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 Steven Galson（医学博士、公共卫生硕士）指出，静脉血栓栓塞事件 (VTE) 每年导致至少 100,000 名美国人死亡。由于许多死亡是突然发生的，因此最好的管理就是预防。在这项随机对照试验中，华盛顿大学研究人员将测试提高 VTE 预防安全性和有效性的策略，方法是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/或临床特征调整华法林的剂量。他们还建议测试美国骨科医师学会 (AAOS) 的建议，即使用低水平的抗凝药物（即目标国际标准化比率 (INR) < 2.0）来预防骨科患者的 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。华盛顿大学的研究人员提议对 1500 名在 Barnes-Jewish 医院接受全髋关节或膝关节置换手术的患者进行随机对照试验。通过研究这一高危人群并在术后通过多普勒超声筛查无症状深静脉血栓形成，拟议的试验将适当地阐明两种预防 VTE 的新策略。研究人员将使用 2 x 2 析因设计对患者进行随机分组：(1) 华法林的药物遗传学与临床剂量； (2) 目标 INR 为 2.5 vs. < 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治疗如何影响非致命性 VTE、非致命性大出血和血管性死亡的风险。尽管 FDA 已批准对影响华法林剂量的变异进行基因检测，但之前（或计划中的）试验尚未确定该策略是否会影响结果。目标 2：确定目标 INR < 2.0 的华法林治疗在预防骨科患者 VTE 方面是否不劣于目标 INR 2.5。尽管美国胸科医师学会 (ACCP) 建议 INR 目标为 2.5，但 AAOS 建议 < 2.0，并且这些相互冲突的目标从未在初级 VTE 预防试验中进行过比较。公共健康相关性：2008 年 9 月 15 日，代理卫生局局长 Steven Galson（医学博士、公共卫生硕士）指出，血栓（深静脉血栓形成和肺栓塞）每年导致至少 100,000 名美国人死亡。由于许多死亡是突然发生且无法治疗的，因此最好的治疗方法是预防。在这笔拨款中，华盛顿大学的研究人员制定了策略，通过根据每个人的遗传和临床特征定制血液稀释剂，以提高血栓预防的安全性和有效性。

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.