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Prevention of Venous Thromboembolism Following Orthopaedic Surgery

Clinical Potential of Direct Thrombin Inhibitors

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Abstract

Patients undergoing total hip or total knee replacement are at high risk of venous thromboembolism (VTE), and are therefore considered to be populations well suited for the evaluation and dose optimisation of new anticoagulants. Deep vein thrombosis may lead to life-threatening pulmonary embolism, disabling morbidity in the form of the post-thrombotic syndrome, and risk of recurrent thrombotic events. There is increasing evidence that anticoagulant treatment for the prevention of VTE should be extended from 1 to at least 4 weeks after surgery. Anticoagulation with vitamin K antagonists (such as warfarin), low molecular weight heparin or unfractionated heparin effectively lowers the risk of VTE, but these anticoagulants have limitations such as the need for coagulation monitoring and subsequent dose adjustment (vitamin K antagonists), difficulty of continuing prophylaxis out of hospital because of the requirement for parenteral administration, and risk of heparin-induced thrombocytopenia. The development of new anticoagulants has been pursued with the aim of finding more effective, safer and/ or more convenient therapies.

Thrombin is a central regulator in the coagulation and inflammation process and several direct thrombin inhibitors (DTIs) with distinct pharmacological profiles, as well as pharmacological differences from the conventional anticoagulants, are currently in clinical use for certain indications or are under development. Clinical experience with parenterally administered DTIs has accumulated since the mid 1990s, although only desirudin (a recombinant hirudin) is currently approved for use in patients undergoing orthopaedic surgery. Two oral DTIs, ximelagatran and dabigatran etexilate, are in clinical development. Dabigatran etexilate has recently been evaluated in phase II clinical trials in patients undergoing total hip replacement. Several large phase III trials have now demonstrated the efficacy and safety of ximelagatran in the prevention of VTE following total hip or knee replacement. Ximelagatran can be used with an oral fixed dose without the need for coagulation monitoring or dose adjustment. Hence, it offers significant potential to facilitate the management of anticoagulation in or out of hospital.

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References

  1. Seyfer AE, Seaber AV, Dombrose FA, et al. Coagulation changes in elective surgery and trauma. Ann Surg 1981; 193: 210–3

    Article  PubMed  CAS  Google Scholar 

  2. Dahl OE, Pedersen T, Kierulf P, et al. Sequential intrapulmonary and systemic activation of coagulation and fibrinolysis during and after total hip replacement surgery. Thromb Res 1993; 70: 451–8

    Article  PubMed  CAS  Google Scholar 

  3. McNally MA, Mollan RA. Total hip replacement, lower limb blood flow and venous thrombogenesis. J Bone Joint Surg Br 1993; 75: 640–4

    PubMed  CAS  Google Scholar 

  4. Dahl OE, Aspelin T, Arnesen H, et al. Increased activation of coagulation and formation of late deep venous thrombosis following discontinuation of thromboprophylaxis after hip replacement surgery. Thromb Res 1995; 80: 299–306

    Article  PubMed  CAS  Google Scholar 

  5. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119: 132S–75S

    Article  PubMed  CAS  Google Scholar 

  6. Puolakka TJ, Pajamaki KJ, Halonen PJ, et al. The Finnish Arthroplasty Register: report of the hip register. Acta Orthop Scand 2001;72: 433–41

    Article  PubMed  CAS  Google Scholar 

  7. Lucht U. The Danish Hip Arthroplasty Register. Acta Orthop Scand 2000; 71: 433–9

    Article  PubMed  CAS  Google Scholar 

  8. Ostendorf M, Johnell O, Malchau H, et al. The epidemiology of total hip replacement in The Netherlands and Sweden: present status and future needs. Acta Orthop Scand 2002; 73: 282–6

    Article  PubMed  Google Scholar 

  9. Mahomed NN, Barrett JA, Katz JN, et al. Rates and outcomes of primary and revision total hip replacement in the United States medicare population. J Bone Joint Surg Am 2003; 85-A: 27–32

    PubMed  Google Scholar 

  10. Robertsson O, Dunbar MJ, Knutson K, et al. Past incidence and future demand for knee arthroplasty in Sweden: a report from the Swedish Knee Arthroplasty Register regarding the effect of past and future population changes on the number of arthroplasties performed. Acta Orthop Scand 2000; 71: 376–80

