[PROWESS, ENHANCE and ADDRESS: clinical implications for the treatment with drotrecogin alfa (activated)]

Drotrecogin alfa (activated) (DrotAA) represents a therapeutic advance in the treatment of severe sepsis. In the pivotal PROWESS trial DrotAA had demonstrated a significant decrease in 28-day mortality, most evident in the subgroup of patients at higher risk of death. Thus, DrotAA was licensed throughout Europe for treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The ADDRESS trial was mandated by the FDA to investigate prospectively the treatment effect of DrotAA in patients at low risk of death, e.g. single organ failure. The trial was prematurely stopped due to futility, because no reduction in mortality was observed in this non-indicated patient population. The ENHANCE open-label trial enrolled similar patients to the PROWESS trial and the observed 28-day mortality was consistent with the results seen in the PROWESS trial. Survival rates for patients receiving DrotAA early within 24 h from the first sepsis-induced organ dysfunction were significantly higher than in patients treated later. In this overview we will discuss the results of the ENHANCE and ADDRESS trials in the context of the PROWESS study and clinical implications for the treatment with DrotAA.