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

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.

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.

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).

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.