The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model

Abstract

Summary. Although hirudin is better than heparin at preventing recurrent ischemia in patients with unstable angina, hirudin produces more bleeding. The purpose of this study was to use a rabbit arterial thrombosis prevention and ear bleeding model to determine whether for equivalent efficacy, melagatran, a synthetic direct thrombin inhibitor, is safer than hirudin. A combination of balloon injury and stasis was used to induce thrombosis in the distal aorta, and patency and blood flow were continuously monitored with ultrasonic flow probes. Rabbits were randomized to melagatran (in total doses of 78-313 nmol kg À1 ), hirudin (in total doses of 18-107 nmol kg À1 ), or saline over 90 min. To assess safety, blood loss from standardized ear incisions was measured. Both melagatran and hirudin produced dose-dependent increases in patency and blood flow. At doses that maintained the highest levels of patency, however, melagatran produced 2-3-fold less bleeding than hirudin. Thus, at maximally effective doses, melagatran causes less bleeding than hirudin in this model. These findings raise the possibility that some direct thrombin inhibitors are safer than others.

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

“…Consequently, one way of improving the efficacy of rt-PA may be to combine this treatment with a low-molecular weight direct thrombin inhibitor that inhibits active fibrinbound thrombin [142].…”

Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis

“…Melagatran inhibits thrombin activity and thrombin generation resulting in inhibition of fibrin formation and platelet activation [7,9–11]. Unlike antithrombin‐dependent anticoagulants, DTIs such as melagatran inhibit both free and clot‐bound thrombin [12–14]. Melagatran has been shown to have a predictable and stable pharmacokinetic profile after oral administration of ximelagatran [8,10,11,15].…”

“…Melagatran has been shown to have a predictable and stable pharmacokinetic profile after oral administration of ximelagatran [8,10,11,15]. An important pharmacological property of melagatran is its reversible binding to thrombin, which may be clinically relevant as preclinical and clinical data suggest a lower risk of bleeding associated with reversible vs. irreversible DTIs [6,14]. Ximelagatran is currently in clinical development for the prevention and treatment of thromboembolic disorders [16–18].…”

Oral Direct Thrombin Inhibitor Ximelagatran Compared with Warfarin for the Prevention of Venous Thromboembolism After Total Knee Arthroplasty

“…Ximelagatran, an orally administered direct thrombin inhibitor, is rapidly absorbed and converted into its active form, melagatran 13 , which inhibits both free and clot-bound thrombin 14 . Ximelagatran has predictable pharmacokinetics, no clinically known relevant interactions with food, and a low potential for drug interactions 13,15 , and it can be used without coagulation monitoring or dose adjustment.…”