Download PDF
CC BY 4.0 · Thromb Haemost
DOI: 10.1055/s-0044-1785511
Stroke, Systemic or Venous Thromboembolism

Pharmacokinetics of Edoxaban 15 mg in Very Elderly Patients with Nonvalvular Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Study

Takeshi Yamashita
1   Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan
,
Yoshiyuki Igawa
2   Quantitative Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan
,
Masayuki Fukuzawa
3   Japan Business Unit, Primary Medical Science Department, Cardiovascular Group, Daiichi Sankyo Co., Ltd., Tokyo, Japan
,
Takuya Hayashi
4   Data Analysis Group, Data Intelligence Department, Global DX, Daiichi Sankyo Co., Ltd., Tokyo, Japan
,
Stefanie Hennig
5   Certara, Inc., Princeton, New Jersey, United States
,
Ken Okumura
6   Division of Cardiology, Saiseikai Kumamoto Hospital, Kumamoto, Japan
› Author Affiliations Funding This research was supported by Daiichi Sankyo Co., Ltd.
› Further Information
   Permissions and Reprints


Abstract

Background We evaluated the pharmacokinetics (PK) of low-dose (15 mg) edoxaban in very elderly patients (≥80 years) with nonvalvular atrial fibrillation (NVAF) and high bleeding risk.

Methods This subanalysis of the phase 3, randomized, double-blind, placebo-controlled, multicenter ELDERCARE-AF study evaluated edoxaban plasma concentrations and compared them with the Japanese population of the ENGAGE AF-TIMI 48 and Japanese severe renal impairment (SRI) studies.

Results The PK analysis population included 451 patients, 53.8% of whom concomitantly used antiplatelet drugs, 41.0% had SRI, and 38.0% had low body weight. Edoxaban plasma concentrations at trough and 1 to 3 hours post-dose in ELDERCARE-AF were 17.3 ± 13.9 (n = 427) and 93.3 ± 57.8 ng/mL (n = 447), respectively. These values were slightly higher than the 15 mg group in ENGAGE AF-TIMI 48 (n = 79; 12.4 ± 12.1 and n = 115; 78.7 ± 45.0 ng/mL, respectively), lower than the ENGAGE AF-TIMI 48 high-dose reduced to 30 mg group (n = 83; 25.1 ± 36.6 and n = 111; 150 ± 91.6 ng/mL, respectively), but similar to the Japanese SRI study (n = 39; 18.4 ± 11.2 and n = 40; 96.8 ± 48.3 ng/mL, respectively). ELDERCARE-AF patients with SRI and low body weight (≤45 kg) had higher concentrations than those without, and those taking antiplatelet drugs had lower concentrations than those who were not.

Conclusion PK data support edoxaban 15 mg once daily for very elderly NVAF patients with high bleeding risk, with caution for patients with SRI and/or low body weight.

Keywords

edoxaban - nonvalvular atrial fibrillation - elderly - pharmacokinetics

Data Availability Statement

Anonymized data related to the present study will be made available to other researchers at https://search.vivli.org/ upon reasonable request to the corresponding author and pending approval by Daiichi Sankyo Co., Ltd.


Authors' Contribution

T.Y., M.F., and K.O. participated in the design and conduct of the study; Y.I., T.H. and S.H. conducted data analysis; all authors interpreted the data; all authors drafted the manuscript; and all authors revised the manuscript and approved the final version.


