Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis.
OBJECTIVE
To evaluate the safety and potential efficacy of antithrombin III (AT III) in reducing mortality in patients with severe sepsis.


METHODS
Prospective, randomized, placebo-controlled, double-blind, phase II, multicenter, multinational clinical trial.


METHODS
Seven academic medical center intensive care units (ICU) in Belgium, Denmark, the Netherlands, Norway and Sweden.


METHODS
42 patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III or placebo.


METHODS
Patients received either an intravenous loading dose of 3000 IU AT III followed by a maintenance dose of 1500 IU every 12 h for 5 days or equivalent amounts of placebo.


RESULTS
All patients were evaluated for safety and for 30-day all-cause mortality.


CONCLUSIONS
The administration of AT III was safe and well-tolerated. It was followed by a 39 % reduction in 30-day all-cause mortality (NS). The reduction in mortality was accompanied by a considerably shorter stay in the ICU. Patients treated with AT III exhibited a better performance in overall severity of illness and organ failure scores (Acute Physiology and Chronic Health Evaluation II, multiple organ failure, organ system failure), which was noticeable soon after initiation of treatment. Patients treated with AT III demonstrated a better resolution of pre-existing organ failures and a lower incidence of new organ failures during the observation period. A meta-analysis comprising this and two other double-blind, placebo-controlled trials with AT III with a total of 122 patients suffering from severe sepsis confirms the positive trend. The results of the meta-analysis demonstrate a 22.9 % reduction in 30-day all-cause mortality in patients treated with AT III. Although still too small to be confirmative, the meta-analysis clearly points to the fact that a sufficiently powered phase III trial is warranted to prove whether AT III has a beneficial role in the treatment of severe sepsis.
Clinical Research Department, Centeon Pharma GmbH, Marburg, Germany. bernd.eisele@solvay.com
B
B
Eisele
M
M
Lamy
L G
LG
Thijs
H O
HO
Keinecke
H P
HP
Schuster
F R
FR
Matthias
F
F
Fourrier
H
H
Heinrichs
U
U
Delvos
D018806:APACHE; D000368:Aged; D000990:Antithrombin III / Q000627:therapeutic use*; D002423:Cause of Death; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007902:Length of Stay / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000209:etiology; D011446:Prospective Studies; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D016019:Survival Analysis
D000990:Antithrombin III