Skip to main content
SpringerLink
Log in

Clinical implications of assessment of apixaban levels in elderly atrial fibrillation patients: J-ELD AF registry sub-cohort analysis

  • Pharmacodynamics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To investigate the distribution of plasma apixaban levels and their relationships with clinical outcomes in elderly patients with atrial fibrillation (AF).

Method

The J-ELD AF Registry is a multicenter prospective observational study of Japanese non-valvular AF patients aged ≥75 years taking an on-label dose of apixaban (3015 patients from 110 institutions). Among them, plasma apixaban levels at trough were estimated by anti-Xa assay (Api-AXA) in 943 patients. Patients with standard (5 mg bid; n = 431) and reduced (2.5 mg bid; n = 512) dose were further divided into two groups with low and high Api-AXA levels (boundary: median value).

Results

The incidence rates (per 100 person-years) of events in the low- and high-Api-AXA groups were as follows: 1.48 and 1.99 (log-rank test, P = 0.695) for stroke or systemic embolism, 0.98 and 1.49 (P = 0.652) for bleeding requiring hospitalization, and 0.49 and 0.99 (P = 0.565) for total deaths in patients with standard dose, versus 0.84 and 1.68 (P = 0.414), 0.42 and 4.64 (P = 0.004), and 2.52 and 6.65 (P = 0.035) in patients with a reduced dose, respectively. In multivariate Cox regression analysis among patients with a reduced dose, a high Api-AXA level was independently associated with bleeding requiring hospitalization (HR 12.12, 95% CI: 1.56–94.22) and nonsignificantly with total deaths.

Conclusions

A high trough apixaban level in patients indicated for standard dose was not associated with adverse events, while a high apixaban level in patients indicated for a reduced dose was associated with bleeding requiring hospitalization.

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

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

References

  1. Hart RG, Pearce LA, Aguilar MI (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 146:857–867

    Article  Google Scholar 

  2. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383:955–962

    Article  CAS  Google Scholar 

  3. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P, ESC Scientific Document Group (2016) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 37:2893–2962

    Article  Google Scholar 

  4. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY (2010) A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the euro heart survey. Chest 138:1093–1100

    Article  Google Scholar 

  5. Gage BF, Yan Y, Milligan PE, Waterman AD, Culverhouse R, Rich MW, Radford MJ (2006) Clinical classification schemes for predicting hemorrhage: results from the National Registry of atrial fibrillation (NRAF). Am Heart J 151:713–719

    Article  Google Scholar 

  6. Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, Singer DE (2011) A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (anticoagulation and risk factors in atrial fibrillation) study. J Am Coll Cardiol 58:395–401

    Article  Google Scholar 

  7. O'Brien EC, Simon DN, Thomas LE, Hylek EM, Gersh BJ, Ansell JE, Kowey PR, Mahaffey KW, Chang P, Fonarow GC, Pencina MJ, Piccini JP, Peterson ED (2015) The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation. Eur Heart J 36:3258–3264

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hijazi Z, Oldgren J, Lindback J, Alexander JH, Connolly SJ, Eikelboom JW, Ezekowitz MD, Held C, Hylek EM, Lopes RD, Siegbahn A, Yusuf S, Granger CB, Wallentin L (2016) The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 387:2302–2311

    Article  CAS  Google Scholar 

  9. Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, Ezekowitz MD, Nehmiz G, Wang S, Wallentin L, RE-LY Investigators (2014) The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 63:321–328

    Article  CAS  Google Scholar 

  10. Ruff CT, Giugliano RP, Braunwald E, Morrow DA, Murphy SA, Kuder JF, Deenadayalu N, Jarolim P, Betcher J, Shi M, Brown K, Patel I, Mercuri M, Antman EM (2015) Association between edoxaban dose, concentration, anti-factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 385:2288–2295

    Article  CAS  Google Scholar 

  11. Yoshioka H, Sato H, Hatakeyama H, Hisaka A (2018) Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients. Blood Adv 2:1066–1075

    Article  CAS  Google Scholar 

  12. Okumura K, Yamashita T, Suzuki S, Akao M, Investigators JEA (2020) A multicenter prospective cohort study to investigate the effectiveness and safety of apixaban in Japanese elderly atrial fibrillation patients (J-ELD AF registry). Clin Cardiol 43:251–259

    Article  Google Scholar 

  13. Akao M, Yamashita T (2016) Okumura K and J-ELDAF Investigators. Study design of J-ELD AF: a multicenter prospective cohort study to investigate the efficacy and safety of apixaban in Japanese elderly patients. J Cardiol 68:554–558

    Article  Google Scholar 

  14. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H (2009) Hishida a and collaborators developing the Japanese equation for estimated GFR. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982–992

    Article  CAS  Google Scholar 

  15. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41

    Article  CAS  Google Scholar 

  16. Douxfils J, Chatelain C, Chatelain B, Dogne JM, Mullier F (2013) Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 110:283–294

    Article  CAS  Google Scholar 

  17. Alexander JH, Andersson U, Lopes RD, Hijazi Z, Hohnloser SH, Ezekowitz JA, Halvorsen S, Hanna M, Commerford P, Ruzyllo W, Huber K, Al-Khatib SM, Granger CB, Wallentin L (2016) Apixaban 5 mg 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 1:673–681

    Article  Google Scholar 

  18. Alexander KP, Brouwer MA, Mulder H, Vinereanu D, Lopes RD, Proietti M, Al-Khatib SM, Hijazi Z, Halvorsen S, Hylek EM, Verheugt FWA, Alexander JH, Wallentin L, Granger CB (2019) Outcomes of apixaban versus warfarin in patients with atrial fibrillation and multi-morbidity: insights from the ARISTOTLE trial. Am Heart J 208:123–131

