Journal Mobile Options
Table of Contents
Vol. 34, Suppl. 1, 2005
Issue release date: February 2005
Section title: Paper
Pathophysiol Haemost Thromb 2005;34:2–9
(DOI:10.1159/000083078)

Current Issues in Anticoagulation

Agnelli G.
Stroke Unit and Cardiovascular Medicine, University of Perugia, Italy
email Corresponding Author

Abstract

Anticoagulation therapy with unfractionated heparin, low-molecular-weight heparins and oral vitamin K antagonists is currently the mainstay of treatment and prevention of thromboembolic disorders (such as deep vein thrombosis, pulmonary embolism and stroke prevention in patients with atrial fibrillation). Although these therapies have proven benefits, they also have important limitations that result in their underuse in routine clini- cal practice. Consequently, many patients identified by guidelines as requiring anticoagulant therapy receive no or inadequate treatment. Heparins require parenteral administration and pose the risk of heparin-induced thrombocytopenia. Vitamin K antagonists have a narrow separation of antithrombotic and haemorrhagic effects and numerous food and drug-drug interactions, and require frequent coagulation monitoring and dose adjustment to ensure effective antithrombotic protection while minimizing the risk of bleeding complications. In response to these limitations, several new anticoagulants have recently been developed, including selective factor Xa inhibitors such as fondaparinux and ximelagatran, the first oral agent in the new class of direct thrombin inhibitors and the first new oral anticoagulant for almost 60 years. Ximelagatran possesses many of the properties of an ideal agent for anticoagulation therapy. With its oral formulation, consistent and predictable pharmacological profile and no coagulation monitoring, ximelagatran has the potential to increase the use and duration of anticoagulation treatment in thromboembolic disorders and to reduce the burden associated with long-term management.

© 2005 S. Karger AG, Basel

Abstract of Paper

References

  1. Agnelli G, Sonaglia F: Perspectives on antithrombotic agents: from unfractionated heparin to new antithrombotics. Haematologica 2002;87:757–770.
  2. Hyers TM, Agnelli G, Hull RD, Morris TA, Samama M, Tapson V, Weg JG: Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119:176S–193S.
  3. Picker SM, Gathof BS: Pathophysiology, epidemiology, diagnosis and treatment of heparin-induced thrombocytopenia (HIT). Eur J Med Res 2004;9:180–185.
  4. Wittkowsky AK: Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med 2003;3:221–230.

    External Resources

  5. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG: Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469–473.
  6. Yuan Z, Bowlin S, Einstadter D, Cebul RD, Conners AR Jr, Rimm AA: Atrial fibrillation as a risk factor for stroke: a retrospective cohort study of hospitalized Medicare beneficiaries. Am J Public Health 1998;88:395–400.
  7. Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–988.
  8. Lightowlers S, McGuire A: Cost-effectiveness of anticoagulation in nonrheumatic atrial fibrillation in the primary prevention of ischemic stroke. Stroke 1998;29:1827–1832.
  9. Hart RG, Benavente O, McBride R, Pearce LA: Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131:492–501.
  10. Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE: Antithrombotic therapy in atrial fibrillation. Chest 2001;119:194S–206S.

    External Resources

  11. Ageno W, Ambrosini F, Nardo B, Imperiale D, Dentali F, Mera V, Cattaneo R, Barlocco E, Steidl L, Venco A: Atrial fibrillation and antithrombotic treatment in Italian hospitalized patients: a prospective, observational study. J Thromb Thrombolysis 2001;12:225–230.
  12. The Clinical Quality Improvement Network (CQIN) Investigators: Thromboembolic prophylaxis in 3575 hospitalized patients with atrial fibrillation. Can J Cardiol 1998;14:695–702.

