Journal Article

Recombinant Human Activated Protein C for Adults with Septic Shock. A Randomized Controlled Trial

Siami, Shidasp, Constantin, Jean-Michel, Amathieu, Roland, Martin, Claude, Forceville, Xavier, Petitpas, Franck, Bellissant, Eric, Colin, Gwenhael, Megarbane, Bruno, Souweine, Bertrand, Brun-Buisson, Christian, Annane, Djillali, Timsit, Jean-François, Renault, Alain, Cariou, Alain, Misset, Benoit, Chastre, Jean, Mourvillier, Bruno, Chagnon, Jean-Luc, Charpentier, Claire, Tesnière, Antoine, Bohe, Julien

2013

Overview

Abstract 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 with www.clinicaltrials.gov (NCT00625209).

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Anesthesia & intensive care / Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Anesthésie & soins intensifs / Anti-Infective Agents - therapeutic use / Anti-Inflammatory Agents - therapeutic use / Bacterial diseases / Bacterial sepsis / Biological and medical sciences / Blood pressure / Cardiology and cardiovascular system / Clinical trials / Committees / Double-Blind Method / Drug dosages / Drug Therapy, Combination - methods / Drug withdrawal / Emergency and intensive care: infection, septic shock / Emerging diseases / FDA approval / Female / Fludrocortisone - therapeutic use / Human bacterial diseases / Human health and pathology / Human health sciences / Humans / Hydrocortisone - therapeutic use / Infectious diseases / Intensive care medicine / Life Sciences / Male / Medical sciences / Middle Aged / Mortality / Physiology / Pneumology / Protein C - therapeutic use / Proteins / Pulmonology and respiratory tract / Recombinant Proteins - therapeutic use / Safety-Based Drug Withdrawals / Sciences de la santé humaine / Sepsis / Shock, Septic - drug therapy / Steroids / Systematic review / Toxicology / Treatment Outcome