Drotrecogin alpha activated (DAA), trade name
Xigris, is a recombinant human
protein C that has been the subject of controversy since 2001, when it became the first biologic agent approved for the treatment of
severe sepsis and
septic shock. The PROWESS trial showed a 6.1 % absolute reduction in 28-day mortality, although these findings were not replicated in later trials, ultimately leading to the withdrawal of DAA in 2011. Observational trials, however, have consistently shown a mortality benefit with the use of DAA, leading to the following questions: Did DAA truly fail and, if so, why? While these questions may never be definitively answered on the basis of available evidence, several factors may explain the conflicting results. In clinical practice, DAA may have been preferentially given to subjects more likely to survive. Contemporary treatments, including early
antibiotic administration and volume
resuscitation, may have mitigated the inflammatory processes leading to disordered coagulation and microvascular
thrombosis and, thus, reduced or abolished the therapeutic opportunity for DAA. Later randomized clinical trials of DAA focused on the clinical phenotype of refractory
shock, largely due to a strong efficacy signal in this subset from PROWESS; however, this clinical phenotype may not be tightly linked, at least after contemporary early
resuscitation strategies, to the mechanistic phenotype of dysregulated coagulation that may have been a better target for DAA. Future trials of
biologic therapies in
severe sepsis and
septic shock should use a combination of clinical phenotype and
biomarkers to identify responsive populations that may benefit from such
therapies.