Current role of activated protein C therapy for severe sepsis and septic shock.

Drotrecogin alfa (activated) (DrotAA) has been approved for therapy of severe sepsis and septic shock for 7 years, but controversy persists regarding efficacy and safety. Only a single randomized, controlled trial (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; PROWESS) has shown evidence of efficacy, and the risk of complications (especially hemorrhage) is recognized. Moreover, subsequent prospective studies (albeit in children and lower-risk adult patient populations) have been nonconfirmatory. Opinion is polarized whether DrotAA is effective and should be used. Safety data are not in dispute (DrotAA therapy increases risk of bleeding complications), but controversy exists regarding efficacy, the ethics of marketing the drug, and the design and conduct of current and future trials designed to resolve efficacy questions. DrotAA is approved therapy in the United States, the European Union, and many other countries, and clinicians should keep the drug in their armamentarium, balancing risk and benefit, for therapy of patients with severe sepsis or septic shock who are at high risk of death until the controversy is resolved by randomized, prospective trials now in progress.