TY - JOUR

T1 - Bleeding Risk Following Systemic Fluconazole or Topical Azoles in Patients with Atrial Fibrillation on Apixaban, Rivaroxaban, or Dabigatran

AU - Holt, Anders

AU - Strange, Jarl E.

AU - Rasmussen, Peter Vibe

AU - Blanche, Paul

AU - Nouhravesh, Nina

AU - Jensen, Mads Hashiba

AU - Schjerning, Anne Marie

AU - Schou, Morten

AU - Torp-Pedersen, Christian

AU - Gislason, Gunnar H.

AU - Hansen, Morten Lock

AU - McGettigan, Patricia

AU - Lamberts, Morten

N1 - Funding Information: Funding: The lead investigator, AH, and this study have been funded by external, independent grants from “Ib Mogens Kristiansens Almene Fond” (J. nr. 30206-383), “Helsefonden” (20-B-0035) “Snedkermester Sophus Jacobsen og hustru Astrid Jacobsen Fond” (J 167/1), “Marie og M.B. Richters Fond” (J. nr. 2020-0379), and “Dagmar Marshalls Fond.” None of the funds has had any influence on the conduction of this study. Funding Information: Funding: The lead investigator, AH, and this study have been funded by external, independent grants from ?Ib Mogens Kristiansens Almene Fond? (J. nr. 30206-383), ?Helsefonden? (20-B-0035) ?Snedkermester Sophus Jacobsen og hustru Astrid Jacobsen Fond? (J 167/1), ?Marie og M.B. Richters Fond? (J. nr. 2020-0379), and ?Dagmar Marshalls Fond.? None of the funds has had any influence on the conduction of this study. Conflicts of Interest: CTP declares grants received in relation to a clinical study comparing rivaroxaban and acetyl salicylic acid along with a grant from Novo Nordisk for studying estrogen and endometrial cancer. All other authors declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. Publisher Copyright: © 2021 The Authors

PY - 2022

Y1 - 2022

N2 - 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 years; interquartile range [IQR] 70-84) compared with rivaroxaban users (median age: 75 years; IQR 68-82) and patients on dabigatran (median age: 73 years; IQR 66-80). Apixaban users had a significantly increased risk of bleeding following exposure to systemic fluconazole: odds ratio (OR) 3.5; 95% confidence interval (CI), 1.4-10.6. No increased risk was found 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. As to 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), respectively. 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.

AB - 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 years; interquartile range [IQR] 70-84) compared with rivaroxaban users (median age: 75 years; IQR 68-82) and patients on dabigatran (median age: 73 years; IQR 66-80). Apixaban users had a significantly increased risk of bleeding following exposure to systemic fluconazole: odds ratio (OR) 3.5; 95% confidence interval (CI), 1.4-10.6. No increased risk was found 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. As to 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), respectively. 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.

KW - Atrial fibrillation

KW - Azole agents

KW - Drug safety

KW - Drug–drug interactions

KW - Fluconazole

KW - NOAC

U2 - 10.1016/j.amjmed.2021.11.008

DO - 10.1016/j.amjmed.2021.11.008

M3 - Journal article

C2 - 34861201

AN - SCOPUS:85122514918

VL - 135

SP - 595

EP - 602

JO - American Journal of Medicine

JF - American Journal of Medicine

SN - 0002-9343

IS - 5

ER -