Ximelagatran/melagatran: A review of its use in the prevention of venous thromboembolism in orthopaedic surgery

Drugs

Volumn 64, Issue 6, 2004, Pages 649-678

  Evans, Hannah C ^a   Perry, Caroline M ^a   Faulds, Diana ^a  

^a ADIS INTERNATIONAL LIMITED   (New Zealand)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; ATORVASTATIN; CYTOCHROME P450; DALTEPARIN; DIAZEPAM; DICLOFENAC; DIGOXIN; ENOXAPARIN; HIRUDIN; LEPIRUDIN; LOW MOLECULAR WEIGHT HEPARIN; MELAGATRAN; NIFEDIPINE; THROMBIN; THROMBIN INHIBITOR; TISSUE PLASMINOGEN ACTIVATOR; WARFARIN; XIMELAGATRAN;

BLEEDING; BLOOD TRANSFUSION; CLINICAL TRIAL; CONSTIPATION; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG TOLERABILITY; DRUG URINE LEVEL; FEVER; FIBRINOLYSIS; HEMATOMA; HUMAN; KIDNEY CLEARANCE; LIVER FAILURE; NAUSEA; OBESITY; ORTHOPEDIC SURGERY; POSTOPERATIVE COMPLICATION; REVIEW; SIDE EFFECT; THROMBOCYTE ACTIVATION; THROMBOCYTE AGGREGATION; URINARY TRACT INFECTION; VENOUS THROMBOEMBOLISM;

ANTICOAGULANTS; AZETIDINES; BENZYLAMINES; DRUG INTERACTIONS; DRUG THERAPY, COMBINATION; ENOXAPARIN; GLYCINE; HUMANS; ORTHOPEDIC PROCEDURES; RANDOMIZED CONTROLLED TRIALS; THROMBIN; THROMBOEMBOLISM; VENOUS THROMBOSIS; WARFARIN;

EID: 1842785009     PISSN: 00126667     EISSN: None     Source Type: Journal    
DOI: 10.2165/00003495-200464060-00010     Document Type: Review

References (65)

