Will direct thrombin inhibition change the boundaries of oral anti-coagulation?

There are many indications for anti-coagulation, such as the prevention of stroke in atrial fibrillation (AF), treatment of venous thrombo-embolic disease and thrombo-prophylaxis for mechanical heart valves. Therapy may be required for many months, if not lifelong, and safe oral preparations are therefore desirable.1 Until recently, the choice of oral anti-coagulant treatment has been confined to vitamin K antagonists, such as warfarin, and these are prescribed for ∼1% of the UK population as a whole and 8% of those aged over 80 years.2 Warfarin acts as an anti-coagulant by inhibiting the vitamin K-dependent modification of proenzymes (Factors II, VII, IX and X) to active serine proteases of the coagulation cascade.3 Treatment with warfarin is, however, complicated by a narrow therapeutic range, numerous interactions with food and other drugs, and a highly variable dose-response relationship.1 The aim of this article is to describe how a novel class of anti-coagulant, the direct thrombin inhibitors, may change the management of patients with AF and following surgery. The limitations of existing anti-coagulants have stimulated the search for novel therapies that target specific steps in the coagulation cascade, particularly factors Xa and IIa (thrombin). Thrombin is the final enzyme of the clotting cascade and thus represents an excellent therapeutic target. Inhibition of thrombin prevents the formation of fibrin, blocks the feedback activation of factors V, VIII and XI, and attenuates the aggregation of platelets. Inhibition of thrombin may be indirect, using heparin (and, in effect, factor Xa inhibitors); or direct, using parenterally administered hirudin or novel oral agents, such as ximelagatran and dabigatran. Direct thrombin inhibitors are small, synthetic molecules that offer rapid, reversible, competitive inhibition of thrombin, few interactions with food or other drugs, no metabolism by the cytochrome P450 system and a predictable pharmacodynamic effect that does not require …