Skip to main content

Advertisement

SpringerLink
Log in

Minimal Adherence Threshold to Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation to Reduce the Risk of Thromboembolism and Death: A Nationwide Cohort Study

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

Abstract

Purpose

Poor adherence to non-vitamin K antagonist oral anticoagulants (NOACs) may raise thromboembolic risks in patients with atrial fibrillation (AF). However, the minimal adherence to maintain the protective effect of NOACs is currently unknown. Therefore, we investigated thresholds of NOAC adherence in association with thromboembolic and mortality risks.

Methods

Patients with AF initiating NOACs between 2013 and 2019 were identified in Belgian nationwide data. Adherence was measured using the proportion of days covered (PDC) after one year of treatment. Inverse probability of treatment weighted Cox regression was used to investigate outcomes.

Results

92,111 persons were included (250,750 person-years). Compared to NOAC users with a one-year PDC of 100%, significantly higher risks of stroke or systemic embolism were observed among NOAC users with PDCs of 85–89% (adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI) (1.19–1.54)), 80–84% (aHR 1.31, 95%CI (1.08–1.58)) and < 80% (aHR 1.64, 95%CI (1.34–2.01)), while no significant differences were observed among NOAC users with one-year PDCs of 95–99% (aHR 1.02, 95%CI (0.94–1.12)) or 90–94% (aHR 1.06, 95%CI (0.95–1.18)). Significantly higher risks of all-cause mortality were observed with decreasing levels of NOAC adherence, which were already higher among NOAC users with a one-year PDC of 90–94% versus 100% (aHR 1.09, 95%CI (1.01–1.17)). Findings were similar with once-daily and twice-daily dosed NOACs.

Conclusion

Poor adherence to NOACs is associated with increased risks of thromboembolism and all-cause mortality. The minimal adherence threshold should be ≥ 90%, preferably even ≥ 95%.

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

Data 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: european pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2021;23(10):1612–76.

  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 Arrhythm Cardiac Electrophysiol : J Working Groups Cardiac Pacing Arrhythm Cardiac Cell Electrophysiol Eur Soc Cardiol. 2022;24(6):887–98.

    Google Scholar 

  3. Grymonprez M, De Backer TL, Capiau A, et al. Trends in oral anticoagulant use in patients with atrial fibrillation in Belgium from 2013 to 2019: a nationwide cohort study. Br J Clin Pharmacol. 2023;89(4):1360–73.

    Article  PubMed  Google Scholar 

  4. 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 

  5. Holthuis E, Smits E, Spentzouris G, et al. Increased risk of Stroke due to non-adherence and non-persistence with direct oral anticoagulants (DOACs): real-world analyses using a nested case-control study from the Netherlands, Italy and Germany. Drugs - real world outcomes; 2022.

  6. Lee WK, Woo SI, Hyun DK, Jung SY, Kim MS, Lee J. Impact of treatment adherence on the effectiveness and safety of oral anticoagulants in patients with atrial fibrillation: a retrospective cohort study. European heart journal Quality of care & clinical outcomes; 2022.

  7. Yang SY, Kang DW, Nam JH, et al. Adherence is an optimal factor for maximizing the effective and safe use of oral anticoagulants in patients with atrial fibrillation. Sci Rep. 2022;12(1):3413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Akao M, Tsuji H, Kusano K et al. Clinical characteristics and outcomes of japanese atrial fibrillation patients with poor medication adherence: a sub-analysis of the GENERAL study. J Cardiol. 2022.

  9. Arbel A, Abu-Ful Z, Preis M, Cohen S, Saliba W. Adherence with direct oral anticoagulants in patients with atrial fibrillation: Trends, risk factors, and outcomes. J Arrhythmia. 2022;38(1):67–76.

    Article  Google Scholar 

  10. Alberts MJ, Peacock WF, Fields LE, et al. Association between once- and twice-daily direct oral anticoagulant adherence in nonvalvular atrial fibrillation patients and rates of ischemic stroke. Int J Cardiol. 2016;215:11–3.

