Pharmacogenetics, Biomarkers, and Antithrombotic Therapy

描述(由申请人提供)： 总体目标是提高抗凝治疗的安全性和有效性。这项拟议的项目将是对两项试验的辅助研究，NHLBI资助的预防试验和VA资助的THINRS Trialx预防(预防复发性静脉血栓栓塞症)是对有自发性静脉血栓栓塞史的受试者进行的低强度华法林与安慰剂的随机比较，这些受试者以前完成了华法林治疗的标准疗程。调查人员已经将508名预防参与者的DNA存档。THINRS(Home INR研究)是对抗凝诊所的华法林治疗与患者对其国际标准化比率(INR)的自我测试进行的随机比较。THINRS将从32个退伍军人医学中心招募约3200名患有房颤或人工心脏瓣膜的参与者，并有望获得DNA和血浆。尽管过去50年在剂量和监测方面有所改进，但华法林治疗仍然伴随着很高的出血率，特别是在治疗的头几周到几个月。一位少校 在诱导过程中INR通常是超治疗的，原因是治疗华法林的剂量变化很大，不能仅基于临床因素来预测。在目标1中，研究人员将使用药物遗传学来预测华法林的维持剂量。他们还将研究影响华法林剂量、出血和INR值的基因多态之间的关系。在目标2中，他们将验证额外的遗传和非遗传生物标记物，这些标记物可以识别患有缺血性或出血性不良事件的高风险患者。通过对AIM 2使用嵌套的病例对照设计，他们将使服用华法林的患者的生物标记物与发生的不良事件相关。在目标3中，他们将确定自我检测是否对具有预示不良事件的生物标记物的患者特别有益。他们预计，在自我检测的推动下，每周进行的INR测试将改善AIMS 1和AIMS 2中实验室标记物对不良事件的易感性。通过阐明华法林毒性和有效性的决定因素，拟议的研究将帮助临床医生根据患者潜在的不良事件风险定制抗血栓治疗的积极程度。

DESCRIPTION (provided by applicant): The overall objective is to improve the safety and the effectiveness of anticoagulant therapy. The proposed project will be an ancillary study of 2 trials, the NHLBI-funded PREVENT trial and the VA-funded THINRS trialx PREVENT (Prevention of Recurrent Venous Thromboembolism) is a randomized comparison of low-intensity warfarin vs. placebo in subjects with a history of spontaneous venous thromboembolism who previously completed a standard course of warfarin therapy. The investigators have archived DNA from 508 PREVENT participants. THINRS (The Home INR Study) is a randomized comparison of warfarin management by an anticoagulation clinic versus patient self-testing of their International Normalized Ratio (INR). THINRS will enroll about 3200 participants with atrial fibrillation or a prosthetic heart valve from 32 VA Medical Centers and prospectively will obtain DNA and plasma. Despite improvements in dosing and monitoring over the past 50 years, warfarin therapy is still accompanied by a high rate of bleeding, especially during the first weeks to months of therapy. A major reason why the INR often is supratherapeutic during induction is that the therapeutic warfarin dose is widely variable and cannot be predicted based on clinical factors alone. In Aim 1, the investigators will use pharmacogenetics to predict the maintenance warfarin dose. They also will examine the relationship between polymorphisms that affect warfarin dose, hemorrhage, and INR values. In Aim 2 they will validate additional genetic and non-genetic biomarkers that identify patients at high risk of suffering ischemic or hemorrhagic adverse events. By using a nested, case-control design for Aim 2, they will correlate biomarkers with incident adverse events in patients taking warfarin. In Aim 3, they will determine whether self-testing will be especially beneficial in patients who have biomarkers presaging an adverse event. They anticipate that the weekly INR testing facilitated by self-testing will ameliorate the vulnerability to adverse events conferred by the laboratory markers in Aims 1 and 2. By elucidating the determinants of warfarin toxicity and effectiveness, the proposed study will help clinicians tailor the aggressiveness of antithrombotic therapy to patient's underlying risk of adverse events.