gms | German Medical Science

Several new anticoagulants have entered the clinical arena or are under clinical development. These drugs include indirect (fondaparinux) and direct oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban), and the direct thrombin inhibitor dabigatran. Especially the oral direct FXa and FIIa inhibitors overcome many of the shortcomings of heparins and vitamin K antagonists (VKAs). They are administered orally at a fixed dose; regular monitoring is not necessary; interaction with other drugs or nutrition occur less than with VKAs and they are at least as effective as VKAs for most indications tested. They are associated with about 50% less intracranial bleeding than VKA and overall bleeding complications are not a major issue in Phase IV observational "real life" studies. Nevertheless, they are still associated with bleeding complications. Bleeding- can occur spontaneously or as a result of trauma or urgent surgery. In such situations rapid reversal of the anticoagulant effect is highly desirable. For unfractionated heparin protamine, and for VKAs prothrombin complex concentrates are available as specific antidotes. Under clinical development are: for the direct and indirect FXa inhibitors a modified recombinant FXa (andexanet alpha), which lacks enzymatic activity; and for dabigatran a Fab fragment of a monoclonal antibody (idarucizumab). In addition a small molecule (aripazine) has entered phase I clinical trials, which seems to inhibit nearly all anticoagulants but VKAs and argatroban. The lecture will review summarizes the current options and strategies in development to antagonize anticoagulants with a focus on the status of the development of antidotes for the oral direct FXa and FIIa inhibitors. In addition to rapid reversal of anticoagulants monitoring is desirable in case of bleeding, urgent surgery, or new thrombotic complications to guide further management. All of the new anticoagulants can be monitored by specific assays, i.e. anti-factor Xa activity for the FXa inhibitors and the diluted thrombin time for dabigatran. These assays are, however, not widely available in smaller hospitals and the standard clotting assays such as aPTT and prothrombin time cannot be used to monitor the new anticoagulants. The most important monitoring test for patients receiving the new anticoagulants is the creatinin clearance to recognize renal impairment with the risk of drug accumulation, With the more widespread availibility of appropriate monitoring tools, refined guidelines for monitoring and the availability of specific antidotes, the risk-benefit ratio will further develop towards favoring the new anticoagulants.