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Table of Contents
Vol. 34, Suppl. 1, 2005
Issue release date: February 2005
Pathophysiol Haemost Thromb 2005;34:10–17
(DOI:10.1159/000083079)

Ximelagatran in Orthopaedic Surgery

Eriksson B.
Department of Orthopedics, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
email Corresponding Author

Abstract

Ximelagatran represents the first new oral anticoagulant since the introduction of warfarin almost 60 years ago, and has been evaluated for the treatment and prevention of a range of venous and arterial thromboembolic disorders. The MElagatran THRomboprophylaxis in Orthopaedic surgery (METHRO) and EXpanded PRophylaxis Evaluation Surgery Study (EXPRESS) studies have investigated the efficacy and safety of subcutaneous (s.c.) melagatran followed by oral ximelagatran in preventing venous thromboembolism (VTE) in patients undergoing total hip replacement or total knee replacement. In METHRO II, immediate pre-operative-initiated s.c. melagatran followed by post-operative ximelagatran dose-dependently reduced VTE, with the highest dose (melagatran 3 mg/ximelagatran 24 mg twice daily) associated with a significantly reduced incidence of VTE compared with the low-molecular-weight heparin (LMWH) dalteparin (15.1 vs. 28.2%; p < 0.0001). In METHRO III, the efficacy of s.c. melagatran 3 mg/ximelagatran 24 mg twice daily initiated post-operatively (4–12 h after surgery) was comparable to that of the LMWH enoxaparin initiated 12 h before surgery (total VTE incidence, 31.0 and 27.3%, respectively). Rates of severe bleeding were also comparable between treatments (melagatran/ximelaga tran = 1.4%; enoxaparin = 1.7%). Treatment with melagatran/ximelagatran was significantly more effective when initiated earlier (4–8 h) rather than later (8–12 h) after surgery (total VTE incidence, 27.5 vs. 35.4%; p = 0.0034). Based on the results of METHRO II and III, the EXPRESS study evaluated the efficacy and bleeding profile of s.c. melagatran 2 mg immediately before surgery, followed by s.c. melagatran 3 mg on the evening of the day of surgery and then ximelagatran 24 mg twice daily. This regimen was significantly more effective than enoxaparin (total VTE incidence, 20.3 vs. 26.6%; p < 0.0004). Excessive bleeding (as judged by the investigator) was more frequent with melagatran/ximelagatran, but rates of fatal bleeding, critical-site bleeding and bleeding requiring re-operation did not differ between the groups. Taken together, the METHRO and EXPRESS studies demonstrate that melagatran/ximelagatran has comparable or superior efficacy to LMWHs in the prevention of VTE in orthopaedic surgery patients, and that the timing and dose of melagatran is important in optimizing the balance of efficacy and bleeding risk.


 goto top of outline Abstract

Ximelagatran represents the first new oral anticoagulant since the introduction of warfarin almost 60 years ago, and has been evaluated for the treatment and prevention of a range of venous and arterial thromboembolic disorders. The MElagatran THRomboprophylaxis in Orthopaedic surgery (METHRO) and EXpanded PRophylaxis Evaluation Surgery Study (EXPRESS) studies have investigated the efficacy and safety of subcutaneous (s.c.) melagatran followed by oral ximelagatran in preventing venous thromboembolism (VTE) in patients undergoing total hip replacement or total knee replacement. In METHRO II, immediate pre-operative-initiated s.c. melagatran followed by post-operative ximelagatran dose-dependently reduced VTE, with the highest dose (melagatran 3 mg/ximelagatran 24 mg twice daily) associated with a significantly reduced incidence of VTE compared with the low-molecular-weight heparin (LMWH) dalteparin (15.1 vs. 28.2%; p < 0.0001). In METHRO III, the efficacy of s.c. melagatran 3 mg/ximelagatran 24 mg twice daily initiated post-operatively (4–12 h after surgery) was comparable to that of the LMWH enoxaparin initiated 12 h before surgery (total VTE incidence, 31.0 and 27.3%, respectively). Rates of severe bleeding were also comparable between treatments (melagatran/ximelaga tran = 1.4%; enoxaparin = 1.7%). Treatment with melagatran/ximelagatran was significantly more effective when initiated earlier (4–8 h) rather than later (8–12 h) after surgery (total VTE incidence, 27.5 vs. 35.4%; p = 0.0034). Based on the results of METHRO II and III, the EXPRESS study evaluated the efficacy and bleeding profile of s.c. melagatran 2 mg immediately before surgery, followed by s.c. melagatran 3 mg on the evening of the day of surgery and then ximelagatran 24 mg twice daily. This regimen was significantly more effective than enoxaparin (total VTE incidence, 20.3 vs. 26.6%; p < 0.0004). Excessive bleeding (as judged by the investigator) was more frequent with melagatran/ximelagatran, but rates of fatal bleeding, critical-site bleeding and bleeding requiring re-operation did not differ between the groups. Taken together, the METHRO and EXPRESS studies demonstrate that melagatran/ximelagatran has comparable or superior efficacy to LMWHs in the prevention of VTE in orthopaedic surgery patients, and that the timing and dose of melagatran is important in optimizing the balance of efficacy and bleeding risk.

