Skip to main content
SpringerLink
Log in

Pharmacodynamic Drug-Drug Interactions and Bleeding Outcomes in Patients with Atrial Fibrillation Using Non-Vitamin K Antagonist Oral Anticoagulants: a Nationwide Cohort Study

  • Original Article
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

Pharmacodynamic drug-drug interactions (PD DDIs) may influence the safety of non-vitamin K antagonist oral anticoagulants (NOACs), but the extent to which PD DDIs increase bleeding risks, remains unclear. Therefore, the impact of PD DDIs on bleeding outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated.

Methods

Using Belgian nationwide data, NOAC-treated AF patients were included between 2013–2019. Concomitant use of PD interacting drugs when initiating NOAC treatment was identified.

Results

Among 193,072 patients, PD DDIs were identified in 114,122 (59.1%) subjects. After multivariable adjustment, concomitant use of PD interacting drugs was associated with significantly higher risks of major or clinically-relevant non-major bleeding (adjusted hazard ratio (aHR) 1.19, 95% confidence interval (CI) (1.13–1.24)), gastrointestinal (aHR 1.12, 95%CI (1.03–1.22)), urogenital (aHR 1.21, 95%CI (1.09–1.35)) and other bleeding (aHR 1.28, 95%CI (1.20–1.36)), compared to NOAC-treated AF patients without PD interacting drug use. Increased bleeding risks were most pronounced with P2Y12 inhibitors (aHR 1.62, 95%CI (1.48–1.77)) and corticosteroids (aHR 1.53, 95%CI (1.42–1.66)), followed by selective serotonin or serotonin and norepinephrine reuptake inhibitors (SSRI/SNRI, aHR 1.26, 95%CI (1.17–1.35)), low-dose aspirin (aHR 1.14, 95%CI (1.08–1.20)) and non-steroidal anti-inflammatory drugs (NSAID, aHR 1.10, 95%CI (1.01–1.21)). Significantly higher intracranial bleeding risks in NOAC users were observed with SSRI/SNRIs (aHR 1.50, 95%CI (1.25–1.81)) and corticosteroids (aHR 1.49, 95%CI (1.21–1.84)).

Conclusion

Concomitant use of PD interacting drugs, especially P2Y12 inhibitors and corticosteroids, was associated with higher major, gastrointestinal, urogenital, and other bleeding risks in NOAC-treated AF patients. Remarkably, higher intracranial bleeding risks were observed with SSRI/SNRIs and corticosteroids.

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

Fig. 1
Fig. 2

Similar content being viewed by others

Material and/or Code availability

Requests for the data underlying this article should be directed to the administrators of the InterMutualistic Agency (IMA) database or Minimal Hospital Dataset and is subject to approval.

References

  1. 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, Arrhythmias, Card Electrophysiol: J Work Groups Card Pacing, Arrhythmias, Card Cell Electrophysiol Eur Soc Cardiol. 2021;23(10):1612–76.

    Google Scholar 

  2. Grymonprez M, Simoens C, Steurbaut S, De Backer TL, Lahousse L. Worldwide trends in oral anticoagulant use in patients with atrial fibrillation from 2010 to 2018: a systematic review and meta-analysis. Europace : Eur Pacing, Arrhythmias, Card Electrophysiol: J Work Groups Card Pacing, Arrhythmias, Card Cell Electrophysiol Eur Soc Cardiol. 2022;24(6):887–98.

    Google Scholar 

  3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51.

    Article  CAS  PubMed  Google Scholar 

  4. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104.

    Article  CAS  PubMed  Google Scholar 

  5. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92.

    Article  CAS  PubMed  Google Scholar 

  6. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.

    Article  CAS  PubMed  Google Scholar 

  7. Grymonprez M, De Backer TL, Bertels X, Steurbaut S, Lahousse L. Long-term comparative effectiveness and safety of dabigatran, rivaroxaban, apixaban and edoxaban in patients with atrial fibrillation: A nationwide cohort study. Front Pharmacol. 2023;14:1125576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chan YH, See LC, Tu HT, et al. Efficacy and safety of apixaban, dabigatran, rivaroxaban, and warfarin in asians with nonvalvular atrial fibrillation. J Am Heart Assoc. 2018;7(8):e008150. https://doi.org/10.1161/JAHA.117.008150.

