Ximelagatran^[*] zur Therapie und Sekundärprophylaxe der tiefen Venenthrombose

Zusammenfassung

Die Therapie und Rezidivprophylaxe der venösen Thromboembolie mit Heparin/niedermolekularem Heparin und Vitamin- K-Antagonisten wird durch eine Anzahl von Faktoren beeinträchtigt. Orale direkte Thrombininhibitoren (ODTI) weisen ein verbessertes pharmakologisches Prinzip auf und könnten eine Alternative in der Therapie der venösen Thromboembolie darstellen. Das THRIVE(Thrombin Inhibition in Venous thromboembolism)-Programm entwickelte mit mehreren Studien den ODTI Ximelagatran in dieser Indikation, das in der Übersicht dargestellt ist. Die Dosisfindung wurde in der THRIVE-I- und die Anwendbarkeit bei der hämodynamisch stabilen Lungenembolie in der THRIVE-IV-Studie untersucht. Eine randomisierte doppelblinde Studie prüfte Ximelagatran zur Therapie der proximalen Venenthrombose über 6 Monate im Vergleich zu Enoxaparin/Warfarin (THRIVE treatment). Die doppelblinde THRIVE-III-Studie verglich Ximelagatran mit Plazebo über 18 Monate nach initialer 6-monatiger konventioneller Antikoagulation der Beinvenenthrombose (BVT). 2 × 36 mg Ximelagatran ist der konventionellen 6-monatigen Rezidivprophylaxe der frischen BVT in Wirksamkeit und Verträglichkeit nicht unterlegen. 2 × 24 mg Ximelagatran reduziert über weitere 18 Monate die Thromboembolierezidive im Vergleich zu Plazebo ohne Zunahme von Blutungskomplikationen. Ein symptomloser, reversibler Anstieg der Alaninaminotransferase tritt bei etwa 6% bis 9,6% der Patienten nach 2 bis 4 Monaten auf.

Summary

The treatment of acute venous thromboembolism and prophylaxis of recurrent events with heparin/low molecular weight heparin followed by vitamin-K antagonists is limited by a number of factors. Oral direct thrombin inhibitors (ODTI) showed a better pharmacological activity and might be an alternative in the treatment of venous thromboembolism. The THRIVE (Thrombin Inhibition in Venous Thromboembolism) program performed some studies developing the ODTI ximelagatran for this indication, it is presented in the overview. The aim of the THRIVE I study was the dose finding, that of the THRIVE IV study the applicability in the haemodynamic stabile pulmonary embolism. A prospective, randomized, double-blind trial was performed to compare oral ximelagatran with enoxaparin/warfarin for a 6-months treatment of acute venous thrombosis (THRIVE treatment). Another double blind study compared ximelagatran with placebo over 18 months after a 6-months anticoagulant therapy of acute deep vein thrombosis. The efficacy and safety of treatment of patients with acute deep venous thrombosis with 2 × 36 mg ximelagatran is not inferior to a conventional anticoagulant for prophylaxis of recurrent events over 6-months. 2 × 24 mg ximelagatran significantly reduce recurrent thromboembolic events compared to placebo without increasing the risk for haemorrhage. A reversible symptomless increase of alanineaminotransferase occurs in 6% to 9,6% of patients between months 2 and 4.

Résumé

Le traitement du thromboembolism veineuse et la prophylaxie recidive avec de l‘héparine/l‘héparine á bas poids moléculaire et des antagonistes de vitamine-K est limité par un certain nombre de facteurs. Les inhibiteurs directs oraux de thrombine (ODTI) ont montré une meilleure activité pharmacologique et pourraient être une alternative dans le traitement du thromboembolism veineux. L‘inhibition de thrombine dans le programme veineux de Thromboembolism (THRIVE) a réalisé quelques études développant l‘ODTI Ximelagatran pour cette indication, il est présentée dans la vue d‘ensemble. Le but de la THRIVE I étude était la dose trouvant, celui de l‘étude de la THRIVE IV l‘applicabilité dans l‘embolisme pulmonaire stabile hémodynamique. Une étude, randomisée, à double anonymat a été exécutée pour comparer Ximelagatran oral à Enoxaparin/Warfarin pour un traitement de 6-mois de la thrombose veineuse aiguë (THRIVE treatment). Une deuxième étude randomisée, à double anonymat a comparé Ximelagatran au placebo plus de 18 mois après une thérapie de l‘anticoagulant de 6 mois de la thrombose profonde. 2 × 36 mg Ximelagatran était aussi efficace et coffre-fort que la thérapie conventionnelle d‘anticoagulant pour une prophylaxie de 6 mois des événements récurrents. 2 × 24 mg Ximelagatran a sensiblement réduit des événements récurrents comparés au placebo sans augmenter le risque hémorragiques. Une augmentation réversible d’ alaninaminotransferase été vue entre les mois 2 et 4. * Ximelagatran ist aktuell in Deutschland für die Thromboembolieprophylaxe in der orthopädischen Chirurgie zugelassen. Für weitere Indikationen ist die Zulassung beantragt. (Anm. d. Red.)