Copyright © 2005 S. Karger AG, Basel


 goto top of outline References
  1. White RH: The epidemiology of venous thromboembolism. Circulation 2003;107:I4–I8.

    External Resources

  2. White RH, Zhou H, Romano PS: Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost 2003;90:446–455.
  3. 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

  4. Iorio A, Agnelli G: Pharmacokinetic optimisation of the treatment of deep vein thrombosis. Clin Pharmacokinet 1997;32:145–172.
  5. Haycraft JB: On the action of a secretion obtained from the medicinal leech on the coagulation of the blood. Proc R Soc London 1884;36:478–487.
  6. Shionoya T: Studies in experimental extracorporeal thrombosis. III. Effects of certain anticoagulants (heparin and hirudin) on extracorporeal thrombosis and on the mechanisms of thrombosis. J Exp Med 1927;49:19–26.

    External Resources

  7. Riehl-Bellon N, Carvallo D, Acker M, Van Dorsselaer A, Marquet M, Loison G, Lemoine Y, Brown SW, Courtney M, Roitsch C: Purification and biochemical characterization of recombinant hirudin produced by Saccha romyces cerevisiae. Biochemistry 1989;28:2941–2949.
  8. Maraganore JM, Bourdon P, Jablonski J, Ramachandran KL, Fenton JW: Design and characterization of hirulogs: A novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990;29:7095–7101.
  9. Fitzgerald D, Murphy N: Argatroban: A synthetic thrombin inhibitor of low relative molecular mass. Coron Artery Dis 1996;7:455–458.
  10. Bajusz S: Chemistry and biology of the peptide anticoagulant D-MePhe-Pro-Arg-H (GYKI-14766). Adv Exp Med Biol 1993;340:91–108.
  11. Weitz JI: A novel approach to thrombin inhibition. Thromb Res 2003;109(suppl 1):S17–S22.

    External Resources

  12. Eriksson BI, Wille-Jørgensen P, Kälebo P, Mouret P, Rosencher N, Bösch P, Baur M, Ekman S, Bach D, Lindbratt S, Close P: A comparison of recombinant hirudin with a low- molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997;337:1329–1335.
  13. Gustafsson D, Bylund R, Antonsson T, Nilsson I, Nyström JE, Eriksson U, Bredberg U, Teger-Nilsson AC: A new oral anticoagulant: The 50-year challenge. Nat Rev Drug Discov 2004;3:1–11.

    External Resources

  14. Eriksson UG, Bredberg U, Hoffmann KJ, Thuresson A, Gabrielsson M, Ericsson H, Ahnoff M, Gislén K, Fager G, Gustafsson D: Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2003;31:294–305.
  15. 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.
  16. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Mouret P, Rosencher N, Eskilson C, Nylander I, Frison L, Ogren 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.
  17. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Lassen MR, Mouret P, Rosencher N, Kalebo P, Panfilov 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.
  18. Francis CW, Davidson BL, Berkowitz SD, Lotke PA, Ginsberg JS, Lieberman JR, Webster AK, Whipple JP, Peters GR, Colwell CW Jr: Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double-blind trial. Ann Intern Med 2002;137:648–655.
  19. 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.
  20. Raskob GE, Hirsh J: Controversies in timing of the first dose of anticoagulant prophylaxis against venous thromboembolism after major orthopedic surgery. Chest 2003;124:379S–385S.
  21. Dahl OE, Bergqvist D: Current controversies in deep vein thrombosis prophylaxis after orthopaedic surgery. Curr Opin Pulm Med 2002;8:394–397.
  22. 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 in close proximity to surgery vs warfarin in hip arthroplasty patients: A double-blind, randomized comparison. The North American Fragmin Trial Investigators. Arch Intern Med 2000;160:2199–2207.
  23. Eriksson BI, Ekman S, Lindbratt S, Baur M, Bach D, Torholm C, Kalebo P, Close P: Prevention of thromboembolism with use of recombinant hirudin. Results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement. J Bone Joint Surg Am 1997;79:326–333.
  24. Eriksson BI, Ekman S, Kälebo P, Zachrisson B, Bach D, Close P: Prevention of deep-vein thrombosis after total hip replacement: Direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996;347:635–639.
  25. Eriksson BI, Kälebo P, Ekman S, Lindbratt S, Kerry R, Close P: Direct thrombin inhibition with Rec-hirudin CGP 39393 as prophylaxis of thromboembolic complications after total hip replacement. Thromb Haemost 1994;72:227–231.
  26. Eriksson BI, Dahl OE: Prevention of venous thromboembolism following orthopaedic surgery: Clinical potential of direct thrombin inhibitors. Drugs 2004;64:577–595.
  27. Sarich TC, Eriksson UG, Mattsson C, Wolzt M, Frison L, Fager G, Gustafsson D: Inhibition of thrombin generation by the oral direct thrombin inhibitor ximelagatran in shed blood from healthy male subjects. Thromb Haemost 2002;87:300–305.
  28. Eikelboom JW, Quinlan DJ, Douketis JD: Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: A meta-analysis of the randomised trials. Lancet 2001;358:9–15.
  29. Hull RD, Pineo GF, Stein PD, Mah AF, MacIsaac SM, Dahl OE, Butcher M, Brant RF, Ghali WA, Bergqvist D, Raskob GE: Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: A systematic review. Ann Intern Med 2001;135:858–869.

