Skip to main content
SpringerLink
Log in

Prevalence and factors associated with inappropriate dosing of apixaban and rivaroxaban in hospitalized older adults with atrial fibrillation: a cross-sectional study

  • Original Research Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

A Correction to this article was published on 21 December 2023

This article has been updated

Abstract

Introduction

Atrial fibrillation (AF) is a common condition among older adults, requiring anticoagulation therapy to prevent thromboembolic events. Direct oral anticoagulants (DOACs) are now recommended as first-line therapy for this purpose. Apixaban and rivaroxaban are two direct-factor Xa inhibitors whose dosing is based on various factors (age, weight, creatinine, and creatinine clearance) that can affect the pharmacokinetics of the medication. This study aimed to evaluate factors associated with inappropriate dosing of apixaban or rivaroxaban based on the summary of product characteristics.

Methods

A retrospective, single-center study included 777 hospitalizations of patients treated with apixaban or rivaroxaban for AF between 1 January 2018 and 31 December 2022. Primary endpoint assessed whether the dose of apixaban or rivaroxaban was within the summary of product characteristics used by European Medicine Agency (EMA).

Results

Inappropriate dosing of apixaban or rivaroxaban is noted for approximately 30% of hospitalizations mostly underdosing. Factors associated with the risk of inappropriate dosing were the presence of cognitive impairment [adjusted odds ratio (OR*) 1.65, 95% confidence interval (CI) 1.19–2.29, p value (p) = 0.002], weight per kilogram increase (OR* 1.03, 95% CI 1.01–1.04, p < 0.0001), and history of bleeding under apixaban or rivaroxaban (OR* 1.94, 95% CI 1.24–3.03, p = 0.003).

Conclusion

This study highlighted the high prevalence of inappropriate apixaban or rivaroxaban doses in older adults, particularly underdosing, which increases the risk of thromboembolism.

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

Similar content being viewed by others

Change history

References

  1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 study. Circulation. 2014;129(8):837–47. https://doi.org/10.1161/CIRCULATIONAHA.113.005119.

    Article  PubMed  Google Scholar 

  2. Patel MR, Mahaffey KW, Garg J, ROCKET AF Investigators, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. https://doi.org/10.1056/NEJMoa1009638.

    Article  CAS  PubMed  Google Scholar 

  3. Granger CB, Alexander JH, McMurray JJV, ARISTOTLE Committees and Investigators, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92. https://doi.org/10.1056/NEJMoa1107039.

    Article  CAS  PubMed  Google Scholar 

  4. Sharma M, Cornelius VR, Patel JP, et al. Efficacy and harms of direct oral anticoagulants in the elderly for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism: systematic review and meta-analysis. Circulation. 2015;132(3):194–204. https://doi.org/10.1161/CIRCULATIONAHA.114.013267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mitchell A, Watson MC, Welsh T, et al. Effectiveness and safety of direct oral anticoagulants versus vitamin k antagonists for people aged 75 years and over with atrial fibrillation: a systematic review and meta-analyses of observational studies. J Clin Med. 2019;8(4):554. https://doi.org/10.3390/jcm8040554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ingrasciotta Y, Crisafulli S, Pizzimenti V, et al. Pharmacokinetics of new oral anticoagulants: implications for use in routine care. Expert Opin Drug Metab Toxicol. 2018;14(10):1057–69. https://doi.org/10.1080/17425255.2018.1530213.

    Article  CAS  PubMed  Google Scholar 

  7. Alexander JH, Andersson U, Lopes RD, et al. Apixaban 5mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial. JAMA Cardiol. 2016;1(6):673–81. https://doi.org/10.1001/jamacardio.2016.1829.

    Article  PubMed  Google Scholar 

  8. Girgis IG, Patel MR, Peters GR, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF. J Clin Pharmacol. 2014;54(8):917–27. https://doi.org/10.1002/jcph.288.

    Article  CAS  PubMed  Google Scholar 

  9. Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J. 2013;11(1):10. https://doi.org/10.1186/1477-9560-11-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kubitza D, Becka M, Roth A, et al. The influence of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct Factor Xa inhibitor. J Clin Pharmacol. 2013;53(3):249–55. https://doi.org/10.1002/jcph.5.

    Article  CAS  PubMed  Google Scholar 

  11. Dent E, Hoogendijk EO, Visvanathan R, et al. Malnutrition screening and assessment in hospitalised older people: a review. J Nutr Health Aging. 2019;23(5):431–41. https://doi.org/10.1007/s12603-019-1176-z.

    Article  CAS  PubMed  Google Scholar 

  12. O’Sullivan ED, Hughes J, Ferenbach DA. Renal aging: causes and consequences. J Am Soc Nephrol. 2017;28(2):407–20. https://doi.org/10.1681/ASN.2015121308.

