The new oral anticoagulants in atrial fibrillation: once daily or twice daily?

The new anticoagulants (NOACs) tested for prevention or treatment of venous thromboembolism (VTE), stroke prevention in atrial fibrillation (AF), and acute coronary syndromes (ACS) differ in bioavailability, metabolism, route of excretion and interaction with other drugs, but have remarkably similar pharmacokinetics, with very similar half lives. However the choice of dosing regimens in different clinical conditions has been different for the various NOACs, and has been established on the basis of widely different considerations, including the clinical setting (venous versus arterial thrombosis), the indications (prophylaxis versus treatment), the likelihood of concomitant antiplatelet drugs, and marketing opportunities; these latter were based on the knowledge that patients' compliance is generally better with once daily than with twice daily dosing. Current prevailing wisdom is that peak plasma drug concentrations are important determinants of bleeding: since a fractioning of the total daily dose into a twice daily regimen reduces peak plasma drug concentrations compared with once daily dosing, this should maximize safety. However, recent pharmacokinetic analyses of a phase II study with edoxaban in AF found that bleeding, with the same daily dosing, was less frequent with once daily dosing than with twice daily dosing, and correlated - better than other pharmacokinetic parameters - through drug concentrations. Higher rates of bleeding have been also reported with the twice daily versus once daily dosing of darexaban in a phase II study in ACS. These results may lead to a rethinking on the pathophysiology of bleeding in the setting of anticoagulation.