This study documented the adverse consequences of off-label edoxaban underdosing in AF patients, showing increased thrombotic risk without meaningful bleeding reduction, reinforcing adherence to approved dosing criteria.
The impact of off-label underdosing of direct oral anticoagulants (DOACs) on clinical outcomes in patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) remains unclear.
The EPIC-CAD trial (Edoxaban vs Edoxaban with antiPlatelet agent In patients with atrial fibrillation and Chronic stable Coronary Artery Disease) randomised patients with AF and stable CAD to receive either edoxaban monotherapy or dual antithrombotic therapy (edoxaban plus single antiplatelet agent). Off-label underdosing was defined as low-dose edoxaban (30 mg once daily) without standard criteria for dose reduction. The primary outcome was a composite of death, myocardial infarction, stroke, systemic embolism, unplanned revascularisation and major or clinically relevant non-major bleeding at 12 months.
Among the 1040 randomised patients, 694 patients (66.7%) without dose-reduction criteria were included; of whom, 121 patients (17.4%) received edoxaban underdosing. At 12 months, the incidence of primary outcome was similar between standard-dose and under-dose edoxaban groups (10.5% vs 9.2%, adjusted HR 0.77, 95% CI 0.39 to 1.54). There was no significant difference in major ischaemic events (1.4% vs 1.7%, HR 1.14, 95% CI 0.22 to 5.91) and major or clinically relevant non-major bleeding (9.0% vs 8.4%, HR 0.87, 95% CI 0.42 to 1.78). Regardless of edoxaban underdosing, edoxaban monotherapy was associated with lower risk of primary net-clinical outcomes and bleeding compared with dual antithrombotic therapy.
In patients with AF and stable CAD, there was no significant difference in the rate of primary outcome between off-label underdose and standard-dose edoxaban. The benefit of edoxaban monotherapy over dual antithrombotic therapy was consistent regardless of edoxaban underdosing. However, given the analyses were underpowered and the CI was wide, the results cannot be considered clinically directive. TRIAL REGISTRATION NUMBER: URL: https://www. CLINICALTRIALS: gov; unique identifiers: NCT03718559.
