An Updated Pooled Analysis of Off-Label Under and Over-Dosed Direct Oral Anticoagulants in Patients with Atrial Fibrillation

INTRODUCTION: Off-label, under-, and overdosed direct oral anticoagulants (DOACs) are commonly prescribed to patients with atrial fibrillation (AF), but real-world evidence on their effectiveness and safety is limited. METHODS: MEDLINE, Embase, and Cochrane Library databases were systematically searched from 01 July 2020 to 28 February 2022 to update a previous systematic review with the same search strategy from the inception to 30 June 2020. Eligible studies were those that reported effectiveness (stroke/systemic embolism and myocardial infarction) or safety (gastrointestinal or major bleeding and death) outcomes of off-label doses of DOACs compared to on-label doses in AF patients. A random-effects meta-analysis was performed to estimate the pooled hazard ratio (HR) and 95% confidence interval (CI). Subgroup analyses were performed by specific DOACs and geographic regions. RESULTS: Twenty-two studies were included. Off-label, underdosed DOACs, compared to on-label doses, were not associated with an increased risk of stroke (HR 1.03, 95%CI: 0.88-1.17) but were associated with an increased risk of death (HR 1.26, 95%CI: 1.09-1.43). However, risk varied depending on the active ingredient. No other safety outcomes were associated with underdosed DOACs. No significant differences were observed by geographic regions. Compared to on-label DOACs, overdosing increased the risk of stroke (HR 1.17, 95%CI: 1.04-1.31), major bleeding (HR 1.18, 95%CI: 1.05-1.31), and death (HR 1.19, 95%CI: 1.03-1.35). Risk varied between geographical regions. CONCLUSIONS: Off-label underdoses, compared to on-label dosing of DOACs, did not increase the risk of stroke but did increase overall mortality. Overdosed DOACs, compared to on-label doses, were associated with an increased risk of stroke, major bleeding, and death. Future studies must examine these associations, focusing on specific active ingredients and geographic settings.