Human recombinant activated protein C for severe sepsis

Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been used to reduce the high rate of death by severe sepsis or septic shock. This is an update of a Cochrane review (originally published in 2007 and updated in 2008).

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

For this updated review we searched CENTRAL (The Cochrane Library 2010, Issue 6); MEDLINE (1966 to June 2010); EMBASE (1980 to July 1, 2010); BIOSIS (1965 to July 1, 2010); CINAHL (1982 to 16 June 2010) and LILACS (1982 to 16 June 2010). There was no 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 considered all-cause mortality at day 28, at the end of study follow up, and hospital mortality as the primary outcomes.

We independently performed study selection, risk of bias assessment and data extraction. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model.

We identified one new RCT in this update. We included a total of five RCTs involving 5101 participants. For 28-day mortality, APC did not reduce the risk of death in adult participants with severe sepsis (pooled RR 0.97, 95% confidence interval (CI) 0.78 to 1.22; P = 0.82, I(2) = 68%). APC use was associated with an increased risk of bleeding (RR 1.47, 95% CI 1.09 to 2.00; P = 0.01, I(2) = 0%). In paediatric patients, APC did not reduce the risk of death (RR 0.98, 95% CI 0.66 to 1.46; P = 0.93). Although the included trials had no major limitations most of them modified their original completion or recruitment protocols.

This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. Additionally, APC is 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.Warning: On October 25th 2011, the European Medicines Agency issued a press release on the worldwide withdrawal of Xigris (activated protein C / drotrecogin alfa) from the market by Eli Lilly due to lack of beneficial effect on 28-day mortality in the PROWESS-SHOCK study. Furthermore, Eli Lily has announced the discontinuation of all other ongoing clinical trials. The final results of the PROWESS-SHOCK study are expected to be published in 2012. This systematic review will be updated when results of the PROWESS-SHOCK or other trials are published.