Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Cleveland, OH, USA.
Mount Sinai School of Medicine, New York, NY, USA.
Lancet. 2016 Jan 23;387(10016):349-356. doi: 10.1016/S0140-6736(15)00515-2. Epub 2015 Nov 5.
REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding.
We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions.
1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002).
The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin.
Regado Biosciences Inc.
REG1 是一种新型抗凝系统，由凝血因子 IXa 的 RNA 适体抑制剂 peginterferon alfa-2b 和互补序列逆转寡核苷酸 anivamersen 组成。我们检验了这样一个假设，即在经皮冠状动脉介入治疗期间，使用 peginterferon alfa-2b 近乎完全抑制凝血因子 IXa，然后用 anivamersen 部分逆转，与比伐卢定相比，是否会减少缺血事件，而不会增加出血。
我们在北美和欧洲的 225 家医院进行了一项随机、开放标签、活性对照、多中心、优效性试验，比较 REG1 与比伐卢定。我们计划以 1:1 的比例随机分配 13200 名接受经皮冠状动脉介入治疗的患者，分别接受 REG1（peginterferon alfa-2b 1mg/kg 推注[>99%的凝血因子 IXa 抑制]，经皮冠状动脉介入治疗后用 anivamersen 逆转 80%）或比伐卢定治疗。排除标准包括 48 小时内发生 ST 段抬高型心肌梗死。主要疗效终点是随机分组后第 3 天全因死亡、心肌梗死、卒中和计划外靶病变血运重建的复合终点。主要安全性终点是大出血。分析采用意向治疗。该试验在 ClinicalTrials.gov 注册，标识符为 NCT01848106。由于严重过敏反应，在招募了 3232 名患者后，试验提前终止。
1616 名患者被分配接受 REG1 治疗，1616 名患者被分配接受比伐卢定治疗，其中分别有 1605 名和 1601 名患者接受了指定的治疗。在接受 REG1 治疗的 1605 名患者中，有 10 名（1%）发生严重过敏反应，而接受比伐卢定治疗的 1601 名患者中，有 1 名（<1%）发生严重过敏反应。两组主要复合终点无差异，接受 REG1 治疗的 1616 名患者中有 108 名（7%）和接受比伐卢定治疗的 1616 名患者中有 103 名（6%）报告了主要终点事件（比值比[OR] 1.05，95%CI 0.80-1.39；p=0.72）。两组大出血情况相似（REG1 治疗组有 7 名[<1%]，比伐卢定治疗组有 2 名[<1%]；OR 3.49，95%CI 0.73-16.82；p=0.10），但 REG1 组大出血或轻微出血增加（REG1 组有 104 名[6%]，比伐卢定组有 65 名[4%]；1.64，1.19-2.25；p=0.002）。
目前配方的可逆凝血因子 IXa 抑制剂 REG1 与严重过敏反应有关。尽管由于提前终止，统计效力有限，但没有证据表明 REG1 与比伐卢定相比，能减少缺血事件或出血。
Regado Biosciences Inc.
