Drotrecogin alfa: a second look. More clinical trials in severe sepsis: mostly negative results.

(1) The initial evaluation of drotrecogin alfa in the treatment of severe sepsis did not convincingly demonstrate the therapeutic potential of this recombinant form of activated protein C. It mainly included one study (PROWESS), a double-blind placebo-controlled trial, involving 1690 patients with sepsis of varying severities. In this trial, drotrecogin alfa seemed to reduce the overall mortality rate at 28 days from 31% to 25%. However, these results were undermined by methodological flaws, and retrospective subgroup analyses suggested that only the most seriously ill patients were likely to benefit from treatment with drotrecogin alfa. (2) The one-year results of the PROWESS trial showed a difference in the mortality rate in the subpopulation of patients with an APACHE II (Acute Physiology and Chronic Health Evaluation) score of at least 25 (48% versus 59%), but these results were undermined by the same methodological flaws. A more detailed retrospective subgroup analysis again suggested that patients with multiple organ failure would benefit from treatment with drotrecogin alfa. (3) Another retrospective subgroup analysis of the PROWESS trial suggests that adding drotrecogin alfa does not increase the efficacy of a heparin-containing regimen. There are no comparable data on the addition of drotrecogin alfa to steroid therapy. (4) Another placebo-controlled trial (the ADDRESS study) only included less severely ill patients; all 2640 participants had an APACHE II score of less than 25, or only one organ failure. There was no evidence of a reduction in mortality with drotrecogin alfa (overall mortality rate 18%). (5) A paediatric placebo-controlled trial was interrupted after 477 children had been enrolled, because drotrecogin alfa was ineffective and caused severe bleeding. (6) Data from ongoing comparative and non comparative studies confirm the increased risk of severe bleeding during drotrecogin alfa therapy, affecting about 7% of patients. (7) In practice, despite trials involving thousands of patients, there are still no firmly identified patient subgroups in which drotrecogin alfa is clearly beneficial. In contrast, the increased bleeding risk is well documented. Drotrecogin alfa should not be routinely used in the management of patients with severe sepsis.