Skip Navigation

European Heart Journal 1999 20(7):506-518; doi:10.1053/euhj.1998.1336
Copyright © 1999 by the European Society of Cardiology.
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (19)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Linder, R.
Right arrow Articles by Wallentin, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Linder, R.
Right arrow Articles by Wallentin, L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

The effect of a low molecular mass thrombin inhibitor, inogatran, and heparin on thrombin generation and fibrin turnover in patients with unstable coronary artery disease

R. Lindera,f1, J. Oldgrenb, N. Egbergc, L. Gripd, G. Larsone, A. Siegbahnf and L. Wallentinb

a Department of Cardiology, Karolinska Hospital, Stockholm, Sweden
b Department of Laboratory Medicine, Karolinska Hospital, Stockholm, Sweden
c Department of Cardiology, Uppsala University Hospital, Uppsala, Sweden
d Department of Laboratory Medicine, Uppsala University Hospital, Uppsala, Sweden
e Department of Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden
f Department of Laboratory Medicine, Sahlgrenska University Hospital, Göteborg, Sweden

revised September 22, 1998; accepted September 30, 1998

Abstract

Aim This study evaluated a novel specific thrombin inhibitor, inogatran, in comparison with unfractionated heparin, with regard to markers for coagulation activity in patients with unstable coronary artery disease.

Methods and Results In the Thrombin Inhibition In Myocardial ischaemia (TRIM) study patients were randomized to one of three different doses of inogatran or to unfractionated heparin, given intravenously over 72h. In a subpopulation of 320 patients, markers for coagulation activity were measured at baseline, during and after the study infusion.

Prothrombin fragment 1+2, indicating thrombin generation, decreased in the low, medium and high dose inogatran groups and in the heparin group during the first 6h of treatment by 12%, 15%, 21% and 26%, respectively. From 6h to 72h after the start of infusion the levels changed by –7%, –6%, –4% and +34%, respectively. The increase in the heparin group continued after the infusion was stopped. Thrombin–antithrombin complex, also indicating thrombin generation, decreased by 0%, 2%, 18% and 22%, respectively, during the first 6h of treatment. During the same period soluble fibrin, an intermediate in fibrin formation, increased both in the low and medium inogatran group by 9%, while a decrease by 4% and 18%, respectively, was seen in the high dose inogatran group and in the heparin group. Fibrin dissolution, as measured by fibrin D-dimer, decreased during the first 24h of treatment by 20%, 18%, 18% and 20%, respectively. The first 24h after discontinuation of infusion, fibrin D-dimer increased by 6%, 23%, 25% and 44%, respectively.After 72h, at the end of infusion, patients treated with inogatran, to a larger extent than those given heparin, had suffered from death, myocardial infarction or refractory angina pectoris. After 7 days this trend was less marked.

Conclusion The more pronounced decrease in thrombin generation and fibrin turnover during the first 6h of infusion, and the later increase in thrombin generation and fibrin turnover, in the heparin group, as compared to the inogatran groups, may be related to the lower clinical event rate during infusion with heparin compared with inogatran and the recurrence of ischaemic events, early after cessation of heparin infusion.

Key Words: Unstable coronary artery disease, heparin, direct thrombin inhibition, biochemical markers, thrombin generation, fibrin

f1 Correspondence : Rikard Linder, MD, Department of Cardiology, Karolinska Hospital, S-171 76 Stockholm, Sweden.