 goto top of outline Author Contacts

Dr. Bengt Eriksson
Department of Orthopedics
Sahlgrenska University Hospital/Östra
SE–41685 Gothenburg (Sweden)
Tel. +46 31 343 4408, Fax +46 31 343 4092, E-Mail b.eriksson@orthop.gu.se


 goto top of outline Article Information

Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 0, Number of References : 29


 goto top of outline 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

Ximelagatran represents the first new oral anticoagulant since the introduction of warfarin almost 60 years ago, and has been evaluated for the treatment and prevention of a range of venous and arterial thromboembolic disorders. The MElagatran THRomboprophylaxis in Orthopaedic surgery (METHRO) and EXpanded PRophylaxis Evaluation Surgery Study (EXPRESS) studies have investigated the efficacy and safety of subcutaneous (s.c.) melagatran followed by oral ximelagatran in preventing venous thromboembolism (VTE) in patients undergoing total hip replacement or total knee replacement. In METHRO II, immediate pre-operative-initiated s.c. melagatran followed by post-operative ximelagatran dose-dependently reduced VTE, with the highest dose (melagatran 3 mg/ximelagatran 24 mg twice daily) associated with a significantly reduced incidence of VTE compared with the low-molecular-weight heparin (LMWH) dalteparin (15.1 vs. 28.2%; p < 0.0001). In METHRO III, the efficacy of s.c. melagatran 3 mg/ximelagatran 24 mg twice daily initiated post-operatively (4–12 h after surgery) was comparable to that of the LMWH enoxaparin initiated 12 h before surgery (total VTE incidence, 31.0 and 27.3%, respectively). Rates of severe bleeding were also comparable between treatments (melagatran/ximelaga tran = 1.4%; enoxaparin = 1.7%). Treatment with melagatran/ximelagatran was significantly more effective when initiated earlier (4–8 h) rather than later (8–12 h) after surgery (total VTE incidence, 27.5 vs. 35.4%; p = 0.0034). Based on the results of METHRO II and III, the EXPRESS study evaluated the efficacy and bleeding profile of s.c. melagatran 2 mg immediately before surgery, followed by s.c. melagatran 3 mg on the evening of the day of surgery and then ximelagatran 24 mg twice daily. This regimen was significantly more effective than enoxaparin (total VTE incidence, 20.3 vs. 26.6%; p < 0.0004). Excessive bleeding (as judged by the investigator) was more frequent with melagatran/ximelagatran, but rates of fatal bleeding, critical-site bleeding and bleeding requiring re-operation did not differ between the groups. Taken together, the METHRO and EXPRESS studies demonstrate that melagatran/ximelagatran has comparable or superior efficacy to LMWHs in the prevention of VTE in orthopaedic surgery patients, and that the timing and dose of melagatran is important in optimizing the balance of efficacy and bleeding risk.



 goto top of outline Author Contacts

Dr. Bengt Eriksson
Department of Orthopedics
Sahlgrenska University Hospital/Östra
SE–41685 Gothenburg (Sweden)
Tel. +46 31 343 4408, Fax +46 31 343 4092, E-Mail b.eriksson@orthop.gu.se


 goto top of outline Article Information

Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 0, Number of References : 29


 goto top of outline 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

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. White RH: The epidemiology of venous thromboembolism. Circulation 2003;107:I4–I8.

    External Resources

  2. White RH, Zhou H, Romano PS: Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost 2003;90:446–455.
  3. 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

  4. Iorio A, Agnelli G: Pharmacokinetic optimisation of the treatment of deep vein thrombosis. Clin Pharmacokinet 1997;32:145–172.
  5. Haycraft JB: On the action of a secretion obtained from the medicinal leech on the coagulation of the blood. Proc R Soc London 1884;36:478–487.
  6. Shionoya T: Studies in experimental extracorporeal thrombosis. III. Effects of certain anticoagulants (heparin and hirudin) on extracorporeal thrombosis and on the mechanisms of thrombosis. J Exp Med 1927;49:19–26.

