Warfarin vs. Aspirin in Reduced Ejection Fraction (WARCEF)

描述（由申请人提供）：心力衰竭（HF）和低左心室（LV）射血分数（EF）与卒中和死亡的显著风险相关。然而，抗血栓/抗血小板治疗减少不良事件的价值仍存在争议。华法林和阿司匹林最常使用，但没有确切的数据。慢性心力衰竭抗血小板试验（WATCH）试图解决这一问题，但由于招募不良而提前终止。心脏射血分数降低试验（WARCEF）中华法林与阿司匹林的比较旨在解决这一问题。这项随机、双盲、多中心临床试验的主要目的是确定华法林（INR 2.5-3.0;目标INR 2.75）或阿司匹林（每天325 mg）在预防LV EF<35%患者的全因死亡率和卒中（缺血性和出血性）联合终点方面是否具有上级优势。主要零假设是，在EF</= 35%的患者中，华法林和阿司匹林治疗在首次发生死亡或卒中（缺血性和出血性）的时间上没有差异。在a= 0.05的双侧条件下，针对这两种治疗之间的非零差异的备择假设进行检验，以检测17.82%的风险率降低。首要次要目的是回答华法林或阿司匹林在降低死亡、卒中、MI和HF住院治疗的联合终点方面是否具有上级优势。审判开始于03/02。然而，研究进展缓慢，存在各种行政问题。06/'05年，S. Homma作为心脏病学PI被带到监督临床操作。随后，所有研究中心的监管文件都得到了遵守，并定期进行计划的监查访视。还对严重不良事件进行了裁定，以确保患者安全。为提高数据质量，对组织结构进行了其他改革。为了在新的资助周期中提高组织效率，计划将受赠机构迁往哥伦比亚大学（从UMDNJ），那里的统计分析中心（J.L.T.汤普森，PI）也位于。目前，北美有74个中心，欧洲有66个中心正在招募。此时，入组了1，242例患者（8/01/2006）。根据REALISTIC入组率，预计到2011年8月，患者总数为3，246人。最短随访期为1年，最长为6年。然而，考虑到实际事件发生率和治疗中断率，在申请的资助期内，达到的把握度可能低于80%。患者将需要额外随访12个月（超过5年结束时），以达到>80%的功效。随访期为2 - 6年。因此，如有需要，我们计划在本周期后申请额外拨款，以取得适当的权力。随着WATCH的结束，这项研究仍然是唯一一项评估抗凝治疗在低EF患者中作用的研究，这对越来越多的HF患者的治疗具有重要意义。

DESCRIPTION (provided by applicant): Heart failure (HF) and low left ventricular (LV) ejection fraction (EF) are associated with significant risk for stroke and death. However, the value of antithrombotic / antiplatelet therapy to reduce adverse events remains controversial. Warfarin and aspirin are most often used without definitive data. Antiplatelet Trial in Chronic Heart Failure (WATCH) attempted to address this issue, but was prematurely terminated due to poor recruitment. Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction Trial (WARCEF) is designed to address this issue. The primary aim of this randomized, double-blind, multi-center clinical trial is to determine whether warfarin (INR 2.5-3.0; target INR 2.75) or aspirin (325 mg per day) is superior for preventing the combined end point of all-cause mortality and stroke (both ischemic and hemorrhagic) in patients with LV EF<35%. The primary null hypothesis is that in patients with EF</=35%, there will be no difference between warfarin and aspirin therapies in time to the first occurrence of death or stroke (ischemic and hemorrhagic). This is tested against the alternative hypothesis of a non-zero difference between these two treatments, at a=.05 two-sided, to detect a 17.82% hazard rate reduction. The top secondary aim is to answer if warfarin or aspirin is superior for reducing combined endpoint of death, stroke, Ml, and HF hospitalization. This trial started in 03/'02. However, study progress was slow and a variety of administrative problems existed. In 06/'05, S. Homma was brought in as a Cardiology PI to oversee the clinical operations. Subsequently, regulatory documents from all sites were brought to compliance and regularly scheduled monitoring visits implemented. Serious adverse events were also adjudicated to assure patient safety. Other changes in organizational structure were implemented to increase data quality. To increase organizational efficiency in the new funding cycle, the grantee institution is planned to be moved to Columbia Univ. (from UMDNJ), where Statistical Analysis Center (J.L.T. Thompson, PI) is also located. Currently, 74 centers in North America, and 66 in Europe are recruiting. At this time, 1,242 patients are enrolled (8/01/'06). Based on the REALISTIC enrollment rate, the total patient number by 08/'11 is expected to be 3,246. Minimum follow up period is 1 year and maximum 6 years. However, given the actual event rates and interruption of therapy rate, the achieved power is likely to be under 80% within the requested funding period. Patients will need be followed for 12 additional months (beyond the end of 5-years) to achieve >80% power. Follow up period will then range from 2 to 6 years. As such, if necessary, we plan to request additional funding after this cycle to obtain appropriate power. With ending of WATCH, this study remains the only study assessing the role of anticoagulation in patients with low EF, with major implications for how the growing number of HF patients will be treated.