BRIDGE TRIAL

描述（由申请人提供）：因择期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 400,000 名患者。当停止使用华法林且抗凝治疗效果不佳时，临床医生越来越多地在手术前后使用低分子量肝素 (LMWH) 作为“桥梁”。这种经验性策略有几个缺点，包括缺乏预防动脉血栓栓塞的有效功效、医疗保健系统的额外成本以及围手术期出血可能增加的可能性。不幸的是，没有高质量的临床试验可以提供 1A 级证据来指导患者护理。我们假设，与术前和术后使用 LMWH 的策略相比，在房颤患者围手术期简单地停用华法林不会显着增加动脉血栓栓塞的风险，并且会预防出血并发症。为了解决这个重要问题，我们提出了一项多中心、前瞻性、双盲、安慰剂对照随机临床试验，将 3,282 名房颤患者在手术前后随机分配至治疗剂量 LMWH 或匹配安慰剂（每组 1641 名患者）。北美的 40 个招生中心将在 44 个月内进行招募。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；或计划进行手术，排除使用术后治疗剂量 LMWH。主要疗效结局是动脉血栓栓塞（中风、TIA 或全身性栓塞），主要安全性结局是大出血（有症状、临床明显或致命）。我们将进行非劣效性疗效分析，以证明“不桥接”与桥接策略具有相同的动脉血栓栓塞风险。将使用每个方案人群的疗效结果和意向治疗人群的安全终点来分析临床结果。试验结果的传播将针对接受长期华法林治疗的房颤患者的医生和其他提供者。这项随机试验将桥接疗法与“无桥接”策略进行比较，将为这些患者的管理建立明确的护理标准。该申请是向统计数据协调中心单独提交的配套申请。 临床医生经常在接受长期华法林治疗的患者的选择性手术前后使用低分子量肝素作为“桥梁”。然而，尚不清楚这种做法是否有效，并且实际上可能会导致围手术期出血的风险增加。这项前瞻性、随机、双盲研究将为接受华法林治疗的房颤患者明确回答这个问题。

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.