  9. Paschke LM, Klimke K, Altiner A, von Stillfried D, Schulz M. Comparing stroke prevention therapy of direct oral anticoagulants and vitamin K antagonists in patients with atrial fibrillation: a nationwide retrospective observational study. BMC Med. 2020;18(1):254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Warkentin L, Hueber S, Deiters B, Klohn F, Kühlein T. Vitamin-K-antagonist phenprocoumon versus low-dose direct oral anticoagulants (DOACs) in patients with atrial fibrillation: a real-world analysis of German claims data. Thromb J. 2022;20(1):31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ujeyl M, Koster I, Wille H, et al. Comparative risks of bleeding, ischemic stroke and mortality with direct oral anticoagulants versus phenprocoumon in patients with atrial fibrillation. Eur J Clin Pharmacol. 2018;74(10):1317–25.

    Article  CAS  PubMed  Google Scholar 

  12. Alexander JH, Lopes RD, Thomas L, et al. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2014;35(4):224–32.

    Article  CAS  PubMed  Google Scholar 

  13. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation. 2013;127(5):634–40.

    Article  CAS  PubMed  Google Scholar 

  14. Shah R, Hellkamp A, Lokhnygina Y, et al. Use of concomitant aspirin in patients with atrial fibrillation: findings from the ROCKET AF trial. Am Heart J. 2016;179:77–86.

    Article  CAS  PubMed  Google Scholar 

  15. Xu H, Ruff CT, Giugliano RP, et al. Concomitant use of single antiplatelet therapy with edoxaban or warfarin in patients with atrial fibrillation: analysis from the ENGAGE AF-TIMI48 Trial. J Am Heart Assoc. 2016;5(2):e002587. https://doi.org/10.1161/JAHA.115.002587.

  16. Yasuda S, Kaikita K, Akao M, et al. Antithrombotic therapy for atrial fibrillation with stable coronary disease. N Engl J Med. 2019;381(12):1103–13.

    Article  CAS  PubMed  Google Scholar 

  17. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet (London, England). 2013;381(9872):1107–15.

    Article  CAS  PubMed  Google Scholar 

  18. Lopes RD, Heizer G, Aronson R, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019;380(16):1509–24.

    Article  CAS  PubMed  Google Scholar 

  19. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377(16):1513–24.

    Article  CAS  PubMed  Google Scholar 

  20. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375(25):2423–34.

    Article  CAS  PubMed  Google Scholar 

  21. Grymonprez M, Capiau A, Steurbaut S, et al. Adherence and persistence to oral anticoagulants in patients with atrial fibrillation: A Belgian nationwide cohort study. Front Cardiovasc Med. 2022;9:994085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. InterMutualistic Agency (IMA/AIM). Available from: https://ima-aim.be/. Accessed 25 November 2021.

  23. The Minimal Hospital Dataset. Available from: https://www.health.belgium.be/en/node/23607. Accessed 25 November 2021.

  24. The Sectoral Committee of Social Security and Health, Section Health ('Informatieveiligheidscomité'). Available from: https://www.ehealth.fgov.be/ehealthplatform/nl/informatieveiligheidscomite. Accessed 25 November 2021.

  25. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet (London, England). 2007;370(9596):1453–7.

    Article  Google Scholar 

  26. Hellfritzsch M, Pottegård A, Haastrup SB, Rasmussen L, Grove EL. Cohort selection in register-based studies of direct oral anticoagulant users with atrial fibrillation: an inevitable trade-off between selection bias and misclassification. Basic Clin Pharmacol Toxicol. 2020;127(1):3–5.

    Article  CAS  PubMed  Google Scholar 

  27. van Rein N, Heide-Jorgensen U, Lijfering WM, Dekkers OM, Sorensen HT, Cannegieter SC. Major bleeding rates in atrial fibrillation patients on single, dual, or triple antithrombotic therapy. Circulation. 2019;139(6):775–86.