    Article  PubMed  CAS  Google Scholar 

  11. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119: 8S–21S

    Article  PubMed  CAS  Google Scholar 

  12. Ansell J, Hirsh J, Dalen J, et al. Managing oral anticoagulant therapy. Chest 2001; 119: 22S–38S

    Article  PubMed  CAS  Google Scholar 

  13. Eriksson BI, Wille-Jørgensen P, Kälebo P, et al. 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: 1329–35

    Article  PubMed  CAS  Google Scholar 

  14. Turpie AG, Gallus AS, Hoek JA; Pentasaccharide Investigators. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 2001; 344: 619–25

    Article  PubMed  CAS  Google Scholar 

  15. Committee for Proprietary Medicinal Products. Points to consider on clinical investigation of medical products for prophylaxis of intra- and postoperative venous thromboembolic risk. London: The European Agency for Evaluation of Medicinal Products, 2000 Jun 29. Guideline no. CPMP/EWP/707/98

  16. Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 1991; 30: 10363–70

    Article  PubMed  CAS  Google Scholar 

  17. Fenton JW 2nd, Ofosu FA, Brezniak DV, et al. Thrombin and antithrombotics. Semin Thromb Hemost 1998; 24: 87–91

    Article  PubMed  CAS  Google Scholar 

  18. Kaplan KL. Direct thrombin inhibitors. Expert Opin Pharmacother 2003; 4: 653–66

    Article  PubMed  CAS  Google Scholar 

  19. Lefkovits J, Topol EJ. Direct thrombin inhibitors in cardiovascular medicine. Circulation 1994; 90: 1522–36

    Article  PubMed  CAS  Google Scholar 

  20. Samama MM, Kher A. Anticoagulation: the old and the new. Hamostaseologie 1998; 18: S27–32

    CAS  Google Scholar 

  21. Eriksson BI, Kälebo P, Ekman S, et al. Direct thrombin inhibition with Rec-hirudin CGP 39393 as prophylaxis of thromboembolic complications after total hip replacement. Thromb Haemost 1994; 72: 227–31

    PubMed  CAS  Google Scholar 

  22. Neuhaus KL, 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 Krankenhausarzte (ALKK). Circulation 1994; 90: 1638–42

    Article  PubMed  CAS  Google Scholar 

  23. Neuhaus KL, Molhoek GP, Zeymer U, et al. Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial. J Am Coll Cardiol 1999; 34: 966–73

    Article  PubMed  CAS  Google Scholar 

  24. Cannon CP, McCabe CH, Henry TD, et al. A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial. J Am Coll Cardiol 1994; 23: 993–1003

    Article  PubMed  CAS  Google Scholar 

  25. Antman EM. Hirudin in acute myocardial infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation. 1996; 94: 911–21

    Article  PubMed  CAS  Google Scholar 

  26. Serruys PW, Herrman JP, Simon R, et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty: Helvetica Investigators. N Engl J Med 1995; 333: 757–63

    Article  PubMed  CAS  Google Scholar 

  27. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996; 335: 775–82

    Article  Google Scholar 

  28. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomized trial. Lancet 1999; 353: 429–38

    Article  Google Scholar 

  29. Greinacher A, Volpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation 1999; 99: 73–80

    Article  PubMed  CAS  Google Scholar 

  30. Greinacher A, Janssens U, Berg G, et al. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia: Heparin-Associated Thrombocytopenia Study (HAT) investigators. Circulation 1999; 100: 587–93

    Article  PubMed  CAS  Google Scholar 

  31. Ginsberg JS, Nurmohamed MT, Gent M, et al. Use of Hirulog in the prevention of venous thrombosis after major hip or knee surgery. Circulation 1994; 90: 2385–9

    Article  PubMed  CAS  Google Scholar 

  32. Ginsberg JS, Nurmohamed MT, Gent M, et al. Effects on thrombin generation of single injections of Hirulog in patients with calf vein thrombosis. Thromb Haemost 1994; 72: 523–5

    PubMed  CAS  Google Scholar 

  33. Bittl JA, StronyJ,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

    Article  PubMed  CAS  Google Scholar 

  34. Bittl JA, Chaitman BR, Feit F, et al. 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

    Article  PubMed  CAS  Google Scholar 

  35. Direct Thrombin Inhibitor Trialists’ Collaborative Group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet 2002; 359: 294–302

    Article  Google Scholar 

  36. Lincoff AM, Kleiman NS, Kottke-Marchant K, et al. Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET). Am Heart J 2002; 143: 847–53

