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Melagatran, the active form of the oral direct thrombin inhibitor ximelagatran An alternative to hirudin in prevention of arterial thrombosis with a wider therapeutic window

, : Melagatran, the active form of the oral direct thrombin inhibitor ximelagatran An alternative to hirudin in prevention of arterial thrombosis with a wider therapeutic window. Blood 98(11 Part 1): 41a-42a, November 16

Hirudin, an essentially irreversible inhibitor of thrombin, is superior to heparin for the treatment of unstable angina. However, the increase in efficacy observed with hirudin is partially offset by an increase in bleeding. The study was conducted to determine whether, for equivalent efficacy, melagatran, a reversible direct thrombin inhibitor, is better tolerated compared with hirudin in an arterial thrombosis prevention and ear bleeding rabbit model. Thrombosis in the distal aorta was triggered by a combination of balloon injury and stasis produced by an external constricting device. Patency in the damaged segment was monitored continuously using a flow probe placed distal to the constrictor. Rabbits were given intravenously either melagatran (0.1-0.3 mumol/kg) or hirudin (0.02-0.1 mumol/kg) 5 min prior to applying the external constricting device and throughout a 90 min observation period. Control rabbits were given equivalent volumes of saline in place of anticoagulant. To assess the tolerability of these regimens, cumulative blood loss from five full-thickness cuts in the ear made 15 min after the start of treatment was measured over 30 min. Both drugs increased patency in a dose-dependent fashion but differed with respect to their effect on bleeding. At doses that produced 80-100% patency and complete thrombus resolution, 2-3-fold less bleeding was observed with melagatran than with hirudin. This difference may reflect the fact that melagatran inhibits fibrin-bound and fluid-phase thrombin equally, whereas hirudin is less effective against fibrin-bound thrombin. Consequently, the higher concentrations of hirudin needed to inhibit thrombosis are associated with increased bleeding. The observation that at equally effective anticoagulant doses, melagatran causes less bleeding than hirudin suggests that reversible direct thrombin inhibitors may have a wider therapeutic window than irreversible thrombin inhibitors in the prevention of arterial thrombosis.


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