    Article  PubMed  Google Scholar 

  11. Deshpande CG, Kogut S, Laforge R, Willey C. Impact of medication adherence on risk of ischemic stroke, major bleeding and deep vein thrombosis in atrial fibrillation patients using novel oral anticoagulants. Curr Med Res Opin. 2018;34(7):1285–92.

    Article  PubMed  Google Scholar 

  12. Borne RT, O’Donnell C, Turakhia MP, et al. Adherence and outcomes to direct oral anticoagulants among patients with atrial fibrillation: findings from the veterans health administration. BMC Cardiovasc Disord. 2017;17(1):236.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hurtado-Navarro I, Garcia-Sempere A, Rodriguez-Bernal C, Santa-Ana-Tellez Y, Peiro S, Sanfelix-Gimeno G. Estimating adherence based on prescription or dispensation information: impact on thresholds and outcomes. A real-world study with Atrial Fibrillation Patients treated with oral anticoagulants in Spain. Front Pharmacol. 2018;9:1353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shore S, Carey EP, Turakhia MP, et al. Adherence to dabigatran therapy and longitudinal patient outcomes: insights from the veterans health administration. Am Heart J. 2014;167(6):810–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wirbka L, Haefeli WE, Meid AD. Estimated thresholds of minimum necessary adherence for effective treatment with direct oral Anticoagulants - A Retrospective Cohort Study in Health Insurance Claims Data. Patient Prefer Adherence. 2021;15:2209–20.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Komen JJ, Heerdink ER, Klungel OH et al. Long-term persistence and adherence with non-vitamin K oral anticoagulants in patients with atrial fibrillation and their associations with stroke risk. Eur Heart J Cardiovasc Pharmacotherapy. 2020.

  17. Vrijens B, Heidbuchel H. Non-vitamin K antagonist oral anticoagulants: considerations on once- vs. twice-daily regimens and their potential impact on medication adherence. Europace: Eur Pacing Arrhythm Cardiac Electrophysiol : J Working Groups Cardiac Pacing Arrhythm Cardiac Cell Electrophysiol Eur Soc Cardiol. 2015;17(4):514–23.

    Google Scholar 

  18. Capiau A, Mehuys E, Van Tongelen I, et al. Community pharmacy-based study of adherence to non-vitamin K antagonist oral anticoagulants. Heart. 2020;106(22):1740–6.

    Article  CAS  PubMed  Google Scholar 

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

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

  21. 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.

  22. 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 

  23. Vrijens B, De Geest S, Hughes DA, et al. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol. 2012;73(5):691–705.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Arnet I, Kooij MJ, Messerli M, Hersberger KE, Heerdink ER, Bouvy M. Proposal of standardization to assess Adherence with Medication Records: methodology matters. The Annals of Pharmacotherapy. 2016;50(5):360–8.

    Article  PubMed  Google Scholar 

  25. Kim D, Yang PS, Jang E et al. The optimal drug adherence to maximize the efficacy and safety of non-vitamin K antagonist oral anticoagulant in real-world atrial fibrillation patients. Europace: european pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2019.

  26. 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 

  27. Hsu JY, Liu PP, Liu AB, Lin SM, Huang HK, Loh CH. Lower risk of dementia in patients with Atrial Fibrillation taking non-vitamin K antagonist oral anticoagulants: a Nationwide Population-Based Cohort Study. J Am Heart Assoc. 2021;10(5):e016437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Millenaar D, Schumacher H, Brueckmann M, et al. Cardiovascular Outcomes according to Polypharmacy and Drug Adherence in patients with Atrial Fibrillation on Long-Term Anticoagulation (from the RE-LY trial). Am J Cardiol. 2021;149:27–35.

    Article  CAS  PubMed  Google Scholar 

  29. Emren SV, Senoz O, Bilgin M, et al. Drug adherence in patients with Nonvalvular Atrial Fibrillation taking non-vitamin K antagonist oral anticoagulants in Turkey: NOAC-TR. Clin Appl Thromb Hemost. 2018;24(3):525–31.

