Citation: Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gårdlund B, Marshall JC, Rhodes A, Artigas A, Payen D, Tenhunen J, Al-Khalidi HR, Thompson V, Janes J, Macias WL, Vangerow B, Williams MD: Drotrecogin alfa (activated) in adult patients with septic shock. N Engl J Med 2012, 366:2055-2064.
Background: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock.
Objective: To test the hypothesis that DrotAA, as compared with placebo, would reduce mortality in patients with septic shock.
Design: A randomized, double-blind, placebo-controlled, multicenter trial, conducted from March 2008 through August 2011. Patients were followed until either 90 days or death.
Setting: Patients were enrolled from 208 sights in Europe, North and South America, Australia, New Zealand, and India.
Subjects: Subjects included 1,697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours.
Intervention: DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours.
Outcomes: Death from any cause 28 days after randomization.
Results: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval (CI), 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81).
Conclusions: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.