GENETICS-InFORMATICS TRIAL (GIFT) OF WARFARIN TO PREVENT DVT

描述(由申请人提供)：2008年9月15日，代理卫生局局长史蒂文·加尔森，医学硕士，指出静脉血栓栓塞症事件(VTE)每年导致至少10万美国人死亡。因为其中许多死亡发生得很突然，所以最好的管理方法是预防。在这项随机对照试验中，华盛顿大学的研究人员将通过使用非营利性网络应用程序(www.WarfarinDosing.org)根据每个人的药物遗传学和/或临床特征定制华法林的剂量，以测试提高静脉血栓栓塞症预防的安全性和有效性的策略。他们还提议测试美国整形外科医生学会(AAOS)的建议，即在骨科患者中使用低水平的抗凝药物(即目标国际标准化比率(INR)和2.0)来预防VTE。因此，华法林预防DVT的遗传学-信息学试验(GIFT)的总体目标是阐明提高华法林治疗安全性和有效性的新策略。华盛顿大学研究人员提议对在巴恩斯-犹太医院接受全髋关节或膝关节置换手术的1500名患者进行随机对照试验。通过对这一高危人群的研究和术后多普勒超声对无症状深静脉血栓形成的筛查，拟议的试验将适当地阐明两种预防静脉血栓形成的新策略。研究人员将使用2×2析因设计将患者随机分为：(1)华法林的药物遗传学剂量与临床剂量；以及(2)目标INR为2.5对2.0。该提案有两个具体目标：目标1：确定基于药物遗传学的华法林疗法如何影响非致命性VTE、非致命性大出血和血管死亡的风险。尽管FDA已经批准了对影响华法林剂量的变异进行基因测试，但还没有事先(或计划中的)试验来确定这一策略是否会影响结果。目的2：确定目标INR为2.0的华法林治疗在预防骨科患者VTE方面是否不逊于目标INR为2.5的治疗。尽管美国胸科医师学会(ACCP)建议INR为2.5，但AAOS建议为2.0，这些相互矛盾的目标从未在一级静脉血栓栓塞预防试验中进行过比较。与公共卫生相关：2008年9月15日，代理卫生局局长、医学博士、公共卫生硕士Steven Galson指出，血栓(深静脉血栓和肺栓塞)每年导致至少10万美国人死亡。由于这些死亡中的许多发生在无法治疗的突然情况下，所以最好的治疗方法是预防。在这笔赠款中，华盛顿大学的研究人员开发了一些策略，通过根据每个人的基因和临床特征定制血液稀释剂，来提高预防血栓的安全性和有效性。

DESCRIPTION (provided by applicant): On September 15, 2008, acting Surgeon General, Steven Galson, MD MPH, noted that venous thromboembolic events (VTE) contribute to the death of at least 100,000 Americans each year. Because many of these deaths occur suddenly, the best management is prevention. In this randomized, controlled trial, Washington University researchers will test strategies to improve the safety and effectiveness of VTE prevention by using a non-profit web application (www.WarfarinDosing.org) to tailor the dose of warfarin to each person's pharmacogenetic and/or clinical profile. They also propose to test the recommendation of the American Academy of Orthopedic Surgeons (AAOS) to use low levels of anticoagulation (i.e., a target International Normalized Ratio (INR) < 2.0) for VTE prevention in orthopedic patients. Thus, the overall objective of the Genetics-InFormatics Trial (GIFT) of Warfarin to Prevent DVT is to elucidate novel strategies to improve the safety and effectiveness of warfarin therapy. Washington University researchers propose a randomized controlled trial of 1500 patients having total hip or knee replacement surgery at Barnes-Jewish Hospital. By studying this high- risk population and screening for asymptomatic deep venous thrombosis by Doppler ultrasound post-operatively, the proposed trial will be appropriately powered to elucidate two novel strategies to prevent VTE. The researchers will use a 2 x 2 factorial design to randomize patients to: (1) pharmacogenetic vs. clinical dosing of warfarin; and (2) to a target INR of 2.5 vs. < 2.0. The proposal has two specific aims: Aim 1: To determine how pharmacogenetic-based warfarin therapy affects risk of non-fatal VTE, non-fatal major hemorrhage, and vascular death. Although the FDA has approved genetic testing for variants that affect warfarin dose, no prior (or planned) trial has been powered to determine whether this strategy affects outcomes. Aim 2: To determine whether warfarin therapy with a target INR of < 2.0 is non-inferior to a target INR of 2.5 at preventing VTE in orthopedic patients. Although the American College of Chest Physician (ACCP) recommends a target INR of 2.5, the AAOS recommends < 2.0 and these conflicting goals have never been compared in a trial of primary VTE prevention. PUBLIC HEALTH RELEVANCE: On September 15, 2008, Acting Surgeon General Steven Galson, MD, MPH noted that blood clots (deep venous thrombosis and pulmonary embolism) contribute to the death of at least 100,000 Americans each year. Because many of these deaths occur suddenly where treatment is impossible, the best treatment is prevention. In this grant, Washington University researchers develop strategies to improve the safety and effectiveness of clot prevention by customizing blood thinners to each person's genetic and clinical profile.