    Article  CAS  Google Scholar 

  19. Jaspers Focks J, Brouwer MA, Wojdyla DM, Thomas L, Lopes RD, Washam JB, Lanas F, Xavier D, Husted S, Wallentin L, Alexander JH, Granger CB, Verheugt FW (2016) Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial. BMJ 353:i2868

    Article  Google Scholar 

  20. Hohnloser SH, Oldgren J, Yang S, Wallentin L, Ezekowitz M, Reilly P, Eikelboom J, Brueckmann M, Yusuf S, Connolly SJ (2012) Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized evaluation of long-term anticoagulation therapy) trial. Circulation 125:669–676

    Article  CAS  Google Scholar 

  21. Mahaffey KW, Stevens SR, White HD, Nessel CC, Goodman SG, Piccini JP, Patel MR, Becker RC, Halperin JL, Hacke W, Singer DE, Hankey GJ, Califf RM, Fox KA, Breithardt G, Investigators RA (2014) Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial. Eur Heart J 35:233–241

    Article  CAS  Google Scholar 

  22. Jones WS, Hellkamp AS, Halperin J, Piccini JP, Breithardt G, Singer DE, Fox KA, Hankey GJ, Mahaffey KW, Califf RM, Patel MR (2014) Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF. Eur Heart J 35:242–249

    Article  CAS  Google Scholar 

  23. Bahit MC, Lopes RD, Wojdyla DM, Hohnloser SH, Alexander JH, Lewis BS, Aylward PE, Verheugt FW, Keltai M, Diaz R, Hanna M, Granger CB, Wallentin L (2013) Apixaban in patients with atrial fibrillation and prior coronary artery disease: insights from the ARISTOTLE trial. Int J Cardiol 170:215–220

    Article  Google Scholar 

  24. Hu PT, Lopes RD, Stevens SR, Wallentin L, Thomas L, Alexander JH, Hanna M, Lewis BS, Verheugt FW, Granger CB, Jones WS (2017) Efficacy and safety of Apixaban compared with warfarin in patients with atrial fibrillation and peripheral artery disease: insights from the ARISTOTLE trial. J Am Heart Assoc 6

  25. Zelniker TA, Ruff CT, Wiviott SD, Blanc JJ, Cappato R, Nordio F, Mercuri MF, Lanz H, Antman EM, Braunwald E, Giugliano RP (2019) Edoxaban in atrial fibrillation patients with established coronary artery disease: insights from ENGAGE AF-TIMI 48. Eur Heart J Acute Cardiovasc Care 8:176–185

    Article  Google Scholar 

  26. CASRAI. CRediT [Internet]. 2019

Download references

Acknowledgements

We would like to thank the J-ELD AF investigators for their support in patient registration and data collection in the main study used in this sub-cohort analysis. This study was conducted by the Cardiovascular Institute Academic Organization (CVI ARO), Tokyo, Japan, subsidized and funded by pharmaceutical and medical device companies.

Funding

Bristol-Myers Squibb K.K. provided monetary support for this study. This study was supported in part by the Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus from the Japan Agency for Medical Research and Development, AMED (15656344 and JP17ek0210082). The present study was funded by Bristol-Myers Squibb, who had no role in the design, conduct, or reporting of the study.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, The Cardiovascular Institute, 3-2-19 Nishiazabu, Minato-ku, Tokyo, 106-0031, Japan

    Shinya Suzuki & Takeshi Yamashita

  2. Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

    Masaharu Akao

  3. Division of Cardiology, Saiseikai Kumamoto Hospital, Kumamoto, Japan

    Ken Okumura

Authors
  1. Shinya Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeshi Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masaharu Akao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ken Okumura
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of J-ELD AF investigators

Contributions

Contributions by each author according to the Contributor Roles Taxonomy (CRediT) [26]:

• SS: conceptualization, data curation, formal analysis, investigation, methodology, writing—original draft;

• TY: conceptualization, funding acquisition, investigation, methodology, project administration, supervision, writing—review and editing;

• MA: conceptualization, investigation, project administration, writing—review and editing;

• KO: conceptualization, funding acquisition, investigation, project administration, supervision, writing—review and editing.

Corresponding author

Correspondence to Shinya Suzuki.

Ethics declarations

Prior to the start of the main study, the investigators in charge received a review from the ethics committee of their main participating facility and acquired approval. Prior to enrollment, the contents of the study were explained to the patients using explanatory documents and consent documents, and written consent was obtained. If a patient withdrew consent during the observation period, all existing data collected from the patient were discarded. The study plan and its design were registered in the UMIN Clinical Trials Registry (UMIN000017895).

Conflict of interest

SS received research funding from Daiichi-Sankyo and Mitsubishi-Tanabe. TY received lecture fees from Bristol-Myers Squibb, Daiichi-Sankyo, Bayer, Pfizer, Ono Pharmaceutical, and Toa Eiyo and research funding from Bayer and Daiichi Sankyo. MA received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare, and Daiichi-Sankyo. KO received lecture fees from Daiichi-Sankyo, Boehringer Ingelheim, and Johnson and Johnson.

Additional information

Publisher’s note

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

Electronic supplementary material

ESM 1

(PPTX 104 kb)

ESM 2

(DOCX 41 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suzuki, S., Yamashita, T., Akao, M. et al. Clinical implications of assessment of apixaban levels in elderly atrial fibrillation patients: J-ELD AF registry sub-cohort analysis. Eur J Clin Pharmacol 76, 1111–1124 (2020). https://doi.org/10.1007/s00228-020-02896-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-020-02896-y

Keywords

Search

Navigation