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

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.