    Article  PubMed  CAS  Google Scholar 

  37. Lincoff AM, Bittl JA, Harrington RA, et al., the REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/ IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289: 853–63

    Article  PubMed  CAS  Google Scholar 

  38. White HD, Aylward PE, Frey MJ, et al. Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO): Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators. Circulation 1997; 96: 2155–61

    Article  PubMed  CAS  Google Scholar 

  39. White H, and the Hirulog and Early Reperfusion or Occlusion (HERO)-2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet 2001; 358: 1855–63

    Article  PubMed  CAS  Google Scholar 

  40. Jang IK, Brown DF, Giugliano RP, et al. A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with novastan and TPA (MINT) study. J Am Coll Cardiol 1999; 33: 1879–85

    Article  PubMed  CAS  Google Scholar 

  41. Lewis BE, Wallis DE, Berkowitz SD, et al., and the ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103: 1838–43

    Article  PubMed  CAS  Google Scholar 

  42. Lewis BE, Matthai WH Jr, Cohen M, et al., and the ARG-216/ 310/311 Study Investigators. Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Catheter Cardiovasc Interv 2002; 57: 177–84

    Article  PubMed  Google Scholar 

  43. Eriksson BI, Agnelli G, Cohen AT, et al., and the The 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; 1: 2490–6

    Article  PubMed  CAS  Google Scholar 

  44. Francis CW, Berkowitz SD, Comp PC, et al., and the EXULT A Study Group. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003; 349: 1703–12

    Article  PubMed  CAS  Google Scholar 

  45. Eriksson H, Wåhlander K, Gustafsson D, et al., for the THRIVE Investigators. A randomised, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 2003; 1: 41–47

    Article  PubMed  CAS  Google Scholar 

  46. Eriksson H, Schulman S, Lapidus L, et al. Efficacy and tolerability of the oral direct thrombin inhibitor ximelagatran for the treatment of venous thromboembolism [abstract]. Blood Coagul Fibrinolysis 2002; 13: A10

    Google Scholar 

  47. Schulman S, Wahlander K, Lundstrom T, et al., and the THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003; 349: 1713–21

    Article  PubMed  CAS  Google Scholar 

  48. Olsson SB, and the Executive Steering Committee on behalf of the 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

    Article  PubMed  CAS  Google Scholar 

  49. Wallentin L, Wilcox RG, Weaver WD, et al., and the ESTEEM Investigators. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003; 362: 789–97

    Article  PubMed  CAS  Google Scholar 

  50. Kumar R, Beguin S, Hemker HC. The effect of fibrin clots and clot-bound thrombin on the development of platelet procoagulant activity. Thromb Haemost. 1995; 74: 962–8

    PubMed  CAS  Google Scholar 

  51. 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; 119:64S–94S

    Article  PubMed  CAS  Google Scholar 

  52. Weitz JI, Hudoba M, Massel D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin Ill-independent inhibitors. J Clin Invest 1990; 86: 385–91

    Article  PubMed  CAS  Google Scholar 

  53. Klement P, Carlsson S, Rak J, et al. The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model. J Thromb Haemost 2003; 1: 587–94

    Article  PubMed  CAS  Google Scholar 

  54. Berry CN, Girardot C, Lecoffre C, et al. Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant Hirudin. Thromb Haemost 1994; 72: 381–6

    PubMed  CAS  Google Scholar 

  55. Gladwell TD. Bivalirudin: a direct thrombin inhibitor. Clin Ther 2002; 24: 38–58

    Article  PubMed  CAS  Google Scholar 

  56. Dager WE, White RH. Treatment of heparin-induced thrombocytopenia. Ann Pharmacother 2002; 36: 489–503

    Article  PubMed  CAS  Google Scholar 

  57. 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

    PubMed  CAS  Google Scholar 

  58. Berry CN, Girard D, Lochot S, et al. Antithrombotic actions of argatroban in rat models of venous, ‘mixed’ and arterial thrombosis, and its effects on the tail transection bleeding time. Br J Pharmacol 1994; 113: 1209–14

    Article  PubMed  CAS  Google Scholar 

  59. Hursting MJ, Alford KL, Becker JC, et al. Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor. Semin Thromb Hemost 1997; 23: 503–16

    Article  PubMed  CAS  Google Scholar 

  60. Carlsson S, Elg M, Mattsson C. Effects of ximelagatran, the oral form of melagatran, in the treatment of caval vein thrombosis in conscious rats. Thromb Res 2002; 107: 163–8

