Effectiveness and Safety of Off-Label Dose-Reduced Direct Oral Anticoagulants in Atrial Fibrillation

ABSTRACT BACKGROUND Direct oral anticoagulants (DOACs) reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation but may result in serious bleeding complications. Off-label dose-reduced use of DOAC to mitigate bleeding is common in routine clinical practice although data regarding its consequences on patient outcomes is limited. Therefore, our objective was to evaluate the effectiveness and safety of off-label dose-reduced versus per-label standard-dose DOAC treatment. METHODS The study cohort included newly diagnosed patients with non-valvular atrial fibrillation that had initiated DOAC therapy between 2011 and 2017 in Clalit Health Services. Effectiveness was defined as the composite outcome of all-cause mortality, stroke or myocardial infarction. The safety outcome was defined as bleeding events requiring hospitalization. Patients were followed until March 30, 2018 or until occurrence of an outcome event. Hazard ratios (HR) were adjusted for 21 variables, including co-morbidities, concomitant medications and socio-economic factors, using multivariate regression. RESULTS A total of 8,425 patients met the study criteria. 5,140 (61%) patients were treated with DOACs at per-label dosing and 3,285 (39%) patients were treated with off-label dose-reduced DOAC. Off-label dose-reduced treatment was associated with a higher rate of the composite effectiveness outcome: adjusted HR=1.57 (95% CI: 1.34- 1.83, P CONCLUSIONS Almost 4 out of 10 patients were treated with off-label dose-reduced DOAC, which was associated with reduced effectiveness without a safety benefit. Compliance with per-label dosage may significantly improve outcomes of this population.