    External Resources

  13. Stafford RS, Singer DE: Recent national patterns of warfarin use in atrial fibrillation. Circulation 1998;97:1231–1233.
  14. Antani MR, Beyth RJ, Covinsky KE, Anderson PA, Miller DG, Cebul RD, Quinn LM, Landefeld CS: Failure to prescribe warfarin to patients with nonrheumatic atrial fibrillation. J Gen Intern Med 1996;11:713–720.
  15. Whittle J, Wickenheiser L, Venditti LN: Is warfarin underused in the treatment of elderly persons with atrial fibrillation? Arch Intern Med 1997;157:441–445.
  16. Albers GW, Yim JM, Belew KM, Bittar N, Hattemer CR, Phillips BG, Kemp S, Hall EA, Morton DJ, Vlasses PH: Status of antithrombotic therapy for patients with atrial fibrillation in university hospitals. Arch Intern Med 1996;156:2311–2316.
  17. Lackner TE, Battis GN: Use of warfarin for nonvalvular atrial fibrillation in nursing home patients. Arch Fam Med 1995;4:1017–1026.
  18. Gurwitz JH, Monette J, Rochon PA, Eckler MA, Avorn J: Atrial fibrillation and stroke prevention with warfarin in the long-term care setting. Arch Intern Med 1997;157:978–984.
  19. Sudlow M, Rodgers H, Kenny RA, Thomson R: Population based study of use of anticoagulants among patients with atrial fibrillation in the community. Br Med J 1997;314:1529–1530.
  20. Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch Intern Med 1987;147:1561–1564.
  21. White RH, McBurnie MA, Manolio T, Furberg CD, Gardin JM, Kittner SJ, Bovill E, Knepper L: Oral anticoagulation in patients with atrial fibrillation: adherence with guidelines in an elderly cohort. Am J Med 1999;106:165–171.
  22. Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ: Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425–1434.
  23. Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, Moia M, Guazzaloca G, Bertoldi A, Tomasi C, Scannapieco G, Ageno W: Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. N Engl J Med 2001;345:165–169.
  24. Bounameaux H, de Moerloose P, Sarasin FP: Optimal duration of oral anticoagulant therapy following deep vein thrombosis of lower limbs. Blood Coagul Fibrinolysis 1996;7:507–514.
  25. Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA Jr, Wheeler HB: Prevention of venous thromboembolism. Chest 2001;119:132S–175S.

    External Resources

  26. Dahl OE, Andreassen G, Aspelin T, Muller C, Mathiesen P, Nyhus S, Abdelnoor M, Solhaug JH, Arnesen H: Prolonged thromboprophylaxis following hip replacement surgery – results of a double-blind, prospective, randomised, placebo-controlled study with dalteparin (Fragmin). Thromb Haemost 1997;77:26–31.
  27. Planes A, Vochelle N, Darmon JY, Fagola M, Bellaud M, Huet Y: Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo. Lancet 1996;348:224–228.
  28. Hull RD, Pineo GF, Francis C, Bergqvist D, Fellenius C, Soderberg K, Holmqvist A, Mant M, Dear R, Baylis B, Mah A, Brant R: Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs. in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators. Arch Intern Med 2000;160:2208–2215.
  29. Anderson FA Jr, Hirsh J, White K, Fitzgerald RH Jr: Temporal trends in prevention of venous thromboembolism following primary total hip or knee arthroplasty 1996–2001: findings from the Hip and Knee Registry. Chest 2003;124:349S–356S.

