Activated Protein C and Septic Shock: A Propensity-Matched Cohort Study,

Septic shock is a highly inflammatory and pro-coagulant state associated with high mortality. In a single randomized controlled clinical trial, recombinant human activated protein C (rhAPC, drotrecogin alfa) reduced mortality in patients with severe sepsis at high risk of death. Further clinical trials in patients with a lower severity of illness and in children have failed to reproduce these results, and the effectiveness of rhAPC remains the subject of ongoing debate. Insufficient data exists regarding the use of rhAPC outside of a clinical trial.

To evaluate the effectiveness of rhAPC on mortality in a cohort of patients with septic shock.

We conducted a retrospective, propensity-matched, multi-center cohort study in 28 academic and community intensive care units in 3 countries. Propensity scores were based more 33 variables that were either known or suspected to be associated with rhAPC use. Our primary outcomes were mortality over 30 days and 30-day mortality stratified by APACHE II quartile. Secondary outcomes were hospital and ICU mortality and length of stay, ventilator free and vasopressor free days, and the use of acute dialysis.

Using a propensity matched Cox proportional hazard model we observed a 5.9% absolute reduction in 30-day mortality associated with activated protein C use [115/342 (33.6%) vs. 135/342 (39.5%), HR 0.83, 95% CI 0.65–1.07, p=0.15]; however this reduction failed to reach statistical significance. Similarly, we observed non-significant reductions in mortality among the 3 lowest APACHE II quartiles (APACHE II <20: 12.5% vs. 18.2%, HR 0.66, 95%CI 0.29 – 1.49, p=0.32; APACHE II 21–25: 20% vs 33.3%, HR 0.55, 95% CI 0.30–1.02, p=0.06; and APACHE II 26–30: 36.7% vs. 48.7%, HR 0.73, 95% CI 0.45 – 1.19, p=0.21). Hospital mortality (40.6% vs. 46.8%, HR 0.83, 95%CI 0.66–1.04, p=0.10) and ICU mortality (31.0 vs. 35.1%, HR 0.87, 95%CI 0.67–1.13, p=0.28) were not significantly reduced among patients who received rhAPC compared to matched controls. The use of rhAPC was not associated with significant differences in ICU or hospital length of stay, ventilator free days, vasopressor free days or the use of acute dialysis.

In this retrospective, multi-center propensity matched cohort study, the use of rhAPC in patients with septic shock was not associated with statistically significant reductions in 30-day mortality. However, the absolute reduction in 30-day mortality was in similar to that observed in previously published clinical trials. Prospective clinical trials evaluating the efficacy of rhAPC are currently ongoing and will serve to define the role of rhAPC in patients with septic shock.

Kumar:Pfizer: Research Funding; Astellas: Research Funding; GSK: Research Funding; Roche: Research Funding.