    Article  CAS  PubMed  Google Scholar 

  13. Denic A, Glassock RJ, Rule AD. Structural and functional changes with the aging kidney. Adv Chronic Kidney Dis. 2016;23(1):19–28. https://doi.org/10.1053/j.ackd.2015.08.004.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Voukalis C, Lip GY, Shantsila E. Drug-drug interactions of non-vitamin K oral anticoagulants. Expert Opin Drug Metab Toxicol. 2016;12(12):1445–61. https://doi.org/10.1080/17425255.2016.1225037.

    Article  CAS  PubMed  Google Scholar 

  15. Stöllberger C. Drug interactions with new oral anticoagulants in elderly patients. Expert Rev Clin Pharmacol. 2017;10(11):1191–202. https://doi.org/10.1080/17512433.2017.1370369.

    Article  CAS  PubMed  Google Scholar 

  16. Gallo P, De Vincentis A, Pedone C, REPOSI Investigators, et al. Drug-drug interactions involving CYP3A4 and p-glycoprotein in hospitalized elderly patients. Eur J Intern Med. 2019;65:51–7. https://doi.org/10.1016/j.ejim.2019.05.002.

    Article  CAS  PubMed  Google Scholar 

  17. Kundu A, Sardar P, Chatterjee S, et al. Minimizing the risk of bleeding with NOACs in the elderly. Drugs Aging. 2016;33(7):491–500. https://doi.org/10.1007/s40266-016-0376-z.

    Article  CAS  PubMed  Google Scholar 

  18. Bayer AG. Xarelto 20 mg film-coated tablets SmPC. https://www.ema.europa.eu/en/documents/product-information/xarelto-epar-prod-uct-information_en.pdf. Accessed 29 Mar 2023.

  19. Bristol-Myers Squibb/Pfizer EEIG. Eliquis 5 mg film-coated tablets SmPC. https://www.ema.europa.eu/en/documents/product-infor-mation/eliquis-epar-product-information_en.pdf. Accessed 29 Mar 2023.

  20. Barra ME, Fanikos J, Connors JM, et al. Evaluation of dose-reduced direct oral anticoagulant therapy. Am J Med. 2016;129(11):1198–204. https://doi.org/10.1016/j.amjmed.2016.05.041.

    Article  CAS  PubMed  Google Scholar 

  21. Yao X, Shah ND, Sangaralingham LR, et al. Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. J Am Coll Cardiol. 2017;69(23):2779–90. https://doi.org/10.1016/j.jacc.2017.03.600.

    Article  CAS  PubMed  Google Scholar 

  22. Hanigan S, Das J, Pogue K, et al. The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding. J Thromb Thrombolysis. 2020;49(4):636–43. https://doi.org/10.1007/s11239-020-02037-3.

    Article  CAS  PubMed  Google Scholar 

  23. Wyse DG. Pharmacotherapy for rhythm management in elderly patients with atrial fibrillation. J Interv Card Electrophysiol. 2009;25(1):25–9. https://doi.org/10.1007/s10840-008-9329-8.

    Article  PubMed  Google Scholar 

  24. Kaatz S, Ahmad D, Spyropoulos AC, Subcommittee on Control of Anticoagulation, et al. 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. 2015;13(11):2119–26. https://doi.org/10.1111/jth.13140.

    Article  CAS  PubMed  Google Scholar 

  25. Schulman S, Angerås U, Bergqvist D, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, et al. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost. 2010;8(1):202–4. https://doi.org/10.1111/j.1538-7836.2009.03678.x.

    Article  CAS  PubMed  Google Scholar 

  26. Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15(4):361–87. https://doi.org/10.1002/(SICI)1097-0258(19960229)15:4%3c361::AID-SIM168%3e3.0.CO;2-4.

    Article  PubMed  Google Scholar 

  27. Zhang XL, Zhang XW, Wang TY, et al. Off-label under- and overdosing of direct oral anticoagulants in patients with atrial fibrillation: a meta-analysis. Circ Cardiovasc Qual Outcomes. 2021;14(12): e00797. https://doi.org/10.1161/CIRCOUTCOMES.121.007971.

    Article  Google Scholar 

  28. Montero-Odasso M, Speechley M. Falls in cognitively impaired older adults: implications for risk assessment and prevention. J Am Geriatr Soc. 2018;66(2):367–75. https://doi.org/10.1111/jgs.15219.

