Clinical outcomes according to dose reduction criteria of apixaban in Japanese elderly patients with atrial fibrillation: J-ELD AF Registry subanalysis


Dose reduction of apixaban is applied in atrial fibrillation (AF) patients fulfilling ≥ 2 of the following criteria: (1) age ≥ 80 years, (2) body weight ≤ 60 kg and (3) serum creatinine ≥ 1.5 mg/dL. However, the clinical significance of each criterion remains unclear. The J-ELD AF Registry is a prospective observational study of elderly (≥ 75 years) Japanese AF patients receiving on-label dose of apixaban. In patients receiving the standard dose (5 mg bid, n = 1243), the incidence rates (% per patient-year) of stroke or systemic embolism in those fulfilling none [n = 516] or one of the above criteria (1) [n = 328], (2) [n = 378] and (3) [n = 21] were 1.24, 2.32, 1.41 and 4.93 (log-rank P = 0.422), respectively, and those of bleeding requiring hospitalization were 1.03, 0.99, 1.98 and 4.93 (P = 0.318), respectively. In patients receiving a reduced dose (2.5 mg bid, n = 1,515), the incidences of stroke or systemic embolism in those fulfilling (1)/(2) [n = 1,331], (1)/(3) [n = 65], (2)/(3) [n = 23] and all three criteria [n = 96] were 1.38, 1.64, 4.67 and 3.51 (P = 0.295), respectively, and those of bleeding requiring hospitalization were 2.04, 1.64, 0.00 and 4.71 (P = 0.318), respectively. Univariate analysis demonstrated that the types or combinations of each criterion was not significantly associated with the incidence of thromboembolic or bleeding events. The types or combinations of the three apixaban dose reduction criteria did not have significant impact on effectiveness and safety in Japanese elderly AF patients receiving on-label dose of apixaban, although the impact of the creatinine criterion remains uncertain due to the few number of the patients.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2


  1. 1.

    Kannel WB, Wolf PA, Benjamin EJ, Levy D (1998) Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 82:2N-9N

    CAS  Article  Google Scholar 

  2. 2.

    Wolf PA, Abbott RD, Kannel WB (1991) Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 22:983–988

    CAS  Article  Google Scholar 

  3. 3.

    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

    CAS  Article  Google Scholar 

  4. 4.

    Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992

    CAS  Article  Google Scholar 

  5. 5.

    Cirincione B, Kowalski K, Nielsen J, Roy A, Thanneer N, Byon W, Boyd R, Wang X, Leil T, LaCreta F, Ueno T, Oishi M, Frost C (2018) Population pharmacokinetics of apixaban in subjects with nonvalvular atrial fibrillation. CPT Pharmacomet Syst Pharmacol 7:728–738

    CAS  Article  Google Scholar 

  6. 6.

    Inoue H, Umeyama M, Yamada T, Hashimoto H, Komoto A, Yasaka M (2019) Safety and effectiveness of apixaban in Japanese patients with nonvalvular atrial fibrillation in clinical practice: a regulatory postmarketing surveillance, the STANDARD study. J Arrhythm 35:506–514

    Article  Google Scholar 

  7. 7.

    Okumura K, Yamashita T, Suzuki S, Akao M (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 

  8. 8.

    Akao M, Yamashita T, Okumura K (2016) 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 

  9. 9.

    Akao M, Chun Y, Wada H, Esato M, Hashimoto T, Abe M, Hasegawa K, Tsuji H, Furuke K (2013) Current status of clinical background of patients with atrial fibrillation in a community-based survey: the Fushimi AF Registry. J Cardiol 61:260–266

    Article  Google Scholar 

  10. 10.

    Koretsune Y, Yamashita T, Akao M, Atarashi H, Ikeda T, Okumura K, Shimizu W, Tsutsui H, Toyoda K, Hirayama A, Yasaka M, Yamaguchi T, Teramukai S, Kimura T, Kaburagi J, Takita A, Inoue H (2019) Baseline demographics and clinical characteristics in the All Nippon AF in the Elderly (ANAFIE) Registry. Circ J 83:1538–1545

    Article  Google Scholar 

  11. 11.

