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Figure 1. Novel oral anticoagulants at more advanced stages of clinical clinical development.
(Figure omitted. See article PDF.)
Figure 2. Sites of action of novel oral anticoagulants in the coagulation cascade. TF: Tissue factor.
(Figure omitted. See article PDF.)
Oral anticoagulation with warfarin has for decades remained the reference standard therapy for long-term management of patients with diseases with high thromboembolic potential [1]. However, warfarin is affected by a number of well-known shortcomings, including dietary/drug interactions and need for international normalized ratio (INR) monitoring and dose adjustment. The initial enthusiasm for ximelagatran, an orally available direct inhibitor of thrombin with no need for lifelong coagulation monitoring, has been frustrated by early reports of liver toxicity, leading to the withdrawal of the drug from the European market, setting the field back for several years [2,3]. Anticoagulation with warfarin still has, at present, many unsatisfactory aspects. Partly due to these limitations, only approximately half of patients who would benefit from warfarin therapy actually receive the drug [4].
In recent years, there has been a renewed enthusiasm towards the clinical development of novel orally available pharmacological agents, which act by directly inhibiting key coagulation factors such as thrombin (i.e., dabigatran) or Factor Xa (i.e., rivaroxaban and apixaban) and have the potential to address an unmet clinical need by being more patient-friendly for chronic use (Figures 1 & 2). Evidence from large Phase III trials regarding the efficacy and safety of these easier-to-manage anticoagulant drugs is quickly accumulating in multiple clinical scenarios across different patient populations, confusing a comprehensive 'state-of-the-art'overview of these agents as alternatives to warfarin. The advent of a host of other similar agents in various stages of development (i.e., AZD0837, edoxaban, betrixaban, darexaban, LY517717 and TAK442) makes the need to update the knowledge available on the subject even more urgent. This article provides an updated overview of the currently available safety and efficacy evidence on the use of novel oral anticoagulants in patients at risk for thromboembolic events.
Novel oral anticoagulants: from clinical testing to regulatory approval
Regulatory approval of new anticoagulant agents requires a convincing demonstration of their efficacy and safety in pertinent populations. After preclinical and Phase I studies, further stages of the marketing approach require the performance of Phase II and III...