a high effi cacy to safety index, with PHA-739358 Danusertib freedom from hemorrhagic or non hemorrhagic side effects. Other desirable attributes would include a predictable dose response that allows dosing without the need for laboratory monitoring, a rapid onset of action so that parenteral bridging therapy is not necessary, and minimal interaction with other drugs or food. The future availability of the novel antithrombotics described in this article could provide patients with anticoagulants possessing many of these attributes. These anticoagulants are administered either once or twice daily in a convenient oral form and have a rapid onset of action. Because they directly target one specific factor in the coagulation cascade, their pharmacology is likely to be more predictable, negating the need for monitoring.
Close relationships between phamacokinetic and pharmacodynamic measurements have been demonstrated for dabigatran and rivaroxaban. Plasma concentrations of dabigatran correlate well with activated partial thromboplastin time and ecarin clotting time, and rivaroxaban plasma concentrations show a close correlation with FXa activity and prothrombin time. These fi ndings highlight Raltitrexed the predictable pharmacology of dabigatran and rivaroxaban compared with the VKAs. In addition, it has been demonstrated that dabigatran and rivaroxaban have no clinically relevant interaction with food, and a low propensity for drug drug interactions, although concomitant use of dabigatran with ASA signifi cantly increases the risk of bleeding compared with dabigatran alone.
Drug drug interactions and the effect of food on apixaban have not currently been reported. Phase III clinical trials of dabigatran and rivaroxaban for the prevention of VTE have also demonstrated that non hemorrhagic side effects are rare, and that the risk of bleeding is similar compared with enoxaparin. Rivaroxaban and dabigatran are currently being evaluated in phase III trials for VTE treatment, secondary VTE prevention, prevention of stroke in AF, and prevention of stroke and systemic embolism in non valvular AF. Phase III trials for the prevention of VTE, the prevention of stroke in AF, and the prevention of stroke and systemic embolism in non valvular AF are ongoing for apixaban. Conclusions Despite their unpredictable pharmacologic profi le and associated risks, VKAs are still widely used anticoagulants.
They can be administered orally, usually reducing the length of hospital stay. Although if managed well VKAs are highly effective, the need for frequent monitoring of the INR has a negative impact on their cost effectiveness. In addition, noncompliance with VKA therapy results in many patients not receiving optimal anticoagulation and increases the risk of uncontrolled bleeding. UFH, LMWHs and fondaparinux are much safer and easier to manage than VKAs but they require parenteral administration, making them less convenient for use outside the hospital. There is a signifi cant unmet need for a convenient, predictable anticoagulant that is both effective and safe for the prevention and treatment of thromboembolic disorders. Several novel oral anticoagulants have recently demonstrated effi cacy and safety at least equivalent to standard treatments in randomized phase III trials and are now in the advanced stages of clinical development. The predictable pharmacologic profi le and anticoagulant effect of these agents removes the need for monitoring, and the associated hospital costs and inconvenience