    Yamashita Y, Hamatani Y, Esato M, Chun YH, Tsuji H, Wada H, Hasegawa K, Abe M, Lip GY, Akao M (2016) Clinical characteristics and outcomes in extreme elderly (age ≥ 85) Japanese patients with atrial fibrillation: the Fushimi AF Registry. Chest 149:401–412

    Article  Google Scholar 

  12. 12.

    Halvorsen S, Atar D, Yang H, De Caterina R, Erol C, Garcia D, Granger CB, Hanna M, Held C, Husted S, Hylek EM, Jansky P, Lopes RD, Ruzyllo W, Thomas L, Wallentin L (2014) 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 35:1864–1872

    CAS  Article  Google Scholar 

  13. 13.

    Hohnloser SH, Fudim M, Alexander JH, Wojdyla DM, Ezekowitz JA, Hanna M, Atar D, Hijazi Z, Bahit MC, Al-Khatib SM, Lopez-Sendon JL, Wallentin L, Granger CB, Lopes RD (2019) Efficacy and safety of apixaban versus warfarin in patients with atrial fibrillation and extremes in body weight. Circulation 139:2292–2300

    CAS  Article  Google Scholar 

  14. 14.

    Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, Keltai M, Lanas F, Lopes RD, Lopez-Sendon J, Granger CB, Wallentin L (2012) Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 33:2821–2830

    CAS  Article  Google Scholar 

  15. 15.

    Akao M, Yamashita T, Suzuki S, Okumura K (2020) Impact of creatinine clearance on clinical outcomes in elderly atrial fibrillation patients receiving apixaban: J-ELD AF Registry subanalysis. Am Heart J 223:23–33

    CAS  Article  Google Scholar 

  16. 16.

    Inoue H, Umeyama M, Yamada T, Hashimoto H, Komoto A, Yasaka M (2019) Safety and effectiveness of reduced-dose apixaban in Japanese patients with nonvalvular atrial fibrillation in clinical practice: a sub-analysis of the STANDARD study. J Cardiol 75:208–215

    Article  Google Scholar 

  17. 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. 18.

    Siontis KC, Zhang X, Eckard A, Bhave N, Schaubel DE, He K, Tilea A, Stack AG, Balkrishnan R, Yao X, Noseworthy PA, Shah ND, Saran R, Nallamothu BK (2018) Outcomes associated with apixaban use in end-stage kidney disease patients with atrial fibrillation in the United States. Circulation 138:1519–1529

    CAS  Article  Google Scholar 

  19. 19.

    Zeitouni M, Giczewska A, Lopes RD, Wojdyla DM, Christersson C, Siegbahn A, De Caterina R, Steg PG, Granger CB, Wallentin L, Alexander JH (2020) Clinical and pharmacological effects of apixaban dose adjustment in the ARISTOTLE trial. J Am Coll Cardiol 75:1145–1155

