In general, anticoagulant therapy has focused on initial parenteral anticoagulation followed by an extended period of oral anticoagulation therapy. To date, drugs which block the production of thrombin have been the mainstay of treatment programmes.
Current oral medications available offer little predictability in regards to dosing requirements/regimens for patients and require close monitoring. This has prompted the development of new and improved anticoagulant medications and an need to design an oral antithrombotic medication that is safe, effective, predictable, reversible and associated with less invasive monitoring.
Researchers are developing medications that work as direct thrombin inhibitors or direct and indirect factor Xa inhibitors. The aim is for parental medications with a longer half life which will either simplify initial treatment or provide prophylaxis of venous thromboembolism (VTE), or a rapid acting oral anticoagulation with peak plasma levels achieved within 2-4 h similar to low molecular weight heparin (LMWH). This would eliminate the need for parenteral cover. Oral anticoagulation medication without the requirement for serum coagulationmonitoring and dose adjustment will streamline management of patients and increase their safety.
- Direct thrombininhibitors (DTI) inhibit thrombin by directlybinding to the freely circulating and clot-bound thrombin. They do not require antithrombin as a co-factor and there is no platelet aggregation or inhibition of platelet factor 4. This provides a more predictable response and no development of heparin induced thrombocytopenia (HITs).
- Parenteral use is currently approved for Lepirudin in patients with HITs.
- Lepirudin is a genetically-engineered form of hirudin. Natural hirudin is produced by the leech Hirudo medicinalis. Hirudin is one of the compounds responsible for the leech’s ability to prevent clotting while “sucking blood”.
- Additional parenteral DTI drugs currently undergoing phase II/III trials are Flovagatran and Pegmusirudin (SPP-200).
- The next generation oral direct thrombin inhibitor is dabigatran etexilate.
- Dabigatran directly inhibits thrombin by binding to its active site. It is administered daily and does not require anticoagulation monitoring.
- It becomes active once absorbed into the gastrointestinal tract, with a half life of approximately 8hrs and undergoing renal elimination.
- Phase III trials were positive for its use in venous thromboembolism (VTE); VTE prevention in orthopaedic patients and phase III trials for stroke prevention in patients with atrial fibrillation [NEJM].
Direct Factor Xa inhibitors
- Direct factor Xa inhibitors….do exactly that, and have no effect on other components of the coagulation cascade. They can inactivate circulating and bound forms of factor Xa.
- Rivaroxaban has high oral bioavailability and a rapid, predictable, dose-related action. Half-lifeis 5 – 9 hours and it is excreted via the kidneys.
- Rivaroxaban has now been approved for prophylactic prevention of VTE in post knee and hip surgery and is in phase II/III trials for the treatment of VTE and stroke prevention in atrial fibrillation and in patients with acute coronary syndrome.
Indirect Factor Xa inhibitors
- Indirect Factor Xa inhibitors target factor Xa and exert antithrombotic effects by inhibiting thrombin generation and therefore fibrin formation.
- Fondaparinux , is an antithrombin-binding synthetic pentasaccharide. which binds to AT 111 and potentiates its antifactor Xa activity. It reversibly binds to antithrombin causing conformational changes that potentiates its antifactor Xa activity. As a daily SC injection its an alternative to heparin due to its equivalent or greater efficacy than the LMWH enoxaparin in the prevention of VTE – Development is now focused on a long mode of action medication that would allow weekly dosing.
- SSR 126517 is in phase II/III trials for treatment of VTE/Pulmonary embolus and can be given weekly with little requirement for anticoagulation monitoring
Though most research has been focused on the drugs that work on thrombin and factor Xa other drugs are being developed that target other parts of the clotting cascade. The major complication of these medications continues to be bleeding. Only SSR 126517 has a specific antidote. Research is continuing in developing drugs that reduce the risk of bleeding and have the ability for reversal.
- Anticoagulation reversal
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- Turpie A, Oral, Direct Facotr Xa Inhibitors in Devlopment for the Prevention and Treatemnt of Thromboembolic Disease. Arteriosclerosis, Thrombosis and Vascular Biology. 2007;27 1238-1247. [Reference]
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- Weitz J, Factor Xa or thrombin: Is thrombin a better target? Journal of thrombosis and haemostaisis. 2007;5 (1) 65-67 [Reference]