Human recombinant activated protein C for severe sepsis.

BACKGROUND: Sepsis is a common, expensive and frequently fatal condition. There is an urgent need for developing new therapies to further reduce severe sepsis-induced mortality. One of those approaches is the use of human recombinant activated protein C (APC).

OBJECTIVES: We assessed the clinical effectiveness of APC for the treatment of patients with severe sepsis or septic shock.

SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 2); MEDLINE (1966 to 2005); EMBASE (1980 to 2005) and LILACS (1982 to 2005). We contacted researchers and organizations working in the field. We did not have any language restriction.

SELECTION CRITERIA: We included randomized controlled trials (RCTs) assessing the effects of APC for severe sepsis in adults and children. We excluded neonates.

DATA COLLECTION AND ANALYSIS: We independently performed study selection, quality assessment and data extraction. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using I-squared (I(2)). We used a random-effects model.

MAIN RESULTS: We included four studies involving 4911 participants (4434 adults and 477 paediatric patients). For 28-day mortality, APC did not reduce the risk of death in adult participants with severe sepsis (pooled RR 0.92, 95% confidence interval (CI) 0.72 to 1.18; P = 0.50, I(2) = 72%). The effectiveness of APC did not seem to be associated with the degree of severity of sepsis (two studies): for an APACHE II score less than 25 the RR was 1.04 (95% CI 0.89 to 1.21; P = 0.70), and in participants with an APACHE II score of 25 or more the RR was 0.90 (95% CI 0.54 to 1.49; P = 0.68). APC use was, however, associated with a higher risk of bleeding (RR 1.48 (95% CI 1.07 to 2.06; P = 0.02, I(2) = 8%). Two studies were stopped early because there was little chance of reaching the efficacy endpoint by completion of the trial.

AUTHORS' CONCLUSIONS: This review suggests that APC should not be used in sepsis with an APACHE II score of less than 25 or, in paediatric patients. There is very weak evidence supporting APC use in patients with severe sepsis and at high-risk of death. As a result, policy-makers, clinicians and academics should be cautious when promoting the use of APC to patients with severe sepsis and an APACHE II score of 25 or greater. There is a need for further RCTs to answer with certainty what the role of APC is for patients with severe sepsis and an APACHE II score of at least 25. Those RCTs should be designed and conducted by non-profit organizations.