title: 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.
abstract: OBJECTIVE
  To provide further evidence for the efficacy and safety of drotrecogin alfa (activated) treatment in severe sepsis.
  
  
  METHODS
  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.
  
  
  METHODS
  ENHANCE took place in 25 countries at 361 sites.
  
  
  METHODS
  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.
  
  
  METHODS
  Drotrecogin alfa (activated) was infused at a dose of 24 mug/kg/hr for 96 hrs.
  
  
  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.
authors.affiliation: Department of Intensive Care, Erasme University Hospital and University of Brussels, Brussels, Belgium.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vincent
authors.forename: Gordon R
authors.initials: GR
authors.lastname: Bernard
authors.forename: Richard
authors.initials: R
authors.lastname: Beale
authors.forename: Christopher
authors.initials: C
authors.lastname: Doig
authors.forename: Christian
authors.initials: C
authors.lastname: Putensen
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Dhainaut
authors.forename: Antonio
authors.initials: A
authors.lastname: Artigas
authors.forename: Roberto
authors.initials: R
authors.lastname: Fumagalli
authors.forename: William
authors.initials: W
authors.lastname: Macias
authors.forename: Theressa
authors.initials: T
authors.lastname: Wright
authors.forename: Kar
authors.initials: K
authors.lastname: Wong
authors.forename: David P
authors.initials: DP
authors.lastname: Sundin
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Turlo
authors.forename: Jonathan
authors.initials: J
authors.lastname: Janes
mesh_terms: D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D020300:Intracranial Hemorrhages / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated