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Recommendations for the safe use of direct oral anticoagulants in patients with cirrhosis based on a systematic review of pharmacokinetic, pharmacodynamic and safety data

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Abstract

Purpose

The popularity of direct oral anticoagulants (DOACs) is increasing among patients with cirrhosis. Cirrhosis has a major impact on the pharmacokinetics of drugs, potentially increasing adverse events. Safe use of drugs in cirrhosis requires a diligent risk-benefit analysis. The aim of this study is to develop practice recommendations for safe use of DOACs in cirrhosis based on a systematic review of pharmacokinetic, pharmacodynamic and safety data.

Methods

We conducted a systematic literature search to identify studies on pharmacokinetics, pharmacodynamics and safety of DOACs in cirrhosis. Data were collected and presented in summary tables by severity of cirrhosis using the Child–Turcotte–Pugh (CTP) classification. A multidisciplinary expert panel evaluated the results and classified the DOACs according to safety.

Results

Fifty four studies were included. All DOACs were classified as ‘no additional risks known’ for CTP A. For CTP B, apixaban, dabigatran and edoxaban were classified as ‘no additional risks known’. Apixaban and edoxaban showed fewer adverse events in patients with cirrhosis, while dabigatran may be less impacted by severity of cirrhosis based on its pharmacokinetic profile. Rivaroxaban was classified as ‘unsafe’ in CTP B and C based on significant pharmacokinetic alterations. Due to lack of data, apixaban, dabigatran and edoxaban were classified as ‘unknown’ for CTP C.

Conclusion

DOACs can be used in patients with CTP A cirrhosis, and apixaban, dabigatran and edoxaban can also be used in CTP B. It is recommended to avoid rivaroxaban in CTP B and C. There is insufficient evidence to support safe use of other DOACs in CTP C cirrhosis.

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Availability of data and materials

No datasets were generated or analysed during the current study.

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Acknowledgements

Authors would like to thank professor doctor David M Burger for his input and expertise during the initial steps in developing practice recommendations for DOACs in patients with cirrhosis.

Funding

No funding was received.

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Author notes

  1. Maaike M. E. Diesveld and Daniëlle W. M. Jacobs- Pijnenburg are considered as joint first author.

Authors and Affiliations

  1. Health Base Foundation, Papiermolen 36, Houten, The Netherlands

    Maaike M. E. Diesveld & Sander D. Borgsteede

  2. Lead Healthcare, Baarn, The Netherlands

    Daniëlle W. M. Jacobs- Pijnenburg

  3. Deventer Hospital, Department of Clinical Pharmacy, Deventer, The Netherlands

    Rianne A. Weersink

  4. Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands

    Rianne A. Weersink

  5. Erasmus University Medical Center, Department of Hospital Pharmacy, Rotterdam, The Netherlands

    Ina Barzel & Midas B. Mulder

  6. Radboud University Medical Center, Department of Gastroenterology, Nijmegen, The Netherlands

    Joost P. H. Drenth

  7. University of Groningen, University Medical Center Groningen, Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Groningen, The Netherlands

    Ton Lisman

  8. Erasmus University Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, The Netherlands

    Herold J. Metselaar

  9. Dutch Medicines Evaluation Board, Utrecht, The Netherlands

    Margje H. Monster-Simons

  10. University of Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands

    Margje H. Monster-Simons

  11. Pharmacy Zorgapotheken Flevoland, Almere, The Netherlands

    Eline Okel

  12. University of Groningen, Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, -Epidemiology & -Economics, Groningen, The Netherlands

    Katja Taxis

Authors
  1. Maaike M. E. Diesveld
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Contributions

M.D. and D.J. drafted the manuscript. R.A., I.B., J.D., T.L., H.M., M.M.S., M.M., E.O., K.T. and S.B. participated in data analysis and interpretation and critically revised the manuscript. Supervision was done by S.B. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Sander D. Borgsteede.

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Due to the nature of this review, no ethic approval was obtained for this systematic review.

Competing interests

J.D. participates in COIN-B, is editor for the journal for UEG and his institution received fees from Camurus.

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Diesveld, M.M.E., Pijnenburg, D.W.M.J., Weersink, R.A. et al. Recommendations for the safe use of direct oral anticoagulants in patients with cirrhosis based on a systematic review of pharmacokinetic, pharmacodynamic and safety data. Eur J Clin Pharmacol (2024). https://doi.org/10.1007/s00228-024-03648-y

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