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.


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.
Vincent
Jean-Louis
JL
Department of Intensive Care, Erasme University Hospital and University of Brussels, Brussels, Belgium.
Bernard
Gordon R
GR
Beale
Richard
R
Doig
Christopher
C
Putensen
Christian
C
Dhainaut
Jean-Francois
JF
Artigas
Antonio
A
Fumagalli
Roberto
R
Macias
William
W
Wright
Theressa
T
Wong
Kar
K
Sundin
David P
DP
Turlo
Mary Ann
MA
Janes
Jonathan
J
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
D000890:Anti-Infective Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated