Recombinant activated protein C: the key is clinical assessment of risk of death, not subset analysis

The PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial demonstrated a 6.1% absolute decrease in mortality with a p value of 0.005 [1]. Recombinant activated protein C (rhAPC) was approved by the FDA for use in patients with 'sepsis induced organ dysfunction associated with a high risk of death, such as an APACHE [Acute Physiology and Chronic Health Evaluation] II of ≥ 25'. APACHE II ≥ 25 was used as one marker of high risk of death because a subset data analysis demonstrated that the treatment benefit in the PROWESS trial was predominantly in this group of patients. The European regulatory body approved rhAPC for multiple organ failure (again based on subset data analysis from the PROWESS trial demonstrating increased treatment effect as the number of organ failures increased). The Surviving Sepsis Campaign (SSC) Guidelines for the Management of Severe Sepsis and Septic Shock recommend the use of rhAPC in patients with high risk of death due to sepsis-induced organ dysfunction [2]. Since the publication of the SSC guidelines additional large clinical trials of rhAPC have concluded: the ENHANCE (Extended Evaluation of Recombinant Human Activated Protein C), ADDRESS (Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis) and pediatric trials [3-5]. The ENHANCE trial provided supportive evidence for the favorable benefit/risk ratio observed in the PROWESS trial and suggested that earlier therapy was more effective [3]. The ENHANCE trial also revealed a somewhat greater incidence of serious hemorrhage with rhAPC than was evident in the PROWESS trial. The results of the ADDRESS trial, designed with the purpose of prospectively studying the effect of rhAPC in patients with severe sepsis at low risk of death, supported the FDA labeling that rhAPC was not of utility in such patients [4]. However, a post hoc subset analysis of patients who were admitted to a trial designed to target a low risk of death but who al