The FDA has approved drotrecogin alfa (activated) (Xigris, Eli Lilly, Indianapolis), a recombinant form of human activated protein C, for the reduction of mortality in adults with severe sepsis (associated with acute organ dysfunction).

The effectiveness of the drug was shown in a multicenter, randomized, double-blind, placebo-controlled trial of 1690 adult patients with severe sepsis. Entry criteria included a systemic inflammatory response presumed due to infection and at least one of the following: cardiovascular, respiratory, or renal dysfunction; thrombocytopenia; or metabolic acidosis.

Patients received a 96-hour infusion of Xigris at 24 µg/kg per hour (the recommended dosage) or placebo within 48 hours after onset of the first sepsis-induced organ dysfunction. The primary efficacy end point was all-cause mortality assessed 28 days after the start of Xigris administration. The study was terminated after a planned interim analysis because of significantly lower mortality in patients who received Xigris (210 [25%] of 850) vs placebo (259 [31%] of 840). The observed reduction in mortality was limited to severe sepsis patients who had a higher risk of death based on acute physiology and chronic health status at study entry.

Bleeding is the most common serious adverse effect associated with Xigris therapy, and the drug is contraindicated in patients with conditions in which bleeding presents high risk of death or significant morbidity. Patients taking Xigris may develop serious bleeding, including intracranial hemorrhage (approximately 1%). During the 28-day study period, 25% of the Xigris-treated vs 18% of the placebo-treated patients experienced at least one bleeding event, in most cases ecchymoses or gastrointestinal tract bleeding.

Xigris is not indicated for all patients with severe sepsis, but only for those with relatively high risk of death. Safety and effectiveness of the drug have not been established in children.