    Article  PubMed  Google Scholar 

  29. McGrattan AM, McGuinness B, McKinley MC, et al. Diet and inflammation in cognitive ageing and Alzheimer’s disease. Curr Nutr Rep. 2019;8(2):53–65. https://doi.org/10.1007/s13668-019-0271-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Viticchi G, Falsetti L, Burattini M, et al. Atrial fibrillation on patients with vascular dementia: a fundamental target for correct management. Brain Sci. 2020;10(7):420. https://doi.org/10.3390/brainsci10070420.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Steinberg BA, Hellkamp AS, Lokhnygina Y, ROCKET AF Steering Committee and Investigators, et al. Use and outcomes of antiarrhythmic therapy in patients with atrial fibrillation receiving oral anticoagulation: results from the ROCKET AF trial. Heart Rhythm. 2014;11(6):925–32. https://doi.org/10.1016/j.hrthm.2014.03.006.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Flaker G, Lopes RD, Hylek E, ARISTOTLE Committees and Investigators, et al. Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial. J Am Coll Cardiol. 2014;64(15):1541–50. https://doi.org/10.1016/j.jacc.2014.07.967.

    Article  CAS  PubMed  Google Scholar 

  33. Volgman AS, Nair G, Lyubarova R, et al. Management of atrial fibrillation in patients 75 years and older: JACC state-of-the-art review. J Am Coll Cardiol. 2022;79(2):166–79. https://doi.org/10.1016/j.jacc.2021.10.037.

    Article  PubMed  Google Scholar 

  34. Douxfils J, Ageno W, Samama CM, et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost. 2018;16(2):209–19. https://doi.org/10.1111/jth.13912.

    Article  CAS  PubMed  Google Scholar 

  35. Tseng CI, Roddick AJ, Bottomley MJ, et al. Safety and pharmacokinetic profile of apixaban in end-stage renal disease: a real-world analysis. EJHaem. 2022;4(1):291–3. https://doi.org/10.1002/jha2.606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge Sonia Taguemount and Laurence Bournazel for their help in screening patients admitted to the acute geriatric unit at Charles Foix Hospital (Ivry-sur-Seine, APHP Sorbonne University).

Author information

Authors and Affiliations

  1. Acute Geriatrics Unit, Charles Foix Hospital, APHP Sorbonne University, Ivry-sur-Seine, France

    Théodore Decaix, Kenza Kemache, Pierre Gay, Flora Ketz & Éric Pautas

  2. CNRS, CitCoM, Paris-Cité University, 75006, Paris, France

    Théodore Decaix & Olivier Laprévote

  3. Department of biology, 15-20 National Hospital Center of Ophtalmology, Paris, France

    Olivier Laprévote

  4. Therapeutic Innovations in Hemostasis, Inserm UMR-S 1140, Paris-Cité University, Paris, France

    Éric Pautas

  5. Medical School, Sorbonne University, Paris, France

    Éric Pautas

Authors
  1. Théodore Decaix
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenza Kemache
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierre Gay
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Olivier Laprévote
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Flora Ketz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Éric Pautas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Théodore Decaix.

Ethics declarations

Funding

This research received no external funding.

Conflict of interest

Éric Pautas has received honoraria for participating in expert meetings on dabigatran (from Boehringer Ingelheim), rivaroxaban (from Bayer Healthcare AG), apixaban (Bristol Myers Squibb-Pfizer), and warfarin (Merck). Théodore Decaix, Kenza Kemache, Pierre Gay, Olivier Laprévote, and Flora Ketz declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript.

Data availability

The data presented in this study are available on request from the corresponding author.

Ethics approval

Study methodology corresponds to studies not involving human subjects (MR–004). The study was conducted in accordance with the Declaration of Helsinki and the database was declared to the French National Commission on Computing and Liberty (CNIL) of the Assistance Publique–Hôpitaux de Paris (APHP) for this study (no. 20230403102132).

Consent to participate

No subjects involved in this study objected to the retrospective processing of their data.

Consent for publication

Not applicable.

Code availability

Not applicable.

Author contributions

Conceptualization, T.D., F.K. and E.P.; methodology, T.D., F.K. and E.P.; software, T.D.; validation, T.D., E.P.; formal analysis, T.D.; investigation, T.D., K.K., P.G.; resources, F.K., E.P.; data curation, F.K., E.P.; writing—original draft preparation, T.D., E.P.; writing—review and editing, T.D., K.K., O.L., F.K., and E.P.; visualization, T.D.; supervision, O.L., E.P.; project administration, E.P. All authors have read and agreed to the published version of the manuscript.

Additional information

The original online version of this article was revised to correct the author name Kenza Kemache.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 23 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

Decaix, T., Kemache, K., Gay, P. et al. Prevalence and factors associated with inappropriate dosing of apixaban and rivaroxaban in hospitalized older adults with atrial fibrillation: a cross-sectional study. Drugs Aging 41, 55–64 (2024). https://doi.org/10.1007/s40266-023-01081-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40266-023-01081-x

Search

Navigation