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Thromb Haemost 2006; 95(03): 447-453
DOI: 10.1160/TH05-10-0664
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Antithrombotic effects of ximelagatran plus acetylsalicylic acid (ASA) and clopidogrel plus ASA in a human ex vivo arterial thrombosis model

Karin Wåhlander
1   AstraZeneca R&D Mölndal, Mölndal, Sweden
,
Maria Eriksson-Lepkowska
1   AstraZeneca R&D Mölndal, Mölndal, Sweden
,
Per Nyström
1   AstraZeneca R&D Mölndal, Mölndal, Sweden
,
Ulf G. Eriksson
1   AstraZeneca R&D Mölndal, Mölndal, Sweden
,
Troy C. Sarich
2   AstraZeneca LP, Wilmington, Delaware, USA
,
Juan J. Badimon
3   Cardiovascular Institute, Mount Sinai School of Medicine, New York, USA
,
Inge Kalies
1   AstraZeneca R&D Mölndal, Mölndal, Sweden
,
Margareta Elg
1   AstraZeneca R&D Mölndal, Mölndal, Sweden
,
Anders Bylock
1   AstraZeneca R&D Mölndal, Mölndal, Sweden
› Author Affiliations
Further Information

Publication History

Received 10 October 2005

Accepted after resubmission 12 January 2006

Publication Date:
29 November 2017 (online)

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Summary

It was the objective of this study to compare the antithrombotic effects and bleeding profiles of the oral direct thrombin inhibitor ximelagatran, an anticoagulant, and the antiplatelet agent clopidogrel on top of steady-state acetylsalicylic acid (ASA) in a human arterial thrombosis model. Healthy male volunteers (n=62) received ASA (160 mg once daily),plus either clopidogrel for 6 days (loading dose 300 mg, then 75 mg once daily), or a single dose of ximelagatran (36 or 72 mg) on Day 6. Changes in total thrombus area (TTA) under low shear rate (LSR; 212 s-1) and high shear rate (HSR; 1690 s-1) conditions were measured, using the ex vivo Badimon perfusion chamber model pre-dose and 2 and 5 hours after dosing on Day 6, and capillary bleeding times (CBT) were determined. Ximelagatran plus ASA significantly reduced TTA under LSR and HSR, compared with ASA alone. Ximelagatran plus ASA reduced TTA more than clopidogrel plus ASA under LSR after2 hours (36 mg, P=0.0011; 72 mg, P<0.0001) and 5 hours (72 mg, P=0.0057), and under HSR after 2 and 5 hours (72 mg, P<0.05). Compared with ASA alone, CBT was markedly prolonged by clopidogrel plus ASA (ratio 6.4; P<0.0001) but only slightly by ximelagatran plus ASA (72 mg ximelagatran,ratio 1.4;P=0.0010).Both drug combinations were well tolerated. Oral ximelagatran plus ASA has a greater antithrombotic effect in this human ex vivo thrombosis model and a less prounounced prolongation of bleeding time than clopidogrel plus ASA.

Keywords

Clinical trials - oral anticoagulants - coagulation inhibitors - thrombin
 

  • References

  • 1 Rosendaal F. Thrombosis in the young: epidemiology and risk factors, a focus on venous thrombosis. Thromb Haemost 1997; 78: 1-6.
    Thieme ConnectPubMedSearch in Google Scholar
  • 2 Nordström M, Lindblad B, Bergqvist D. et al. A prospective study of the incidence of deep-vein thrombosis with a defined urban population. J Intern Med 1992; 232: 155-60.
    CrossrefPubMedSearch in Google Scholar
  • 3 Anderson F, Wheeler H, Goldberg R. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism, The Worcester DVT study. Arch Intern Med 1991; 151: 933-8.
    CrossrefPubMedSearch in Google Scholar
  • 4 Becker R, Bovill E, Seghatchian M. et al. Pathobiology of thrombin in acute coronary syndromes. Am HeartJ 1998; 136: S19-S311.
    CrossrefPubMedSearch in Google Scholar
  • 5 Cairns J, Theroux P, Lewis JH. et al. Antithrombotic agents in coronary artery disease. Chest 2001; 119 (Suppl. 01) 28S-52S.
    PubMedSearch in Google Scholar
  • 6 Braunwald E, Antman E, Beasley J. et al. ACC/ AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction- summary article:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 2002; 106: 1893-900.
    CrossrefPubMedSearch in Google Scholar
  • 7 Bertrand ME, Simoons ML, Fox KA. et al. Task Force on the Management of Acute Coronary Syndromes of the European Society of Cardiology Task force report: Management of acute coronary syndromes in patients presenting without persistent STsegment elevation. Eur Heart J 2002; 23: 1809-40.
    CrossrefPubMedSearch in Google Scholar
  • 8 Van de Werf F, Ardissino D, Betriu A. et al. Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology Task force report: Management of acute myocardial infarction in patients with ST-segment elevation. Eur Heart J 2003; 24: 28-66.
    PubMedSearch in Google Scholar
  • 9 Hart R, Benavente O, McBride R. et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131: 492-501.
    PubMedSearch in Google Scholar
  • 10 Hirsh J, Dalen J, Anderson DR, Poller L. et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119 (Suppl. 01) 8S-21S.
    CrossrefPubMedSearch in Google Scholar
  • 11 Hirsh J, Warkentin TE, Shaughnessy SG. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119 (Suppl. 01) 64S-94S.
    CrossrefPubMedSearch in Google Scholar
  • 12 CURE aStudy investigators. Effect of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
    CrossrefPubMedSearch in Google Scholar
  • 13 Gustafsson D, Nyström J, Carlsson S. et al. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95:intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb Res 2001; 101: 171-81.
    CrossrefPubMedSearch in Google Scholar
  • 14 Eriksson BI, Agnelli G, Cohen AT. et al. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement The METHRO III study. Thromb Haemost 2003; 89: 288-96.
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Eriksson BI, Agnelli G, Cohen AT. et al. EXPRESS Study Group The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study. J Thromb Haemost 2003; 01: 1490-6.
    PubMedSearch in Google Scholar
  • 16 Francis CW, Berkowitz SD, Comp PC. et al. EXULT A Study Group Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement: EXULT A. N Engl J Med 2003; 349: 1703-12.
    CrossrefPubMedSearch in Google Scholar
  • 17 Fiessinger J-N, Huisman MV, Davidson BL. et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized controlled trial. JAMA 2005; 293: 681-9.
    CrossrefPubMedSearch in Google Scholar
  • 18 Schulman S, Wåhlander K, Lundstrom T. et al. THRIVE III Investigators Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003; 349: 1713-21.
    CrossrefPubMedSearch in Google Scholar
  • 19 Executive Steering Committee. SPORTIF III Investigators Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362: 1691-8.
    CrossrefPubMedSearch in Google Scholar
  • 20 Wallentin L, Wilcox R, Weaver W. et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003; 362: 789-97.
    CrossrefPubMedSearch in Google Scholar
  • 21 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Boström SL, Hansson GFH, Kjaer M. et al. Effects of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and dalteparin, on the endogenous thrombin potential in venous blood from healthy male subjects. Blood Coagul Fibrinolysis 2003; 14: 457-62.
    CrossrefPubMedSearch in Google Scholar
  • 23 Boström SL, Dagnelid E, Hansson GFH. et al. Inhibition of thrombin-induced feedback activation of factor V: a potential pathway for inhibition of thrombin generation by melagatran. Blood Coagul Fibrinolysis 2004; 15: 15-30.
    CrossrefPubMedSearch in Google Scholar
  • 24 Sarich TC, Wolzt M, Eriksson UG. et al. Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects. J Am Coll Cardiol 2003; 41: 557-64.
    CrossrefPubMedSearch in Google Scholar
  • 25 Sarich TC, Osende JI, Eriksson UG. et al. Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis. J Thromb Haemost 2003; 01: 999-1004.
    CrossrefPubMedSearch in Google Scholar
  • 26 Badimon L, Turito V, Rosemark JA. et al. Characterization ofa tubular flow chamber for studying platelet interaction with biologic and prosthetic materials: deposition of indium 111-labelled platelets on collagen, subendothelium, and expanded polytetrafluoroethylene. J Lab Clin Med 1987; 110: 706-18.
    PubMedSearch in Google Scholar
  • 27 Lev E, Osende J, Richard M. et al. Administration of abciximab to patients receiving tirofiban or eptifibatide: effect on platelet function. J Am Coll Cardiol 2001; 37: 847-55.
    CrossrefPubMedSearch in Google Scholar
  • 28 Osende J, Badimon J, Fuster V. et al. Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control. J Am Coll Cardiol 2001; 38: 1307-12.
    CrossrefPubMedSearch in Google Scholar
  • 29 Rauch U, Osende J, Chesebro J. et al. Statins and cardiovascular diseases: multiple effects of lipid-lowering therapy by statins. Atherosclerosis 2000; 153: 181-9.
    CrossrefPubMedSearch in Google Scholar
  • 30 Dangas G, Badimon J, Coller B. et al. Administration of abciximab during percutaneous coronary intervention reduces both ex vivo platelet thrombus formation and fibrin deposition Implications for a potential anticoagulant effect of abciximab. Arterioscler Thromb Vasc Biol 1998; 18: 1342-9.
    CrossrefPubMedSearch in Google Scholar
  • 31 Helft G, Osende JI, Worthley SG. et al. Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin. Arterioscler Thromb Vasc Biol 2000; 20: 2316-21.
    CrossrefPubMedSearch in Google Scholar
  • 32 Larsson M, Logren U, Ahnoff M. et al. Determination of melagatran, a novel, direct thrombin inhibitor, in human plasma and urine by liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 766: 47-55.
    CrossrefPubMedSearch in Google Scholar
  • 33 Nylander S, Mattsson C. Thrombin-induced platelet activation and its inhibition by anticoagulants with different modes of action. Blood Coagul Fibrinolysis 2003; 14: 159-67.
    CrossrefPubMedSearch in Google Scholar
  • 34 Cleland JGF, Alison PC, Lammiman M. et al. Clinical trials update from the European Society of Cardiology meeting 2005: CARE-HF extention study, ESSENTIAL, CIBIS-III, S-ICD, ISSUE-2, STRIDE-2, SOFA, IMAGINE, PREAMI, SIRIUS-II and ACTICE. European Journal of Heart Failure 2005; 1070-75.
    PubMedSearch in Google Scholar
  • 35 Johansson LC, Frison L. Logren, et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinetics 2003; 42: 381-92.
    CrossrefPubMedSearch in Google Scholar
  • 36 Wodlinger A, Pieper J. The role of clopidogrel in the management of acute coronary syndromes. Clin Ther 2003; 25: 2155-81.
    CrossrefPubMedSearch in Google Scholar