    External Resources

  30. Koopman MM, Buller HR: Short- and long-acting synthetic pentasaccharides. J Intern Med 2003;254:335–342.
  31. Lee A, Agnelli G, Buller H, Ginsberg J, Heit J, Rote W, Vlasuk G, Costantini L, Julian J, Comp P, van Der MJ, Piovella F, Raskob G, Gent M: Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation 2001;104:74–78.
  32. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW Jr: Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349:1703–1712.
  33. Eriksson BI, Bergqvist D, Kälebo P, Dahl OE, Lindbratt S, Bylock A, Frison L, Eriksson UG, Welin L, Gustafsson D: Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002;360:1441–1447.
  34. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Mouret P, Rosencher N, Eskilson C, Nylander I, Frison L, Ögren M: Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement. Thromb Haemost 2003;89:288–296.
  35. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Lassen MR, Mouret P, Rosencher N, Kalebo P, Paniflov S, Eskilson C, Andersson M, Freij A: 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;1:2490–2496.
  36. Petersen P, Grind M, Adler J: Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose-guiding, tolerability, and safety study. J Am Coll Cardiol 2003;41:1445–1451.
  37. Olsson SB: 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;362:1691–1698.
  38. The Executive Steering Committee on behalf of the SPORTIF V Investigators: Stroke prevention using the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation (SPORTIF V). Circulation 2003;108(suppl):2723 (J).
  39. Francis CW, Ginsberg JS, Berkowitz SD, Bounameaux H, Davidson BL, Eriksson H, Fiessinger J-N, Huisman MV, Lundstrom T, Nystrom P, the THRIVE Treatment Study Investigators: Efficacy and safety of the oral direct thrombin inhibitor ximelagatran compared with current standard therapy for acute, symptomatic deep vein thrombosis, with or without pulmonary embolism: The THRIVE Treatment Study. Blood 2003;102:abstract 7.
  40. Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H, THRIVE III Investigators: Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713–1721.
  41. Eriksson UG, Bredberg U, Gislén K, Johansson LC, Frison L, Ahnoff M, Gustafsson D: Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003;59:35–43.
  42. Eriksson BI, Arfwidsson AC, Frison L, Eriksson UG, Bylock A, Kalebo P, Fager G, Gustafsson D: A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I. MElagatran for THRombin inhibition in Orthopaedic surgery. Thromb Haemost 2002;87:231–237.
  43. Elg M, Gustafsson D, Carlsson S: Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 1999;94:187–197.

  

Author Contacts

Prof. Giancarlo Agnelli
Stroke Unit and Cardiovascular Medicine
University of Perugia, Via Enrico dal Pozzo
IT–06123 Perugia (Italy)
Tel. +39 075 5783395, Fax +39 075 5722011, E-Mail agnellig@unipg.it

  

Article Information

Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 1, Number of References : 43

  

Publication Details

Pathophysiology of Haemostasis and Thrombosis

Vol. 34, No. Suppl. 1, Year 2005 (Cover Date: February 2005)

Journal Editor: Rosing, J. (Maastricht)
ISSN: 1424–8832 (print), 1424–8840 (Online)

For additional information: http://www.karger.com/pht


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Anticoagulation therapy with unfractionated heparin, low-molecular-weight heparins and oral vitamin K antagonists is currently the mainstay of treatment and prevention of thromboembolic disorders (such as deep vein thrombosis, pulmonary embolism and stroke prevention in patients with atrial fibrillation). Although these therapies have proven benefits, they also have important limitations that result in their underuse in routine clini- cal practice. Consequently, many patients identified by guidelines as requiring anticoagulant therapy receive no or inadequate treatment. Heparins require parenteral administration and pose the risk of heparin-induced thrombocytopenia. Vitamin K antagonists have a narrow separation of antithrombotic and haemorrhagic effects and numerous food and drug-drug interactions, and require frequent coagulation monitoring and dose adjustment to ensure effective antithrombotic protection while minimizing the risk of bleeding complications. In response to these limitations, several new anticoagulants have recently been developed, including selective factor Xa inhibitors such as fondaparinux and ximelagatran, the first oral agent in the new class of direct thrombin inhibitors and the first new oral anticoagulant for almost 60 years. Ximelagatran possesses many of the properties of an ideal agent for anticoagulation therapy. With its oral formulation, consistent and predictable pharmacological profile and no coagulation monitoring, ximelagatran has the potential to increase the use and duration of anticoagulation treatment in thromboembolic disorders and to reduce the burden associated with long-term management.

© 2005 S. Karger AG, Basel


  

Author Contacts

Prof. Giancarlo Agnelli
Stroke Unit and Cardiovascular Medicine
University of Perugia, Via Enrico dal Pozzo
IT–06123 Perugia (Italy)
Tel. +39 075 5783395, Fax +39 075 5722011, E-Mail agnellig@unipg.it

  

Article Information

Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 1, Number of References : 43

  

Publication Details

Pathophysiology of Haemostasis and Thrombosis

Vol. 34, No. Suppl. 1, Year 2005 (Cover Date: February 2005)

Journal Editor: Rosing, J. (Maastricht)
ISSN: 1424–8832 (print), 1424–8840 (Online)

