BRIDGE TRIAL

描述（由申请方提供）：因择期手术或其他侵入性操作而暂时中断华法林治疗是一种常见的临床问题，每年影响北美约400，000例患者。临床医生越来越多地使用低分子量肝素（LMWH）作为手术或程序前后的“桥梁”，当华法林停药且抗凝治疗效果不佳时。这种经验策略有几个缺点，包括缺乏有效的预防动脉血栓栓塞，医疗保健系统的额外成本，以及增加围手术期出血的可能性。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的策略相比，房颤患者在围手术期简单停用华法林不会显著增加动脉血栓栓塞的风险，并且可以预防出血性并发症。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，将3，282例房颤患者随机分配至手术前后的治疗剂量LMWH或匹配的安慰剂组（每组1641例患者）。北美的40个招募中心将在44个月内招募。排除标准包括：机械心脏瓣膜;近期中风或大出血;重度肾功能不全、血小板减少症;或计划手术，排除使用术后治疗剂量LMWH。主要疗效结局为动脉血栓栓塞（卒中、TIA或全身性栓塞），主要安全性结局为大出血（症状性、临床明显或致死性）。我们将进行非劣效性疗效分析，以证明“无桥接”的动脉血栓栓塞风险与桥接策略相同。将使用符合方案人群分析疗效结局，使用意向治疗人群分析安全性终点。试验结果的传播将针对管理长期华法林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治疗与“无桥接”策略，将为这些患者的管理建立明确的护理标准。本申请是单独提交给统计数据协调中心的配套申请。 临床医生经常使用低分子量肝素作为慢性华法林治疗患者的择期手术前后的“桥梁”。然而，尚不清楚这种做法是否有效，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.