References

  1. Neri Serneri GF, Gensini F, Poggesi L. Effect of heparin, aspirin, or alteplase in reduction of myocardial ischemia in refractory unstable angina. Lancet. 1990;335:615–618[CrossRef][ISI][Medline]
  2. Neri Serneri GF, Modesti A, Gensini F. Randomized comparison of subcutaneous heparin, intravenous heparin, and aspirin in unstable angina. Lancet. 1995;345:1201–1204[CrossRef][ISI][Medline]
  3. Théroux P, Waters D, Qui S, McCans J, de Guise P, Juneau M. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation. 1993;88:2045–2048[Abstract/Free Full Text]
  4. Wallentin L, Ohlsson J, Swahn E. Low-molecular weight heparin during instability in coronary artery disease. Lancet. 1996;347:561–568[CrossRef][ISI][Medline]
  5. 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;5:879–887[ISI][Medline]
  6. N Engl J Med. 1996;335:775–782[Abstract/Free Full Text]
  7. Bittl J, Strony J, Brinker J. Treatment with bivalirudin (hirulog) as compared with heparin during coronary angio-plasty for unstable or postinfarction angina. N Engl J Med. 1995;333:764–769[Abstract/Free Full Text]
  8. Topol EJ, Fuster V, Harrington R. Recombinant hirudin for unstable angina pectoris. Circulation. 1994;89:1557–1566[Abstract/Free Full Text]
  9. Théroux P, Pérez-Villa F, Waters D, Lespérance J, Shabani F, Bonan R. Randomized double-blind comparison of two doses of hirulog with heparin as adjunctive therapy to streptokinase to promote early patency of the infarct related artery in acute myocardial infarction. Circulation. 1995;91:2132–2139[Abstract/Free Full Text]
  10. Eur Heart J. 1997;18:1416–1425[Abstract/Free Full Text]
  11. Ødegard OR, Lie M, Abildgaard U. Heparin cofactor activity measured with an amidolytic method. Thromb Res. 1975;6:287–294[CrossRef][ISI][Medline]
  12. Pelzer H, Schwarz A, Stüber W. Determination of Human Prothrombin Activation Fragments 1+2 in Plasma with an antibody against a Synthetic peptide. Thromb Haemost. 1991;65:153–159[ISI][Medline]
  13. Pelzer H, Schwarz A, Heimburger N. Determination of human Thrombin–Antithrombin III complex in plasma with an enzyme-linked immunosorbent assay. Thromb Haemost. 1988;59:101–106[ISI][Medline]
  14. Wiman B, Ranby M. Determination of soluble fibrin in plasma by rapid and quantative spectrophotometric assay. Thromb Haemost. 1986;55:189–193[ISI][Medline]
  15. Elms MJ, Bunce IH, Bundesen PG. Measurement of crosslinked fibrin degradation products- an immunoassay using monoclonal antibodies. Thromb Haemost. 1983;50:591[ISI][Medline]
  16. Gold H, Torres F, Garabedian H. Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris. J Am Coll Cardiol. 1993;21:1039–1047[Abstract]
  17. Zoldhelyi P, Bichler J, Owen W. Persistent thrombin generation in humans during specific thrombin inhibition with hirudin. Circulation. 1994;90:2671–2678[Abstract/Free Full Text]
  18. Circulation. 1994;90:1631–1637[Abstract/Free Full Text]
  19. Rao AK, Sun L, Chesebro JH. Distinct effects of recombinant desulfatohirudin (Revasc) and heparin on plasma levels of fibrinopeptide A and prothrombin fragment F1.2 in unstable angina. Circulation. 1996;94:2389–2395[Abstract/Free Full Text]
  20. Elg M, Gustavsson 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;Suppl:496–2026
  21. Callas DD, Hoppensteadt D, Fareed J. Comparative studies on the anticoagulant and protease generation inhibitory actions of newly developed site-directed thrombin inhibitory drugs. Efegatran, argatroban, hirulog, and hirudin. Semin Thromb Hemost. 1995;21:177–183[ISI][Medline]
  22. Marciniak E, Gockerman JP. Heparin-induced decrease in circulating antithrombin III. Lancet. 1977;II:581–584
  23. Blombäck B, Blombäck M, Lagergren H, Olsson P. The heparin co-factor activity in plasma and its relation to the anticoagulant effects of intravenously injected heparin. Acta Physiol Scand. 1963;58:306–318[ISI][Medline]
  24. Grip L, Blombäck M, Egberg N, Olsson , Svane B, Velander M. Antithrombin III supplementation for patients undergoing PTCA for unstable angina pectoris. Eur Heart J. 1997;18:443–449[Abstract/Free Full Text]
  25. Bovill EG, Tracy PR, Hayes ET, Jenny JR, Bhushan FH, Mann GK. Evidence that meizothrombin is an intermediate product in the clotting of whole blood. Arterioscler Thromb Vasc Biol. 1995;15:754–758[Abstract/Free Full Text]
  26. Doyle FM, Haley EP. Meizothrombin: active intermediate formed during prothrombinase-catalyzed activation of prothrombin. Methods Enzymol. 1993;222:299–312[ISI][Medline]
  27. Théroux P, Latour J, Léger-Gauthier C, De Lara J. Fibrinopeptid A and platelet factor levels in unstable angina pectoris. Circulation. 1987;75:156–162[Abstract/Free Full Text]
  28. Neri Serneri GF, Gensini F, Carnovali M. Association between time of increased fibrinopeptide A levels in plasma and episodes of spontaneous angina: a controlled prospective study. Am Heart J. 1987;113:672–678[CrossRef][ISI][Medline]
  29. Ardissino D, Merlini PA, Bamba G. Thrombin activity and early outcome in unstable angina pectoris. Circulation. 1996;93:1634–1639[Abstract/Free Full Text]
  30. Wilensky LR, Bourdillon DVP, Vix AV, Zeller AJ. Intra-coronary artery thrombus formation in unstable angina: a clinical, biochemical and angiographic correlation. J Am Coll Cardiol. 1993;21:692–699[Abstract]