For additional information: http://www.karger.com/pht


Article / Publication Details

First-Page Preview
Abstract of Paper

Published online: 4/4/2005
Issue release date: February 2005

Number of Print Pages: 8
Number of Figures: 4
Number of Tables: 1

ISSN: 1424-8832 (Print)
eISSN: 1424-8840 (Online)

For additional information: http://www.karger.com/PHT


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Agnelli G, Sonaglia F: Perspectives on antithrombotic agents: from unfractionated heparin to new antithrombotics. Haematologica 2002;87:757–770.
  2. Hyers TM, Agnelli G, Hull RD, Morris TA, Samama M, Tapson V, Weg JG: Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119:176S–193S.
  3. Picker SM, Gathof BS: Pathophysiology, epidemiology, diagnosis and treatment of heparin-induced thrombocytopenia (HIT). Eur J Med Res 2004;9:180–185.
  4. Wittkowsky AK: Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med 2003;3:221–230.

    External Resources

  5. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG: Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469–473.
  6. Yuan Z, Bowlin S, Einstadter D, Cebul RD, Conners AR Jr, Rimm AA: Atrial fibrillation as a risk factor for stroke: a retrospective cohort study of hospitalized Medicare beneficiaries. Am J Public Health 1998;88:395–400.
  7. Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–988.
  8. Lightowlers S, McGuire A: Cost-effectiveness of anticoagulation in nonrheumatic atrial fibrillation in the primary prevention of ischemic stroke. Stroke 1998;29:1827–1832.
  9. Hart RG, Benavente O, McBride R, Pearce LA: Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131:492–501.
  10. Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE: Antithrombotic therapy in atrial fibrillation. Chest 2001;119:194S–206S.

    External Resources

  11. Ageno W, Ambrosini F, Nardo B, Imperiale D, Dentali F, Mera V, Cattaneo R, Barlocco E, Steidl L, Venco A: Atrial fibrillation and antithrombotic treatment in Italian hospitalized patients: a prospective, observational study. J Thromb Thrombolysis 2001;12:225–230.
  12. The Clinical Quality Improvement Network (CQIN) Investigators: Thromboembolic prophylaxis in 3575 hospitalized patients with atrial fibrillation. Can J Cardiol 1998;14:695–702.

    External Resources

  13. Stafford RS, Singer DE: Recent national patterns of warfarin use in atrial fibrillation. Circulation 1998;97:1231–1233.
  14. Antani MR, Beyth RJ, Covinsky KE, Anderson PA, Miller DG, Cebul RD, Quinn LM, Landefeld CS: Failure to prescribe warfarin to patients with nonrheumatic atrial fibrillation. J Gen Intern Med 1996;11:713–720.
  15. Whittle J, Wickenheiser L, Venditti LN: Is warfarin underused in the treatment of elderly persons with atrial fibrillation? Arch Intern Med 1997;157:441–445.
  16. Albers GW, Yim JM, Belew KM, Bittar N, Hattemer CR, Phillips BG, Kemp S, Hall EA, Morton DJ, Vlasses PH: Status of antithrombotic therapy for patients with atrial fibrillation in university hospitals. Arch Intern Med 1996;156:2311–2316.
  17. Lackner TE, Battis GN: Use of warfarin for nonvalvular atrial fibrillation in nursing home patients. Arch Fam Med 1995;4:1017–1026.
  18. Gurwitz JH, Monette J, Rochon PA, Eckler MA, Avorn J: Atrial fibrillation and stroke prevention with warfarin in the long-term care setting. Arch Intern Med 1997;157:978–984.
  19. Sudlow M, Rodgers H, Kenny RA, Thomson R: Population based study of use of anticoagulants among patients with atrial fibrillation in the community. Br Med J 1997;314:1529–1530.
  20. Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch Intern Med 1987;147:1561–1564.
  21. White RH, McBurnie MA, Manolio T, Furberg CD, Gardin JM, Kittner SJ, Bovill E, Knepper L: Oral anticoagulation in patients with atrial fibrillation: adherence with guidelines in an elderly cohort. Am J Med 1999;106:165–171.
  22. Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ: Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425–1434.
  23. Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, Moia M, Guazzaloca G, Bertoldi A, Tomasi C, Scannapieco G, Ageno W: Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. N Engl J Med 2001;345:165–169.
  24. Bounameaux H, de Moerloose P, Sarasin FP: Optimal duration of oral anticoagulant therapy following deep vein thrombosis of lower limbs. Blood Coagul Fibrinolysis 1996;7:507–514.
  25. Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA Jr, Wheeler HB: Prevention of venous thromboembolism. Chest 2001;119:132S–175S.

