A PoTENtial Antidote

The direct oral anticoagulants (DOACs), which include dabigatran, rivaroxaban, apixaban, and edoxaban, can be given in fixed doses without routine coagulation monitoring. In clinical trials, the DOACs have been shown to be at least as effective as vitamin K antagonists (VKAs), such as warfarin, for stroke prevention in nonvalvular atrial fibrillation and for treatment of venous thromboembolism, and to produce less serious bleeding. With similar efficacy, better safety, and greater convenience, the DOACs are now replacing VKAs for these indications. Although the risk of serious bleeding, particularly intracranial bleeding, is reduced with the DOACs, drug reversal is needed when major bleeding occurs or if patients require urgent surgery. Idarucizumab is widely available for dabigatran reversal, but there are no licensed reversal agents for rivaroxaban, apixaban, or edoxaban. FXa is a recombinant factor (F) Xa variant with a novel mechanism of action. A prohemostatic agent, FXa, shows promise for controlling bleeding not only with the DOACs, but also in hemophilia patients with inhibitors. Thrombosis is the underlying cause of venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, and most heart attacks and strokes. On a global basis, thrombosis accounts for 1 of 4 deaths, and this number is likely to rise with the aging population. With this burden of disease, it is not surprising that more and more patients are on long-term anticoagulant therapy for the prevention or treatment of thrombosis. For over 65 years, VKAs such as warfarin were the only available oral anticoagulants. Although effective, VKAs are difficult to manage because the dose varies from patient to patient depending on dietary vitamin K intake, drug–drug interactions, and common polymorphisms that influence the metabolism of the VKAs. Consequently, frequent coagulation monitoring and dose adjustments are needed to ensure that a therapeutic concentration has been achieved. Such monitoring is inconvenient for patients and physicians and costly for healthcare systems. The limitations of VKAs prompted development of the DOACs, which were designed to simplify anticoagulation therapy because they can be administered in fixed doses without the need for routine coagulation monitoring. Since 2009, 4 DOACs have been licensed: dabigatran, which inhibits thrombin, and rivaroxaban, apixaban and edoxaban, which inhibit FXa. In randomized clinical trials that included over 100 000 patients, the DOACs were at least as effective as VKAs, but produced less serious bleeding, particularly less intracranial bleeding. These findings have been confirmed in large observational studies, suggesting that the results of the randomized trials can be translated to the community. With similar efficacy, less bleeding, and greater convenience, most guidelines now give preference to the DOACs over VKAs for stroke prevention in atrial fibrillation and for venous thromboembolism treatment. It is not surprising, therefore, that the prescriptions for DOACs are outnumbering those for VKAs in some countries. Although bleeds with the DOACs tend to be less severe than those with VKAs, serious bleeding still occurs, and patients taking DOACs may require urgent surgery. Consequently, the lack of specific reversal agents for the DOACs has been a concern. Idarucizumab, a monoclonal antibody fragment against dabigatran, has recently been licensed for dabigatran reversal in patients with serious bleeding or in those requiring urgent surgery. However, reversal agents for rivaroxaban, apixaban, and edoxaban are lacking. The reversal agent in the most advanced stage of development is andexanet. Andexanet is a recombinant FXa variant with its active site serine residue replaced with an alanine residue to eliminate catalytic activity and its membrane-binding Gla domain removed to prevent incorporation into the prothrombinase complex. By competing with FXa for binding of rivaroxaban, apixaban, or edoxaban, andexanet sequesters the drugs until they can be A PoTENtial Antidote A Prohemostatic Factor Xa Variant for Reversal of Direct Oral Anticoagulants