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。拟议项目将是一项由2项试验组成的辅助研究，即NHLBI资助的PREVENT试验和VA资助的THINRS试验。PREVENT（预防复发性静脉血栓栓塞）是一项在有自发性静脉血栓栓塞病史且既往完成过华法林标准疗程的受试者中对低强度华法林与安慰剂进行的随机比较。研究人员已将508名预防参与者的DNA存档。THINRS（家庭INR研究）是一项随机比较抗凝门诊华法林管理与患者自测国际标准化比值（INR）的研究。THINRS将从32个VA医疗中心招募约3200名患有房颤或人工心脏瓣膜的参与者，并将前瞻性地获得DNA和血浆。 尽管在过去的50年里，华法林治疗的剂量和监测有所改善，但仍然伴随着高出血率，特别是在治疗的最初几周到几个月期间。一个主要 在诱导期间INR通常是超治疗的原因是华法林治疗剂量变化很大，不能仅根据临床因素预测。在目标1中，研究者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值的多态性之间的关系。 在目标2中，他们将验证其他遗传和非遗传生物标志物，以识别患有缺血性或出血性不良事件的高风险患者。通过对目标2使用巢式病例对照设计，他们将使生物标志物与服用华法林的患者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志物的患者特别有益。他们预计，通过自我检测促进的每周INR检测将改善目标1和2中实验室标志物赋予的不良事件的脆弱性。 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调整抗血栓治疗的积极性。

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.