• Jean-Francois Dhainaut, Massimo Antonelli, Patrick Wright, Arnaud Desachy, Jean Reignier, Sylvain Lavoue, Julien Charpentier, Mark Belger, Michael Cobas-Meyer, Cornelia Maier, Mariano A Mignini, and Jonathan Janes.
• Hôpital Cochin, Université Paris Descartes, 27 Rue du Faubourg Saint Jacques, 75679, Paris Cedex 14, France. dhainaut@aeres-evaluation.fr
• Intensive Care Med. 2009 Jul 1;35(7):1187-95.

ObjectiveTo determine the efficacy and safety of extended drotrecogin alfa (activated) (DAA) therapy.DesignMulticentre, randomised, double-blind, placebo-controlled study.SettingSixty-four intensive care units in nine countries.PatientsAdults with severe sepsis and vasopressor-dependent hypotension after a 96-h infusion of standard DAA.InterventionsA 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 ResultsAt 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.ConclusionsExtended 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.

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