Recent progress in anticoagulant therapy: oral direct inhibitors of thrombin and factor Xa

Abstract

While parenteral anticoagulants such as unfractionated and low molecular weight heparins and the oral vitamin K antagonists are effective for the prevention and treatment of thrombosis, they have a number of limitations. Up until recently, vitamin K antagonists (e.g. warfarin) have been the only available oral anticoagulants. These drugs have a delayed onset of action, food and drug interactions, and variable pharmacokinetics/pharmacodynamics such that regular laboratory monitoring and dose adjustments are required to maintain the International Normalized Ratio (INR) in the therapeutic range. New oral anticoagulants that selectively inhibit either thrombin (dabigatran etexilate) or factor Xa (rivaroxaban, apixaban) have now gained approval in many countries for some clinical indications. Unlike warfarin, these drugs have a rapid onset of action and a relatively wide therapeutic range such that coagulation monitoring is not required. These agents are more convenient for patients and health care providers, but also have potential for improving clinical outcomes and being more cost-effective than existing agents. This will result in major changes in the way that thrombosis is managed, both with respect to prevention and treatment. The new oral inhibitors of thrombin and factor Xa, however, have limitations and the absence of a need for regular laboratory monitoring makes medication compliance extremely important for maintaining efficacy given their relatively short half-lives. Furthermore there will be challenges in managing patients on these agents who develop recurrent thrombosis or major bleeding until methods to monitor and assess the levels of the new agents are readily available and specific antidotes are developed.