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A Randomized Controlled Trial

Brian L. Warren, MD; Alain Eid, MD; Pierre Singer, MD; Subramanion S. Pillay, MBChB,RCP,RCS; Peder Carl, MD; Ivan Novak, MD; Pavel Chalupa, MD,PhD; Alan Atherstone, MD,ChB,FRCS; Istvan Pénzes, DSc; Andrezej Kübler, MD,PhD; Sigurd Knaub, PhD; Heinz-Otto Keinecke; Hubert Heinrichs, MD; Fritz Schindel; Mathias Juers, MD; Roger C. Bone, MD; Steven M. Opal, MD; for the KyberSept Trial Study Group

JAMA. 2001;286:1869-1878.

Context  Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock. Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients.

Objective  To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock.

Design and Setting  Double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000.

Patients  A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin).

Main Outcome Measure  All-cause mortality 28 days after initiation of study medication.

Results  Overall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P = .94). Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups. In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P = .08). This trend became significant after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo group; P = .03). In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001).

Conclusions  High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin.

Author Affiliations: Department of Surgery, Tygerberg Hospital and the University of Stellenbosch, Tygerberg, South Africa (Dr Warren); Critical Care Division, University of Oklahoma Health Science Center, Oklahoma City (Dr Eid); Critical Care Medicine, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel (Dr Singer); Department of Surgery, Livingston Hospital, Port Elizabeth, South Africa (Dr Pillay); Critical Care Medicine, Hvidovre University Hospital, Hvidovre, Denmark (Dr Carl); Intensive Care Unit, Charles University Hospital, Pilsen, Czech Republic (Dr Novak); Clinic of Infectious Diseases, Brno-Bohunice, Czech Republic (Dr Chalupa); Department of Surgery, Frere Hospital, East London, South Africa (Dr Atherstone); Department of Anaesthesiology and Intensive Care, Semmelweiss Medical University, Budapest, Hungary (Dr Pénzes); Department of Anaesthesiology and Intensive Therapy, Wroclaw University of Medicine, Wroclaw, Poland (Dr Kübler); Aventis Behring, Marburg, Germany (Drs Knaub, Heinrichs, Juers, and Messrs Keinecke and Schindel); Critical Care Division, Rush Medical Center, Chicago, Ill (Dr Bone); and Infectious Disease Division, School of Medicine, Brown University, Providence, RI (Dr Opal).
   Dr Bone is deceased.

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