Off-Label Under- and Overdosing of Direct Oral Anticoagulants in Patients With Atrial Fibrillation: A Meta-Analysis

Background: Prescriptions of off-label under- and overdosing of direct oral anticoagulants (DOACs) are common for patients with atrial fibrillation, but their efficacy and safety remain unknown. Methods: Databases were searched for randomized controlled trial or adjusted observational study that compared an off-label versus on-label dosing of DOACs through June 15, 2021. The primary efficacy outcome was ischemic stroke/system embolism (IS/SE), and primary safety outcome was major bleeding. Net clinical outcome was generally defined as the composite of IS/SE, major bleeding, and all-cause death. Hazard ratios (HRs) with 95% CIs were pooled with random-effects models with Hartung-Knapp-Sidik-Jonkman method for adjustment. Results: Sixteen studies with 130 609 patients were included. Compared with on-labeling dosing, off-label underdosing of DOACs was associated with a higher risk of IS/SE (HR, 1.22 95% CI, 1.05–1.42, P =0.01). The incidence of major bleeding was similar (HR, 0.95 95% CI, 0.82–1.11, P =0.48). Off-label underdosing was associated with a higher risk of net clinical outcome (HR, 1.19 95% CI, 1.04–1.40, P =0.04) and all-cause death (HR, 1.24 95% CI, 1.04–1.48, P =0.02). Stratified analysis of off-label underdosing of DOACs for IS/SE showed subgroup differences among different DOAC types and study regions. Limited data showed that off-label overdosing was associated with a higher risk of IS/SE (HR, 1.26 95% CI, 1.11–1.43, P =0.003) and major bleeding (HR, 1.30 95% CI, 1.04–1.62, P =0.025). Conclusions: Compared with on-label dosing, off-label underdosing of DOACs increased the risk of thromboembolic events but did not decrease the risk of bleeding. Limited data for off-label overdosing showed higher risks of thromboembolic and bleeding. Further studies are warranted to confirm the results of off-label overdosing DOACs and subgroup results of underdosing DOACs.