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

Crit Care Med. 2005 Oct;33(10):2266-77. doi: 10.1097/01.ccm.0000181729.46010.83.


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.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Infective Agents / adverse effects
  • Anti-Infective Agents / therapeutic use*
  • Drug Administration Schedule
  • Female
  • Follow-Up Studies
  • Humans
  • Intracranial Hemorrhages / chemically induced
  • Male
  • Middle Aged
  • Protein C / adverse effects
  • Protein C / therapeutic use*
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / therapeutic use
  • Sepsis / drug therapy*
  • Sepsis / mortality
  • Survival Rate
  • Treatment Outcome


  • Anti-Infective Agents
  • Protein C
  • Recombinant Proteins
  • drotrecogin alfa activated