The inability of the
heparin-
antithrombin complex to inhibit
fibrin-bound
thrombin limits the utility of
heparin for treatment of arterial
thrombosis. In contrast with
heparin,
melagatran, a
direct thrombin inhibitor (DTI), is equally effective at inhibiting fluid-phase
thrombin and
thrombin bound to
fibrin. This reflects the ability of
melagatran, a reversible, active site-directed DTI, to access the active site of
thrombin even when it is
fibrin-bound. Because bivalent DTIs, such as
hirudin, compete with
fibrin for access to the
fibrin-binding site on
thrombin, bivalent DTIs produce less inhibition of
fibrin-bound
thrombin than free
thrombin when given in low doses. Consequently, higher doses of
hirudin are needed for complete inhibition of
fibrin-bound
thrombin resulting in a steep dose-response curve. This phenomenon, combined with the fact that
hirudin irreversibly inhibits
thrombin, may account for
hirudin's narrow therapeutic window. In a rabbit arterial
thrombosis prevention and ear
bleeding model,
melagatran produced less
bleeding than
hirudin when the two agents were given at doses that produced nearly complete inhibition of
thrombosis. The more favourable benefit-to-risk profile of
melagatran in this model likely reflects better access to
fibrin-bound
thrombin and the reversible nature of the
melagatran/
thrombin complex. The theoretical advantages of
melagatran may endow it with mechanistic advantages over
heparin, and safety advantages over
hirudin. Large-scale clinical trials are under way to evaluate the utility of an orally active
prodrug form of
melagatran for prevention and treatment of venous and arterial
thrombosis.