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

Holt, Anders; Strange, Jarl Emanuel; Rasmussen, Peter; Blanche, Paul; Nouhravesh, Nina; Jensen, Mads Hashiba; Schjerning, Anne-Marie; Schou, Morten; Torp‐Pedersen, Christian; Gislason, Gunnar; Hansen, Morten Lock; McGettigan, Patricia; Lamberts, Morten

doi:10.1016/j.amjmed.2021.11.008

Cited by 9 publications

(13 citation statements)

References 27 publications

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“…This analysis observed that apixaban users had a higher risk of bleeding following exposure to fluconazole (OR 3.5) while no differences were found among rivaroxaban and dabigatran users [85]. Topical azole exposure did not increase bleeding risk with any DOACs [85].…”

Section: Potential Drug-drug Interaction With Antibiotics and Antifun...mentioning

confidence: 86%

“…Thus, patients treated with rivaroxaban in combination with multiple modulators of P-gp (cyclosporin) and CYP3A4 (fluconazole) require particular care. The clinical impact of the combination of therapy with DOACs and fluconazole has been recently investigated by using the nationwide Danish registers [85]. This analysis observed that apixaban users had a higher risk of bleeding following exposure to fluconazole (OR 3.5) while no differences were found among rivaroxaban and dabigatran users [85].…”

Section: Potential Drug-drug Interaction With Antibiotics and Antifun...mentioning

confidence: 99%

“…The clinical impact of the combination of therapy with DOACs and fluconazole has been recently investigated by using the nationwide Danish registers [85]. This analysis observed that apixaban users had a higher risk of bleeding following exposure to fluconazole (OR 3.5) while no differences were found among rivaroxaban and dabigatran users [85]. Topical azole exposure did not increase bleeding risk with any DOACs [85].…”

Section: Potential Drug-drug Interaction With Antibiotics and Antifun...mentioning

confidence: 99%

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Drug-Drug Interactions of Direct Oral Anticoagulants (DOACs): From Pharmacological to Clinical Practice

Ferri

Colombo

Tenconi³

et al. 2022

Pharmaceutics

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The direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, are becoming the most commonly prescribed drugs for preventing ischemic stroke in patients with non-valvular atrial fibrillation (NVAF) and for the treatment and prevention of venous thromboembolism (VTE). Rivaroxaban was also recently approved for the treatment of patients with a recent acute coronary syndrome (ACS). Their use demonstrated to have a favorable risk-benefit profile, with significant reductions in stroke, intracranial hemorrhage, and mortality compared to warfarin, but with increased gastrointestinal bleeding. Nevertheless, their safety profile is compromised in multimorbidity patients requiring contemporary administration of several drugs. Comorbidity and polypharmacy have a high prevalence in elderly patients, who are also more susceptible to bleeding events. The combination of multiple treatments can cause relevant drug–drug interactions (DDIs) by affecting the exposure or the pharmacological activities of DOACs. Although important differences of the pharmacokinetic (PK) properties can be observed between DOACs, all of them are substrate of P-glycoprotein (P-gp) and thus may interact with strong inducers or inhibitors of this drug transporter. On the contrary, rivaroxaban and, to a lower extent, apixaban, are also susceptible to drugs altering the cytochrome P450 isoenzyme (CYP) activities. In the present review, we summarize the potential DDI of DOACs with several classes of drugs that have been reported or have characteristics that may predict clinically significant DDIs when administered together with DOACs. Possible strategies, including dosage reduction, avoiding concomitant administration, or different time of treatment, will be also discussed to reduce the incidence of DDI with DOACs. Considering the available data from specific clinical trials or registries analysis, the use of DOACs is associated with fewer clinically relevant DDIs than warfarin, and their use represents an acceptable clinical choice. Nevertheless, DDIs can be significant in certain patient conditions so a careful evaluation should be made before prescribing a specific DOAC.

