Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement

Summary

We evaluated whether a postoperative regimen with melagatran followed by oral ximelagatran, two new direct thrombin inhibitors, was an optimal regimen for thromboprophylaxis in major orthopaedic surgery. In a double-blind study, 2788 patients undergoing total hip or knee replacement were randomly assigned to receive for 8 to 11 days either 3 mg of subcutaneous melagatran started 4-12 h postoperatively, followed by 24 mg of oral ximelagatran twice-daily or 40 mg of subcutaneous enoxaparin once-daily, started 12 h preoperatively. Ximelagatran was to be initiated within the first two postoperative days. The primary efficacy endpoint was venous thromboembolism (deep-vein thrombosis detected by mandatory venography, pulmonary embolism or unexplained death). The main safety endpoint was bleeding. Venous thromboembolism occurred in 355/1146 (31.0%) and 306/1122 (27.3%) patients in the ximelagatran and enoxaparin group, respectively, a difference in risk of 3.7% in favour of enoxaparin (p = 0.053). Bleeding was comparable between the two groups.

Keywords

Venous thromboembolism - joint replacement surgery - thrombin inhibitors - ximelagatran/melagatran - enoxaparin

• References

• 1 Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA. et al. Sixth ACCP Consensus Conference on antithrombotic therapy. Prevention of venous thromboembolism. Chest 2001; 119 Suppl 132S-75S.
• 2 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.
• 3 Hull RD, Pineo GF, Stein PD, Mah AF, Maclsaac SM, Dahl OE. 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.
• 4 Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J. et al. Sixth ACCP Consensus Conference on antithrombotic therapy. Oral Anticoagulants. Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119: 8S-21S.
• 5 Ansell J, Hirsh J, Dalen J, Bussey H, Anderson D, Poller L. et al. Sixth ACCP Consensus Conference on antithrombotic therapy. Managing oral anticoagulant therapy. Chest 2001; 119: 22S-38S.
• 6 Gustafsson D, Nyström J-E, Carlsson S, Bredberg U, Eriksson U, Gyzander E. et al. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb Res 2001; 101: 171-81.
• 7 Eriksson BI, Ogren M, Eriksson UG, Kalebo P, Ahnfelt L, Bjorstrom S. et al. Prophylaxis of venous thromboembolism with subcutaneous melagatran in total hip or total knee replacement: results from Phase II studies. Thromb Res 2002; 105: 371-8.
• 8 Eriksson BI, Arfwidsson A-C, Frison L, Eriksson UG, Bylock A, Kälebo P. 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. Thromb Haemost 2002; 87: 231-7.
• 9 Heit JA, Colwell CW, Francis CW, Ginsberg JS, Berkowitz SD, Whipple J. et al. for the AstraZeneca Arthroplasty Study Group. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement. Arch Intern Med 2001; 161: 2215-21.
• 10 Eriksson BI, Bergqvist D, Kälebo P, Dahl OE, Lindbratt S, Bylock A. 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; 360: 1441-7.
• 11 Hull RD, Brant RF, Pineo GF, Stein PD, Raskob GE, Valentine KA. Preoperative vs postoperative initiation of low-molecular-weight heparin prophylaxis against venous thromboembolism in patients undergoing elective hip replacement. Arch Intern Med 1999; 159: 137-41.
• 12 Hull RD, Pineo GF, Francis C, Bergqvist D, Fellenius C, Soderberg K. et al. for the North American Fragmin Trial Investigators. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients. A double-blind, randomized comparison. Arch Intern Med 2000; 160: 2199-207.
• 13 Hull RD, Pineo GF, Stein PD, Mah AF, MacIsaac SM, Dahl OE. 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.
• 14 Kälebo P, Anthmyr BA, Eriksson BI, Zachrisson BE. Optimization of ascending phlebography of the leg for screening of deep vein thrombosis in thromboprophylactic trials. Acta Radiol 1997; 38: 320-6.
• 15 Rabinov K, Paulin S. Roentgen diagnosis of venous thromboembolism in the leg. Arch Surg 1972; 104: 134-44.
• 16 Biello DR, Mattar AG, McKnight RC, Siegel BA. Ventilation-perfusion studies in suspected pulmonary embolism. Am J Roentgenol 1979; 133: 1033-7.
• 17 Lassen MR, Bauer KA, Eriksson BI, Turpie AGG. for the European Pentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002; 359: 1715-20.
• 18 Turpie AGG, Bauer KA, Eriksson BI, Lassen MR. for the PENTATHLON 2000 Study 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.
• 19 Bauer KA, Eriksson BI, Lasen MR, Turpie AGG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-10.
• 20 Eriksson BI, Wille-Jorgensen P, Kalebo P, Mouret P, Rosencher N, Bosch P. et al. A comparison of recombinant hirudin with low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997; 337: 1329-35.
• 21 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: 635-9.
• 22 Eriksson BI, Kälebo P, Anthymyr 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.
• 23 Eriksson UG, Bredberg U, Gislén K, Johansson L C, 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 in press
• 24 Johansson LC, Frison L, Logren U, Fager G, Gustafsson D, Eriksson UG.. The influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokin 2003 in press
• 25 Eriksson UG, Frison L, Gustafsson D, Man-dema 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; 86 Suppl Abstract P3092