1. Agnelli G. Unresolved issues in the prevention and treatment of venous thromboembolism. Semin Thromb Hemost 2002 Jun; 28 Suppl. 2: 33-40
2. Arnold DM, Kahn SR, Shrier I. Missed opportunities for prevention of venous thromboembolism: an evaluation of the use of thromboprophylaxis guidelines. Chest 2001 Dec; 120 (6): 1964-71
3. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001 Jan; 119 (1 Suppl.): 132S-75S
4. Lee AYY, Hirsh J. Diagnosis and treatment of venous thromboembolism. Annu Rev Med 2002; 53: 15-33
5. Gustafsson D, Antonsson T, Bylund R, et al. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 1998 Jan; 79 (1): 110-8
6. Eriksson UG, Bredberg U, Hoffmann KJ, et al. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2003 Mar; 31 (3); 294-305
7. Sorbera LA, Bayès M, Castañer J, et al. Melagatran and ximelagatran: anticoagulant, thrombin inhibitor. Drugs Future 2001; 26 (12): 1155-70
8. Gustafsson D, Elg M. The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review. Thromb Res 2003 Jul 15; 109 Suppl. 1: S9-15
9. Eriksson H, Eriksson UG, Frison L, et al. Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT. Thromb Haemost 1999 Mar; 81 (3): 358-63
10. Eriksson UG, Bredberg U, Gislén K, et al. Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003 May; 59 (1): 35-43
11. Johansson S, Wåhlander K, Larson G, et al. Pharmacokinetics and anticoagulant effect of the direct thrombin inhibitor melagatran following subcutaneous administration to healthy young men. Blood Coagul Fibrinolysis 2003 Oct; 14 (7): 677-84
12. 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 Feb 19; 41 (4): 557-64
13. Eriksson BI, Arfwidsson AC, Frison L, et al. 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 Feb; 87 (2): 231-7
14. 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 (8): 755-64
15. Boström SL, Göran FH, Hansson GFH, 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
16. Bostrom SL, Sarich TC, Woltz M. The effects of melagatran, the active form of H376/95, an oral, direct thrombin inhihibitor, on thrombin generation [abstract no. 232]. Blood 2000; 96 (11 Pt 1): 56
17. 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; 1: 999-1004
18. Sarich TC, Eriksson UG, Mattsson C, et al. Inhibition of thrombin generation by the oral direct thrombin inhibitor ximelagatran in shed blood from healthy male subjects. Thromb Haemost 2002 Feb; 87 (2): 300-5
19. Nylander S, Mattson C. Thrombin-induced platelet activation and its inhibition by antocoagulants with different modes of action. Blood Coagul Fibrinolysis 2003 Mar; 14 (2): 159-67
20. Mattson C, Berntsson P. Melagatran, the active form of the oral, direct thrombin inhibitor H 376/95, enhances fibrinolysis via inhibition of thrombin-induced activation of pro-CPU [abstract no. 4109]. Blood 2000 Nov 16; 96 (11 Pt 2): 98-9
21. Mattsson C, Bjorkman JA, Abrahamsson T, et al. Melagatran, the active form of the oral, direct thrombin inhibitor H 376/95, enhances the thrombolytic effects of tissue type plasminogen activator: a possible mechanism being inhibition of thrombin-mediated pro-CPU activation [abstract no. 217]. Blood 2000 Nov 16; 96 (11 Pt 1): 52
22. Lebrazi JJ, Elalamy I, Samama MM. The in vitro inhibitory effect of melagatran on clot bound thrombin [abstract no. 102]. Haemostasis 2000; 30 Suppl. 1: 54
23. Klement P, Carlsson S, Pak 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
24. Li-Saw-Hee FL, Lip GYH. Melagatran (Astra). Curr Opin Cardiovasc Pulm Renal Investig Drugs 1999; 1 (1): 88-92
25. Gustafsson D, Nystrom JE, 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 Feb 1; 101 (3): 171-81
26. Johansson LC, 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 (5): 475-84
27. 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 (4): 381-92
28. Eriksson UG, Johansson S, Attman PO, et al. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran. Clin Pharmacokinet 2003; 42 (8): 743-53
29. Johansson S, Schützer K, Kessler M-E, et al. No influence of alcohol intake on the pharmacokinetics or pharmacodynamics of the oral direct thrombin inhibitor, ximelagatran, in healthy volunteers [abstract no. P1991; plus poster presented at the XIX Congress of the International Society on Thrombosis and Haemostasis; 2003 Jul 12-18; Birmingham, UK]. J Thromb Haemost 2003; 1 Suppl. 1:
30. Sarich TC, Schützer K-M, Dorani H, et al. No pharmacokinetic or pharmacodynamic interaction between atorvastatin and ximelagatran, an oral direct thrombin inhibitor [abstract no. 4217]. Blood 2003 Nov 16; 102 (11): 127b
31. Sarich TC, Schützer K-M, Wollbratt M, et al. No pharmacokinetic or pharmacodynamic interaction between digoxin and ximelagatran, an oral direct thrombin inhibitor [abstract no. 4215]. Blood 2003 Nov 16; 102 (11): 127b
32. Soslau G, Goldenberg SJ, Navas E, et al. (Xi)Melagatran inhibition of alpha-thrombin-Gp Ib and beta-, gamma-thrombin-par-4 platelet aggregation pathways [abstract no. 971]. Blood 2002; 100 (11): 255a
33. Peters G, Whipple J, Eriksson U. Pharmacokinetics of H 376/ 95: a novel oral direct thrombin inhibitor in patients undergoing total knee arthroplasty [abstract no. PII-11]. Clin Pharmacol Ther 2001 Feb; 69 (2): P35