    Article  CAS  PubMed  Google Scholar 

  30. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487–97.

    Article  CAS  PubMed  Google Scholar 

  31. Park JH, Han SW, Lee KY, et al. Impact of non-vitamin K antagonist oral anticoagulant withdrawal on stroke outcomes. Front Neurol. 2018;9:1095.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Yao X, Abraham NS, Alexander GC et al. Effect of adherence to oral anticoagulants on risk of stroke and major bleeding among patients with Atrial Fibrillation. J Am Heart Assoc. 2016;5(2).

  33. Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation. 2014;129(18):1850–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cools F, Johnson D, Camm AJ, et al. Risks associated with discontinuation of oral anticoagulation in newly diagnosed patients with atrial fibrillation: results from the GARFIELD-AF Registry. J Thromb Haemostasis: JTH. 2021;19(9):2322–34.

    Article  CAS  Google Scholar 

  35. Vene N, Mavri A, Gubensek M, et al. Risk of thromboembolic events in patients with non-valvular atrial Fibrillation after Dabigatran or Rivaroxaban Discontinuation - Data from the Ljubljana Registry. PLoS ONE. 2016;11(6):e0156943.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Cavallari I, Ruff CT, Nordio F, et al. Clinical events after interruption of anticoagulation in patients with atrial fibrillation: an analysis from the ENGAGE AF-TIMI 48 trial. Int J Cardiol. 2018;257:102–7.

    Article  PubMed  Google Scholar 

  37. Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, oral, direct factor Xa Inhibition compared with vitamin K antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol. 2013;61(6):651–8.

    Article  CAS  PubMed  Google Scholar 

  38. Goto S, Merrill P, Wallentin L, et al. Antithrombotic therapy use and clinical outcomes following thrombo-embolic events in patients with atrial fibrillation: insights from ARISTOTLE. Eur Heart J Cardiovasc Pharmacotherapy. 2018;4(2):75–81.

    Article  Google Scholar 

  39. Shrank WH, Patrick AR, Brookhart MA. Healthy user and related biases in observational studies of preventive interventions: a primer for physicians. J Gen Intern Med. 2011;26(5):546–50.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Katerenchuk V, Duarte GS, Martins EPG et al. Satisfaction of patients with nonvitamin K anticoagulants compared to vitamin K antagonists: a systematic review and Meta-analysis. Thromb Haemost. 2020.

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), 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, Ghent, 9000, Belgium

    Maxim Grymonprez, Andreas Capiau, Delphine Vauterin, Frauke Van Vaerenbergh, Els Mehuys, Koen Boussery & Lies Lahousse

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

    Stephane Steurbaut

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

    Stephane Steurbaut

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

    Tine L. De Backer

  5. Department of Epidemiology, Erasmus Medical Center, Doctor Molewaterplein 40, Rotterdam, 3015, The Netherlands

    Lies Lahousse

Authors
  1. Maxim Grymonprez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephane Steurbaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreas Capiau
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Delphine Vauterin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frauke Van Vaerenbergh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Els Mehuys
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Koen Boussery
    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. M.G. performed the statistical analysis, interpretation and writing under the supervision of LL. SS, AC, DV, FVV, EM, KB, TDB and LL revised the manuscript critically. All authors contributed to the article and approved the final version of the manuscript.

Corresponding author

Correspondence to Lies Lahousse.

Ethics declarations

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, SS has 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 health care providers. Neither author has received any fees personally.

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 [21].

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Additional information

Publisher’s Note

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

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Supplementary Material 2

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., Steurbaut, S., Capiau, A. et al. Minimal Adherence Threshold to Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation to Reduce the Risk of Thromboembolism and Death: A Nationwide Cohort Study. Cardiovasc Drugs Ther (2023). https://doi.org/10.1007/s10557-023-07507-3

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10557-023-07507-3

Keywords

Search

Navigation