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

Summary

The novel, oral direct thrombin inhibitor, ximelagatran (formerly H 376/95), represents an advance in antithrombotic therapy through its oral availability. After oral administration, ximelagatran is converted to its active form, melagatran. Melagatran can also be administered subcutaneously (sc). The results from the first clinical study with ximelagatran are reported. In this randomized, parallel-group, controlled study, 103 patients scheduled for elective total hip or total knee replacement received sc melagatran (1, 2 or 4 mg bid) for 2 days commencing immediately before surgery, followed by oral ximelagatran (6, 12 or 24 mg bid) for 6-9 days. Another 33 patients received dalteparin 5000 IU sc once daily, started the evening before surgery, for 8-11 days. At bilateral venography, deep vein thrombosis was found in 20.5% (16/78) of patients who had received sc melagatran and oral ximelagatran and in 18.5% (5/27) of patients in the dalteparin group. The study did not evaluate a dose-response for efficacy, and no differences between the three dose levels of melagatran and ximelagatran were shown. No pulmonary embolism was diagnosed during treatment. Total bleeding in the sc melagatran plus oral ximelagatran groups showed no dose-response and was similar to that seen in the dalteparin group. The pharmacokinetic properties of melagatran in the surgery patients were consistent with those observed for healthy subjects, and the APTT ratio, which increased non-linearly with plasma melagatran concentration, showed a consistent concentration-effect relationship during the treatment period. Ximelagatran and melagatran were well tolerated. In conclusion, ximelagatran and its active form melagatran appear to be promising agents for the prevention of venous thromboembolism following orthopaedic surgery.

Keywords

Deep vein thrombosis - thrombin inhibitors - melagatran - ximelagatran - H 376/95 - oral direct thrombin inhibition

• References

• 1 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.
• 2 Weinmann EE, Salzman EW. Deep-vein thrombosis. N Engl J Med 1994; 331: 1630-41.
• 3 European Consensus Statement. Prevention of venous thromboembolism. Int Angiol 1992; 11: 151-9.
• 4 Weitz J, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-91.
• 5 Finkle CD, St Pierre A, Leblond L, Deschenes I, DiMaio J, Winocour PD. BCH-2763, a novel potent parenteral thrombin inhibitor, is an effective antithrombotic agent in rodent models of arterial and venous thrombosis - comparisons with heparin, r-hirudin, hirulog, inogatran and argatroban. Thromb Haemost 1998; 79: 431-8.
• 6 Fareed J, Callas D, Hoppensteadt DA, Lewis BE, Bick RL, Walenga JM. Antithrombin agents as anticoagulants and antithrombotics: implications in drug development. Semin Hematol 1999; 36 (Suppl. 01) 42-6.
• 7 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.
• 8 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.
• 9 Gustafsson D, Nyström J-E, Carlsson S, Bredberg U, Eriksson U, Gyzander E, Elg M, Antonsson T, Hoffmann K-J, Ungell A-L, Sörensen H, Någård S, Abrahamsson A, Bylund R. 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.
• 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. 01) 26a.
• 11 Bredberg U, Eriksson UG, Taure K, Johansson L, Frison L, Gustafsson D. Effects of melagatran, a novel direct thrombin inhibitor, in healthy volunteers following intravenous, subcutaneous and oral administration. Blood 1999; 94 (Suppl. 01) 28a.
• 12 Eriksson BI, Carlsson S, Halvarsson M, Risberg B, Mattson 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.
• 13 Elg M, Gustafsson D, Carlsson S. Antithrombotic effects of thrombin inhibitors and warfarin in the rat. Thromb Res 1999; 94: 187-97.
• 14 Eriksson BI, Ögren M, Kälebo P, Ahnfelt L, Björkström S, Sjöstedt A, Folestad A, Arfwidsson A-C, Elvander CSareyko, Frison L. Prophylaxis of venous thromboembolism with melagatran, given subcutaneously after total hip or total knee replacement: results from Phase II studies. Thromb Res Submitted. 2001
• 15 Eriksson H, Eriksson UG, Frison L, Hansson PO, Held P, Holmström M, Hägg A, Jonsson T, Lapidus L, Leijd B, Stockelberg D, Säfwenberg U, Taghavi A, Thorsén M. Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT. Thromb Haemost 1999; 81: 358-63.
• 16 Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972; 104: 134-44.
• 17 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.
• 18 Biello DR, McKnight RC, Siegel BA. Ventilation-perfusion studies in suspected pulmonary embolism. AJR 1979; 133: 1033-7.
• 19 Hull R, Raskob G, Pineo G, Rosenbloom D, Evans W, Mallory T, Anquist K, Smith F, Hughes G, Green D, Elliot CG, Panju A, Brant A. 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.
• 20 Lindbratt S, Eriksson BI, Ekman S, Ahnfeldt L, Close P. Less influence on liver enzymes with recombinant hirudin, CGP 39393 (™Revasc - Ciba), compared to unfractionated heparin, in patients undergoing total hip replacement. Thromb Haemost 1995; 73: 1452 (abstract 2111)
• 21 Gustafsson D, Antonsson T, Bylund R, Eriksson U, Gyzander E, Nilsson I, Elg M, Mattsson C, Deinum J, Pehrsson S, Karlsson O, Nilsson A, Sörensen H. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 1998; 79: 110-8.