Benefit-risk assessment of drotrecogin alfa (activated) in the treatment of sepsis.

Severe sepsis is a common cause of death in critically ill patients. Several mechanisms have been implicated in the development of organ dysfunction in patients with severe sepsis. Among these, activation of inflammation and coagulation, together with endothelial dysfunction, seem to be major contributors. Several anti-inflammatory agents have been tried for the treatment of sepsis, with limited success. Anticoagulant drugs have been shown to be of potential interest for the therapy of severe sepsis. Among these agents, a natural anticoagulant named activated protein C, which is manufactured as a recombinant human protein under the name of drotrecogin alfa (activated), has been a topic of intense interest. Drotrecogin alfa (activated) is an antithrombotic and profibinolytic agent that also possesses anti-inflammatory and antiapoptotic properties. Small trials have shown that drotrecogin alfa (activated) reduces the sepsis-induced alterations in endothelial and microcirculatory function. In this review, the benefit-risk balance of drotrecogin alfa (activated) is assessed. The results of one phase II trial, two phase III trials (one including patients with high and low risk of death, the other restricted to patients with low risk of death) and several cohort studies have been published. The PROWESS (Recombinant human protein C Worldwide Evaluation in Severe Sepsis; phase III) trial showed that drotrecogin alfa (activated) is associated with a reduction in the risk of death in patients with severe sepsis, but this benefit seems to be greater in patients at high risk of death. Acute Physiology and Chronic Health Evaluation (APACHE) II scores and the number of failing organs have been proposed as means to identify patients with sepsis who are at a high risk of death, but these criteria may sometimes not make good indicators, especially as the APACHE II score has not been validated for this purpose. Bleeding is more common in drotrecogin alfa (activated)-treated patients than in placebo recipients; however, many of the additional episodes of bleeding in drotrecogin alfa (activated) recipients are procedure related. Importantly, bleeding did not outweigh the benefits of drotrecogin alfa (activated), as there was an overall survival benefit, provided only patients at high risk of death from sepsis were treated with drotrecogin alfa (activated). The bleeding rate associated with drotrecogin alfa (activated) was slightly higher in cohort studies than in clinical trials, but this may be related to the higher severity of illness in these patients. Thus, in clinical practice, great caution should be taken in the selection of patients to be treated, and unnecessary invasive procedures should be avoided in order to preserve the survival benefit conferred by drotrecogin alfa (activated).