    Article  PubMed  Google Scholar 

  28. Zhang Y, Souverein PC, Gardarsdottir H, van den Ham HA, van der Zee AHM, de Boer A. 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 

  29. Holt A, Blanche P, Zareini B, et al. Gastrointestinal bleeding risk following concomitant treatment with oral glucocorticoids in patients on non-vitamin K oral anticoagulants. Heart. 2022;108(8):626–32.

    Article  CAS  PubMed  Google Scholar 

  30. Dalgaard F, Mulder H, Wojdyla DM, et al. Patients with atrial fibrillation taking nonsteroidal anti-inflammatory drugs and oral anticoagulants in the ARISTOTLE Trial. Circulation. 2020;141(1):10–20.

    Article  CAS  PubMed  Google Scholar 

  31. Holm J, Mannheimer B, Malmström RE, Eliasson E, Lindh JD. 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 

  32. Komen JJ, Hjemdahl P, Mantel-Teeuwisse AK, Klungel OH, Wettermark B, Forslund T. 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 

  33. Quinn GR, Hellkamp AS, Hankey GJ, et al. Selective serotonin reuptake inhibitors and bleeding risk in anticoagulated patients with atrial fibrillation: an analysis from the ROCKET AF Trial. J Am Heart Assoc. 2018;7(15):e008755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee MT, Park KY, Kim MS, You SH, Kang YJ, Jung SY. Concomitant use of NSAIDs or SSRIs with NOACs requires monitoring for bleeding. Yonsei Med J. 2020;61(9):741–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost:JTH. 2015;13(11):2119–26.

    Article  CAS  PubMed  Google Scholar 

  36. Quan H, Li B, Couris CM, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173(6):676–82.

    Article  PubMed  Google Scholar 

  37. Grymonprez M, Petrovic M, De Backer TL, Steurbaut S, Lahousse L. The impact of polypharmacy on the effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Thromb Haemost. 2023. https://doi.org/10.1055/s-0043-1769735.

  38. 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 of Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2021;42(5):373–498.

    Article  PubMed  Google Scholar 

  39. Capiau A, Mehuys E, De Bolle L, Van Tongelen I, De Backer T, Boussery K. Drug-drug interactions with direct oral anticoagulants: development of a consensus list for ambulatory care. Int J Clin Pharm. 2023;45(2):364–74.

    Article  CAS  PubMed  Google Scholar 

  40. Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med. 2007;167(2):117–24.

    Article  CAS  PubMed  Google Scholar 

  41. Andreotti F, Testa L, Biondi-Zoccai GG, Crea F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur Heart J. 2006;27(5):519–26.

    Article  CAS  PubMed  Google Scholar 

  42. Lamberts M, Gislason GH, Lip GY, et al. Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant: a nationwide cohort study. Circulation. 2014;129(15):1577–85.

    Article  CAS  PubMed  Google Scholar 

  43. Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med. 1998;104(3a):2S-8S (discussion 21S-2S).

    Article  CAS  PubMed  Google Scholar 

  44. Kent AP, Brueckmann M, Fraessdorf M, et al. Concomitant oral anticoagulant and nonsteroidal anti-inflammatory drug therapy in patients with atrial fibrillation. J Am Coll Cardiol. 2018;72(3):255–67.

    Article  CAS  PubMed  Google Scholar 

  45. Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Arch Intern Med. 2008;168(2):180–5.

    Article  PubMed  Google Scholar 

  46. Lamberts M, Lip GY, Hansen ML, et al. Relation of nonsteroidal anti-inflammatory drugs to serious bleeding and thromboembolism risk in patients with atrial fibrillation receiving antithrombotic therapy: a nationwide cohort study. Ann Intern Med. 2014;161(10):690–8.

    Article  PubMed  Google Scholar 

  47. Narum S, Westergren T, Klemp M. Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open. 2014;4(5):e004587.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Shin D, Oh YH, Eom CS, Park SM. Use of selective serotonin reuptake inhibitors and risk of stroke: a systematic review and meta-analysis. J Neurol. 2014;261(4):686–95.

