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).