Bleeding risk following systemic fluconazole or topical azoles in patients with atrial fibrillation on apixaban, rivaroxaban or dabigatran.

Abstract Background Bleeding safety in relation to use of systemic fluconazole and topical azoles among patients with atrial fibrillation treated with apixaban, rivaroxaban or dabigatran is insufficiently explored, despite clinical relevance and several reports suggesting associations. Methods Using nationwide, Danish registers we identified patients with atrial fibrillation initiated on apixaban, rivaroxaban or dabigatran from 2012–2018. We investigated associations between bleeding incidents, and systemic fluconazole or topical azole treatment using a case-crossover design with 30-day exposure windows and reported odds ratios (OR) with 95% confidence intervals (CI). Results We included 32,340 (36%), 32,409 (36%) and 24,940 (28%) patients initiated on apixaban, rivaroxaban and dabigatran, respectively. Patients on apixaban were older (median age: 77 [IQR 70–84]) compared with rivaroxaban users (median age: 75 [IQR 68–82]) and patients on dabigatran (median age: 73 [IQR 66–80]). Apixaban users had a significantly increased risk of bleeding following exposure to systemic fluconazole: OR of 3.5 (95% CI 1.4–10.6). No increased risk was found with among rivaroxaban and dabigatran users: ORs of 0.9 (95% CI 0.2–3.0) and 1.7 (95% CI 0.5–5.6), respectively. Bleeding risk pertaining to topical azole exposure among apixaban, rivaroxaban and dabigatran users, no association was found with corresponding ORs of 0.8 (95% CI 0.5–1.3), 1.3 (95% CI 0.9–2.1) and 1.2 (95% CI 0.8–1.8) Conclusion In patients with atrial fibrillation on either apixaban, rivaroxaban or dabigatran, an association between an elevated bleeding risk and use of systemic fluconazole was found among patients on apixaban. We found no increased risk of bleeding following co-exposure to topical azoles.