Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis
Gordon R. Bernard, M.D., Jean-Louis Vincent, M.D., Ph.D., Pierre-Francois Laterre, M.D., Steven P. LaRosa, M.D., Jean-Francois Dhainaut, M.D., Ph.D., Angel Lopez-Rodriguez, M.D., Jay S. Steingrub, M.D., Gary E. Garber, M.D., Jeffrey D. Helterbrand, Ph.D., E. Wesley Ely, M.D., M.P.H., Charles J. Fisher, M.D., for The Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group
Background Drotrecogin alfa (activated), or recombinant humanactivated protein C, has antithrombotic, antiinflammatory, andprofibrinolytic properties. In a previous study, drotrecoginalfa activated produced dose-dependent reductions in the levelsof markers of coagulation and inflammation in patients withsevere sepsis. In this phase 3 trial, we assessed whether treatmentwith drotrecogin alfa activated reduced the rate of death fromany cause among patients with severe sepsis.
Methods We conducted a randomized, double-blind, placebo-controlled,multicenter trial. Patients with systemic inflammation and organfailure due to acute infection were enrolled and assigned toreceive an intravenous infusion of either placebo or drotrecoginalfa activated (24 µg per kilogram of body weight perhour) for a total duration of 96 hours. The prospectively definedprimary end point was death from any cause and was assessed28 days after the start of the infusion. Patients were monitoredfor adverse events; changes in vital signs, laboratory variables,and the results of microbiologic cultures; and the developmentof neutralizing antibodies against activated protein C.
Results A total of 1690 randomized patients were treated (840in the placebo group and 850 in the drotrecogin alfa activatedgroup). The mortality rate was 30.8 percent in the placebo groupand 24.7 percent in the drotrecogin alfa activated group. Onthe basis of the prospectively defined primary analysis, treatmentwith drotrecogin alfa activated was associated with a reductionin the relative risk of death of 19.4 percent (95 percent confidenceinterval, 6.6 to 30.5) and an absolute reduction in the riskof death of 6.1 percent (P=0.005). The incidence of seriousbleeding was higher in the drotrecogin alfa activated groupthan in the placebo group (3.5 percent vs. 2.0 percent, P=0.06).
Conclusions Treatment with drotrecogin alfa activated significantlyreduces mortality in patients with severe sepsis and may beassociated 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.
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