Effects of drotrecogin alfa (activated) in human endotoxemia.

In a phase III clinical trial, drotrecogin alfa (activated) was shown to improve survival and promote faster improvement of cardiovascular and respiratory dysfunction in patients with severe sepsis. To further examine mechanisms involved in the action of this drug, a healthy human endotoxin model was used. Healthy volunteers (eight per group) received drotrecogin alfa (activated) or placebo intravenously for 8 h in a randomized, double-blind, controlled manner. After 2 h of study drug infusion, endotoxin (2 ng/kg) was infused and measurement of physiologic responses and biomarkers continued for 24 h. Consistent with results from severe sepsis clinical trials, drotrecogin alfa (activated) improved mean arterial pressure during the period of infusion after endotoxin exposure. In contrast to severe sepsis clinical trials using drotrecogin alfa (activated) but similar to another human endotoxin study, no significant antithrombotic, profibrinolytic, or anti-inflammatory effects were observed. These results suggest a novel role for drotrecogin alfa (activated) in the human endotoxin model.

Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment.

OBJECTIVE: To provide further evidence for the efficacy and safety of drotrecogin alfa (activated) treatment in severe sepsis. DESIGN: Single-arm, open-label, trial of drotrecogin alfa (activated) treatment in severe sepsis patients. Enrollment began in March 2001 and day-28 follow-up completed in January 2003. SETTING: ENHANCE took place in 25 countries at 361 sites. PATIENTS: Patients with known or suspected infection, three or four systemic inflammatory response syndrome criteria, and one or more sepsis-induced organ dysfunctions. Of 2,434 adults entered, 2,378 received drotrecogin alfa (activated), and of these, 2,375 completed the protocol. INTERVENTIONS: Drotrecogin alfa (activated) was infused at a dose of 24 mug/kg/hr for 96 hrs. MEASUREMENTS AND MAIN RESULTS: The 28-day all-cause mortality approximated that observed in PROWESS (25.3% vs. 24.7%). Although patients in ENHANCE had increased serious bleeding rates compared with patients in the drotrecogin alfa (activated) arm of PROWESS (during infusion, 3.6% vs. 2.4%; postinfusion, 3.2% vs. 1.2%; 28-day, 6.5% vs. 3.5%), increased postinfusion bleeding suggested a higher background bleeding rate. Intracranial hemorrhage was more common in ENHANCE than PROWESS (during infusion, 0.6% vs. 0.2%; 28-day, 1.5% vs. 0.2%). The incidence of fatal intracranial hemorrhage was the same during infusion (0.2%) and higher at 28 days (0.5% vs. 0.2%). ENHANCE patients treated within 0-24 hrs from their first sepsis-induced organ dysfunction had lower observed mortality rate than those treated after 24 hrs (22.9% vs. 27.4%, p = .01). CONCLUSIONS: ENHANCE provides supportive evidence for the favorable benefit/risk ratio observed in PROWESS and suggests that more effective use of drotrecogin alfa (activated) might be obtained by initiating therapy earlier.