Efficacy and safety of recombinant human activated protein C for severe sepsis
- PMID: 11236773
- DOI: 10.1056/NEJM200103083441001
Efficacy and safety of recombinant human activated protein C for severe sepsis
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.
Comment in
- ACP J Club. 2001 Nov-Dec;135(3):81
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Severe sepsis--a new treatment with both anticoagulant and antiinflammatory properties.N Engl J Med. 2001 Mar 8;344(10):759-62. doi: 10.1056/NEJM200103083441009. N Engl J Med. 2001. PMID: 11236781 No abstract available.
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Low-dose heparin for severe sepsis.N Engl J Med. 2002 Sep 26;347(13):1036-7. doi: 10.1056/NEJM200209263471316. N Engl J Med. 2002. PMID: 12324565 No abstract available.
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Canadian Association of General Surgeons Evidence Based Reviews in Surgery. 8. Efficacy and safety of recombinant human activated protein C for severe sepsis.Can J Surg. 2003 Dec;46(6):468-70. Can J Surg. 2003. PMID: 14680357 Free PMC article. No abstract available.
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