Skip to main content
SpringerLink
Log in

Drug–drug interactions with direct oral anticoagulants: development of a consensus list for ambulatory care

  • Research Article
  • Published:
International Journal of Clinical Pharmacy Aims and scope Submit manuscript

Abstract

Background

Direct oral anticoagulants (DOACs) can be involved in clinical relevant drug–drug interactions (DDIs) which may compromise safe and effective use. However, assessing the clinical relevance of DDIs with DOACs and managing these interactions optimally, can be challenging in clinical practice.

Aim

To develop a practice-oriented list of potentially clinically relevant DDIs with DOACs with corresponding management plans for which it is important to screen in ambulatory care.

Method

The RAND/UCLA appropriateness method was used to develop the DOACs DDI list. In a first step a preliminary list was compiled of potentially clinically relevant DDIs per DOAC (apixaban, dabigatran, edoxaban, rivaroxaban) using five reference sources. Subsequently, a two-step modified Delphi process involving a multidisciplinary panel (n = 10) including both pharmacists and physicians with expertise in all decision-making disciplines involved in care for patients using DOACs and with diversity of practice setting, was used to reach expert agreement on a final list of DDIs with corresponding management plans.

Results

After a two-step consensus round, 71 DDIs for 20 different interacting drugs were included: five pharmacodynamic, nine pharmacokinetic inhibitor and six pharmacokinetic inducer interacting drugs. Considerations raised and discussed by the panellists were related to (1) the necessity of the interacting drug, (2) the manageability of the DDI (whether there are any alternatives), (3) the (clinical) evidence-base for the DDI and (4) the (potential) consequences of the DDI.

Conclusion

We developed a consensus list with specific and straightforward management plans on potentially clinically relevant DDIs with DOACs, for use in ambulatory care.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373–498.

    Article  PubMed  Google Scholar 

  2. Kozieł M, Teutsch C, Bayer V, et al. Changes in anticoagulant prescription patterns over time for patients with atrial fibrillation around the world. J Arrhythm. 2021;37(4):990–1006.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955–62.

    Article  CAS  PubMed  Google Scholar 

  4. Steffel J, Collins R, Antz M, et al. 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace Eur Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card Cell Electrophysiol Eur Soc Cardiol. 2021;23(10):1612–76.

    Google Scholar 

  5. Capiau A, Mehuys E, Dhondt E, et al. Physicians’ and pharmacists’ views and experiences regarding use of direct oral anticoagulants in clinical practice. Br J Clin Pharmacol. 2022;88(4):1856–65.

    Article  PubMed  Google Scholar 

  6. Zhang Y, Souverein PC, Gardarsdottir H, et al. Risk of major bleeding among users of direct oral anticoagulants combined with interacting drugs: a population-based nested case-control study. Br J Clin Pharmacol. 2020;86(6):1150–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Komen JJ, Hjemdahl P, Mantel-Teeuwisse AK, et al. Concomitant anticoagulant and antidepressant therapy in atrial fibrillation patients and risk of stroke and bleeding. Clin Pharmacol Ther. 2020;107(1):287–94.

    Article  CAS  PubMed  Google Scholar 

  8. Holm J, Mannheimer B, Malmström RE, et al. Bleeding and thromboembolism due to drug–drug interactions with non-vitamin K antagonist oral anticoagulants-a Swedish, register-based cohort study in atrial fibrillation outpatients. Eur J Clin Pharmacol. 2021;77(3):409–19.

    Article  CAS  PubMed  Google Scholar 

  9. Wiggins BS, Dixon DL, Neyens RR, et al. Select drug–drug interactions with direct oral anticoagulants: JACC review topic of the week. J Am Coll Cardiol. 2020;75(11):1341–50.

    Article  CAS  PubMed  Google Scholar 

  10. Grymonprez M, Vanspranghe K, Steurbaut S, et al. Non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin in patients with atrial fibrillation using P-gp and/or CYP450-interacting drugs: a systematic review and meta-analysis. Cardiovasc Drugs Ther. 2021. https://doi.org/10.1007/s10557-021-07279-8.

    Article  PubMed  Google Scholar 

  11. Sennesael AL, Larock AS, Hainaut P, et al. The impact of strong inducers on direct oral anticoagulant levels. Am J Med. 2021;134(10):1295–9.

    Article  CAS  PubMed  Google Scholar 

  12. Grymonprez M, Vanspranghe K, Capiau A, et al. Impact of P-glycoprotein and/or CYP3A4-interacting drugs on effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: a meta-analysis. Br J Clin Pharmacol. 2022;88(7):3039–51.

    Article  CAS  PubMed  Google Scholar 

  13. Vazquez SR. Drug–drug interactions in an era of multiple anticoagulants: a focus on clinically relevant drug interactions. Blood. 2018;132(21):2230–9.

