ORAL ANTICOAGULANTS:OLD AND NEW THERAPY

The anticoagulant therapy represents the mainstay in the treatment of primary and secondary prevention of stroke in atrial fibrillation (AF), thrombosis of mechanical prosthetic valves and pulmonary embolism in deep vein thrombosis, and in the treatment of unstable angina/NSTEMI. The main goal of anticoagulant therapy is reducing the blood coagulation powerful making the blood more fluiding and avoiding the formation of thrombi, so that patients were protected by thromboembolic events risk. But the ideal anticoagulant therapy might reduce the blood coagulation in a controlled and reversible modality, to minimize the bleeding risk. For about 90 years unfractionated heparin (UFH) and low molecular weight heparins (LMWH) are well-established anticoagulants commonly used to prevent or treat thromboembolic disorders and to prevent clotting of extracorporeal blood during hemodialysis and cardiac surgery. Both UFH and LMWH have serious side effects, such as hemorrage and thrombocytopenia; a possible alternative to heparins in patients with heparin induced thrombocytopenia was Fondaparinux, a synthetic pentasaccharide whose structure and mechanism of action presents several homologies with UFH and LMWH. After heparins, for more than 60 years the most useful anticoagulant drugs in clinical practice were dicumarolics, Warfarin and Acenocoumarol. They act as vitamin K antagonists, inhibiting the hepatic synthesis of several vitamin K-dependent coagulation factors (factor II, VII, IX and X), and still represent the reference therapy for the prevention of stroke and systemic thromboembolism in patients with AF, prevention of thrombosis of mechanical prosthetic valves and treatment and prophylaxis of deep vein thrombosis. But their use in clinical practice has been difficult due to some limitations related to their pharmacokinetics and pharmacodynamics: slow onset of action, unpredictability of drug response primarily determined by the variability in the metabolism cythocrome P450 dependent, and various food and drugs interactions, resulting in the need for a continuous monitoring ofINR and frequent dose adjustments to avoid bleeding risk in case of high dose, or thromboembolic events in case of low dose. As a result, adherence is low and rates of discontinuation high. Although physicians have sometimes tried to use antiplatelet therapy (aspirin and/or clopidogrel) for anticoagulation, this may result in a doubled risk of thromboembolic events. Therefore pharmacological and clinical research directed towards the development of new molecules that are effective, safe, and more convenient to use, and capable of overcoming these limits; in particularly several direct thrombin and factor Xa inhibitors have been investigated. Direct inhibitors of thrombin act modulating the transformation of fibrinogen in fibrin, and inhibit the thrombin-mediated activation of V, VII, XI and XII factors; the first experimental oral active drug was Ximelagatran, but the relief of important hepatotoxicity conducted to the stoppage of development programs by the pharmaceutical company. The real turning point is represented by Dabigatran, a powerful anticoagulant that reversible inhibit thrombin activity (and also its generation), both in free form and bound to fibrin. Its clinical indications are stroke prevention in non valvular AF and prevention of venous thromboembolism following hip/knee replacement surgery. The inhibition of factor Xa (FXa) is a particularly efficient mechanism of inactivation of the coagulative cascade; this is the first factor of the “common pathway”, the junction of extrinsic and intrinsic pathways, and act converting the prothrombin in thrombin. Emerging oral drugs belonging to this cathegory are Rivaroxaban, Apixaban, Edoxaban, Betrixaban and Darexaban. Rivaroxaban and Apixaban selectively and competitively bind to FXa thereby inhibiting thrombin formation; these drugs are alternative options of LMWH for stroke prevention in non valvular AF, prophylaxis following hip/knee replacement, and treatment of venous thromboembolism. Phase III clinical trials have been performed comparing Edoxaban with other anticoagulants, whereas Betrixaban and Darexaban are currently being studied in phase II several clinical trials to evaluate their effectiveness in the prevention of VTE after orthopedic surgery and stroke in AF.