1 Department of Intensive Care and2 INSERM CIC-IT 0805 Clinical Investigation Centre, Raymond Poincaré University Hospital, Versailles Saint-Quentin University, Garches, France3 Service de Réanimation Médicale, CHU de Grenoble, Grenoble, France4 Service de Réanimation Médicale et Toxicologique, Hôpital Lariboisière, Paris, France5 Service d'Anesthésie Réanimation, Hôpital Nord, Marseille, France6 Service de Réanimation Médicale Polyvalente, Hôpital Saint-Joseph, Paris, France7 Service de Réanimation-Maladies Infectieuses, Hôpital Bichat Claude Bernard, Paris, France8 Service d'Anesthésie-Réanimation, Centre Hospitalier d'Etampes, Etampes, France9 Service de Réanimation Polyvalente, Centre Hospitalier de Valenciennes, Valenciennes, France10 Service d'Anesthésie et Reanimation, Hôpital Hotel Dieu, Clermont-Ferrand, France11 Service de Réanimation Chirurgicale, Hôpital de la Miletrie, Poitiers, France12 Service de Réanimation, CHU Clermont-Ferrand, Clermont-Ferrand, France13 Service d'Anesthésie Réanimation, Hôpital Jean Verdier, Bondy, France14 Service de Réanimation Polyvalente, Centre Hospitalier de Meaux, Meaux, France15 Service de Réanimation Chirurgicale, Hôpital Central, Nancy, France16 Service d'Anesthésie Réanimation, Hôpital Cochin, Paris, France17 Service de Réanimation Médicale, CHU Pitié Salpêtrière, Paris, France18 Service de Réanimation Médicale Sud, Centre Hospitalier Lyon-Sud, Pierre Bénite, France19 Service de Réanimation, Centre Hospitalier René Dubos, Cergy Pontoise, France20 Service de Réanimation, Hôpital Cochin, Paris, France21 Department of Clinical Pharmacology, and INSERM CIC-P 0203 Clinical Investigation Centre, University Hospital, Rennes 1 University, Rennes, France; and22 Service de Réanimation Médicale, Hôpital Henri Mondor, Créteil, France
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Rationale:A decade after drotrecogin alfa (activated) (DAA) was released on the market worldwide, its benefit-to-risk ratio remains a matter of debate.Objectives:The current investigator-led trial was designed to evaluate the efficacy and safety of DAA, in combination with low-dose steroids, in adults with persistent septic shock.Methods:This was a multicenter (24 intensive care units), placebo-controlled, double-blind, 2 × 2 factorial design trial in which adults with persistent septic shock and no contraindication to DAA were randomly assigned to DAA alone (24 μg/kg/h for 96 h), hydrocortisone and fludrocortisone alone, their respective combinations, or their respective placebos. Primary outcome was mortality rate on Day 90.Measurements and Main Results:On October 25, 2011, the trial was suspended after the withdrawal from the market of DAA. The Scientific Committee decided to continue the trial according to a two parallel group design comparing low-dose steroids with their placebos and to analyze the effects of DAA on patients included before trial suspension. At the time trial was suspended, 411 patients had been recruited, 208 had received DAA, and 203 had received its placebo. There was no significant interaction between DAA and low-dose steroids (P= 0.47). On Day 90, there were 99 deaths (47.6%) among the 208 patients receiving DAA and 94 deaths (46.3%) among the 203 patients receiving placebo (P= 0.79). There was no evidence of a difference between DAA and its placebo for any secondary outcomes or serious adverse events.Conclusions:In adults with established and severe septic shock, DAA showed no evidence of benefit or harm.Clinical trial registered withwww.clinicaltrials.gov(NCT00625209).