New approaches to oral anticoagulation: Direct thrombin inhibitors

Thrombin is responsible for the conversion of fibrinogen to fibrin -the essential step in thrombus formation. Thrombin is also a potent platelet agonist, and even small amounts of thrombin can amplify coagulation by feedback activation of factors V and VIII. Because of its central roles in coagulation and platelet activation, thrombin is an attractive target for new anticoagulants. All anticoagulants exert their effects bydirectly or indirectly reducing thrombin generation and/or inhibiting thrombin activity. Vitamin K antagonists, low-molecular-weight heparins (LMWHs), and unfractionated heparin attenuate thrombin generation or indirectly inhibit thrombin activity. None of these agents inhibits clot-bound thrombin. Direct thrombin inhibitors (DTIs) inhibit thrombin by binding to exosite 1 (which acts as a dock for substrates such as fibrinogen) and/or the active site of thrombin, Because of their antithrombin-independent mode of action, DTIs inactivate both free and clot-bound thrombin. Further, unlike heparin, they do not bind to plasma proteins, resulting in a more predictable anticoagulant effect, and are not neutralized by platelet factor 4, thus posing no risk of heparin-induced thrombocytopenia. The clinical potential of DTIs is highlighted by the results of trials of ximelagatran, an oral DTI. Ximelagatran was at least as effective as LMWH or warfarin for preventing venous thromboembolism (VTE) and as effective as warfarin for preventing stroke and systemic embolism in patients with atrial fibrillation (AF). Unfortunately, ximelagatran was withdrawn worldwide because of potential liver toxicity. Dabigatran etexilate is a new oral DTI prodrug that is rapidly absorbed and converted to dabigatran. Dabigatran is a potent, competitive, and reversible inhibitor of thrombin. The plasma half-life of dabigatran is 12-17 hours allowing for once-daily dosing, and elimination is primarily via the kidneys. The clinical potential of dabigatran etexilate is being investigated in the RE-VOLUTION (TM) clinical trial program, involving more than 38,000 patients worldwide. Results from the RE-MODEL (TM) and RE-NOVATE (TM) trials showed that dabigatran etexilate (at once-daily doses of 220 mg or 150 mg) is as effective as the European regimen of enoxaparin at reducing the risk of VTE after hip or knee replacement surgery, and has a similar safety profile. Based on these findings, dabigatran etexilate has been approved in Europe and Canada for thromboprophylaxis after hip or knee replacement surgery. Ongoing RE-VOLUTION trials are assessing the efficacy and safety of dabigatran etexilate for secondary VTE prevention, acute VTE treatment, secondary prevention of cardiac events in patients with acute coronary syndrome, and stroke prevention in patients with AF. With many of these studies well underway, it is clear that dabigatran etexilate is not associated with hepatic toxicity. How dabigatran etexilate will compare with warfarin remains to be determined. However, the promising results with dabigatran etexilate for VTE prophylaxis bring us one step closer to finding a replacement for warfarin.