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

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: http://dx.doi.org/10.1160/TH05-07-0530
Issue: 2006: 95/5 (May) pp. 755-916
Pages: 850-856

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

Johannes N. Hoffmann1,2,3 , Christian J. Wiedermann4 , Mathias Juers5 , Helmut Ostermann 2 , Joachim Kienast 6 , Josef Briegel3 , Richard Strauss 7 , Brian L. Warren8 , Steven M. Opal9 ; for the KyberSept investigators
1 Departments of Surgery, 2 Haematology/Oncology and 3 Anaesthesiology, Ludwig-Maximilian University of Munich, Munich, Germany; 4 Department of Medicine, Central Hospital of the Province of Bolzano, Bolzano, Italy; 5 Department of Medical Affairs, ZLB

Keywords

Survival, heparin, bleeding, antithrombin III, severe sepsis

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 thromboembolicday-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. 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

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