    External Resources

  7. Riehl-Bellon N, Carvallo D, Acker M, Van Dorsselaer A, Marquet M, Loison G, Lemoine Y, Brown SW, Courtney M, Roitsch C: Purification and biochemical characterization of recombinant hirudin produced by Saccha romyces cerevisiae. Biochemistry 1989;28:2941–2949.
  8. Maraganore JM, Bourdon P, Jablonski J, Ramachandran KL, Fenton JW: Design and characterization of hirulogs: A novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990;29:7095–7101.
  9. Fitzgerald D, Murphy N: Argatroban: A synthetic thrombin inhibitor of low relative molecular mass. Coron Artery Dis 1996;7:455–458.
  10. Bajusz S: Chemistry and biology of the peptide anticoagulant D-MePhe-Pro-Arg-H (GYKI-14766). Adv Exp Med Biol 1993;340:91–108.
  11. Weitz JI: A novel approach to thrombin inhibition. Thromb Res 2003;109(suppl 1):S17–S22.

    External Resources

  12. Eriksson BI, Wille-Jørgensen P, Kälebo P, Mouret P, Rosencher N, Bösch P, Baur M, Ekman S, Bach D, Lindbratt S, Close P: A comparison of recombinant hirudin with a low- molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997;337:1329–1335.
  13. Gustafsson D, Bylund R, Antonsson T, Nilsson I, Nyström JE, Eriksson U, Bredberg U, Teger-Nilsson AC: A new oral anticoagulant: The 50-year challenge. Nat Rev Drug Discov 2004;3:1–11.

    External Resources

  14. Eriksson UG, Bredberg U, Hoffmann KJ, Thuresson A, Gabrielsson M, Ericsson H, Ahnoff M, Gislén K, Fager G, Gustafsson D: Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2003;31:294–305.
  15. 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.
  16. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Mouret P, Rosencher N, Eskilson C, Nylander I, Frison L, Ogren 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.
  17. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Lassen MR, Mouret P, Rosencher N, Kalebo P, Panfilov 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.
  18. Francis CW, Davidson BL, Berkowitz SD, Lotke PA, Ginsberg JS, Lieberman JR, Webster AK, Whipple JP, Peters GR, Colwell CW Jr: Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double-blind trial. Ann Intern Med 2002;137:648–655.
  19. 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.
  20. Raskob GE, Hirsh J: Controversies in timing of the first dose of anticoagulant prophylaxis against venous thromboembolism after major orthopedic surgery. Chest 2003;124:379S–385S.
  21. Dahl OE, Bergqvist D: Current controversies in deep vein thrombosis prophylaxis after orthopaedic surgery. Curr Opin Pulm Med 2002;8:394–397.
  22. 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 in close proximity to surgery vs warfarin in hip arthroplasty patients: A double-blind, randomized comparison. The North American Fragmin Trial Investigators. Arch Intern Med 2000;160:2199–2207.
  23. Eriksson BI, Ekman S, Lindbratt S, Baur M, Bach D, Torholm C, Kalebo P, Close P: Prevention of thromboembolism with use of recombinant hirudin. Results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement. J Bone Joint Surg Am 1997;79:326–333.
  24. Eriksson BI, Ekman S, Kälebo P, Zachrisson B, Bach D, Close P: Prevention of deep-vein thrombosis after total hip replacement: Direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996;347:635–639.
  25. Eriksson BI, Kälebo P, Ekman S, Lindbratt S, Kerry R, Close P: Direct thrombin inhibition with Rec-hirudin CGP 39393 as prophylaxis of thromboembolic complications after total hip replacement. Thromb Haemost 1994;72:227–231.
  26. Eriksson BI, Dahl OE: Prevention of venous thromboembolism following orthopaedic surgery: Clinical potential of direct thrombin inhibitors. Drugs 2004;64:577–595.
  27. Sarich TC, Eriksson UG, Mattsson C, Wolzt M, Frison L, Fager G, Gustafsson D: Inhibition of thrombin generation by the oral direct thrombin inhibitor ximelagatran in shed blood from healthy male subjects. Thromb Haemost 2002;87:300–305.
  28. Eikelboom JW, Quinlan DJ, Douketis JD: Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: A meta-analysis of the randomised trials. Lancet 2001;358:9–15.
  29. Hull RD, Pineo GF, Stein PD, Mah AF, MacIsaac SM, Dahl OE, Butcher M, Brant RF, Ghali WA, Bergqvist D, Raskob GE: Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: A systematic review. Ann Intern Med 2001;135:858–869.