Impaired generation of activated Protein C (aPC) may contribute to the high mortality in severe sepsis. During the development of drotrecogin alfa (activated) [DrotAA, recombinant human aPC], it was hypothesized that patients deficient in PC (the inactive zymogen) would benefit more from DrotAA treatment than those not deficient. However, data from PROWESS demonstrated similar benefit with DrotAA regardless of baseline PC. We assessed early changes in PC for PROWESS patients to explore why baseline PC deficiency was not predictive of a larger DrotAA treatment effect.
PROWESS patients with PC measures at baseline and end of infusion were studied (n=1574). PC levels expressed as % (<80%=deficient). Patients classified based on PC deficiency at baseline, and 28-day mortality was assessed in subgroups based on changes in PC. Multivariable Cox and logistic regressions and Chi-square tests were performed.
In placebo patients PC>80% at baseline, development of PC deficiency by Day 4 was associated with higher mortality versus patients remaining >80% (p=0.047). In placebo patients PC deficient at baseline, improvement to PC>80% by Day 4 was associated with reduced mortality vs patients remaining deficient (p<0.0001). Non-deficient PC patients receiving DrotAA were less likely to develop PC deficiency (66% for DrotAA vs 55% for placebo) and more likely to improve if they were deficient (34% vs 24%). In placebo patients, PC deficiency was a significant risk factor for mortality (Hazard ratio=1.70, p<0.0001), and DrotAA was associated with significant reduction in odds ratio of PC deficiency versus placebo (0.69, p<0.0001).
In PROWESS, PC levels >80% at end of infusion were associated with improved survival; DrotAA patients were more likely to achieve this endpoint. DrotAA also improved survival for patients becoming deficient during infusion.
DrotAA appears to increase PC levels towards normal in patients with PC deficiency at baseline, and reduce the percentage of non-deficient patients progressing to PC deficiency. In patients that remained PC deficient from baseline through end of infusion, DrotAA was associated with a more modest reduction in mortality. End of Infusion PC StatusBaseline PC StatusPC≥80%PC<80%Placebo Mortality (n=total patients)DrotAA Mortality (n=total patients)Placebo Mortality (n=total patients)DrotAA Mortality (n=total patients)PC≥80%19% n=5815% n=5936% n=4716% n=31PC<80%17% n=16311% n=24037% n=50733% n=469
W.L. Macias, William Macias and David Nelson are employees