    Article  CAS  PubMed  Google Scholar 

  14. Niu J, Straubinger RM, Mager DE. Pharmacodynamic drug–drug interactions. Clin Pharmacol Ther. 2019;105(6):1395–406.

    Article  PubMed  Google Scholar 

  15. Johnell K, Klarin I. The relationship between number of drugs and potential drug–drug interactions in the elderly: a study of over 600,000 elderly patients from the Swedish Prescribed Drug Register. Drug Saf. 2007;30(10):911–8.

    Article  PubMed  Google Scholar 

  16. Papastergiou J, Kheir N, Ladova K, et al. Pharmacists’ confidence when providing pharmaceutical care on anticoagulants, a multinational survey. Int J Clin Pharm. 2017;39(6):1282–90.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Chen A, Stecker E, Warden BA. Direct oral anticoagulant use: a practical guide to common clinical challenges. J Am Heart Assoc. 2020;9(13):e017559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Capiau A, De Backer T, Grymonprez M, et al. Appropriateness of direct oral anticoagulant dosing in patients with atrial fibrillation according to the drug labelling and the EHRA practical guide. Int J Cardiol. 2021;328:97–103.

    Article  PubMed  Google Scholar 

  19. Fitch K, Bernstein SJ, Aguilar MD, et al. The RAND/UCLA appropriateness method user’s manual. Santa Monica: RAND Corporation; 2001. ISBN 0-8330-2918-5.

    Google Scholar 

  20. Elsevier Inc. Clinical pharmacology—drug interaction report. 2021. https://www.clinicalkey.com/pharmacology/. Accessed 11 Aug 2022.

  21. MedicinesComplete. Stockley's drug interactions. 2021. https://www.medicinescomplete.com/. Accessed 11 Aug 2022.

  22. Health Base. Commentaren Medicatiebewaking. 2020. https://www.commentarenmedicatiebewaking.nl/. Accessed 11 Aug 2022.

  23. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330–93.

    Article  CAS  PubMed  Google Scholar 

  24. Li A, Li MK, Crowther M, et al. Drug–drug interactions with direct oral anticoagulants associated with adverse events in the real world: a systematic review. Thromb Res. 2020;194:240–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Agbabiaka TB, Wider B, Watson LK, et al. Concurrent use of prescription drugs and herbal medicinal products in older adults: a systematic review. Drugs Aging. 2017;34(12):891–905.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Bezabhe WM, Bereznicki LR, Radford J, et al. Five-year trends in potential drug interactions with direct-acting oral anticoagulants in patients with atrial fibrillation: an Australian-wide study. J Clin Med. 2020;9(11):3568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jou J, Johnson PJ. Nondisclosure of complementary and alternative medicine use to primary care physicians: findings from the 2012 National Health Interview Survey. JAMA Intern Med. 2016;176(4):545–6.

    Article  PubMed  Google Scholar 

  28. Andersson ML, Böttiger Y, Lindh JD, et al. Impact of the drug-drug interaction database SFINX on prevalence of potentially serious drug–drug interactions in primary health care. Eur J Clin Pharmacol. 2013;69(3):565–71.

    Article  CAS  PubMed  Google Scholar 

  29. Slight SP, Seger DL, Nanji KC, et al. Are we heeding the warning signs? Examining providers’ overrides of computerized drug–drug interaction alerts in primary care. PLoS ONE. 2013;8(12):e85071.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank the following experts who participated in the Delphi process: Thierry Christiaens, Tine De Backer, Leen De Bolle, Sara Desmaele, An De Sutter, Dimitri Hemelsoet, Souad Moudallel, Mirko Petrovic, Annemie Somers and Ellen Van Leeuwen.

Funding

No specific funding was received.

Author information

Authors and Affiliations

  1. Pharmaceutical Care Unit, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium

    Andreas Capiau, Els Mehuys, Leen De Bolle, Inge Van Tongelen & Koen Boussery

  2. Department of Cardiology, Heart Centre, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium

    Tine De Backer

  3. Department of Internal Medicine and Paediatrics, Faculty of Medicine and Health Sciences, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium

    Tine De Backer

Authors
  1. Andreas Capiau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Els Mehuys
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leen De Bolle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Inge Van Tongelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tine De Backer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Koen Boussery
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas Capiau.

Ethics declarations

Conflicts of interest

The authors have no conflicts of interest to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Capiau, A., Mehuys, E., De Bolle, L. et al. Drug–drug interactions with direct oral anticoagulants: development of a consensus list for ambulatory care. Int J Clin Pharm 45, 364–374 (2023). https://doi.org/10.1007/s11096-022-01511-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11096-022-01511-7

Keywords

Search

Navigation