BRIDGE TRIAL

描述(由申请人提供)：临时中断华法林对择期手术或其他侵入性手术的治疗是一个常见的临床问题，每年影响北美约40万名患者。越来越多的临床医生使用低分子肝素(LMWH)作为手术或手术前后的桥梁，此时华法林被抑制，而抗凝在其他方面是次要的。这种经验性策略有几个缺点，包括缺乏被证实的预防动脉血栓栓塞症的有效性，医疗保健系统的额外成本，以及围手术期出血增加的可能性。不幸的是，目前还没有高质量的临床试验来提供指导患者护理的1A级证据。我们假设，与手术前后使用低分子肝素相比，在房颤患者围手术期简单地停用华法林并不会显著增加动脉血栓栓塞症的风险，并能预防出血并发症。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，将3282名房颤患者在手术前后随机分配治疗剂量低分子肝素或匹配的安慰剂(每臂1641名患者)。北美的40个招生中心将在44个月内招生。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；或计划手术，排除使用术后治疗性剂量的低分子肝素。主要疗效结果是动脉血栓栓塞症(中风、短暂性脑缺血发作或全身栓塞)，而主要安全结果是大出血(有症状、临床表现或致命)。我们将进行一项非劣势疗效分析，以证明“不搭桥”与搭桥策略具有相同的动脉血栓栓塞症风险。临床结果将使用疗效结果的按方案总体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使用华法林长期治疗房颤患者的医生和其他提供者。这项随机试验比较了桥接疗法和“无桥接”策略，将为这些患者的管理建立一个明确的护理标准。本申请是向单独提交的统计数据协调中心提出的配套申请。 临床医生经常使用低分子肝素作为慢性华法林治疗患者的选择性手术前后的“桥梁”。然而，目前尚不清楚这种做法是否有效，而且它实际上可能导致围手术期出血的风险增加。这项前瞻性、随机、双盲研究将明确回答正在接受华法林治疗的房颤患者的这个问题。

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.