In the European Union, drotrecogin alfa (activated) (DAA) is licensed (intravenous infusion, 96 hours) for adults with severe sepsis with multiple organ failure. In the PROWESS trial, DAA treatment was associated with significant mortality reduction and more rapid improvement in cardiovascular function over 7 days (decreased need for vasopressors). But 22% of DAA-treated patients remained on vasopressors at end infusion. The primary aim of this study was to investigate, in severe sepsis patients with persistent vasopressor dependency at the end of 96-hour commercial DAA treatment, whether continued administration of DAA for up to a further 72 hours results in more rapid resolution of vasopressor dependency compared with placebo (no DAA after commercial DAA infusion). Secondary objectives were mortality, biomarker changes, and safety.
A multicentre, double-blind, randomized, placebo-controlled study. Owing to slower than anticipated recruitment, the planned sample size was reduced from 275 to 200.
Two hundred and one patients (64 centers, nine countries) were entered, 199 randomized, 193 received study medication for any length time (ITT population). There were clinically relevant differences in baseline characteristics, with more DAA patients having a cardiovascular SOFA score of 4 compared with placebo (78.7% vs 64.3%, P = 0.03), having higher median doses of norepinephrine (0.26 μg/kg/min vs 0.16 μg/kg/min, P = 0.03) and tending to have lower protein C levels (66.8% vs 72.9%, P = 0.23). There was no statistically significant difference for primary endpoint resolution of vasopressor dependency (log-rank P = 0.42), nor in the proportion of resolvers (34.0% DAA vs 40.4% placebo, P = 0.36). Day 28 mortality was 39.8% in the DAA group, 32.3% in the placebo group (P = 0.28). The DAA group had significantly lower percentage change in D-dimers (21.9% vs 63.2%, P < 0.001), driven primarily by a larger increase in the placebo group. By end infusion, protein C levels were similar (81.7% DAA vs 79.4% placebo, P = 0.23). One serious bleeding event occurred during the infusion period in each group.
Continued DAA for up to a further 72 hours after commercial drug administration did not result in more rapid resolution of vasopressor-dependent hypotension, despite anticipated effects on D-dimer and protein C levels, and was associated with an acceptable safety profile. The reduction in the planned sample size combined with baseline imbalances in protein C levels and vasopressor requirements may have limited our ability to show clinical benefit.