Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.
BACKGROUND
In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death.


METHODS
We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score <25 or single-organ failure) to receive an intravenous infusion of placebo or DrotAA (24 microg per kilogram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, multicenter trial. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. In-hospital mortality within 90 days after the start of the infusion was measured, and safety information was collected.


RESULTS
Enrollment in the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA. The study enrolled 2640 patients and collected data on 2613 (1297 in the placebo group and 1316 in the DrotAA group) at the 28-day follow-up. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group; P=0.34; relative risk, 1.08; 95 percent confidence interval, 0.92 to 1.28) or in in-hospital mortality (20.5 percent vs. 20.6 percent; P=0.98; relative risk, 1.00; 95 percent confidence interval, 0.86 to 1.16). The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4 percent vs. 1.2 percent, P=0.02) and the 28-day study period (3.9 percent vs. 2.2 percent, P=0.01).


CONCLUSIONS
The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.
Abraham
Edward
E
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver 80262, USA. edward.abraham@UCHSC.edu
Laterre
Pierre-François
PF
Garg
Rekha
R
Levy
Howard
H
Talwar
Deepak
D
Trzaskoma
Benjamin L
BL
François
Bruno
B
Guy
Jeffrey S
JS
Brückmann
Martina
M
Rea-Neto
Alvaro
A
Rossaint
Rolf
R
Perrotin
Dominique
D
Sablotzki
Armin
A
Arkins
Nancy
N
Utterback
Barbara G
BG
Macias
William L
WL
D018806:APACHE; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D017052:Hospital Mortality; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011486:Protein C / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012307:Risk Factors; D018805:Sepsis / Q000145:classification / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D017211:Treatment Failure
D000890:Anti-Infective Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated