BEST-CLI Trial - Cost-Effectiveness of Treatments for Critical Limb Ischemia

描述(由申请人提供)： 这项重新提交的申请包括三个应用程序(临床和数据协调中心(CCC、DCC)和成本效益分析核心)。我们建议在美国和加拿大进行一项大型(N=2100)简单的优势试验--最好的开放手术与最好的血管内血管重建术，以防止严重肢体缺血(CLI)的目标肢体的死亡、截肢或进一步的血管重建，满足目前评估比较有效性的任务。试验领导层由一个紧密整合和经验丰富的研究小组组成，他们分别设在CCC(布里格姆妇女医院、BWH、波士顿大学医学中心、BUMC和马萨诸塞州MGH的马萨诸塞州医院)、DCC(新英格兰研究所，Inc.，马萨诸塞州沃特敦)和该领域的专家执行委员会。BWH的卫生经济小组将与疾病预防控制中心密切合作，解决生活质量和成本效益(C-E)的评估问题。这项试验将在美国和加拿大的大约120个地点进行，以先前的可行性数据为基础，并努力解决目前这一领域研究的局限性。外周动脉疾病的患病率在70岁以上为15%-20%，吸烟者和糖尿病患者的患病率更高。在接受CLI的患者中，40%的患者需要截肢，年死亡率超过20%。随着血管内血运重建技术的出现，我们从我们完成的调查中证明，在大多数CLI病例中，从业者目前在最佳治疗方面是平衡的。这项最佳试验将首次通过以下方式为心脏直视手术的CLI管理提供急需的临床指导：务实的设计，包括一系列既定的技术；新的主要终点--男性(包括截肢或主要再次干预、搭桥手术/移植物翻修或血栓切除/溶栓)在内的主要肢体不良事件)无存活率；多学科招募血管外科医生、介入心脏科医生和放射科医生；以及一种创新的、成本效益高的心脏直视手术方法。其他终点包括其他临床事件发生率、功能状态以及QOL和C-E，所有这些都使用标准定义和仪器。将与北美的140个合格中心接洽，以确保启动120个中心，并确保每个地点在27个月内每月招募1名受试者。试验期为4.25年-2.25年，最低随访时间为2.0年。将对两个队列进行研究：全静脉(N=1620)和人工管道(N=480)。在每个队列中，试验根据2个因素(4个层次)分层：组织丢失与孤立的休息疼痛和腹股沟下伴有/不伴有显著的股下动脉闭塞疾病。在全静脉队列中，BEST有85%的能力检测主要终点(无男性存活)的EVT与开放风险比1.25，并考虑了交叉率，以及2%的后续损失。在假体导管队列中，有80%的功率可以检测到主要终点的危险比为0.70。这次重新提交充分解决了所有先前审查者关注的问题，以成功和高效地执行将为CLI社区提供重要信息的试验。

DESCRIPTION (provided by applicant): This resubmission is comprised of three applications (Clinical and Data Coordinating Centers (CCC, DCC) and Cost-Effectiveness Analysis Core). We propose to conduct a large (N=2100) simple, superiority trial in the US and Canada - BEST - comparing best open surgery to best endovascular revascularization to prevent mortality, limb-amputation or further revascularization in a target limb with critical limb ischemia (CLI), meeting the current mandate for assessing comparative effectiveness. Trial leadership is comprised of a closely integrated and highly experienced group of investigators based at a CCC (Brigham and Women's Hospital, BWH , Boston University Medical Center, BUMC, and Massachusetts Hospital, MGH, Boston, MA), a DCC (New England Research Institutes, Inc., Watertown, MA) and an Executive Committee of experts in the field. The Health Economics Group at BWH will work closely with the DCC to address assessment of quality of life and cost-effectiveness (C-E). The trial will be conducted at approximately 120 sites in the U.S. and Canada, builds upon prior feasibility data and endeavors to address limitations of current research in this area. Peripheral artery disease prevalence is 15-20% over 70 years, with higher rates in smokers and diabetics. In the subset with CLI, 40% require limb amputation and annual mortality exceeds 20%. With the advent of endovascular techniques for revascularization, we demonstrate from our completed surveys that there is current equipoise among practitioners with respect to best therapy in the majority of CLI cases. The BEST trial will provide, for the first time, urgently needed clinical guidance for CLI management in the context of C-E by using: a pragmatic design, including a range of established techniques; a novel primary endpoint - MALE (major adverse limb event including limb amputation or major re-intervention, bypass graft/graft revision or thrombectomy/thrombolysis) - free survival; multi-disciplinary recruitment of vascular surgeons and interventional cardiologists and radiologists; and an innovative, cost-efficient C-E approach. Additional endpoints include other clinical event rates, functional status and QOL and C-E, all using standard definitions and instruments. 140 eligible centers in North America will be approached to ensure 120 are initiated and 80 sites each recruit 1 subject/month over 27 months accrual. Trial duration is 4.25 yrs - 2.25 yrs accrual and 2.0 yrs minimum follow-up. Two cohorts will be studied: All-Vein (N=1620) and Prosthetic Conduit (N=480). Within each cohort, the trial is stratified on 2 factors (4 strata): tissue loss vs. isolated rest pain and infrainguinl with/without significant infrapopliteal occlusive disease. In the All-Vein cohort, BEST has 85% power to detect an EVT vs. OPEN hazard ratio of 1.25 in the primary endpoint (MALE-free survival) with crossover rates accounted for, as well as 2% loss to follow-up. In the Prosthetic Conduit cohort, there is 80% power to detect a hazard ratio of 0.70 for the primary endpoint. This resubmission fully addresses all prior reviewer concerns, to successfully and efficiently execute a trial that will provide important information for the CLI community.