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Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock.

Author(s): Dhainaut JF, Antonelli M, Wright P, Desachy A, Reignier J, Lavoue S, Charpentier J, Belger M, Cobas-Meyer M, Maier C, Mignini MA, Janes J

Affiliation(s): Hopital Cochin, Universite Paris Descartes, 27 Rue du Faubourg Saint Jacques, 75679, Paris Cedex 14, France. dhainaut@aeres-evaluation.fr

Publication date & source: 2009-07, Intensive Care Med., 35(7):1187-95. Epub 2009 Mar 5.

Publication type: Research Support, Non-U.S. Gov't

OBJECTIVE: To determine the efficacy and safety of extended drotrecogin alfa (activated) (DAA) therapy. DESIGN: Multicentre, randomised, double-blind, placebo-controlled study. SETTING: Sixty-four intensive care units in nine countries. PATIENTS: Adults with severe sepsis and vasopressor-dependent hypotension after a 96-h infusion of standard DAA. INTERVENTIONS: A total of 193 patients received an intravenous infusion of extended DAA 24 microg/kg/h or sodium chloride placebo for a maximum of 72 h. MEASUREMENTS AND RESULTS: At extended therapy initiation (baseline), DAA-group patients had lower protein C levels (P = 0.23) and higher vasopressor requirements, particularly for the primary vasopressor used, norepinephrine (P = 0.03), compared with placebo-group patients. DAA treatment did not result in a difference in the primary outcome of time to resolution of vasopressor-dependent hypotension versus placebo (P = 0.419). However, few patients reached resolution (DAA 34%, placebo 40%) as most continued to require vasopressor support after 72 additional hours of treatment. Treatment did not reduce 28-day all-cause mortality and in-hospital mortality or improve organ function compared with placebo, although there was a lower percentage change in D-dimers (P < 0.001) and increases in protein C levels were numerically greater on extended infusion. There was no difference in serious adverse events including bleeding events. CONCLUSIONS: Extended DAA treatment did not result in more rapid resolution of vasopressor-dependent hypotension, despite demonstrating anticipated biological effects on D-dimer and protein C levels. A reduced planned sample size combined with baseline imbalances in protein C levels and vasopressor requirements may have limited the ability to demonstrate a clinical benefit.

Page last updated: 2009-10-20

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