Key result
Coprescription of erythromycin with a direct oral anticoagulant was associated with an increased short-term risk of gastrointestinal bleeding compared to DOAC therapy alone (HR 3.66).
Why the study?
Although drug interactions between clarithromycin, erythromycin, or fluconazole and DOACs are mechanistically plausible, whether they are clinically relevant remained uncertain.
Does coprescription of clarithromycin, erythromycin, or fluconazole increase the risk of bleeding or cardiovascular events in DOAC users?
Cohort (n=483,815)
Yes
Does coprescription of clarithromycin, erythromycin, or fluconazole increase the risk of bleeding or cardiovascular events in DOAC users?
Hazard Ratio: 3.66 (95% CI 1.27–10.51)
Routine coprescription of DOACs with clarithromycin or fluconazole does not appear to confer major short-term clinical risks, but erythromycin coprescription may increase gastrointestinal bleeding risk.
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.
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Wong et al. (2025) conducted a cohort in Patients on direct oral anticoagulants (DOACs) (n=483,815). Erythromycin vs. DOAC alone was evaluated on Gastrointestinal bleeding over 7 days (DOAC + erythromycin vs DOAC alone) (HR 3.66, 95% CI 1.27-10.51). Coprescription of erythromycin with a direct oral anticoagulant was associated with an increased short-term risk of gastrointestinal bleeding compared to DOAC therapy alone (HR 3.66).
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