Activated protein C for severe sepsis: evidence summary

Since its initial approval for severe sepsis recombinant activated protein C (apC) was beset by controversy stemming from questions about PROWESS design and subsequent concerns from additional studies about the risk versus the benefit. Following the new evidence, the Surviving Sepsis Guideline authors, despite accusations of undue influence by Eli Lilly, substantially downgraded their recommendation for apC.

A comprehensive evidence review published as part of Critical Care’s supplement on apC addresses these controversies and suggests the best current approach, pending additional evidence:

In light of the various clinical trials evaluating the efficacy and safety of DrotAA in severe sepsis, we can conclude that DrotAA can reduce mortality in patients with severe sepsis at high risk for death. We can define this risk using severity scores, such as high APACHE II score or multiple organ failure, but probably also by sustained organ dysfunction that is not improving or worsening despite optimal care and adequate source control. However, this survival benefit is achieved at the expense of a slight increase in the risk for bleeding events, which can be minimized by adequate patient selection. If indicated, the drug should be used within the first 24 hours of sepsis-induced organ dysfunction.

The authors go beyond the simple formulaic approach of using APACHE II scores and number of failing organs as suggested in the original labeling. The response to a trial of optimal therapy with antibiotics, source control and other evidence based modalities is suggested as an additional criterion for selection. Rapidly improving organ function in patients who initially “qualify” might exclude patients from treatment. The observation of initial response would need to be brief, as initiation of treatment within 24 hours is important for better outcomes.