    Article  PubMed  CAS  Google Scholar 

  61. 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

    Article  PubMed  CAS  Google Scholar 

  62. Bratt G, Tornebohm E, Widlund L, et al. Low molecular weight heparin (KABI 2165, Fragmin): pharmacokinetics after intravenous and subcutaneous administration in human volunteers. Thromb Res 1986; 42: 613–20

    Article  PubMed  CAS  Google Scholar 

  63. Collignon F, Frydman A, Caplain H, et al. Comparison of the pharmacokinetic profiles of three low molecular mass heparins — dalteparin, enoxaparin and nadroparin — administered subcutaneously in healthy volunteers (doses for prevention of thromboembolism). Thromb Haemost 1995; 73: 630–40

    PubMed  CAS  Google Scholar 

  64. Verstraete M, Nurmohamed M, Kienast J, et al. Biologic effects of recombinant hirudin (CGP 39393) in human volunteers: European Hirudin in Thrombosis Group. J Am Coll Cardiol 1993; 22: 1080–8

    Article  PubMed  CAS  Google Scholar 

  65. Bichler J, Baynes JW, Thorpe SR. Catabolism of hirudin and thrombin-hirudin complexes in the rat. Biochem J 1993; 296: 771–6

    PubMed  CAS  Google Scholar 

  66. Greinacher A, Lubenow N. Recombinant hirudin in clinical practice: focus on lepirudin. Circulation 2001; 103: 1479–84

    Article  PubMed  CAS  Google Scholar 

  67. Lefevre G, Duval M, Gauron S, et al. Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin. Clin Pharmacol Ther 1997; 62: 50–9

    Article  PubMed  CAS  Google Scholar 

  68. Nowak G, Bucha E, Goock T, et al. Pharmacology of r-hirudin in renal impairment. Thromb Res 1992; 66: 707–15

    Article  PubMed  CAS  Google Scholar 

  69. Greinacher A, Eichler P, Albrecht D, et al. Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance. Blood 2003; 101: 2617–9

    Article  PubMed  CAS  Google Scholar 

  70. Eichler P, Friesen HJ, Lubenow N, et al. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 2000; 96: 2373–8

    PubMed  CAS  Google Scholar 

  71. Harenberg J, Huhle G, Wang LC, et al. Re-exposure to recombinant (r)-hirudin in antihirudin antibody-positive patients with a history of heparin-induced thrombocytopenia. Br J Haematol 2000; 109: 360–3

    Article  PubMed  CAS  Google Scholar 

  72. Fox I, Dawson A, Loynds P, et al. Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans. Thromb Haemost 1993; 69: 157–63

    PubMed  CAS  Google Scholar 

  73. Robson R. The use of bivalirudin in patients with renal impairment. J Invasive Cardiol 2000; 12: 33F-6F

    Google Scholar 

  74. Reed MD, Bell D. Clinical pharmacology of bivalirudin. Pharmacotherapy 2002; 22: 105S–11S

    Article  PubMed  CAS  Google Scholar 

  75. Robson R, White H, Aylward P, et al. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender. Clin Pharmacol Ther 2002; 71: 433–9

    Article  PubMed  CAS  Google Scholar 

  76. Kondo LM, Wittkowsky AK, Wiggins BS. Argatroban for prevention and treatment of thromboembolism in heparin-induced thrombocytopenia. Ann Pharmacother 2001; 35: 440–51

    Article  PubMed  CAS  Google Scholar 

  77. McKeage K, Plosker GL. Argatroban. Drugs 2001; 61: 515–22

    Article  PubMed  CAS  Google Scholar 

  78. Tran JQ, Di Cicco RA, Sheth SB, et al. Assessment of the potential pharmacokinetic and pharmacodynamic interactions between erythromycin and argatroban. J Clin Pharmacol 1999; 39: 513–9

    PubMed  CAS  Google Scholar 

  79. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20: 318–29

    Article  PubMed  CAS  Google Scholar 

  80. Eriksson UG, Bredberg U, Gislen K, et al. Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003; 59: 35–43

    PubMed  CAS  Google Scholar 

  81. Eriksson UG, Mandema J, Karlsson MO, et al. Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis. Clin Pharmacokinet 2003; 42: 687–701

