tailor antiplatelet therapy. In Aim 1, thienopyridine-induced platelet inhibition will be quantified using an assay that specifically assesses an intermediate downstream to activation of the P2Y12 ADP receptor (the target of thienopyridines). The degree of platelet inhibition will be correlated with the risk of ischemic and bleeding outcomes. A target range of platelet reactivity will be defined to balance these competing risks and maximize net clinical benefit for patients and then validated. In Aim 2, subjects will be genotyped for polymorphisms in genes involved in thienopyridine metabolism. The association between genetic variants and the degree of platelet inhibition and clinical events in response to thienopyridine efficacy will be examined. In addition, the association between concomitant use of medications that inhibit or require CYP450 metabolism and the degree of platelet inhibition and risk of clinical outcomes with thienopyridine therapy will be examined. In Aim 3, circulating biomarkers of platelet activation and thrombosis will be measured and their association with the incidence of cardiovascular outcomes examined. In addition, the ability of those biomarkers to identify patients who derive greater benefit from prolonged dual antiplatelet therapy will be investigated. PUBLIC HEALTH RELEVANCE: Approximately 1 million percutaneous coronary interventions are performed annually in the United States alone, yet there remains a critical evidence gap in terms of how long patients should be on potent antiplatelet therapy after the procedure. In the context of a clinical trial testing the benefit of prolonged antiplatelet therapy, we plan to measure platelet function, genotypes, and protein biomarkers in order to improve our ability to risk stratify patients and tailor antiplatelet therapy.

描述（由申请人提供）： 该提案的总体目标是在接受经皮冠状动脉干预（PCI）后长期进行双重抗血小板疗法（阿司匹林和硫吡啶）的临床试验的受试者中测量血小板功能，基因型和循环蛋白生物标志物，并与临床上的临床量相关，包括死亡，Myocardial intrare intrare intrancial not，myocardial strent inscardial strent inscardial strent inscardial strent，myocardial strent inscardial，出血，以提高我们的风险分层患者并量身定制抗血小板治疗的能力。在AIM 1中，将使用专门评估下游p2Y12 ADP受体（硫代酮的靶标）的中间体来定量硫吡啶诱导的血小板抑制。血小板抑制程度将与缺血和出血结果的风险相关。将定义目标血小板反应性的目标范围，以平衡这些竞争风险，并最大程度地利用患者的净临床益处，然后进行验证。在AIM 2中，将对参与硫烯吡啶代谢的基因的多态性进行基因分型。遗传变异与血小板抑制程度与响应硫吡啶疗效的临床事件之间的关联。此外，将研究抑制或需要CYP450代谢的药物与血小板抑制程度与硫烯吡啶治疗的临床结局的风险之间的关联。在AIM 3中，将测量血小板激活和血栓形成的循环生物标志物，并与检查的心血管结局的发生率相关。此外，将研究这些生物标志物鉴定出从长时间双重抗血小板疗法中获得更大受益的患者的能力。公共卫生相关性：仅在美国，每年就会每年进行大约100万经皮冠状动脉干预措施，但在手术后，患者应进行有效的抗血小板治疗的时间，但仍存在关键的证据差距。在一项临床试验测试延长抗血小板疗法的好处的背景下，我们计划测量血小板功能，基因型和蛋白质生物标志物，以提高我们的风险分层患者的能力并量身定制抗血小板疗法。