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Meta-Analysis
. 2023 Jan-Dec:29:10760296231179439.
doi: 10.1177/10760296231179439.

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

Nan-Nan Shen  1 , Eliana Ferroni  2 , Claudio Barbiellini Amidei  2 , Cristina Canova  3 , Viviana Peron  3 , Jia-Liang Wang  1 , Hou-Wen Lin  4 , Zhi-Chun Gu  4
Affiliations
Meta-Analysis

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

Nan-Nan Shen et al. Clin Appl Thromb Hemost. 2023 Jan-Dec.

Abstract

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.

Keywords: atrial fibrillation; bleeding; direct oral anticoagulants; off-label; stroke.

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Figures

Figure 1.
Figure 1.
Flow diagram for the selection of eligible studies.
Figure 2.
Figure 2.
Effectiveness and safety of under-dose DOACs and individual DOAC
Figure 3.
Figure 3.
Effectiveness and safety of under-dose DOACs by regions
Figure 4.
Figure 4.
Effectiveness and safety of over-dose DOACs and individual DOAC
Figure 5.
Figure 5.
Effectiveness and safety of over-dose DOACs by regions
See this image and copyright information in PMC

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