Ximelagatran zur Therapie thromboembolischer Erkrankungen

Zusammenfassung

Die initiale Therapie thromboembolischer Erkrankungen wird heute vorzugsweise mit niedermolekularem Heparin subkutan mit überlappender oraler Antikoagulation durchgeführt. Die Dauer der Rezidivprophylaxe mit oraler Antikoagulation beträgt 6 Monate bei Patienten mit proximaler Beinvenenthrombose oder symptomatischer, hämodynamisch stabiler Lungenembolie. Die wesentliche Einschränkung der Therapie stellt die Blutungskomplikation dar. Ximelagatran als oral verfügbarer direkter Thrombininhibitor hat sich zur Therapie der akuten tiefen Beinvenenthrombose im Vergleich zu niedermolekularem Heparin subkutan und überlappender oraler Antikoagulation über insgesamt 4 Wochen als gleich effektiv erwiesen. Ein Therapiezeitraum über 6 Monate wird zurzeit gegen Warfarin doppelblind und double dummy (mit verblindeten INR-Werten) geprüft.

Nach der 6-monatigen oralen Antikoagulation wegen tiefer Beinvenenthrombose kann es bei 25% der Patienten über einen Zeitraum von 2 Jahren zu thromboembolischen Rezidiven kommen. Daher wird Ximelagatran gegen Plazebo über einen Zeitraum von 18 Monaten auf die Inzidenz thromboembolischer Rezidive geprüft.

Summary

Acute venous thromboembolism including asymptomatic and symptomatic pulmonary embolism without respiratory or cardiac failure is currently treated for 6 months, initially with subcutaneous low-molecular-weight heparin followed by oral anticoagulation. The main drawback of oral anticoagulation is caused by severe bleeding complications. Oral Ximelagatran has shown to be as effective and safe for the initial treatment of acute deep venous thrombosis compared to subcutaneous low-molecular-weight heparin followed by oral warfarin over a period of 4 weeks. Currently, oral ximelagatran is investigated versus subcutaneous low-molecular-weight heparin and oral warfarin over 6 months to demonstrate an almost equal efficacy and safety. The study is performed on a double blind and double dummy basis.

Six months after oral anticoagulation of patients with acute deep venous thrombosis, recurrent venous thromboembolism may occur in up to 25% within 2 years. Ximelagatran is currently investigated versus placebo to demonstrate a reduced recurrence rate of venous thromboembolism over a period of 18 months.

Schlüsselwörter

Tiefe Beinvenenthrombose - Lungenembolie - Ximelagatran - Thrombininhibitor - Warfarin

Keywords

Deep vein thrombosis - pulmonary embolism - Ximelagatran - thrombin inhibitor - warfarin

• Literatur

• 1 Dolovich LR, Ginsberg JS, Douketis JD, Helbrook AM, Cheah G. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000; 160: 181-8.
• 2 Elg M, Carlsson S, Gustafsson D. Effects of agents, used to treat bleeding disorders, on bleeding time prolonged by a very high dose of a direct thrombin inhibitor in anesthesized rats and rabbits. Thromb Res 2001; 101: 159-70.
• 3 Eriksson H, Eriksson UG, Frison L, Hansson PO, Held P, Holmstrom M, Hagg A, Jonsson T, Lapidus L, Leijd B, Stockelberg D, Safwenberg U, Taghavi A, Thorsen M. Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT. Thromb Haemost 1999; 81: 358-63.
• 4 Eriksson-Lepkowska M, Thuresson A, Johansson S, Larsson M, Frison L, Bylock A, Eriksson UG. The Effect of the Oral Direct Thrombin Inhibitor Ximelagatran on the Pharmacokinetics of P450-Metabolized Drugs, in Healthy Male Volunteers. Blood 2001; (suppl): 3987 abstract.
• 5 Gustafsson D, Nystrom J, 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. Thromb Res 2001; 101: 171-81.
• 6 Harenberg J, Huisman MV, Tolle AR, Breddin HK, Kirchmaier CM. Reduction in thrombus extension and clinical endpoints in patients after initial treatment for deep vein thrombosis with fixed-dose body weight-independent low-molecular-weight heparin Certoparin. Semin Thromb Hemost 2001; 27: 513-8.
• 7 Harenberg J, Schmidt JA, Koppenhagen K, Tolle A, Huisman MV, Büller HR. Fixed-dose, body weight-independent subcutaneous LMW heparin versus adjusted dose unfractionated intravenous heparin in the initial treatment of proximal venous thrombosis. EASTERN Investigators. Thromb Haemost 2000; 83: 652-6.
• 8 Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, Granger Ch, Ohman EM, Dalen JE. Heparin and low-molecular-weight heparin. Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety. Chest 2001; 119: 564-94.
• 9 Hyers TM, Agnelli G, Hull RD, Morris TA, Samama M, Tapson V, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest 2001; 119: S176-93.
• 10 Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Andersson DR, Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian JA. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901-7.
• 11 Larsson M, Logren U, Ahnoff M, Lindmark B, Abrahamsson P, Svennberg H, Persson BA. Determination of melagatran, a novel, direct thrombin inhibitor, in human plasma and urine by liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 766: 47-55.
• 12 Levine NM, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: S108-21.
• 13 Marder VJ, Soulen RL, Atichartakan V, Budzynski AZ, Parulekar S, Kim IR. Quantitative venography assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med 1977; 89: 1018-29.
• 14 Mismetti P, Laporte-Simitsidis S, Tardy B, Cucherat M, Buchmuller A, Juillard-Delsart D, Decousus H. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost 2000; 83: 14-9.
• 15 Nilsson T, Sjoling-Ericksson A, Deinum J. The mechanism binding of low-molecular-weight active site inhibitors to human alpha-thrombin. J Enzyme Inhib 1998; 13: 11-29.
• 16 Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972; 104: 134-44.
• 17 Schulman S, Granqvist S, Holmström M, Carlsson A, Lindmarker P, Nicol P, Eklund SG, Nordlander S, Larfars G, Leijd B, Linder O, Loogna E. the Duration of Anticoagulation Trial Study Group. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997; 336: 393-8.
• 18 Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Larfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H, Viering S, Nordlander S, Leijd B, Jonsson KA, Hjorth M, Linder O, Boberg J. the Duration of Anticoagulation Trial Study Group. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995; 332: 1661-5.
• 19 Schulman S, Wahlander K, Gustafsson D, Welin L, Frison L, Eriksson H. THRIVE I: Efficacy and tolerability of the novel, oral direct thrombin inhibitor Ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis. Blood 2001; (suppl): 1875 abstract.
• 20 van der Heijden JF, Prins MH, Büller HR. For the initial treatment of venous thromboembolism: are all low-molecular-weight heparin compounds the same?. Thromb Res 2000; 100: V121-30.
• 21 Wahlander K, Lapidus L, Olsson CG, Thuresson A, Eriksson UG, Eriksson H. THRIVE IV: An open-label, pilot study of the treatment of pulmonary embolism with the oral direct thrombin inhibitor Ximelagatran. Blood 2001; (suppl): 1130 abstract.
• 22 Weitz JJ, Hirsh J. New anticoagulant drugs. Chest 2001; 119: 95-107.