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Volume 344:699-709 March 8, 2001 Number 10 Next

	Full Text PDF Editorial by Matthay, M. A. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

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 µg 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.

Source Information

From the Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville (G.R.B., E.W.E.); the Department of Intensive Care, Erasme University Hospital, Brussels, Belgium (J.-L.V.); the Department of Critical Care and Emergency Medicine, Cliniques Universitaires St. Luc, Brussels, Belgium (P.-F.L.); Lilly Research Laboratories, Eli Lilly, Indianapolis (S.P.L., J.D.H., C.J.F.); the Department of Intensive Care, Cochin–Port Royal University Hospital, Paris V University, Paris (J.-F.D.); the Unidad de Cuidados Intensivos, Servicio de Medicina Intensiva, Hospital Infanta Cristina, Badajoz, Spain (A.L.-R.); the Critical Care Division, Baystate Medical Center, Springfield, Mass., and Tufts University School of Medicine, Boston (J.S.S.); and the Division of Infectious Diseases, University of Ottawa, Ottawa Hospital, Ottawa, Ont., Canada (G.E.G.).

Address reprint requests to Dr. Bernard at the Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, T-1208 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232, or at gordon.bernard{at}mcmail.vanderbilt.edu.

Full Text of this Article

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N Engl J Med 2002; 347:1036-1037, Sep 26, 2002. Correspondence

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