Clinical Question: Is there an increased bleeding risk in patients with atrial fibrillation on novel oral anticoagulants (NOACs) that are concurrently on systemic fluconazole or topical azole treatment?
Background: Systemic antifungal therapy with azoles has been associated with an increased risk of bleeding in patients on anticoagulation with NOACs although there is no strict contraindication for concomitant use with fluconazole, the most commonly prescribed systemic azole, and NOACs. Case reports have also suggested an increased bleeding risk association between topical azoles and NOACs, indicating a need for further evaluation.
Study Design: Case-crossover study
Setting: Nationwide database search of Danish administrative health registers
Synopsis: The study included 32,340, 32,409, and 24,940 patients on apixaban, rivaroxaban, and dabigatran, respectively, for the treatment of atrial fibrillation with a median age across all patients of 75. Systemic fluconazole use among the patients in the cohort was similar across all NOACs with 4.9%-5.3% of patients claiming at least one prescription with less than 2% claiming more than one prescription. Treatment with topical azoles was more frequent with 16.1%-17.6% of patients obtaining at least one prescription. Among apixaban users, a significantly increased risk of bleeding following exposure to systemic fluconazole was found with a case-crossover OR of 3.5 (95% CI of 1.4-10.6) for a 30-day exposure window. Interestingly, this increased risk was not noted among rivaroxaban (OR 0.9 with 95% CI 0.2-3.0), despite a common CYP3A4 elimination pathway, and dabigatran (OR 1.7 with 95% CI 0.5-5.6) users. There was no increased bleeding risk noted with topical azole exposure among apixaban, rivaroxaban, or dabigatran users.
The major limitation of the study was that not many patients were exposed to systemic fluconazole with less than 2% claiming more than one prescription within three years of initiation of either NOAC. This led to large confidence intervals making interpretation of the data difficult which may explain the lack of increased bleeding risk noted with rivaroxaban and dabigatran users exposed to systemic fluconazole.
Bottom Line: Systemic fluconazole should be used with caution in patients on NOAC therapy for atrial fibrillation, especially apixaban, due to a potential increased bleeding risk. No increased bleeding risk was noted with topical azole exposure.
Citation: Holt A, et al. Bleeding risk following systemic fluconazole or topical azoles in patients with atrial fibrillation on apixaban, rivaroxaban, or dabigatran. Am J Med. 2022;135(5):595-602.e5. doi:10.1016/j.amjmed.2021.11.008.
Dr. Sundararaghavan is an assistant professor of medicine at the University of Virginia School of Medicine, Charlottesville, Va.