    Article  CAS  PubMed  Google Scholar 

  49. Quinn GR, Singer DE, Chang Y, et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol. 2014;114(4):583–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chang KH, Chen CM, Wang CL, et al. Major bleeding risk in patients with non-valvular atrial fibrillation concurrently taking direct oral anticoagulants and antidepressants. Front Aging Neurosci. 2022;14:791285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hackam DG, Mrkobrada M. Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis. Neurology. 2012;79(18):1862–5.

    Article  CAS  PubMed  Google Scholar 

  52. Allan V, Ramagopalan SV, Mardekian J, et al. Propensity score matching and inverse probability of treatment weighting to address confounding by indication in comparative effectiveness research of oral anticoagulants. J Comp Eff Res. 2020;9(9):603–14.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the administrators, data managers, statisticians and other staff of the InterMutualistic Agency (IMA) and Minimal Hospital Dataset (MHD) for providing the data, especially Birgit Gielen (IMA), David Jaminé (IMA), Iris Grant (IMA), Montse Urbina (IMA), Dirk De Kesel (IMA), Sarah Bel (IMA), Jérôme Paque (IMA), Remi Vandereyd (IMA), Xavier Rygaert (IMA), Delfien Verhelst (MHD), Karin Smets (MHD) and Francis Windey (MHD). Moreover, we would like to thank eHealth for the deterministic linkage of both databases. Lastly, we would like to thank Stephan Devriese (Belgian Health Care Knowledge Centre, KCE) for performing the small cell risk analysis.

Funding

This work was supported by the Research Foundation Flanders (FWO) [Grant number 11C0820N to Maxim Grymonprez].

Author information

Authors and Affiliations

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

    Maxim Grymonprez, Andreas Capiau, Koen Boussery, Els Mehuys, Annemie Somers & Lies Lahousse

  2. Department of Pharmacy, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium

    Andreas Capiau & Annemie Somers

  3. Centre for Pharmaceutical Research, Research Group of Clinical Pharmacology and Clinical Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Jette, Belgium

    Stephane Steurbaut

  4. Department of Hospital Pharmacy, UZ Brussel, Laarbeeklaan 101, 1090, Jette, Belgium

    Stephane Steurbaut

  5. Department of Geriatrics, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium

    Mirko Petrovic

  6. Department of Cardiology, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium

    Tine L. De Backer

  7. Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000, CA, the Netherlands

    Lies Lahousse

Authors
  1. Maxim Grymonprez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Capiau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephane Steurbaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koen Boussery
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Els Mehuys
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Annemie Somers
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mirko Petrovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tine L. De Backer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lies Lahousse
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MG and LL contributed to the concept and design of the study. MG performed the statistical analysis, interpretation and writing under the supervision of LL. AC, SS, KB, AC, EM, AS, MP, TDB and LL revised the manuscript critically. All authors contributed to the article and approved the final manuscript.

Corresponding author

Correspondence to Lies Lahousse.

Ethics declarations

Ethics Approval

This study was approved by the IMA and MHD database administrators and by the ‘Sectoral Committee of Social Security and Health, Section Health’, a subcommittee of the Belgian Commission for the Protection of Privacy (approval code IVC/KSZG/20/344), waiving the need for individual informed consents [24].

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

Outside this manuscript, TDB has served as a chairperson during a lecture for Bayer and Daiichi Sankyo and participated in an expert meeting for Pfizer. Outside this manuscript, LL has been consulted as expert for AstraZeneca. Outside this manuscript, MP and SS have given a lecture sponsored by BMS, LL a lecture sponsored by Chiesi, and SS, LL and MG lectures sponsored by IPSA vzw, a non-profit organization facilitating lifelong learning for pharmacists. No author has received any fees personally.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1672 KB)

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

Grymonprez, M., Capiau, A., Steurbaut, S. et al. Pharmacodynamic Drug-Drug Interactions and Bleeding Outcomes in Patients with Atrial Fibrillation Using Non-Vitamin K Antagonist Oral Anticoagulants: a Nationwide Cohort Study. Cardiovasc Drugs Ther (2023). https://doi.org/10.1007/s10557-023-07521-5

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10557-023-07521-5

Keywords

Search

Navigation