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Thromb Haemost
DOI: 10.1055/a-2679-6101
Stroke, Systemic or Venous Thromboembolism

Major Bleeding Risk During Concomitant Use of Antiarrhythmic Drugs and Oral Factor Xa Inhibitors: A Nationwide Self-Controlled Case Series Study

Yoojung Choi
1   College of Pharmacy, Seoul National University, Seoul, Republic of Korea
,
Jonghyun Jeong
1   College of Pharmacy, Seoul National University, Seoul, Republic of Korea
,
Kyu-Nam Heo
2   Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
,
Jaekyu Shin
3   Department of Clinical Pharmacy, University of California-San Francisco, San Francisco, United States
,
Ju-Yeun Lee
1   College of Pharmacy, Seoul National University, Seoul, Republic of Korea
2   Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
› Author Affiliations
Funding This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) and funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI21C1389) and by the National Research Foundation of Korea grant funded by the Ministry of Science and ICT of the Government of Republic of Korea (grant number RS-2024–00334857).
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Abstract

Background

Bleeding risk may increase when factor Xa (FXa) inhibitors are co-administered with antiarrhythmic drugs (AADs) due to pharmacokinetic interactions, but real-world evidence on these interactions is inconsistent and limited, particularly for edoxaban.

Objective

The aim of this study was to evaluate the overall and temporal risk of major bleeding associated with concomitant use of AADs (amiodarone, dronedarone, diltiazem, verapamil) and FXa inhibitors (apixaban, edoxaban, rivaroxaban) using the self-controlled case series (SCCS) method.

Methods

An SCCS study was conducted using the Korean National Health Insurance Service database. Patients who initiated FXa inhibitors between July 2018 and December 2020, had AAD co-administration, and experienced major bleeding were included. Incidence rate ratios (IRRs) for major bleeding were estimated using conditional Poisson regression, adjusting for time-varying covariates.

Results

A total of 963 patients were analyzed. Concomitant use of amiodarone (IRR 2.16; 95% CI 1.73–2.70), diltiazem (IRR 1.96; 95% CI 1.63–2.35), and verapamil (IRR 1.72; 95% CI 1.15–2.59) was associated with an increased major bleeding risk, while dronedarone was not (IRR 1.20; 95% CI 0.69–2.06). The findings were consistent across different FXa inhibitors. Bleeding risk was highest during the first month of co-administration and decreased over time, remaining significant beyond 3 months for amiodarone.

Conclusion

Concomitant use of FXa inhibitors with amiodarone, diltiazem, or verapamil was related to an increased incidence of major bleeding, particularly during the first month of co-administration. Close monitoring during this period may be warranted for patients at high risk of bleeding.

Keywords

antiarrhythmic drug - factor Xa inhibitor - bleeding - drug interaction - self-controlled case series

Supplementary Material



Publication History

Received: 11 March 2025

Accepted: 07 August 2025

Accepted Manuscript online:
11 August 2025

Article published online:
21 August 2025

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