Human recombinant activated protein C for severe sepsis

Abstract

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). We assessed the clinical effectiveness of APC for the treatment of patients with severe sepsis or septic shock. 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. We included randomized controlled trials (RCTs) assessing the effects of APC for severe sepsis in adults and children. We excluded studies on neonates. 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. 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. This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. Additionally, APC seems to be associated with a higher risk of bleeding. Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC.