Recombinant human activated protein C for adults with septic shock.

Djillali Annane 1 Jean-François Timsit 2 Bruno Megarbane 3 Claude Martin 4 Benoit Misset 5, 6 Bruno Mourvillier 7 Shidasp Siami 8 Jean-Luc Chagnon 9 Jean-Michel Constantin 10 Franck Petitpas 11 Bertrand Souweine 12 Roland Amathieu 13 Xavier Forceville 14 Claire Charpentier 15 Antoine Tesnière 16 Jean Chastre 17 Julien Bohe 18 Gwenhael Colin 19 Alain Cariou 20 Alain Renault 21 Christian Brun-Buisson 22, 23 Eric Bellissant 21
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).
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Submitted on : Sunday, June 23, 2013 - 4:57:44 PM
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Djillali Annane, Jean-François Timsit, Bruno Megarbane, Claude Martin, Benoit Misset, et al.. Recombinant human activated protein C for adults with septic shock.. American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, 2013, 187 (10), pp.1091-7. ⟨10.1164/rccm.201211-2020OC⟩. ⟨hal-00837619⟩

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