Intensive Care Medicine

, Volume 24, Issue 7, pp 663–672

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


    • Clinical Research DepartmentCenteon Pharma GmbH
  • H. Heinrichs
    • Clinical Research DepartmentCenteon Pharma GmbH
  • U. Delvos
    • Clinical Research DepartmentCenteon Pharma GmbH
  • M. Lamy
    • Centre Hospitalier Universitaire de Liège
  • L. G. Thijs
    • Medical Intensive Care UnitFree University of Amsterdam
  • H. O. Keinecke
    • Biometrics DepartmentCenteon Pharma GmbH
  • H. P. Schuster
    • Municipal HospitalHildesheim
  • F. R. Matthias
    • Medical CentreUniversity of Giessen
  • F. Fourrier
    • Service de Réanimation PolyvalenteHôpital B, CHRU

DOI: 10.1007/s001340050642

Cite this article as:
Eisele, B., Heinrichs, H., Delvos, U. et al. Intensive Care Med (1998) 24: 663. doi:10.1007/s001340050642


Objectives: To evaluate the safety and potential efficacy of antithrombin III (AT III) in reducing mortality in patients with severe sepsis.

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

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

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

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

Measurements and 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.

Key words

Antithrombin IIISepsisMultiorgan failureClinical trialMeta-analysis

Copyright information

© Springer-Verlag 1998