    Article  PubMed  CAS  Google Scholar 

  82. Eriksson U, Baathe S, Hamren B, et al. Predictable pharmacokinetics of ximelagatran, an oral direct thrombin inhibitor, in nonvalvular atrial fibrillation patients receiving long-term treatment. Pathophysiol Haemost Thromb 2002; 32: 56

    Article  CAS  Google Scholar 

  83. Bredberg U, Eriksson UG, Taure K, et al. Effects of melagatran, a novel oral direct thrombin inhibitor, in healthy volunteers following subcutaneous and oral administration [abstract]. Blood 1999; 94: 28a

    Google Scholar 

  84. Johansson LC, Frison L, Logren U, et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003; 42: 381–92

    Article  PubMed  CAS  Google Scholar 

  85. Sarich TC, Teng R, Peters GR, et al. No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. Clin Pharmacokinet 2003; 42: 485–92

    Article  PubMed  CAS  Google Scholar 

  86. Johansson L, Andersson M, Fager G, et al. No influence of ethnic origin on the pharmacokinetics and pharmacodynamics of melagatran following oral administration of ximelagatran, a novel oral direct thrombin inhibitor, to healthy male volunteers. Clin Pharmacokinet 2003; 42: 475–84

    Article  PubMed  CAS  Google Scholar 

  87. Wåhlander K, Eriksson-Lepkowska M, Frison L, et al. No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003; 42: 755–64

    Article  PubMed  Google Scholar 

  88. Bredberg E, Andersson TB, Frison L, et al. Ximelagatran, an oral direct thrombin inhibitor, has low potential for cytochrome P450-mediated drug-drug interactions. Clin Pharmacokinet 2003; 42: 765–77

    Article  PubMed  CAS  Google Scholar 

  89. Eriksson UG, Johansson S, Attman P-O, et al. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran. Clin Pharmacokinet 2003; 42: 743–53

    Article  PubMed  CAS  Google Scholar 

  90. Stangier J, Rathgen K, Gansser D, et al. Pharmacokinetics of BIBR953ZW, a novel low molecular weight direct thrombin inhibitor in healthy volunteers [abstract no. OC2347; published on CD-ROM]. Thromb Haemost 2001 Jul; Suppl.

  91. Eriksson BI, Dahl O, Ahnfelt L, et al. Dose escalating safety study of a new oral direct thrombin inhibitor, BIBR 1048, in patients undergoing total hip replacement. Pathophysiol Haemost Thromb 2002; 32: 69

    Google Scholar 

  92. Stangier J, Nehmiz G, Liesenfeld KH, et al. Pharmacokinetics of BIBR 953 ZW, the active form of the oral direct thrombin inhibitor BIBR 1048, in patients undergoing hip replacement [abstract]. J Thromb Haemost 2003 Jul; 1 Suppl.: P1916

  93. Stangier J, Liesenfeld KH, Troconiz CH, et al. The effect of BIBR 953 ZW, the active form of the oral direct thrombin inhibitor BIBR 1048, on the prolongation of aPTT and ECT in orthopedic patients: a population pharmacodynamic study [abstract]. J Thromb Haemost 2003 Jul; 1 Suppl. 1: P1917

    Google Scholar 

  94. Miric A, Lombardi P, Sculco TP. Deep vein thrombosis prophylaxis: a comprehensive approach for total hip and total knee arthroplasty patient populations. Am J Orthop 2000; 29: 269–74

    PubMed  CAS  Google Scholar 

  95. Dahl OE. Cardiorespiratory and vascular dysfunction related to major reconstructive orthopedic surgery. Acta Orthop Scand 1997; 68: 607–14

    Article  PubMed  CAS  Google Scholar 

  96. Iobst CA, Friedman RJ. The role of low molecular weight heparin in total knee arthroplasty. Am J Knee Surg 1999; 12: 55–60

    PubMed  CAS  Google Scholar 

  97. Gross M, Anderson DR, Nagpal S, et al. Venous thromboembolism prophylaxis after total hip or knee arthroplasty: a survey of Canadian orthopedic surgeons. Can J Surg 1999; 42: 457–61

    PubMed  CAS  Google Scholar 

  98. Hull RD, Pineo GF, Stein PD, et al. Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review. Arch Intern Med 2001; 161: 1952–60

    Article  PubMed  CAS  Google Scholar 

  99. Dahl OE, Bergqvist D. Current controversies in deep vein thrombosis prophylaxis after orthopaedic surgery. Curr Opin Pulm Med 2002; 8: 394–7