    External Resources

  26. Dahl OE, Andreassen G, Aspelin T, Muller C, Mathiesen P, Nyhus S, Abdelnoor M, Solhaug JH, Arnesen H: Prolonged thromboprophylaxis following hip replacement surgery – results of a double-blind, prospective, randomised, placebo-controlled study with dalteparin (Fragmin). Thromb Haemost 1997;77:26–31.
  27. Planes A, Vochelle N, Darmon JY, Fagola M, Bellaud M, Huet Y: Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo. Lancet 1996;348:224–228.
  28. Hull RD, Pineo GF, Francis C, Bergqvist D, Fellenius C, Soderberg K, Holmqvist A, Mant M, Dear R, Baylis B, Mah A, Brant R: Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs. in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators. Arch Intern Med 2000;160:2208–2215.
  29. Anderson FA Jr, Hirsh J, White K, Fitzgerald RH Jr: Temporal trends in prevention of venous thromboembolism following primary total hip or knee arthroplasty 1996–2001: findings from the Hip and Knee Registry. Chest 2003;124:349S–356S.

    External Resources

  30. Koopman MM, Buller HR: Short- and long-acting synthetic pentasaccharides. J Intern Med 2003;254:335–342.
  31. Lee A, Agnelli G, Buller H, Ginsberg J, Heit J, Rote W, Vlasuk G, Costantini L, Julian J, Comp P, van Der MJ, Piovella F, Raskob G, Gent M: Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation 2001;104:74–78.
  32. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW Jr: Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349:1703–1712.
  33. Eriksson BI, Bergqvist D, Kälebo P, Dahl OE, Lindbratt S, Bylock A, Frison L, Eriksson UG, Welin L, Gustafsson D: Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002;360:1441–1447.
  34. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Mouret P, Rosencher N, Eskilson C, Nylander I, Frison L, Ögren M: Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement. Thromb Haemost 2003;89:288–296.
  35. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Lassen MR, Mouret P, Rosencher N, Kalebo P, Paniflov S, Eskilson C, Andersson M, Freij A: 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;1:2490–2496.
  36. Petersen P, Grind M, Adler J: Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose-guiding, tolerability, and safety study. J Am Coll Cardiol 2003;41:1445–1451.
  37. Olsson SB: 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;362:1691–1698.
  38. The Executive Steering Committee on behalf of the SPORTIF V Investigators: Stroke prevention using the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation (SPORTIF V). Circulation 2003;108(suppl):2723 (J).
  39. Francis CW, Ginsberg JS, Berkowitz SD, Bounameaux H, Davidson BL, Eriksson H, Fiessinger J-N, Huisman MV, Lundstrom T, Nystrom P, the THRIVE Treatment Study Investigators: Efficacy and safety of the oral direct thrombin inhibitor ximelagatran compared with current standard therapy for acute, symptomatic deep vein thrombosis, with or without pulmonary embolism: The THRIVE Treatment Study. Blood 2003;102:abstract 7.
  40. Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H, THRIVE III Investigators: Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713–1721.
  41. Eriksson UG, Bredberg U, Gislén K, Johansson LC, Frison L, Ahnoff M, Gustafsson D: Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003;59:35–43.
  42. Eriksson BI, Arfwidsson AC, Frison L, Eriksson UG, Bylock A, Kalebo P, Fager G, Gustafsson D: A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I. MElagatran for THRombin inhibition in Orthopaedic surgery. Thromb Haemost 2002;87:231–237.
  43. Elg M, Gustafsson D, Carlsson S: Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 1999;94:187–197.