Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin

Johannes N. Hoffmann; Christian J. Wiedermann; Mathias Juers; Helmut Ostermann; Joachim Kienast; Josef Briegel; Richard Strauss; Brian L. Warren; Steven M. Opal; for the KyberSept investigators

doi:10.1160/TH05-07-0530

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(05): 850-856
DOI: 10.1160/TH05-07-0530

Wound Healing and Inflammation/Infection

Schattauer GmbH

Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin

Johannes N. Hoffmann

¹Departments of Surgery, Ludwig-Maximilian University of Munich, Munich, Germany

²Haematology/Oncology, Ludwig-Maximilian University of Munich, Munich, Germany

³Anaesthesiology, Ludwig-Maximilian University of Munich, Munich, Germany

,

Christian J. Wiedermann

⁴Department of Medicine, Central Hospital of the Province of Bolzano, Bolzano, Italy

,

Mathias Juers

⁵Department of Medical Affairs, ZLB Behring GmbH, Hattersheim, Germany

,

Helmut Ostermann

²Haematology/Oncology, Ludwig-Maximilian University of Munich, Munich, Germany

,

Joachim Kienast

⁶Department of Internal Medicine, Haematology/Oncology, Westfaelische Wilhelms University, Muenster, Germany

,

Josef Briegel

³Anaesthesiology, Ludwig-Maximilian University of Munich, Munich, Germany

,

Richard Strauss

⁷Department of Medicine I, University of Erlangen-Nuremberg, Erlangen, Germany

,

Brian L. Warren

⁸Department of Surgery, University of Stellenbosch, Tygerberg, South Africa

,

Steven M. Opal

⁹Infectious Disease Division, Brown University School of Medicine, Memorial Hospital of Rhode Island, Pawtucket, Rhode Island, USA

,

for the KyberSept investigators

› Author Affiliations

Abstract

Summary

A randomised, prospective, placebo-controlled phase III multicentre clinical trial (KyberSept) has been performed to test the efficacy of high-dose antithrombin therapy in patients with severe sepsis. Concomitant low-dose heparin has been routinely given in two thirds of patients for deep vein thrombosis prophylaxis.This study analyses heparin – antithrombin interactions in terms of long-term mortality, adverse events, and thromboembolic events. From a total of 2,314 patients with severe sepsis (placebo: n=1,157; antithrombin: n=1,157) 1,616 patients (placebo: 811, antithrombin: 805) received heparin concomitantly with study drug (antithrombin 30,000 IU) over four days, whereas 698 patients (346 and 352, respectively) did not. In patients with no concomitant heparin, 28-day mortality was lower with antithrombin than with placebo (37.8% vs. 43.6%; absolute reduction: 5.8%; risk ratio: 0.860 [0.725–1.019]), which increased until day-90 (44.9% vs. 52.5%; absolute reduction: 7.6%; risk ratio: 0.851 [0.735–0.987]). In patients with concomitant heparin, no effect of antithrombin on mortality was seen (28-day mortality: 39.4% vs. 36.6%; absolute increase: 2.8%; risk ratio: 1.08 [0.96–1.22]). Frequency of use of concomitant heparin increased during conduct of the study. Increased bleeding incidences were reported with antithrombin plus concomitant heparin as compared to antithrombin alone. Rates of thromboembolic events were similar when antithrombin was given with or without concomitant heparin. In the treatment of severe sepsis, high-dose antithrombin may sufficiently protect against development of venous thromboembolism when no concomitant heparin is given. Combined administration of the two increases bleeding risk and probably abolishes efficacy of antithrombin.

Keywords

Heparin - antithrombin III - severe sepsis - bleeding - survival

Full Text

References

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