BRIDGE TRIAL

描述（由申请人提供）：因选择性手术或其他侵入性手术而暂时中断华法林治疗是一个常见的临床问题，每年影响北美约40万患者。越来越多的临床医生使用低分子量肝素（LMWH）作为手术前后或手术过程的“桥梁”，当华法林被保留，抗凝治疗是亚治疗。这种经验性策略有几个缺点，包括缺乏已证实的预防动脉血栓栓塞的有效性，增加医疗保健系统的费用，以及可能增加围手术期出血。不幸的是，没有高质量的临床试验提供1A级证据来指导患者护理。我们假设，与术前和术后使用低分子肝素相比，房颤患者围手术期停用华法林不会显著增加动脉血栓栓塞的风险，并能预防出血性并发症。为了解决这一重要问题，我们提出了一项多中心、前瞻性、双盲、安慰剂对照的随机临床试验，在手术前后随机分配3282例房颤患者，分别给予治疗剂量的低分子肝素或匹配的安慰剂（每组1641例）。北美的40个招生中心将在44个月内进行招聘。排除标准包括：机械心脏瓣膜；最近中风或大出血；严重肾功能不全、血小板减少症；或排除术后治疗剂量低分子肝素使用的计划手术。主要疗效终点是动脉血栓栓塞（中风、TIA或全身性栓塞），主要安全性终点是大出血（症状性、临床明显或致命）。我们将进行非劣效性疗效分析，以证明“无桥接”与桥接策略具有相同的动脉血栓栓塞风险。临床结果将使用每个方案的疗效结果人群和安全终点的意向治疗人群进行分析。试验结果的传播将针对管理心房颤动患者慢性华法林治疗的医生和其他提供者。这项比较桥接治疗与“无桥接”策略的随机试验将为这些患者的管理建立一个明确的护理标准。此申请与统计数据协调中心的配套申请一起单独提交。

Description (provided by applicant): Temporary interruption of warfarin therapy for an elective surgical or other invasive procedure is a common clinical problem, affecting ~400,000 patients in North America annually. Increasingly, clinicians employ a low molecular weight heparin (LMWH) as a 'bridge' before and after surgery or a procedure, when warfarin is withheld and anticoagulation is otherwise sub-therapeutic. This empiric strategy has several drawbacks, including lack of proven efficacy to prevent arterial thromboembolism, additional cost to the healthcare system, and the potential for increased peri-operative bleeding. Unfortunately, there are no high-quality clinical trials to provide Level 1A evidence to guide patient care. We hypothesize that simply withholding warfarin in the perioperative setting for patients with atrial fibrillation will not meaningfully increase the risk for arterial thromboembolism, and will forestall hemorrhagic complications, compared to a strategy using LMWH before and after surgery. To address this important question, we propose a multi-center, prospective, double-blind, placebo-controlled randomized clinical trial that randomly allocates 3,282 patients with atrial fibrillation to either therapeutic dose LMWH or matching placebo before and after surgery (1641 patients per arm). Forty enrolling centers in North America will recruit over 44 months. Exclusion criteria include: mechanical heart valve; recent stroke or major bleed; severe renal insufficiency, thrombocytopenia; or planned surgery that precludes use of post-operative therapeutic-dose LMWH. Primary efficacy outcome is arterial thromboembolism (stroke, TIA, or systemic embolism), and primary safety outcome is major bleeding (symptomatic, clinically-overt, or fatal). We will conduct a non-inferiority efficacy analysis to demonstrate that "no bridging" has a risk for arterial thromboembolism equal to a bridging strategy. Clinical outcomes will be analyzed using the per protocol population for the efficacy outcome and the intention-to-treat population for the safety endpoint. Dissemination of trial results will target physicians and other providers who manage patients with atrial fibrillation on chronic warfarin therapy. This randomized trial comparing bridging therapy to a "no bridging" strategy will establish a clear standard-of-care for the management of these patients. This application is in companion application to the Statistical Data Coordinating Center submitted separately. Clinicians frequently use low-molecular weight heparin as a 'bridge' before and after an elective procedure for patients on chronic warfarin therapy. It is unknown if this practice is efficacious, however, and it may actually result in an increased risk for periprocedural hemorrhage. This prospective, randomized, double-blind study will definitively answer this question for patients with atrial fibrillation who are on warfarin therapy.