Comparative Effectiveness and Safety of Off-Label Underdosed Direct Oral Anticoagulants in Asian Patients with Atrial Fibrillation: A Systematic Review and Meta-analysis

Pajaree Mongkhon (), Noppaket Singkham, Kunyarat Ponok, Natpatsorn Liamsrijan, Wipada Phoosa, Sirayut Phattanasobhon, Laura Fanning, Vichai Senthong and Surasak Saokaew
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Pajaree Mongkhon: University of Phayao
Noppaket Singkham: University of Phayao
Kunyarat Ponok: University of Phayao
Natpatsorn Liamsrijan: University of Phayao
Wipada Phoosa: University of Phayao
Sirayut Phattanasobhon: University of Phayao
Laura Fanning: Monash University
Vichai Senthong: Faculty of Medicine Khon Kaen University
Surasak Saokaew: University of Phayao

Drug Safety, 2025, vol. 48, issue 1, No 3, 25-42

Abstract: Abstract Introduction Off-label underdosed direct oral anticoagulants (DOACs) are commonly utilised in Asian patients with atrial fibrillation (AF) since they are prone to bleeding with OACs. However, the efficacy and safety of off-label underdosing DOACs are controversial. This study aimed to compare the effectiveness and safety of off-label underdosed DOACs in Asian patients with AF. Methods PubMed, Embase, Cochrane library, and ClinicalTrials.gov were searched from 2010 to July 5, 2024, for randomised controlled trials or observational studies that compared off-label DOACs and on-label/warfarin in Asian patients with AF. The primary outcomes included ischaemic stroke or systemic embolism (ISSE) and major bleeding (MB), while secondary outcomes included all-cause death, gastrointestinal bleeding (GIB), intracranial haemorrhage (ICH), and myocardial infarction (MI). Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Results Twenty observational studies were included. Seventeen studies compared off-label underdosed DOACs versus on-label DOACs, whereas five studies compared off-label underdosed DOACs versus warfarin. Off-label underdosed DOACs were associated with higher risk of ISSE (pooled HR [pHR] = 1.17; 95% CI: 1.00–1.38, p = 0.048) and ICH (pHR = 1.27; 95% CI: 1.06–1.52, p = 0.010) versus on-label. Subgroup analysis demonstrated increased ISSE risk with off-label underdosed rivaroxaban compared to on-label (pHR = 1.49; 95% CI: 1.07–2.08). Compared to warfarin, off-label underdosed DOACs were associated with decreased risk of MB (pHR = 0.46; 95% CI: 0.32–0.65, p

Date: 2025
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DOI: 10.1007/s40264-024-01476-8

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