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Section: Potential Drug-drug Interaction With Antibiotics and Antifun...mentioning

confidence: 86%

Section: Potential Drug-drug Interaction With Antibiotics and Antifun...mentioning

confidence: 99%

Section: Potential Drug-drug Interaction With Antibiotics and Antifun...mentioning

confidence: 99%

See 1 more Smart Citation

Drug-Drug Interactions of Direct Oral Anticoagulants (DOACs): From Pharmacological to Clinical Practice

Ferri

Colombo

Tenconi³

et al. 2022

Pharmaceutics

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“…Direct oral anticoagulants (DOACs) have fewer drug interactions than warfarin, but interactions do occur. In a large series involving nearly 100,000 individuals receiving a DOAC, individuals receiving apixaban plus fluconazole, a moderate inhibitor of the P450 cytochrome CYP3A4, had a 3.5-fold increased risk of bleeding compared with periods when they were receiving apixaban without fluconazole 1. The increase was greatest in gastrointestinal bleeding requiring hospitalization.…”

Section: Family Medicine — Adult General Internal Medicinementioning

confidence: 99%

“…In a large series involving nearly 100,000 individuals receiving a DOAC, individuals receiving apixaban plus fl uconazole, a moderate inhibitor of the P450 cytochrome CYP3A4, had a 3.5-fold increased risk of bleeding compared with periods when they were receiving apixaban without fl uconazole. 1 The increase was greatest in gastrointestinal bleeding requiring hospitalization. The risk was only seen with systemic fl uconazole plus apixaban; it did not occur with topical fl uconazole plus apixaban or systemic fl uconazole plus another DOAC.…”

Section: )mentioning

confidence: 99%

UpToDate®

2022

The Nurse Practitioner

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UpToDate ® and The Nurse Practitioner are collaborating to present select "What's New" content. UpToDate is an evidence-based, clinical support resource used worldwide by healthcare practitioners to make decisions at the point of care. For complete, current "What's New" content, or to become a subscriber for full content access, visit go.uptodate.com/np. "What's New" is free for all medical professionals.Disclaimer: This content is provided for reference purposes only and represents a portion of the UpToDate topic. Readers should not rely on the content or any information cited here as being applicable to specifi c patient circumstances. All topics are updated as new evidence becomes available and our peer review process is complete.

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Impact of concomitant fluconazole on direct oral anticoagulant bleeding risk

et al. 2022

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Study Objective:The aim of this study was to evaluate the effect on bleeding risk when fluconazole is administered concomitantly with direct oral anticoagulants (DOACs). Design: This was a retrospective cohort study including hospitalized adult patients prescribed a DOAC with or without fluconazole. Setting: The Ohio State University Wexner Medical Center, a tertiary care academic medical center with more than 1800 beds. Patients: Hospitalized patients ages 18-89 years who received apixaban or rivaroxaban with or without fluconazole from October 1, 2016, to September 30, 2021, were included. The minimum duration of DOAC or DOAC with fluconazole therapy was 48 h. Patients were excluded if they received fluconazole <400 mg daily or a DOAC at doses outside those recommended for atrial fibrillation or venous thromboembolism treatment or prophylaxis. Patients were matched based on DOAC received.Intervention: Patients who received a DOAC with fluconazole were compared with those receiving a DOAC alone. The primary outcome was a composite of major, clinically relevant nonmajor, and minor bleeding events at 30 days. Measurements and MainResults: There were 216 patients included, 108 in the DOAC with fluconazole group and 108 in the DOAC alone group. More patients in the DOAC with fluconazole group experienced bleeding at 30 days compared with the DOAC alone group [35/108 (32%) vs. 21/108 (19%), respectively; p = 0.03]; however, after adjusting for proven confounding variables (hemoglobin and concomitant carvedilol) this was found not to be statistically significant [adjusted odds ratio 1.71, 95% confidence interval 0.85-3.40]. Conclusions: Patients receiving a DOAC with fluconazole were not at significantly increased risk for bleeding at 30 days compared with those receiving a DOAC alone after controlling for confounding variables. As an increasing number of patients are prescribed DOACs, the results of this study may inform clinical decision-making on the safety of concomitant DOAC and fluconazole use.

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

Cited by 9 publications

References 27 publications

Drug-Drug Interactions of Direct Oral Anticoagulants (DOACs): From Pharmacological to Clinical Practice

Drug-Drug Interactions of Direct Oral Anticoagulants (DOACs): From Pharmacological to Clinical Practice

UpToDate®

Impact of concomitant fluconazole on direct oral anticoagulant bleeding risk

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