34. Johansson LC, Nyström P, Johnsson G, et al. The PK and PD properties of ximelagatran in young and elderly, healthy Japanese males [abstract no. PI-76; plus poster presented at the 104th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics (ASCPT); 2003 Apr 2-5; Washington, DC]. Clin Pharmacol Ther 2003; 73 (2): P22.
35. Sarich TC, Teng R, Peters GR. 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 (5): 485-92
36. Bredberg E, Andersson TB, Frison L, et al. Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions. Clin Pharmacokinet 2003; 42 (8): 765-77
37. Fager G, Culberg M, Eriksson-Lepkowska M, et al. Pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor, ximelagatran, are not influenced by acetylsalicylic acid. Eur J Clin Pharmacol 2003; 59: 283-9
38. Hellgren M, Johansson S, Eriksson UG, et al. Excretion of the oral direct thrombin inhibitor ximelagatran into breast milk following oral administration to breast-feeding woman [abstract no. P1992; plus poster presented at the XIX Congress of the International Society on Thrombosis and Haemostasis; 2003 Jul 12-18; Birmingham, UK]. J Thromb Haemost 2003; 1 Suppl. 1:
39. Eriksson UG, Mandema JW, Karlsson MO, et al. Pharmacokinetics of melagatran and the effect of ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis. Clin Pharmacokinet 2003; 42 (7): 687-701
40. Clement B, Lopian K. Characterization of in vitro biotransformation of new, orally active, direct thrombin inhibitor ximelagatran, an amidoxime and ester prodrug. Drug Metab Dispos 2003 May; 31 (5): 645-51
41. Eriksson BI, Bergqvist D, Kalebo P, et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002 Nov 9; 360: 1441-7
42. 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 Haemostat 2003; 89 (2): 288-96
43. Eriksson BI, Agnelli G, Cohen AT, et al. on behalf of 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 Dec; 12 (1): 2490-7
44. Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003 Oct 30; 349 (18): 1703-12
45. Colwell CW, Berkowitz SD, Comp PC, et al. 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 no. 39]. Blood 2003 Nov 16; 102 (11)
46. Heit JA, Colwell CW, Francis CW, et al. 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 Oct 8; 161 (18): 2215-21
47. 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 Oct 15; 137 (8): 648-55
48. 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 Oct; 1 (10): 2119-30
49. Nicolaides AN, Breddin HK, Fareed J, et al. Prevention of venous thromboembolism. International consensus statement: guidelines compiled in accordance with the scientific evidence. Int Angiol 2001 Mar; 20 (1): 1-37
50. Efficacy and safety of ximelagatran in METHRO III in certain subgroups of interest. Macclesfield, UK: AstraZeneca, 2004. (Data on file)
51. Bick RL. Proficient and cost-effective approaches for the prevention and treatment of venous thrombosis and thromboembolism. Drugs 2000 Sep; 60 (3): 575-95
52. Sarich TC, Teng R, Peters G, et al. Lack of effect of obesity on the pharmacokinetics and pharmacodynamics of melagatran after oral administration of ximelagatran [abstract no. 183]. Blood 2001 Nov 16; 98 (11 Pt 1): 45
53. Nissen D, editor. Mosby's drug consult. St Louis (MO): Elsevier Science, 2003
54. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1998; 114 (5 Suppl.): 445S-69S
55. Ibbotson T, Goa K. Enoxaparin: an update of its clinical use in the management of acute coronary syndromes. Drugs 2002; 62 (9): 1407-31
56. Dunn C, Jarvis B. Dalteparin: an update of its pharmacological properties and clinical efficacy in the prophylaxis treatment of thromboembolic disease. Drugs 2000 Jul; 60 (1): 203-37
57. Agnelli G, Sonaglia F. Perspectives on antithrombotic agents: from unfractionated heparin to new antithrombotics. Haematologica 2002 Jul; 87 (7): 757-70
58. Steinmetzer T, Hauptmann J, Stürzebecher J. Advances in the development of thrombin inhibitors. Expert Opin Investig Drugs 2001 May; 10 (5): 845-64
59. AstraZeneca. Extending the benefits of antithrombotic therapy: new insights into patient management [poster]. 44th Annual Meeting of the American Society of Hematology; 2002 Dec 6-10; Philadelphia (PA)
60. Kaplan KL, Francis CW. Direct thrombin inhibitors. Semin Hematol 2002 Jul; 39 (3): 187-96
61. Parfitt K, editor. The complete drug reference. 32nd ed. Taunton (MA): Pharmaceutical Press, 1999
62. Groce III JB. Treatment of deep vein thrombosis using low-molecular-weight heparins. Am J Manag Care 2001 Nov; 7 (17 Suppl.): S510-5; discussion S515-23
63. Eriksson BI, Dahl OE. Prevention of venous thromboembolism following orthopaedic surgery: clinical potential for direct thrombin inhibitors. Drugs 2004; 64 (6): 577-95
64. Kher A. Critical appraisal of current antithrombotic trials in patients undergoing total hip replacement. Expert Opin Invest Drugs 2001; 10 (12): 2175-83
65. Hull RD. New insights into extended prophylaxis after orthopaedic surgery: the North American Fragmin Trial experience. Haemostasis 2000; 30 Suppl 2: 95-100; discussion 82-3