The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model

Journal of Thrombosis and Haemostasis

Volumn 1, Issue 3, 2003, Pages 587-594

  Klement, P ^a,b   Carlsson, S ^c   Rak, J ^a   Liao, P ^a   Vlasin, M ^a,b   Stafford, A ^a   Johnston, M ^a   Weitz, J I ^a  

^a MCMASTER UNIVERSITY   (Canada)

^b UNIVERSITY OF VETERINARY AND PHARMACEUTICAL SCIENCES   (Czech Republic)

^c ASTRAZENECA R AND D   (Sweden)

Author keywords

Anticoagulants; Hirudin; Melagatran; Thrombin inhibitors; Thrombosis

Indexed keywords

AZETIDINE DERIVATIVE; BENZYLAMINE DERIVATIVE; DRUG DERIVATIVE; FIBRIN; FIBRINOLYTIC AGENT; GLYCINE; HIRUDIN DERIVATIVE; MELAGATRAN; THROMBIN;

ANIMAL; ANTICOAGULANT THERAPY; ARTERY; ARTICLE; BLEEDING; COMPARATIVE STUDY; DOSE RESPONSE; DRUG ANTAGONISM; MALE; METABOLISM; RABBIT; RISK ASSESSMENT; THROMBOSIS;

ANIMALS; ARTERIES; AZETIDINES; BENZYLAMINES; DOSE-RESPONSE RELATIONSHIP, DRUG; FIBRIN; FIBRINOLYTIC AGENTS; GLYCINE; HEMORRHAGE; HIRUDIN THERAPY; HIRUDINS; MALE; RABBITS; RISK ASSESSMENT; THROMBIN; THROMBOSIS;

EID: 0642372601     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1046/j.1538-7836.2003.00060.x     Document Type: Article

References (35)

1. Fuster V, Stein B, Ambrose JA, Badimon L, Badimon JJ, Chesebro JH. Atherosclerotic plaque rupture and thrombosis. Evolving concepts. Circulation 1990; 82 (Suppl. 3): II47-59.
2. Bar-Shavit R, Eldor A, Vlodavsky I. Binding of thrombin to subendothelial extracellular matrix. Protection and expression of functional properties. J Clin Invest 1989; 84: 1096-104.
3. Weitz J, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-91.
4. Hogg PJ, Jackson CM. Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III implications for heparin efficacy. Proc Natl Acad Sci USA 1989; 86: 3619-23.
5. Weitz JI, Leslie B, Hudoba M. Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation 1998; 97: 544-52.
6. Kumar R, Beguin S, Hemker HC. The influence of fibrinogen and fibrin on thrombin generation - evidence for feedback activation of the clotting system by clot bound thrombin. Thromb Haemost 1994; 72: 713-21.
7. Kumar R, Beguin S, Hemker HC. The effect of fibrin clots and clotbound thrombin on the development of platelet procoagulant activity. Thromb Haemost 1995; 74: 962-8.
8. Eitzman DT, Chi L, Saggin L, Schwartz RS, Lucchesi BR, Fay WP. Heparin neutralization by platelet-rich thrombi. Role of platelet factor 4. Circulation 1994; 89: 1523-9.
9. GUSTO IIa Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators. Circulation 1994; 90: 1631-7.
10. Antman EM. Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial. Circulation 1994; 90: 1624-30.
11. Neuhaus K-L, von Essen R, Tebbe U et al. Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer. Circulation 1994; 90: 1638-42.
12. GUSTO I, Ib Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators. N Engl J Med 1996; 335: 775-82.
13. Antman EM. Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation 1996; 94: 911-21.
14. OASIS-2 Investigators. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularization procedures in patients with acute myocardial ischemia without ST elevation: a randomised trial. Organization to Assess Strategies for Ischemic Syndromes (OASIS)-2 Investigators. Lancet 1999; 353: 429-38.
15. Greinacher A, Lubenow N. Recombinant hirudin in clinical practice: focus on lepirudin. Circulation 2000; 103: 1479-84.
16. Lunven C, Gauffeny C, Lecoffre C, O'Brien DP, Roome NO, Berry CN. Inhibition of argatroban, a specific thrombin inhibitor, of platelet activation by fibrin clot-associated thrombin. Thromb Haemost 1996; 75: 154-60.
17. Gast A, Tschopp TB, Schmid G, Hilpert K, Ackermann J. Inhibition of clot-bound and free (fluid-phase thrombin) by a novel synthetic thrombin inhibitor (Ro 46-6240), recombinant hirudin and heparin in human plasma. Blood Coagul Fibrinolysis 1994; 5: 879-87.
18. Gustafsson D, Antonsson T, Bylund R et al. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 1998; 79: 110-8.
19. Gustafsson D, Nystom J, Carlsson S et al. The direct thrombin inhibitor melagatran and its oral prodrug H376/95. intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb Res 2001; 101: 171-81.
20. Kawasaki K, Miyano M, Hirase M, Iwamoto M. Amino acids and peptides. XVIII. Synthetic peptides related to N-terminal portion of fibrin alpha-chain and their inhibitory effect on fibrinogen/thrombin clotting. Chem Pharm Bull (Tokyo) 1993; 41: 975-7.
21. Becker DL, Fredenburgh JC, Stafford AR, Weitz JI. Exosites 1 and 2 are essential for protection of fibrin-bound thrombin from heparin-catalyzed inhibition by antithrombin and heparin cofactor II. J Biol Chem 1999; 274: 6226-33.
22. Klement P, Liao P, Bajzar L. A novel approach to arterial thrombolysis. Blood 1999; 94: 2735-43.
23. Klement P, Liao P, Hirsh J, Johnston M, Weitz JI. Hirudin causes more bleeding than heparin in a rabbit ear bleeding model. J Lab Clin Med 1998; 132: 181-5.
24. Proctor RR, Rapaport SI. The partial thromboplastin time with kaolin. Am J Clin Pathol 1961; 36: 212-9.
25. Seeger WH, Smith HP. Factors which influence the activity of purified thrombin. Am J Physiol 1942; 137: 348-54.
26. Eisenberg PR, Siegel JE, Abendschein DR, Miletich JP. Importance of factor Xa in determining the procoagulant activity of whole-blood clots. J Clin Invest 1993; 91: 1877-83.
27. Carter CJ, Kelton JG, Hirsh J, Cerskus A, Santos AV, Gent M. The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. Blood 1982; 59: 1239-45.
28. Cade JF, Buchanan MR, Boneu B et al. A comparison of the antithrombotic and haemorrhagic effects of low molecular weight heparin fractions: the influence of the method of preparation. Thromb Res 1984; 35: 613-25.
29. Leizorovicz A. Comparison of the efficacy and safety of low molecular weight heparins and unfractionated heparin in the initial treatment of deep venous thrombosis. An update meta-analysis. Drugs 1996; 7: 30-7.
30. Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130: 800-9.
31. Bittl JA, Strony J, Brinker JA et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med 1995; 333: 764-9.
32. Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142: 952-9.
33. Elg M, Gustafsson D, Deinum J. The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis. Thromb Haemost 1997; 78: 1286-92.
34. Fuentes-Prior P, Iwanaga Y, Huber R et al. Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Nature 2000; 404: 518-25.
35. Elg M, Gustafsson D, Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 1999; 94: 187-97.