重组人活化蛋白C治疗严重脓毒症的疗效与安全性

Efficacy and safety of recombinant human activated protein C for severe sepsis.

作者信息

Bernard G R, Vincent J L, Laterre P F, LaRosa S P, Dhainaut J F, Lopez-Rodriguez A, Steingrub J S, Garber G E, Helterbrand J D, Ely E W, Fisher C J

机构信息

Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

出版信息

N Engl J Med. 2001 Mar 8;344(10):699-709. doi: 10.1056/NEJM200103083441001.

DOI:10.1056/NEJM200103083441001

PMID:11236773

Abstract

BACKGROUND

Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis.

METHODS

We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C.

RESULTS

A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06).

CONCLUSIONS

Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.

摘要

背景

活化蛋白C（drotrecogin alfa），即重组人活化蛋白C，具有抗血栓形成、抗炎和促纤溶特性。在一项先前的研究中，活化蛋白C可使严重脓毒症患者的凝血和炎症标志物水平呈剂量依赖性降低。在这项3期试验中，我们评估了活化蛋白C治疗是否能降低严重脓毒症患者的任何原因所致死亡率。

方法

我们进行了一项随机、双盲、安慰剂对照、多中心试验。纳入因急性感染导致全身炎症和器官功能衰竭的患者，并将其随机分配接受静脉输注安慰剂或活化蛋白C（24微克/千克体重/小时），持续96小时。预先设定的主要终点为任何原因所致死亡，并在输注开始28天后进行评估。对患者进行不良事件监测；监测生命体征、实验室指标及微生物培养结果的变化；以及抗活化蛋白C中和抗体的产生情况。

结果

共有1690例患者接受随机分组治疗（安慰剂组840例，活化蛋白C组850例）。安慰剂组的死亡率为30.8%，活化蛋白C组为24.7%。基于预先设定的主要分析，活化蛋白C治疗使死亡相对风险降低了19.4%（95%置信区间为6.6%至30.5%），死亡风险绝对降低了6.1%（P = 0.005）。活化蛋白C组严重出血的发生率高于安慰剂组（3.5%对2.0%，P = 0.06）。