Abstract 36: Direct Oral Anticoagulant Underdosing Increases Rates of Stroke and Myocardial Infarction With No Reduction in Bleeding Rate

Abstract

Introduction: Direct oral anticoagulants (DOACs) reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) patients. The off-label prescription of lower dose DOACs is very common and usually represents an attempt to mitigate bleeding risk. Data regarding the effects of off-label DOAC lower dose on patient outcomes is limited. We evaluated the effectiveness and safety of off-label lower dose DOAC therapy in NVAF patients treated in routine clinical practice. Hypothesis: Off-label lower dose DOAC use is associated with higher risk of mortality, stroke and myocardial infarction (MI) and is not associated with a reduced bleeding rate. Methods: We identified all newly diagnosed NVAF patients initiating DOAC therapy in Clalit Health Services from 2011 to 2016. Effectiveness was defined as a composite of all-cause mortality, stroke and MI and safety was defined as bleeding requiring hospitalization. Patients were followed until May 15,2017 or until occurrence of an outcome event. The DOAC dose was determined based on electronic drug dispensing records. We compared the outcomes in patients treated with DOACs at per-label standard dose with those treated with off-label lower dose. Hazard ratios (HR) were adjusted for 21 variables, including socio-economic factors, co-morbidities and concomitant medications using multivariate regression. Results: During the study period 3,395 patients were treated with DOACs at per-label standard dose and 2,438 patients were treated with an off-label lower dose. Adjusted HR for the composite of mortality, stroke and MI in patients treated with off-label lower dose was 1.38 (95% CI: 1.13- 1.69, P=0.001), and for bleeding 1.34 (95% CI: 0.92-1.95, P=NS). Conclusions: In this cohort of NVAF patients treated in routine clinical practice, off-label lower dose of DOACs was associated with a higher risk of mortality, stroke and myocardial infarction and was not associated with a reduced bleeding rate. Our findings provide further support for encouraging adherence to the per-label dosage of DOAC therapy.