In patients with atrial fibrillation (AF) on apixaban, rivaroxaban, and dabigatran, incident bleeding was found to be significantly associated with concomitant treatment with systemic fluconazole among only those on apixaban, according to results of a study published in The American Journal of Medicine.

In this case-crossover study, researchers searched nationwide health registers in Denmark to identify patients with AF who initiated treatment with either apixaban, rivaroxaban, or dabigatran between 2012 and 2018. Eligible patients included those aged between 18 and 100 years who had not changed their initial nonvitamin K antagonist oral anticoagulant (NOAC) agent within the past 90 days. Patients excluded from the study were those with a history of valvular AF or coagulopathy, and those who sustained a venous thromboembolism within the past 6 months or had undergone total knee or hip replacement within the past 5 weeks. The researchers sought to determine the relationship between incident bleeding and concomitant treatment with either systemic fluconazole or topical azole for up to 30 days. The primary outcome was hospitalization for incident bleeding within a follow-up period of 90 days.

Among a total of 89,689 patients with AF identified, 32,340 (36%) were on apixaban, 32,409 (36%) were on rivaroxaban, and 24,940 (28%) were on dabigatran, with median ages of 77 (IQR, 70-84) years, 73 (IQR, 66-80) years, and 75 (IQR, 68-82) years, respectively. Of note, the prevalence of comorbidities was increased in patients on apixaban compared with those on rivaroxaban and dabigatran.

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Among patients on apixaban, rivaroxaban, and dabigatran, 1990, 2403, and 2277 were hospitalized because of incident bleeding, respectively, with the gastrointestinal (GI) tract as the most frequently reported bleeding site. Bleeding in the lower GI tract most commonly occurred among patients on dabigatran (21.9%) compared with those on apixaban (13.4%) and rivaroxaban (13.7%). In addition, airway bleeding most commonly occurred among patients on rivaroxaban (25.6%) compared with those on apixaban (20.2%) or dabigatran (14.8%).

Compared with patients on rivaroxaban and dabigatran, those on apixaban who concomitantly received systemic fluconazole within a 30-day exposure window had a significantly increased risk for bleeding (odds ratio [OR], 3.5; 95% CI, 1.4-10.6). There was no increased risk for bleeding following concomitant treatment with systemic fluconazole among patients on dabigatran (OR, 1.7; 95% CI, 0.5-5.6) and those on rivaroxaban (OR, 0.9; 95% CI, 0.2-3.0). Additionally, no significant associations between incident bleeding and concomitant treatment with topical azoles were found among patients on either apixaban (OR, 0.8; 95% CI, 0.5-1.3), rivaroxaban, (OR, 1.3; 95% CI, 0.9-2.1) or dabigatran (OR, 1.2; 95% CI, 0.8-1.8). Although a significant association between topical azoles and incident bleeding was found among patients on rivaroxaban when using 20-day exposure windows (OR, 1.8; 95% CI, 1.1-3.2), no such association was found with 30- or 40-day exposure windows.

This study was limited by the small number of patients exposed to systemic fluconazole and the assumption that patients adhered to their initial NOAC agent for the duration of the study. 

According to the researchers, “[these findings] should encourage [clinicians] to apply close monitoring or other risk mitigation strategies if the coadministration of [systemic fluconazole] is necessary [in patients with AF on apixaban].”

Disclosure: One author declared affiliations with the pharmaceutical industry. Please see the reference for a full list of disclosures.


Holt A, Strange JE, Rasmussen PV, et al. Bleeding risk following systemic fluconazole or topical azoles in patients with atrial fibrillation on apixaban, rivaroxaban, or dabigatran. Am J Med. Published online November 30, 2021. doi:10.1016/j.amjmed.2021.11.008

This article originally appeared on Infectious Disease Advisor