Real-world evidence on off-label underdosing of direct oral anticoagulants in Asian patients with atrial fibrillation: prescribing patterns, determinants, and outcomes

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Atrial fibrillation (n=553). Intervention: Off-label underdosing of direct oral anticoagulants vs. On-label dosing of direct oral anticoagulants. Primary outcome: Ischemic stroke or systemic embolism (ISSE) (aHR 0.48, 95% CI 0.11-2.16, p=0.336).

Q: What does this research mean for the field?

Off-label underdosing of direct oral anticoagulants is not associated with significant differences in ischemic stroke, systemic embolism, or bleeding compared to on-label dosing in Asian patients with atrial fibrillation. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Pajaree Mongkhon; Tanaphorn Koonlachad; Purachai Bvornphattanasakul; Sirayut Phatthanasobhon; Supisara Pholprasittito; Supharat Wattanasombat; Natrawee Bureekam

doi:10.1080/20565623.2026.2708024

August 3, 2026Future Science OAOpen Access

Real-world evidence on off-label underdosing of direct oral anticoagulants in Asian patients with atrial fibrillation: prescribing patterns, determinants, and outcomes

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Key result

Off-label DOAC underdosing shows no significant difference in stroke or systemic embolism risk vs on-label dosing.

aHR 0.48
95% CI 0.11-2.16
P=0.336
n=553

Figures

Graphical abstract published by Future Science OA — Graphical abstract · Published by Future Science OA · CC BY-NC

Why the study?

Off-label underdosing of DOACs is common in Asian patients with AF due to bleeding concerns, but Southeast Asian data remain limited.

Does off-label underdosing of DOACs reduce ischemic stroke, systemic embolism, or bleeding in Asian patients with atrial fibrillation compared to on-label dosing?

Key Points

To evaluate prescribing patterns, independent predictors, and effectiveness and safety outcomes associated with off-label underdosing of direct oral anticoagulants in patients with incident atrial fibrillation.
Conducted a retrospective cohort study using electronic health records (2015–2023) from two tertiary hospitals in Thailand including 553 incident atrial fibrillation patients initiating dabigatran, rivaroxaban, apixaban, or edoxaban.
Categorized dosing into on-label (n = 405), off-label underdosing (n = 113), or off-label overdosing (n = 35) based on guideline dose-reduction criteria.
Assessed ischemic stroke or systemic embolism (ISSE) and any bleeding using propensity score-based inverse probability of treatment weighting (PS-IPTW) Cox proportional hazards models.
Of 553 patients, 73.2% received on-label dosing, 20.4% were underdosed, and 6.3% were overdosed; rivaroxaban accounted for 50.4% of underdosed cases, while age 60–74.9 years (aOR = 2.67, 95% CI: 1.12–6.32, p = 0.026) and diabetes mellitus (aOR = 3.27, 95% CI: 1.02–10.54, p = 0.047) predicted underdosing.
The incidence of ISSE was 1.32 events per 100 person-years in the underdosed group versus 2.99 events per 100 person-years in the on-label group, which was not statistically significant after PS-IPTW (aHR = 0.48, 95% CI: 0.11–2.16, p = 0.336).
Any bleeding incidence was 2.02 events per 100 person-years with underdosing versus 2.34 events per 100 person-years with on-label dosing, showing no significant difference after weighting (aHR = 1.06, 95% CI: 0.30–3.73, p = 0.924).

Study Design

Type

Cohort (n=553)

Multicenter

Yes

Structured PICO

Does off-label underdosing of DOACs reduce ischemic stroke, systemic embolism, or bleeding in Asian patients with atrial fibrillation compared to on-label dosing?

P

Population

553 adult patients with incident atrial fibrillation initiating direct oral anticoagulants, followed for a mean of 1.28 years.

E

Exposure

Off-label underdosing of DOACs (dabigatran, rivaroxaban, apixaban, or edoxaban), defined as dose reductions not aligned with recommended clinical guidelines.

C

Comparator

On-label dosing of DOACs (standard recommended dose or guideline-recommended dose reductions).

O

Outcome

Composite of ischemic stroke and systemic arterial embolism (ISSE), and any bleeding event (systemic/hematologic, intracranial, gastrointestinal, genitourinary, ophthalmic, musculoskeletal, or other clinically significant hemorrhage).composite

Main Result

Hazard Ratio: 0.48 (95% CI 0.11–2.16)

Absolute Event Rate: 1.32% vs 2.99%

p-value: p=0.336

In Asian patients with atrial fibrillation, off-label underdosing of DOACs is common but does not appear to significantly alter the risk of ischemic stroke, systemic embolism, or bleeding compared to on-label dosing.

Limitations

Missing baseline data on body weight and serum creatinine for a subset of patients
Inability to evaluate physician-related determinants of DOAC dosing
Small number of outcome events limiting statistical power
Residual confounding due to imbalanced covariates like congestive heart failure and chronic kidney disease
Conducted in tertiary-care hospitals, limiting generalizability to primary or secondary care

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Implication

Off-label underdosing showed no ISSE difference; hypothesis-generating and should not yet change practice in Asian AF.

Abstract

Background Off-label underdosing of direct oral anticoagulants (DOACs) is common among Asian patients with atrial fibrillation (AF), partly reflecting concerns about bleeding, yet Southeast Asian data remain limited. This study aimed to characterize DOAC dosing patterns, identify predictors of off-label underdosing, and evaluate associated effectiveness and safety outcomes.Methods We conducted a retrospective cohort using electronic health records (EHRs) from two tertiary hospitals in Thailand (2015–2023). Incident AF patients initiating dabigatran, rivaroxaban, apixaban, or edoxaban were included. Doses were classified as on-label, underdosed, or overdosed based on guideline criteria. Propensity score-based inverse probability of treatment weighting (PS-IPTW) Cox proportional hazards regression models was used to evaluate ischemic stroke or systemic embolism (ISSE) and bleeding outcomes.Results Among 553 patients, 20.4% were underdosed, 6.3% overdosed, and 73.2% received on-label dosing. Rivaroxaban was most frequently underdosed. Older age and diabetes mellitus independently predicted underdosing. Compared to on-label dosing, underdosing was not associated with ISSE (adjusted hazard ratio [aHR] 0.48, 95% CI 0.11–2.16; p = 0.336) or bleeding (aHR 1.06, 95% CI 0.30–3.73; p = 0.924).Conclusions Off-label underdosing occurred in one-fifth of patients but was not associated with significant differences in ISSE or bleeding. Larger, prospective studies in broader Asian and non-Asian populations are warranted.

Discussion

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Cite This Study

Mongkhon et al. (2026) conducted a cohort in Atrial fibrillation (n=553). Off-label underdosing of direct oral anticoagulants vs. On-label dosing of direct oral anticoagulants was evaluated on Ischemic stroke or systemic embolism (ISSE) (aHR 0.48, 95% CI 0.11-2.16, p=0.336). Off-label underdosing of direct oral anticoagulants was not associated with a significant difference in the risk of ischemic stroke or systemic embolism compared to on-label dosing.

synapsesocial.com/papers/6a72e802226790f3706577e5 https://doi.org/10.1080/20565623.2026.2708024

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Real-world evidence on off-label underdosing of direct oral anticoagulants in Asian patients with atrial fibrillation: prescribing patterns, determinants, and outcomes

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Real-world evidence on off-label underdosing of direct oral anticoagulants in Asian patients with atrial fibrillation: prescribing patterns, determinants, and outcomes

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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