Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock
To determine the efficacy and safety of extended drotrecogin alfa (activated) (DAA) therapy.
Multicentre, randomised, double-blind, placebo-controlled study.
Sixty-four intensive care units in nine countries.
Adults with severe sepsis and vasopressor-dependent hypotension after a 96-h infusion of standard DAA.
A total of 193 patients received an intravenous infusion of extended DAA 24 µg/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.
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.
KeywordsDrotrecogin alfa (activated) Xigris Sepsis Shock Vasopressor Protein C
The authors acknowledge the efforts of all the investigators, study coordinators, and pharmacists involved in this clinical trial. This study was sponsored by Eli Lilly and Company. The authors would like to thank Nancy Milligan of Dianthus Medical Limited for preparing the first draft of the manuscript on behalf of Eli Lilly and Co Ltd in accordance with the European Medical Writers Association guidelines.
Conflict of interest statement
J.-F. D, and J. C. have served as consultants for Eli Lilly and Company; M. A., P. W., A. D., J. R. and S. L. report no conflict of interests at this time; M. B. is an employee of Eli Lilly and Company; M. C.-M., C. M, M. A. M. and J. J. are employees and stockholders of Eli Lilly and Company.
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