    Article  PubMed  Google Scholar 

  100. Collins R, Scrimgeour A, Yusuf S, et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988; 318: 1162–73

    CAS  Google Scholar 

  101. Eriksson BI, Ekman S, Lindbratt S, et al. 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: 326–33

    CAS  Google Scholar 

  102. Eriksson BI, Ekman S, Kälebo P, et al. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996; 347: 635–9

    Article  PubMed  CAS  Google Scholar 

  103. Eriksson BI, Bergqvist D, Kalebo P, et al.; Melagatran for Thrombin inhibition in Orthopaedic surgery. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomized trial. Lancet 2002; 360: 1441–7

    Article  PubMed  CAS  Google Scholar 

  104. 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. Thromb Haemost 2003; 89: 288–96

    PubMed  CAS  Google Scholar 

  105. Cohen AT, Agnelli G, Dahl OE, et al. Efficacy and safety of the treatment regimen of melagatran and ximelagatran for prevention of thromboembolic events after total hip or knee replacement: a meta-analysis of 3 randomized, double-blind studies, to evaluate the influence of time and dose [abstract]. J Thromb Haemost 2003 Jul; 1 Suppl. 1: P1915

    Google Scholar 

  106. Colwell CW, Berkowitz SD, Davidson BL, et al. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement: a randomized, double-blind study. J Thromb Haemost 2003; 1: 2119–30

    Article  PubMed  CAS  Google Scholar 

  107. Heit JA, Colwell CW, Francis CW, et al., and the AstraZeneca Arthroplasty Study Group. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study. Arch Intern Med 2001; 161: 2215–21

    Article  PubMed  CAS  Google Scholar 

  108. Francis CW, Davidson BL, Berkowitz SD, et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty: a randomized, double-blind trial. Ann Intern Med 2002; 137: 648–55

    PubMed  CAS  Google Scholar 

  109. Colwell CW, Berkowitz SD, Comp PC, et al., and the EXULT B Investigators. Randomized, double-blind comparison of ximelagatran, an oral direct thrombin inhibitor, and warfarin to prevent venous thromboembolism (VTE) after total knee replacement (TKR): EXULT B [abstract]. Blood 2003; 102: 14a

    Google Scholar 

  110. Lassen MR, Bauer KA, Eriksson BI, et al., and the European Pentasaccharide Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomized double-blind comparison. Lancet 2002; 359: 1715–20

    Article  PubMed  CAS  Google Scholar 

  111. Bauer KA, Eriksson BI, Lassen MR, et al., and the Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305–10

    Article  PubMed  CAS  Google Scholar 

  112. Turpie AG, Bauer KA, Eriksson BI, et al., and the PENTATHALON 2000Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002; 359: 1721–6

    Article  PubMed  CAS  Google Scholar 

  113. Elg M, Borjesson I, Pehrsson S, et al. Feiba™ and Autoplex®, superimposed on a high dose of melagatran, the active form of the oral direct thrombin inhibitor H 376/95 reversed bleeding times and blood loss [abstract]. Haemostasis 2000; 30: 10

    Google Scholar 

  114. 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

    Article  PubMed  CAS  Google Scholar 

  115. Hull RD, Pineo GF, Stein PD, et al. 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: 858–69

    PubMed  CAS  Google Scholar 

  116. Bigby J, Dunn J, Goldman L, et al. Assessing the preventability of emergency hospital admissions: a method for evaluating the quality of medical care in a primary care facility. Am J Med 1987; 83: 1031–6

    Article  PubMed  CAS  Google Scholar 

  117. Berwaerts J, Robb OJ, Dykhuizen RS, et al. Course, management and outcome of oral-anticoagulant-related intracranial haemorrhages. Scott Med J 2000; 45: 105–9

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Orthopaedics Surgery, Sahlgrenska University Hospital/Östra, SE-416 85, Göteborg, Sweden

    Bengt I. Eriksson

  2. Department of Orthopaedics, Section for Joint Implants and Medical Science, Buskerud Central Hospital, Drammen, Norway

    Ola E. Dahl

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  1. Bengt I. Eriksson
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  2. Ola E. Dahl
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Correspondence to Bengt I. Eriksson.

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Eriksson, B.I., Dahl, O.E. Prevention of Venous Thromboembolism Following Orthopaedic Surgery. CNS Drugs 64, 577–595 (2004). https://doi.org/10.2165/00003495-200464060-00002

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