Orally Active Direct Thrombin Inhibitors

ABSTRACT

Anticoagulants are widely used for the prevention and treatment of venous and arterial thrombosis. Current treatment strategies often employ a combination of parenteral and oral agents because the only available orally active anticoagulants, vitamin K antagonists, have a delayed onset of action.[1] Furthermore, vitamin K antagonists have a narrow therapeutic window that necessitates careful anticoagulation monitoring, and dosing is problematic because of multiple food and drug interactions. These limitations highlight the need for oral anticoagulants that produce a more predictable anticoagulant response than vitamin K antagonists, thereby obviating the need for laboratory monitoring. Ximelagatran has the potential to meet this need. A prodrug of melagatran, an agent that targets thrombin, ximelagatran exhibits many of the characteristics of an ideal anticoagulant. This article (1) reviews the limitations of vitamin K antagonists, (2) lists the characteristics of an ideal anticoagulant, (3) rationalizes thrombin as a target for new anticoagulants, (4) reviews the preclinical and clinical data with ximelagatran, and (5) provides clinical perspective as to the future of ximelagatran and other orally active anticoagulants currently under development.

KEYWORDS

Thrombin inhibitors - vitamin K antagonists - ximelagatran

REFERENCES

• 1 Hirsh J, Dalen J E, Anderson D R, Poller L, Bussey H, Ansell J, Deykin D. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.  Chest . 2001;  119 8-21
• 2 Albers G, Dalen J E, Laupacis A, Manning W J, Peterson P, Singer D E. Antithrombotic therapy in atrial fibrillation.  Chest . 2001;  119 194-206
• 3 Hyers T M, Agnelli G, Hull R D, Morris T A, Samama M, Tapson V, Weg J G. Antithrombotic therapy for venous thromboembolic disease.  Chest . 2001;  119 176-193
• 4 Wessler S, Gitel S N. Warfarin: from bench to bedside.  N Engl J Med . 1984;  311 645-652
• 5 Zivelin A, Rao V M, Rapaport S I. Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin K-dependent clotting factors.  J Clin Invest . 1993;  92 2131-2140
• 6 Esmon C T, Ding W, Yasuhiro K. The protein C pathway: new insights.  Thromb Haemost . 1997;  78 70-74
• 7 Harrison L, Johnston M, Massicotte M P, Crowther M, Moffat K, Hirsh J. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy.  Ann Intern Med . 1997;  126 133-136
• 8 Suttie J W, Muhah-Schendel L L, Shah D V. Vitamin K deficiency from dietary vitamin K restriction in humans.  Am J Clin Nutr . 1988;  47 475-480
• 9 Wells P S, Holbrook A M, Crowther N R. The interaction of warfarin with drugs and food: a critical review of the literature.  Ann Intern Med . 1994;  121 676-683
• 10 Walsh P N. Roles of platelets and factor XI in the initiation of blood coagulation by thrombin.  Thromb Haemost . 2001;  86 75-82
• 11 Broze Jr J G. Tissue factor pathway inhibitor and the current concept of blood coagulation.  Blood Coagul Fibrinolysis . 1995;  6 (suppl 1) S7-S13
• 12 Weitz J I, 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;  86 385-391
• 13 Kumar R, Beguin S, Hemker C. The effect of fibrin clots and clot-bound thrombin on the development of platelet coagulant activity.  Thromb Haemost . 1995;  74 962-968
• 14 Kumar R, Beguin S, Hemker C. The influence of fibrinogen and fibrin on thrombin generation-evidence for feedback activation of the clotting system by clot bound thrombin.  Thromb Haemost . 1994;  72 713-721
• 15 Nesheim M, Wang W, Boffa M, Nagashima M, Morser J, Bajzar L. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis.  Thromb Haemost . 1997;  78 387-391
• 16 Gustafsson D, Nystrom J, Carlsson S. The direct thrombin inhibitor melagatran and its oral prodrug 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects.  Thromb Res . 2001;  101 171-181
• 17 Fager G, Eriksson-Lepkowska M, Frison L. Influence of acetylsalicylic acid on the pharmacodynamics and pharmacokinetics of melagatran, the active form of the direct thrombin inhibitor H376/95 (abstract).  Eur Heart J . 2000;  21 441
• 18 Eriksson-Lepkowska M, Thuresson A, Bylock A, Frison L, Ericksson U G. The effect of the oral direct thrombin inhibitor, ximelagatran, on the pharmacokinetics of diazepam in healthy male volunteers (abstract).  Thromb Haemost . 2001;  (suppl) P785
• 19 Eriksson-Lepkowska M, Thuresson A, Bylock A, Frison L, Eriksson U G. The effect of oral direct thrombin inhibitor, ximelagatran, on the pharmacokinetics and pharmacodynamics of diclofenac in healthy male volunteers (abstract).  Thromb Haemost . 2001;  (suppl) P786
• 20 Johansson S, Bylock A, Eriksson-Lepkowska M, Thuresson A, Frison L, Ericksson U G. The effect of the oral direct thrombin inhibitor, ximelagatran, on the pharmacokinetics of nifedipine in healthy male volunteers (abstract).  Thromb Haemost . 2001;  (suppl) P784
• 21 Elg M, Borjesson I, Pehrsson S. Feiba reversed bleeding times prolonged by high doses of a thrombin inhibitor and was not prothrombotic (abstract).  Blood . 2000;  96 11
• 22 Elg M, Carlsson S, Gustafsson D. Effect of activated prothrombin complex concentrate or recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor.  Thromb Res . 2001;  101 145-157
• 23 Elg M, Gustafsson D, Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat.  Thromb Res . 1999;  94 187-197
• 24 Klement P, Carlsson S, Liao P. The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model.  Thromb Haemost . 2003;  1 587-594
• 25 Eriksson B I, Lindbratt S, Kalebo P. METHRO II: dose-response study of the novel oral, direct thrombin inhibitor, H376/95 and its subcutaneous formulation, melagatran, compared with dalteparin as thromboembolic prophylaxis after total hip or total knee replacement (abstract).  Haemostasis . 2000;  30 (S1)183
• 26 Eriksson B I, Ogren M, Agnelli G. The oral direct thrombin inhibitor ximelagatran and its subcutaneous form melagatran compared with enoxaparin as prophylaxis after total hip or knee joint replacement (abstract).  Thromb Haemost . 2001;  (suppl) OC1638
• 27 Heit J A, Colwell C WJ, Francis C W. Comparison of the oral direct thrombin inhibitor H376/95 with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase II dose-finding study (abstract).  Blood . 2000;  96 11
• 28 Francis C W, Davidson B L, Berkowitz S D. Randomized, double-blind, comparative study of ximelagatran, an oral direct thrombin inhibitor, and warfarin to prevent venous thromboembolism (VTE) after total knee arthroplasty (TKA) (abstract).  Thromb Haemost . 2001;  (suppl) OC44
• 29 Petersen P. First experience with the oral direct thrombin inhibitor H376/95 compared with warfarin in patients with non-valvular atrial fibrillation (NVAF) (abstract).  J Gen Intern Med . 2001;  16 (s1)164
• 30 Turpie A G, Gallus A S, Hoek J A, Pentasaccharide Investigators. A synthetic pentasaccharide for the prevention of deep vein thrombosis after total hip replacement.  N Engl J Med . 2001;  344 619-625