Potential interactions between antimicrobials and direct oral anticoagulants: Population-based cohort and case-crossover study

Angel Y S Wong; Charlotte Warren-Gash; Krishnan Bhaskaran; Clémence Leyrat; Amitava Banerjee; Liam Smeeth; Ian J Douglas

doi:10.1016/j.hrthm.2025.01.007

Potential interactions between antimicrobials and direct oral anticoagulants: Population-based cohort and case-crossover study

Heart Rhythm. 2025 Jan 11:S1547-5271(25)00021-9. doi: 10.1016/j.hrthm.2025.01.007. Online ahead of print.

Authors

Angel Y S Wong¹, Charlotte Warren-Gash², Krishnan Bhaskaran², Clémence Leyrat², Amitava Banerjee³, Liam Smeeth², Ian J Douglas²

Affiliations

¹ Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK. Electronic address: Angel.Wong@lshtm.ac.uk.
² Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
³ Institute of Health Informatics, Faculty of Population Health Sciences, University College London UCL, London, UK.

PMID: 39805355
DOI: 10.1016/j.hrthm.2025.01.007

Abstract

Background: Although drug interactions between clarithromycin/erythromycin/fluconazole and direct oral anticoagulants (DOACs) are mechanistically plausible, it is uncertain whether they are clinically relevant.

Objective: This study aims to investigate the association among coprescribed DOACs and antimicrobials and bleeding, cardiovascular disease and mortality.

Methods: We identified DOAC users in the Clinical Practice Research Datalink Aurum from January 1, 2011 to March 29, 2021. We used a cohort design to estimate hazard ratios (HRs) for bleeding outcomes (intracranial bleeding, gastrointestinal bleeding, other bleeding), comparing DOACs + clarithromycin/erythromycin/fluconazole users with DOACs users not receiving these antimicrobials. Cardiovascular outcomes were ischaemic stroke, myocardial infarction, venous thromboembolism, cardiovascular mortality, and all-cause mortality. A 6-parameter case-crossover design comparing odds of exposure with different drug initiation patterns for all outcomes in hazard window vs referent window within an individual was also conducted.

Results: Of 483,815 DOAC users, we identified 21,701 coprescribed clarithromycin, 4532 coprescribed erythromycin, and 4840 coprescribed fluconazole. We observed an increased risk of gastrointestinal bleeding over 7 days following coprescription of DOAC + erythromycin vs DOAC alone (HR 3.66; 99% confidence interval [CI] 1.27-10.51), with wide CIs in case-crossover analysis. No evidence of increased risk of bleeding outcomes was seen for DOAC + clarithromycin/fluconazole in cohort and case-crossover analyses. For cardiovascular outcomes, compared with DOAC alone, an increased risk of cardiovascular mortality with DOAC + clarithromycin (HR 3.36; 99% CI 1.73-6.52) and increased risk of all-cause mortality with DOAC + clarithromycin/erythromycin/fluconazole were observed in cohort analysis. However, similar risks were found when initiating erythromycin/fluconazole with and without DOACs.

Conclusion: We found no strong evidence of increased risks of bleeding and cardiovascular outcomes in DOACs + clarithromycin/fluconazole/erythromycin users except a possible short-term increased risk of gastrointestinal bleeding in DOACs + erythromycin users.

Keywords: Anticoagulants; Drug interactions; Fluconazole; Macrolides.