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

基本信息

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
项目类别：
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

项目摘要

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测量参加经皮冠状动脉介入治疗 (PCI) 后长期双重抗血小板治疗（阿司匹林和噻吩并吡啶）临床试验的受试者的血小板功能、基因型和循环蛋白生物标志物，并将这些测量值与临床结果相关联包括死亡、心肌梗塞、中风、支架内血栓形成和出血，以提高我们对患者进行风险分层和定制抗血小板治疗的能力。在目标 1 中，将使用专门评估 P2Y12 ADP 受体（噻吩并吡啶的靶标）激活下游中间体的测定法来量化噻吩并吡啶诱导的血小板抑制。血小板抑制的程度与缺血和出血结果的风险相关。将定义血小板反应性的目标范围，以平衡这些竞争风险并最大限度地提高患者的净临床效益，然后进行验证。在目标 2 中，将对受试者参与噻吩并吡啶代谢的基因多态性进行基因分型。将检查遗传变异与血小板抑制程度和响应噻吩并吡啶功效的临床事件之间的关联。此外，还将检查同时使用抑制或需要 CYP450 代谢的药物与血小板抑制程度以及噻吩并吡啶治疗的临床结果风险之间的关联。在目标 3 中，将测量血小板活化和血栓形成的循环生物标志物，并检查它们与心血管结局发生率的关系。此外，还将研究这些生物标志物识别从长期双重抗血小板治疗中获得更大益处的患者的能力。公共卫生相关性：仅在美国每年就进行约 100 万例经皮冠状动脉介入治疗，但在手术后患者应接受多长时间的有效抗血小板治疗方面仍存在关键的证据差距。在测试长期抗血小板治疗益处的临床试验中，我们计划测量血小板功能、基因型和蛋白质生物标志物，以提高我们对患者进行风险分层和定制抗血小板治疗的能力。