Direct thrombin inhibitors for the prevention of venous thromboembolism after major orthopaedic surgery

Unfractionated heparin, low-molecular-weight heparins and vitamin K antagonists are established antithrombotic agents, but all have a number of limitations. Unfractionated heparin requires parenteral administration, has a short half-life and variable dose-response relationship. Low molecular weight heparins are more effective than low-fixed-dose unfractionated heparin in the prevention of postoperative venous thromboembolism in high-risk surgical patients but they still require subcutaneous administration. Vitamin K antagonists have a narrow therapeutic window and require a careful laboratory monitoring to minimize the risk of bleeding or thrombosis. Direct thrombin inhibitors are selective inhibitors of this key enzyme. Direct thrombin inhibitors inactivate thrombin without requiring any plasma cofactor, inhibit both free and fibrin-bound thrombin, and do not appreciably bind to plasma proteins. Ximelagatran, the first oral direct thrombin inhibitor, is rapidly absorbed and converted to its active form melagatran, which can itself be administered subcutaneously. Ximelagatran has been evaluated in the prevention of venous thromboembolism after major orthopaedic surgery, in the treatment of venous thromboembolism, in the prevention of stroke in patients with atrial fibrillation and in the prevention of recurrence after acute coronary syndromes. In the European studies in major orthopaedic surgery ximelagatran was administered orally after one or two days of melagatran, given subcutaneously. This review will report on the mechanism of action and clinical pharmacology of direct antithrombin agents and on the results of the clinical trials performed with direct thrombin inhibitors in the prevention of venous thromboembolism after major orthopaedic surgery. Taken together, these results indicate that direct thrombin inhibitors, ximelagatran in particular, have the potential to be a valid alternative to low molecular weight heparins and oral anticoagulants in the prevention of venous thromboembolism after major orthopaedic surgery.