Schlüsselwörter

Venenthrombose - Antikoagulation - Thrombininhibitor - Ximelagatran

Keywords

Venous thrombosis - anticoagulation - thrombin inhibitor - ximelagatran

Mots clés

Thrombose de veine profonde - vitamines K antagoniste - thrombine inhibiteur - Ximelagatran

• Literatur

• 1 Dolovich LR, Ginsberg JS, Douketis JD. et al. 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. et al. Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT. Thromb Haemost 1999; 81: 358-63.
• 4 Eriksson H, Wahlander K, Gustafsson D. et al. A randomized controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 2003; 1: 41-7.
• 5 Eriksson-Lepkowska M, Thuresson A, Johansson S. et al. The effect of the oral direct thrombin inhibitor ximelagatran on the pharmacokinetics of P450-metabolized drugs, in healthy male volunteers. Blood. 2001 (suppl): 3987.
• 6 Gustafsson D, Antonsson T, Bylund R. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 1998; 79: 110-8.
• 7 Gustafsson D, Nystrom J, 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; 101: 171-81.
• 8 Harenberg J. Inhibition of blood coagulation by ximelagatran in patients with a first episode of symptomatic acute deep venous thrombosis for prophylaxis of recurrent events. J Thromb Haemost 2003; (suppl 1): P1905.
• 9 Harenberg J, Huisman MV, Tolle AR. et al. 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.
• 10 Harenberg J, Jörg I, Fenyvesi T. Treatment of venous thromboembolism with the oral thrombin inhibitor ximelagatran. Isr Med Assoc J 2002; 4: 1003-5.
• 11 Harenberg J, Schmidt JA, Koppenhagen K. et al. 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.
• 12 Hauptmann J. Pharmacokinetics of an emerging new class of anticoagulant/antithrombotic drugs. Eur J Clin Pharmacol 2002; 57: 751-8.
• 13 Hirsh J, Warkentin TE, Shaughnessy SG. et al. Heparin and low-molecular-weight heparin. Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety. Chest 2001; 119: 64-94.
• 14 Fiessinger JN, Huisman MV, Davidson BL. et al. THRIVE Treatment Study Investigatiors. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 2005; 293: 681-9.
• 15 Buller HR, Agnelli G, Hull RD. et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 (suppl): 401S-28.
• 16 Kearon C, Gent M, Hirsh J. et al. 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.
• 17 Kearon C, Ginsberg JS, Kovacs MJ. et al. Extended Low-Intensity Anticoagulation for Thromboembolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003; 14: 631-9.
• 18 Koscielny J, Latza R, Kiesewetter H. Thrombosis prophylaxis and outpatient medication. Phlebologie 1999; 28: 1-8.
• 19 Larsson M, Logren U, Ahnoff M. et al. 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.
• 20 Levine NM, Raskob G, Landefeld S. et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: 108-21.
• 21 Marder VJ, Soulen RL, Atichartakan V. et al. Quantitative venography assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med 1977; 89: 1018-29.
• 22 Mismetti P, Laporte-Simitsidis S, Tardy B. et al. 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.
• 23 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.
• 24 Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972; 104: 134-44.
• 25 Ridker PM, Goldhaber SZ, Denielson E. et al. for the PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348: 1425-34.
• 26 Schulman S, Granqvist S, Holmström M. et al. and 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.
• 27 Schulman S, Rhedin AS, Lindmarker P. et al. and 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.
• 28 Schulman S, Wahlander K, Lundstrom T. et al. THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003; 349: 1713-21.
• 29 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.
• 30 Wahlander K, Lapidus L, Olsson CG. et al. Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis. Thromb Res 2002; 107: 93-9.
• 31 Weitz JJ, Hirsh J. New anticoagulant drugs. Chest 2001; 119: 95-107.