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

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

• References

• 1 Angus DC, Linde-Zwirble WT, Lidicker J. et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29: 1303-10.
• 2 Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time?. Crit Care Med 1998; 26: 2078-86.
• 3 Bernard GR, Vincent JL, Laterre PF. et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group Efficacy and safety of recombinant activated human proteinC for severe sepsis. New Engl J Med 2001; 344: 699-709.
• 4 Warren BL, Eid A, Singer P. et al. KyberSept Trial Study Group. Caring for the critically ill patient. High-ddose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286: 1869-78.
• 5 Abraham E, Reinhart K, Opal S. et al. OPTIMIST Trial Study Group. Efficacy and safety of Tifacogin (Recombinant Tissue Factor Pathway Inhibitor) in severe sepsis. JAMA 2003; 290: 238-47.
• 6 Roemisch J, Gray E, Hoffmann JN. et al. Antithrombin: a new look at the actions of a serine protease inhibitor. Blood Coagul Fibrinolysis 2002; 13: 657-70.
• 7 Hoffmann JN, Vollmar B, Laschke MW. et al. Adverse effect of heparin on antithrombin action during endotoxemia: microhemodynamic and cellular mechanisms. Thromb Haemost 2002; 88: 242-52.
• 8 Fourrier F, Chopin C, Huart JJ. et al. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 1993; 104: 882-8.
• 9 Inthorn D, Hoffmann JN, Hartl WH. et al. Antithrombin III supplementation in severe sepsis: beneficial effects on organ dysfunction. Shock 1997; 08: 328-34.
• 10 Schuster HP, Eisele B, Keinecke HO. et al. S-AT III study: antithrombin III in patients with sepsis. Int Care Med 1998; 24 (Suppl. 01) 76.
• 11 Eisele B, Lamy M, Thijs LG. et al. Antithrombin III in patients with severe sepsis. Intensive Care Medicine 1998; 24: 663-72.
• 12 Corrigan JJ, Jordan CM. Heparin therapy in septicemia with disseminated intravascular coagulation. N Engl J Med 1970; 15: 778-82.
• 13 Pulletz S, Lehmann C, Volk T. et al. Influence of heparin and hirudin on endothelial binding of antithrombin in experimental thrombinemia. Crit Care Med 2000; 28: 2881-6.
• 14 Opal SM, Kessler CM, Roemisch J. et al. Antithrombin, heparin and heparan sulfate. Crit Care Med. 2002 30. Suppl S325-S331.
• 15 Sleight P. Debate: Subgroup analyses in clinical trials: fun to look at but don’t believe them!. Curr Control Trials Cardiovasc Med 2000; 01: 25-7.
• 16 Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/Norh American multicenter study. JAMA 1993; 270: 2957-63.
• 17 Le Gall JR, Lemeshow S, Leleu G. et al. A Customized probability models for early severe sepsis in adult intensive care patients. JAMA 1995; 273: 644-50.
• 18 Kleinbaum DG, Kupper LL, Morgenstern H. Chapter 15. In: Epidemiologic research. Principles and quantitative methods. Wadsworth, Belmont: 1982: 283-311.
• 19 Davidson BL, Geerts WH, Lensing AWA. Low-dose heparin for severe sepsis. N Engl J Med 2002; 347: 1036-7.
• 20 Freebairn R, Ramsay S, Gomersall C. Low dose heparin for severe sepsis. N Engl J Med 2003; 348: 1185-6.
• 21 Davidson BL, Geerts WH, Lensing AWA. Low-dose heparin for severe sepsis. Authors reply. N Engl J Med 2003; 348: 1185-6.
• 22 Langer M, Riccardi F, Piovella F. et al. Use of anticoagulants in patients with sepsis. JAMA 2002; 287: 448-9.
• 23 Opal SM, Knaub S, Keinecke HO. Use of anticoagulants in patients with sepsis. Authors reply. JAMA 2002; 287: 448-9.
• 24 Opal SM. Unintended bias, clinical trial results, and the heparin post hoc crossover fallacy. Crit Care Med 2004; 32: 874-5.
• 25 Manios SG, Kanakoudi F, Maniati E. Fulminant meningococcemia. Heparin therapy and survival rate. Scand J Infect Dis 1971; 03: 127-33.
• 26 Blum D, Fondu P, Denolin-Reubens R. et al. Early heparin therapy in 60 children with acute meningococcemia. Acta Chirurgica Belgica 1973; 04: 288-97.
• 27 Wada H. Disseminated intravascular coagulation. Clinica Chimica Acta 2004; 344: 13-21.
• 28 Levi M. Pathogenesis and treatment of disseminated intravascular coagulation in the septic patient. J Crit Care 2001; 16: 167-77.
• 29 Blauhut B, Kramar H, Vinazzer H. et al. Substitution of antithrombin III in shock and DIC: a randomized study. Thromb Res 1985; 39: 81-9.
• 30 Schoots IG, Levi M, van Vliet AK. et al. Inhibition of coagulation and inflammation by activated proteinC or antithrombin reduces intestinal ischemia/reperfusion injury in rats. Crit Care Med 2004; 32: 1375-83.
• 31 Derhaschnig U, Pernerstorfer T, Knechtelsdorfer M. et al. Evaluation of anti-inflammatory and antiadhesive effects of heparins in human endotoxemia. Crit Care Med 2003; 31: 1108-12.
• 32 Mammen EF. The haematological manifestations of sepsis. J Antimicrob Chemother 1998; 41: 17-24.
• 33 Luster AD. Mechanisms of disease: chemokines - chemotactic cytokines that mediate inflammation. N EnglJ Med 1998; 338: 436-45.
• 34 Oelschlager C, Romisch J, Staubitz A. et al. Antithrombin III inhibits nuclear factor kB activation in human monocytes and vascular endothelial cells. Blood 2002; 99: 4015-20.