Supplementary Material



Publication History

Received: 21 April 2023

Accepted: 26 February 2024

Article published online:
19 April 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Wasmer K, Eckardt L, Breithardt G. Predisposing factors for atrial fibrillation in the elderly. J Geriatr Cardiol 2017; 14 (03) 179-184
    PubMedGoogle Scholar
  • 2 Chugh SS, Havmoeller R, Narayanan K. et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014; 129 (08) 837-847
    CrossrefPubMedGoogle Scholar
  • 3 Friberg L, Rosenqvist M, Lindgren A, Terént A, Norrving B, Asplund K. High prevalence of atrial fibrillation among patients with ischemic stroke. Stroke 2014; 45 (09) 2599-2605
    CrossrefPubMedGoogle Scholar
  • 4 Björck S, Palaszewski B, Friberg L, Bergfeldt L. Atrial fibrillation, stroke risk, and warfarin therapy revisited: a population-based study. Stroke 2013; 44 (11) 3103-3108
    CrossrefPubMedGoogle Scholar
  • 5 SAVAYSA™ (edoxaban) tablets for oral use. Full prescribing information. Daiichi Sankyo Inc., Parsippany, NJ, United States. Accessed March 29, 2023 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf
    PubMedGoogle Scholar
  • 6 Okumura K, Lip GYH, Akao M. et al. Edoxaban for the management of elderly Japanese patients with atrial fibrillation ineligible for standard oral anticoagulant therapies: rationale and design of the ELDERCARE-AF study. Am Heart J 2017; 194: 99-106
    CrossrefPubMedGoogle Scholar
  • 7 Okumura K, Akao M, Yoshida T. et al; ELDERCARE-AF Committees and Investigators. Low-dose edoxaban in very elderly patients with atrial fibrillation. N Engl J Med 2020; 383 (18) 1735-1745
    CrossrefPubMedGoogle Scholar
  • 8 Koretsune Y, Yamashita T, Kimura T, Fukuzawa M, Abe K, Yasaka M. Short-term safety and plasma concentrations of edoxaban in Japanese patients with non-valvular atrial fibrillation and severe renal impairment. Circ J 2015; 79 (07) 1486-1495
    CrossrefPubMedGoogle Scholar
  • 9 Giugliano RP, Ruff CT, Braunwald E. et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
    CrossrefPubMedGoogle Scholar
  • 10 Yin OQP, Antman EM, Braunwald E. et al. Linking endogenous factor Xa activity, a biologically relevant pharmacodynamic marker, to edoxaban plasma concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial. Circulation 2018; 138 (18) 1963-1973
    CrossrefPubMedGoogle Scholar
  • 11 Matsushima N, Lee F, Sato T, Weiss D, Mendell J. Bioavailability and safety of the factor Xa inhibitor edoxaban and the effects of quinidine in healthy subjects. Clin Pharmacol Drug Dev 2013; 2 (04) 358-366
    CrossrefPubMedGoogle Scholar
  • 12 Morishima Y, Kamisato C. Laboratory measurements of the oral direct factor Xa inhibitor edoxaban: comparison of prothrombin time, activated partial thromboplastin time, and thrombin generation assay. Am J Clin Pathol 2015; 143 (02) 241-247
    CrossrefPubMedGoogle Scholar
  • 13 Halvorsen S, Atar D, Yang H. et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J 2014; 35 (28) 1864-1872
    CrossrefPubMedGoogle Scholar
  • 14 Hori M, Matsumoto M, Tanahashi N. et al; J-ROCKET AF Study Investigators. Rivaroxaban vs. warfarin in Japanese patients with non-valvular atrial fibrillation in relation to age. Circ J 2014; 78 (06) 1349-1356
    CrossrefPubMedGoogle Scholar
  • 15 Eikelboom JW, Wallentin L, Connolly SJ. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123 (21) 2363-2372
    CrossrefPubMedGoogle Scholar
  • 16 Kato ET, Giugliano RP, Ruff CT. et al. Efficacy and safety of edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial. J Am Heart Assoc 2016; 5 (05) e003432
    CrossrefPubMedGoogle Scholar
  • 17 Shimizu T, Tachibana M, Kimura T, Kumakura T, Yoshihara K. Population pharmacokinetics of edoxaban in Japanese atrial fibrillation patients with severe renal impairment. Clin Pharmacol Drug Dev 2017; 6 (05) 484-491
    CrossrefPubMedGoogle Scholar