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

Jean Louis Vincent, Gordon R. Bernard, Richard Beale, Christopher Doig, Christian Putensen, Jean Francois Dhainaut, Antonio Artigas, Roberto Fumagalli, William Macias, Theressa Wright, Kar Wong, David P. Sundin, Mary Ann Turlo, Jonathan Janes

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283 Citations (Scopus)

Abstract

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. Enrolment 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 μg/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 drofrecogin 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 (22.3% 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. Copyright © 2005 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.
Original languageEnglish
Pages (from-to)2266-2277
JournalCritical Care Medicine
Volume33
DOIs
Publication statusPublished - 1 Jan 2005

Keywords

  • Activated protein C
  • Clinical trial
  • Drotrecogin alfa (activated)
  • ENHANCE
  • Early treatment
  • Severe sepsis

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