  31. Merlini PA, Ardissino D, Oltrona L, Broccolino M, Coppola R, Mannucci PM. Heightened thrombin formation but normal plasma levels of activated factor VII in patients with acute coronary syndromes. Arterioscler Thromb Vasc Biol. 1995;15:1675–1679[Abstract/Free Full Text]
  32. Merlini PA, Bauer K, Oltrona L. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation. 1994;90:61–68[Abstract/Free Full Text]
  33. Hoffmeister HM, Jur M, Wendel HP, Heller W, Seipel L. Alterations of coagulation and fibrinolytic and kallekrein-kinin systems in the acute and postacute phases in patients with unstable angina pectoris. Circulation. 1995;91:2520–2527[Abstract/Free Full Text]
  34. Scharfstein JS, Abendschein DR, Eisenberg PR. Usefulness of fibrinogenolytic and procoagulant markers during thrombolytic therapy in predicting clinical outcomes in acute myocardial infarction. TIMI-5 Investigators. Thrombolysis in Myocardial Infarction. Am J Cardiol. 1996;78:503–510[CrossRef][ISI][Medline]
  35. Al-Nozha M, Gader AMA, Al-Momen AK, Noah MS, Jawaid M, Arafa M. Haemostatic variables in patients with unstable angina. Int J Cardiol. 1994;43:269–277[CrossRef][ISI][Medline]
  36. Andersen K, Dellborg M, Emanuelsson H, Grip L, Swedberg K. Thrombin inhibition with inogatran for unstable angina pectoris: evidence for reactivated ischemia after cessation of short-term treatment. Cor Art Dis. 1996;7:673–681
  37. Kruskal JB, Commerford PJ, Franks JJ, Kirsch RE. Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary disease. N Engl J Med. 1987;317:1361–1365[Abstract]
  38. Lee VL, Ewald AG, McKenzie RC, Eisenberg RP. The relationship of soluble fibrin degradation products to the clinical course of myocardial infarction. Arterioscler Thromb Vasc Biol. 1997;17:628–633[Abstract/Free Full Text]
  39. Magari Y, Mizunaga S, Ito M, Shibata T, Ito H. Molecular marker for detecting hypercoagulable state. Jpn J Clin Pathol. 1994;42:22–33
  40. Hunter WM, Greenwood FC. The preparation of iodine-131 labeled human growth hormone of high specific radioactivity. Nature. 1962;194:465–496
  41. Godal HC, Abildgaard U. Gelation of soluble fibrin in plasma by ethanol. Scand J Haematol. 1966;3:342–350[ISI][Medline]
  42. Weitz JI, Cruickshank MK, Thong B. Human tissue-type plasminogen activator releases fibrinopeptides A and B from fibrinogen. J Clin Invest. 1988;82:1700–1707[ISI][Medline]
  43. Alexopoulos D, Ambrose JA, Stump D. Thrombosis-related markers in unstable angina pectoris. J Am Coll Cardiol. 1991;17:866–871[Abstract]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
N. R. Bijsterveld, R. J. G. Peters, S. A. Murphy, P. J. L. M. Bernink, J. G. P. Tijssen, M. Cohen, and TIMI 11B/ESSENCE Study Groups
Recurrent cardiac ischemic events early after discontinuation of short-term heparin treatment in acute coronary syndromes: Results from the thrombolysis in myocardial infarction (TIMI) 11B and efficacy and safety of subcutaneous enoxaparin in Non-Q-Wave coronary events (ESSENCE) studies
J. Am. Coll. Cardiol., December 17, 2003; 42(12): 2083 - 2089.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
K. Kottke-Marchant, M.C. Bahit, C.B. Granger, P. Zoldhelyi, D. Ardissino, L. Brooks, J.H. Griffin, R.F. Potthoff, F. Van de Werf, R.M. Califf, et al.
Effect of hirudin vs heparin on haemostatic activity in patients with acute coronary syndromes
Eur. Heart J., August 1, 2002; 23(15): 1202 - 1212.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
N. R. Bijsterveld, A. H. Moons, J. C. M. Meijers, J. G. P. Tijssen, H. R. Buller, M. Levi, and R. J. G. Peters
Rebound thrombin generation after heparin therapy in unstable angina: A randomized comparison between unfractionated and low-molecular-weight heparin
J. Am. Coll. Cardiol., March 6, 2002; 39(5): 811 - 817.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
J. Oldgren, R. Linder, L. Grip, A. Siegbahn, and L. Wallentin
Coagulation Activity and Clinical Outcome in Unstable Coronary Artery Disease
Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 1059 - 1064.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. C. Bahit, E. J. Topol, R. M. Califf, P. W. Armstrong, D. A. Criger, V. Hasselblad, A. Betriu, J. Hirsh, D. Ardissino, and C. B. Granger
Reactivation of ischemic events in acute coronary syndromes: results from GUSTO-IIb
J. Am. Coll. Cardiol., March 15, 2001; 37(4): 1001 - 1007.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
M.D Flather, J.I Weitz, S Yusuf, J Pogue, B Sussex, J Campeau, J Gill, R Schuld, C.D Joyner, A.L Morris, et al.
Reactivation of coagulation after stopping infusions of recombinant hirudin and unfractionated heparin in unstable angina and myocardial infarction without ST elevation: results of a randomized trial
Eur. Heart J., September 1, 2000; 21(17): 1473 - 1481.
[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (19)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Linder, R.
Right arrow Articles by Wallentin, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Linder, R.
Right arrow Articles by Wallentin, L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?