Activated protein C (Xigris) treatment in sepsis: a drug in trouble.

Drotrecogin alfa (activated) or recombinant human activated protein C (rhAPC) has been registered for use as adjuvant treatment in severe sepsis since 2001 under the trade name Xigris essentially based on the results from one large clinical trial (the PROWESS trial). In a recently published second randomized clinical trial (the ADDRESS trial), enrolling patients with severe sepsis but with less risk of death, no effect of the treatment was shown, not even a trend to a positive effect in the subgroup of patients with a high risk of death that would match the present prescription label for Xigris. In addition, a large randomized, placebo-controlled trial with rhAPC in paediatric sepsis has recently been terminated prematurely because of lack of efficacy. Altogether, the robustness of the data supporting the use of rhAPC in treating patients with severe sepsis may indeed be questioned. A confirmatory clinical trial is required before rhAPC can be used with confidence. The side-effects and the cost of rhAPC are well documented but its efficacy is not.