Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium.
Crit Care Med. 2013 Sep;41(9):2069-79. doi: 10.1097/CCM.0b013e31828e9b03.
To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation.
Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial.
Two hundred and thirty-three ICUs in 17 countries.
All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score.
Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity.
A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline.
ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.
评估重组血栓调节蛋白（ART-123）治疗疑似脓毒症相关性弥散性血管内凝血（DIC）患者的安全性和疗效。
国际多中心、双盲、随机、安慰剂对照、平行分组、筛选试验，Ⅱb 期。
17 个国家的 233 个重症监护病房。
所有因脓毒症且经改良国际血栓与止血协会评分评估疑似 DIC 而入院的成年患者。
患者随机接受静脉注射 ART-123（0.06mg/kg/d）治疗 6 天或安慰剂，此外还接受标准治疗。主要终点为死亡率降低。次要终点包括显性 DIC 的逆转和疾病严重程度降低。
共纳入 750 例患者，其中 9 例未接受分配的治疗，因此 371 例患者接受 ART-123 治疗，370 例患者接受安慰剂治疗。两组患者在任何基线变量上均无明显差异。ART-123 组和安慰剂组 28 天死亡率分别为 17.8%和 21.6%（Cochran-Mantel-Haenszel 双侧检验 P 值为 0.273，有利于 ART-123，达到提示疗效的预设统计学检验标准）。两组患者无事件生存日和存活日无统计学差异。ART-123 组患者的 D-二聚体、凝血酶原片段 F1.2 和 TATc 浓度低于安慰剂组。两组患者在器官功能、炎症标志物、出血或血栓事件或新发感染的发生方面均无差异。事后分析显示，基线时至少有一个器官系统功能障碍且国际标准化比值大于 1.4 的患者从 ART-123 治疗中获益最大。
ART-123 对脓毒症伴疑似 DIC 的重症患者是一种安全的干预措施。该研究提供了提示疗效的证据，支持进一步开发该药治疗脓毒症相关凝血障碍，包括 DIC。未来的研究应集中在使用 ART-123 治疗最有可能对该药物有反应的患者亚组上。
