Activated Protein C (Xigris) for Severe Sepsis/Septic Shock

• Basic idea is that sepsis induces multiple abnormalities and dysfunction in the coagulation cascade which can be detrimental.  Xigris is a protein that promotes finibolysis and inbibits thrombosis, and potentially has benefit in combating the procoagulant and inflammatory response in sepsis.
• Evidence of benefit is mainly from the PROWESS trial (NEJM 2001) which was a RCT of 1690 patients with severe sepsis/septic shock who were randomized to APC vs placebo within 24 hours of presentation; the APC group had lower 28 day mortality (25% vs 31%).  The greatest benefit was seen in patients with a high risk of death, as determined by an APACHE II score of 25 of more.   The APACHE II score is based on 14 variables including vital signs, labs, ABG, glascow coma scale, and other comorbid diseases, and is scored from 0-71; it was derived from a paper published in Crit Care Med 1989.  Subsequently, there are newer mortality prediction scores (APACHE III, SAPS II) but many still use APACHE II because there is a lot of data behind it.
• Subsequently, the ADDRESS trial (NEJM 2005) looked at APC in patients with severe sepsis but an APACHE II score less than 25 and was stopped early due to lack of benefit.
• The main downside (aside from cost) is the risk of bleeding, and in the studies they excluded patients with extreme coagulopathy, thrombocytopenia, etc.
• As such, the indication for Xigris is for patients with severe sepsis/septic shock with an APACHE II score of 25 of more, with no risk factors for bleeding (plts <30, recent anticoagulant therapy, recent surgery, CVA, CNS lesion, GI bleeding, etc).  It is NOT for children (based on RESOLVE study – Lancet 2007 – no benefit in pediatric patients).  Keep in mind that it is extremely expensive as well, and that in the grand scheme of things, the other management aspects of sepsis are more important (i.e. hemodynamic resuscitation, antibiotics, and source control). 

(Chanu Rhee MD, 4/18/11)