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

Journal of Thrombosis and Haemostasis

Volumn 1, Issue 10, 2003, Pages 2119-2130

  Colwell Jr , C W ^a   Berkowitz, S D ^b   Davidson, B L ^c   Lotke, P A ^d   Ginsberg, J S ^e   Lieberman, J R ^f   Neubauer, J ^b   McElhattan, J L ^b   Peters, G R ^b   Francis, C W ^g  

^a SCRIPPS CLINIC   (United States)

^b ASTRAZENECA   (United Kingdom)

^c UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF PENNSYLVANIA   (United States)

^e MCMASTER UNIVERSITY   (Canada)

^f UNIVERSITY OF CALIFORNIA   (United States)

^g UNIVERSITY OF ROCHESTER   (United States)

Author keywords

Deep vein thrombosis; Oral direct thrombin inhibitor; Prophylaxis; Total hip replacement; Venous thromboembolism; Ximelagatran

Indexed keywords

ANTICOAGULANT AGENT; AZETIDINE DERIVATIVE; BENZYLAMINE DERIVATIVE; ENOXAPARIN; HEMOSTATIC AGENT; PRODRUG; THROMBIN; XIMELAGATRAN;

AGED; ARTICLE; BLEEDING; CLINICAL TRIAL; COMPARATIVE STUDY; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG ANTAGONISM; DRUG EFFECT; FEMALE; HIP ARTHROPLASTY; HUMAN; MALE; MIDDLE AGED; ORAL DRUG ADMINISTRATION; PHASE 3 CLINICAL TRIAL; RANDOMIZATION; RANDOMIZED CONTROLLED TRIAL; THROMBOEMBOLISM; VEIN THROMBOSIS; WOUND HEALING;

ADMINISTRATION, ORAL; AGED; ANTICOAGULANTS; ARTHROPLASTY, REPLACEMENT, HIP; AZETIDINES; BENZYLAMINES; DOUBLE-BLIND METHOD; ENOXAPARIN; FEMALE; HEMORRHAGE; HEMOSTATICS; HUMANS; MALE; MIDDLE AGED; PRODRUGS; RANDOM ALLOCATION; THROMBIN; THROMBOEMBOLISM; VENOUS THROMBOSIS; WOUND HEALING;

EID: 0141849427     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1046/j.1538-7836.2003.00368.x     Document Type: Article

References (51)

1. Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA Jr, Wheeler HB. Prevention of venous thromboembolism. Chest 2001; 119: 132S-75S.
2. Gross M, Anderson DR, Nagpal S, O'Brien B. Venous thromboembolism prophylaxis after total hip or knee arthroplasty: a survey of Canadian orthopaedic surgeons. Can J Surg 1999; 42: 457-61.
3. Freedman KB, Brookenthal KR, Fitzgerald RH Jr, Williams S, Lonner JH. A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty. J Bone Joint Surg Am 2000; 82-A: 929-38.
4. Hull R, Raskob G, Pineo G, Rosenbloom D, Evans W, Mallory T, Anquist K, Smith F, Hughes G, Green D et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med 1993; 329: 1370-6.
5. RD Heparin Arthroplasty Group. RD heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty. J Bone Joint Surg Am 1994; 76: 1174-85.
6. Hamulyak K, Lensing AW, van der Meer J, Smid WM, van Ooy A, Hoek JA. Subcutaneous low-molecular weight heparin or oral anticoagulants for the prevention of deep-vein thrombosis in elective hip and knee replacement? Fraxiparine Oral Anticoagulant Study Group. Thromb Haemost 1995; 74: 1428-31.
7. Francis CW, Pellegrini VD Jr, Totterman S, Boyd AD Jr, Marder VJ, Liebert KM, Stulberg BN, Ayers DC, Rosenberg A, Kessler C, Johanson NA. Prevention of deep-vein thrombosis after total hip arthroplasty. Comparison of warfarin and dalteparin. J Bone Joint Surg Am 1997; 79: 1365-72.
8. 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: 2199-207.
9. Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, Deykin D. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119: 8S-21S.
10. Eriksson UG, Johansson L, Frison L, Bredberg U, Gustafsson D. Single and repeated oral dosing of H 376/95, a prodrug of the direct thrombin inhibitor melagatran, to young healthy male subjects. Blood 1999; 94 (Suppl. 1): 26a (Abstract).
11. Eriksson UG, Frison L, Gustafsson D, Mandema J, Karlsson MO, Eriksson BI. The pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor, ximelagatran (pINN, formerly H 376/95), in orthopaedic surgery patients treated to prevent deep vein thrombosis and pulmonary embolism. Thromb Haemost 2001; (Suppl.): P3092 (Abstract).
12. Peters G, Whipple J, Eriksson UG. Pharmacokinetics of H 376/95, a novel oral direct thrombin inhibitor, in patients undergoing total knee arthroplasty. Clin Pharmacol Ther 2001; 69: 35 (Abstract).
13. Gustafsson D, Nyström J-E, Carlsson S, Bredberg U, Eriksson U, Gyzander E, Elg M, Antonsson T, Hoffmann K, Ungell A, Sorensen H, Nagard S, Abrahamsson A, Bylund R. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects. Thomb Res 2001; 101: 171-81.
14. Johansson S, Bylock A, Eriksson-Lepkowska M, Thuresson A, Frison L, Eriksson UG. The effect of the oral direct thrombin inhibitor, ximelagatran (pINN, formerly H 376/95), on the pharmacokinetics of nifedipine, in healthy male volunteers. Thromb Haemost 2001; (Suppl.): P784 (Abstract).
15. Eriksson UG, Fager G, Eriksson-Lepkowska M, Cullberg M, Frison L, Bylock A, Ahnoff M. Effect of acetyl salicylic acid (ASA) on the pharmacodynamics and pharmacokinetics of melagatran, active form of the oral direct thrombin inhibitor, H 376/95. Clin Pharmacol Ther 2001; 69: 24 (Abstract).
16. Eriksson-Lepkowska M, Thuresson A, Bylock A, Frison L, Eriksson UG. The effect of the oral direct thrombin inhibitor, ximelagatran (pINN, formerly H 376/95), on the pharmacokinetics of diazepam in healthy male volunteers. Thromb Haemost 2001; (Suppl.): P785 (Abstract).
17. Eriksson-Lepkowska M, Thuresson A, Bylock A, Frison L, Eriksson UG. The effect of the oral direct thrombin inhibitor, ximelagatran (pINN, formerly H 376/95), on the pharmacokinetics and pharmacodynamics of diclofenac in healthy male volunteers. Thromb Haemost 2001; (Suppl.): P786 (Abstract).
18. 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.
19. 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.
20. Eriksson BI, Carlsson S, Halvarsson M, Risberg B, Mattsson C. Antithrombotic effect of two low molecular weight thrombin inhibitors and a low-molecular weight heparin in a caval vein thrombosis model in the rat. Thromb Haemost 1997; 78: 1404-7.
21. 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 thrombo-embolism after total knee arthroplasty. Ann Intern Med 2002; 137: 648-55.
22. Heit JA, Colwell CW, Francis CW, Ginsberg JS, Berkowitz SD, Whipple JP, Peters GR for the Astra Zeneca Arthroplasty Study Group. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a Phase II dose-finding study. Arch Intern Med 2001; 161: 2215-21.
23. 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: 288-96.
24. Eriksson BI, Bergqvist D, Kalebo 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 throm-boembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002; 360: 1441-7.
25. Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972; 104: 134-44.
26. Kälebo P, Ekman S, Lindbratt S, Eriksson BI, Pauli U, Zachrisson BE, Close P. Percentage of inadequate phlebograms and observer agreement in thromboprophylactic multicenter trials using standardized methodology and central assessment. Thromb Haemost 1996; 76: 893-6.
27. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Statistical Principles for Clinical Trials. Federal Register of the Food and Drug Administration. Vol 63, No. 179, Section 3.3.2., September 16, 1998.
28. Planès A, Samama MM, Lensing AW, Buller HR, Barre J, Vochelle N, Beau B. Prevention of deep vein thrombosis after hip replacement-comparison between two low-molecular heparins, tinzaparin and enoxaparin. Thromb Haemost 1999; 81: 22-5.
29. Physicians' Desk Reference, 55th edn. Montvale, NJ: Medical Economics Co., 2001; Lovenox, 713-5.
30. Clagett GP, Anderson FA, Geerts W, Heit JA, Knudson M, Lieberman JR, Merli GJ, Wheeler HB. Prevention of venous thromboembolism. Chest 1998; 114: 531S-60S.
31. Dechavanne M, Ville D, Berruyer M, Trepo F, Dalery F, Clermont N, Lerat JL, Moyen B, Fischer LP, Kher A et al. Randomized trial of a low-molecular-weight heparin (Kabi 2165) versus adjusted-dose subcutaneous standard heparin in the prophylaxis of deep-vein thrombosis after elective hip surgery. Haemostasis 1989; 19: 5-12.
32. Colwell CW Jr, Spiro TE, Trowbridge AA, Morris BA, Kwaan HC, Blaha JD, Comerota AJ, Skoutakis VA. Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. A clinical trial comparing eficacy and safety. Enoxaparin Clinical Trial Group. J Bone Joint Surg Am 1994; 76: 3-14.
33. Danish Enoxaparin Study Group. Low-molecular-weight heparin (en-oxaparin) vs dextran 70. The prevention of postoperative deep vein thrombosis after total hip replacement. Arch Intern Med 1991; 151: 1621-4.
34. Kakkar VV, Howes J, Sharma V, Kadziola Z. A comparative double-blind, randomised trial of a new second generation low-molecular-weight heparin (bemiparin) and UFH in the prevention ofpost-operative venous thromboembolism. The Bemiparin Assessment group. Thromb Haemost 2000; 83: 523-9.
35. Turpie AG, Gallus AS, Hoek JA. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl Med 2001; 344: 619-25.
36. Lassen MR, Bauer KA, Eriksson BI, Turpie AG, European Pentasac-charide 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.
37. Turpie AG, Bauer KA, Eriksson BI, Lassen MR, PENTATHALON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomized double-blind trial. Lancet 2002; 359: 1721-6.
38. Eriksson BI, Ekman S, Kälebo P, Zachrisson B, Backj D, Close P. Prevention of deep vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996; 347: 635-9.
39. Eriksson BI, Wille-Jörgensen P, Kälebo P, Mouret P, Rosencher N, Bosch 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: 1329-35.
40. 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 eficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement. J Bone Joint Surg Am 1997; 79: 326-33.
41. Howard AW, Aaron SD. Low molecular weight heparin decreases proximal and distal deep venous thrombosis following total knee arthroplasty. A meta-analysis of randomized trials. Thromb Haemost 1998; 79: 902-6.
42. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin: overview of results of randomization trials in general, orthopaedic, and urologic surgery. N Engl J Med 1988; 318: 1162-73.
43. Havig Ö. Deep vein thrombosis and pulmonary embolism: an autopsy study with multiple regression analysis of possible risk factors. Acta Chir Scand Suppl 1977; 478: 1-120.
44. Moser KM, LeMoine JR. Is embolic risk conditioned by location of deep venous thrombosis? Ann Intern Med 1981; 94: 439-44.
45. Eriksson BI, Kälebo P, Anthmyr BA, Wadenvik H, Tengborn L, Risberg B. Prevention of deep-vein thrombosis and pulmonary embolism after total hip replacement: comparison of low-molecular-weight heparin and unfractionated heparin. J Bone Joint Surg Am 1991; 73: 484-93.
46. Levine MN, Hirsh J, Gent M, Turpie AG, Leclerc J, Powers PJ, Jay RM, Neemeh J. Prevention of deep vein thrombosis after elective hip surgery. A randomized trial comparing low molecular weight heparin with standard unfractionated heparin. Ann Intern Med 1991; 114: 545-51.
47. Spiro TE, Johnson GJ, Christie MJ, Lyons RM, MacFarlane DE, Blasier RB, Tremaine MD. Efficacy and safety of enoxaparin to prevent deep venous thrombosis after hip replacement surgery. Enoxaparin Clinical Trial Group. Ann Intern Med 1994; 121: 81-9.
48. Colwell CW Jr, Collis DK, Paulson R, McCutchen JW, Bigler GT, Lutz S, Hardwick ME. Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthro-plasty. Evaluation during hospitalization and three months after discharge. J Bone Joint Surg Am 1999; 81: 932-40.
49. Cohen AT, Edmondson RA, Phillips MJ, Ward VP, Kakkar VV. The changing pattern of venous thromboembolic disease. Haemostasis 1996; 26: 65-71.
50. Lassen MR, Borris LC, Anderson BS, Jensen HP, Skejo Bro HP, Andersen G, Petersen AO, Siem P, Horlyck E, Jensen BV, Thomsen PB, Hansen BR, Erin-Madsen J, Moller JC, Rotwitt L, Christensen F, Nielsen JB, Jorgensen PS, Paaske B, Torholm C, Hvidt P, Jensen NK, Nielsen AB, Appelquist E, Tjalve E et al. Efficacy and safety of prolonged thromboprophylaxis with a low molecular weight heparin (dalteparin) after total hip arthroplasty-the Danish Prolonged Prophylaxis (DaPP) Study. Thromb Res 1998; 89: 281-7.
51. Comp PC, Spiro TE, Friedman RJ, Whitsett TL, Johnson GJ, Gardiner GA Jr., Landon GC, Jove M, Enoxaparin Clinical Trial Group. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group. J Bone Joint Surg Am 2001; 83-A: 336-45.