Recombinant Protein Improves Survival in Severe Sepsis
An international, randomized, double-blind trial involving 1690 adults with severe sepsis found that 24.7% of those who received drotrecogin alfa activated, a recombinant activated protein C, died within 28 days, compared with 30.8% of the placebo group. The significantly greater efficacy of the recombinant protein versus placebo led to suspension of the trial and early release of the article on the journals Web site.
Patients in the protein treatment group seem to have benefited from replacement of a substance present in subnormal levels in most patients with sepsis. About 80% of the patients in both groups had a deficiency of protein C activity before entry into the trial.
During infection, the body releases various cytokines that not only promote inflammation but also can activate one of the coagulation pathways and inhibit fibrinolysis. Activated protein C inhibits inflammation and thrombosis and promotes fibrinolysis, but conversion of protein C to its activated form does not occur at a normal rate during sepsis.
The 96-hour infusion of drotrecogin alfa, at a rate of 24 mcg per kilogram of body weight per hour, produced a higher frequency of serious bleeding than did the placebo infusion of 0.9% sodium chloride injection, but only during drug administration.
Serious bleeding in both groups occurred primarily in the patients having a known predisposition to bleeding, such as those with a gastrointestinal ulcer. Patients with a high risk of bleeding were excluded from the trial, as were those undergoing certain treatments that would affect coagulation.
The research was supported by Eli Lilly and Company, manufacturer of the recombinant protein used in the trial. Lilly expects to receive approval of its licensing application for the biological, known by the proposed brand name Zovant, in the second half of 2001.
- Bernard GR, Vincent J-L, Laterre P-F et al., for the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001; 344:699-709.