    CAS  Article  Google Scholar 

Download references


We would like to thank the J-ELD AF investigators for their support in patient registration and data collection: Caress Sapporo Hokko Memorial Clinic (Ichiro SAKUMA), Tosei General Hospital (Masayoshi AJIOKA), National Cerebral and Cardiovascular Center (Kengo KUSANO), Tokyo Dental College Ichikawa General Hospital (Takahiro OHKI), Kyoto University Graduate School of Medicine (Takeshi KIMURA), Kyoto Medical Center (Masaharu AKAO), Yamamashi Kousei Hospital (Tetsuya ASAKAWA), Tachikawa General Hospital (Masaaki OKABE), Uwajima City Hospital (Akiyoshi OGIMOTO), Toho University Faculty of Medicine (Takanori IKEDA), Nara Medical University Hospital (Taku NISHIDA), Kameda Medical Center (Akira MIZUKAMI), Tabuchi Cardiovascular Internal Medicine Clinic (Toshifumi TABUCHI), The Cardiovascular Institute (Takeshi YAMASHITA), Honjo Daiichi Hospital (Yasushi SUZUKI), Kitasato University (Junya AKO), Keio University Hospital (Seiji TAKATSUKI), Kitaishikai Hospital (Takumi SUMIMOTO), Tokyo Women`s Medical University (Nobuhiwa HAGIWARA), Osaka General Medical Center (Takahisa YAMADA), Chikamori Hospital, Chikamori Health Care Group (Masahiko FUKATANI), Kanto Central Hospital (Nobuhiko ITO), Fukuda Memorial Hospital (Kohsuke NAKAJIMA), Japanese Red Cross Society Yamaguchi Hospital (Hiroyuki MICHISHIGE), National Hospital Organization Osaka National Hospital (Yukihiro KORETSUNE), Nakamura Memorial Hospital (Kenji KAMIYAMA), Ogori Daiichi General Hospital (Naoki SUGI), Yamato Municipal Hospital (Takaaki KUBO), Sendai City Hospital (Tetsuo YAGI), Hekinan Municipal Hospital (Atsushi SUGIURA), National Hospital Organization Tokyo Medical Center (Yukihiko MOMIYAMA), Oita Red Cross Hospital (Tetsu IWAO), Yao Municipal Hospital (Tetsuya WATANABE), Yuri Kumiai General Hospital (Tohru NAKANISHI), Fukushima Medical University Hospital (Yasuchika TAKEISHI), Okamisawa Clinic (Kunihiko KAMEDA), Dokkyo Medical University (Teruo INOUE), Saiseikai Kawaguchi General Hospital (Toshikazu FUNAZAKI), Nara Prefectural Seiwa Medical Center (Naofumi DOI), Osaka Police Hospital (Yoshiharu HIGUCHI), Tokyo Metropolitan Geriatric Hospital (Yusuke Tsuboko), Kitakami Saiseikai Hospital (Yoshihiro SATO), Machii Cardiovascular Internal Medicine Clinic (Kazuo MACHII), Tokyo Metropolitan Health and Medical Treatment Corporation Ebara Hospital (Yasunaga HIYOSHI), Ube-kohsan Central Hospital (Masahiko HARADA), Kitano Hospital, Tazuke Kofukai Medical Research Institute (Moriaki INOKO), Hirakata Kohsai Hospital (Hiroyuki TAKENAKA), Kobe City Medical Center General Hospital (Yutaka FURUKAWA), Kokura Memorial Hospital (Kenji ANDO), Tenri Hospital (Yoshihisa NAKAGAWA), Hyogo Prefectural Amagasaki General Medical Center (Kazuyasu YOSHITANI), Shimabara Hospital (Mamoru TAKAHASHI), Mitsubishi Kyoto Hospital (Shinji MIKI), Koto Memorial Hospital (Tomoyuki MURAKAMI), Sakurabashi Watanabe Hospital (Koichi INOUE), Japan Community Health Care Organization Hoshigaoka Medical Center (Yuzuru TAKANO), Nippon Medical School (Wataru SHIMIZU), Daido Hospital (Tomoharu ARAKAWA), Tokushima University Graduate School (Masataka SATA), Mashiko Hospital (Shogo SHIMIZU), Hirosaki Stroke and Rehabilitation Center (Joji HAGII), Kashiwaba Neurosurgical Hospital (Tetsuyuki YOSHIMOTO), Sendai Cardiovascular Center (Shinya Fujii), Faculty of Medicine, Oita University (Naohiko TAKAHASHI), Tsuji Clinic (Hikari TSUJI), Yamato Kashihara Hospital (Tamio NAKAJIMA), Omori Internal Medicine and Cardiology Clinic (Masayuki WATANABE), Fujita Health University School of Medicine (Eiichi WATANABE), Oita Medical Center (Masaya ARIKAWA), Ota Clinic (Akira OTA), Ozaki Cardiology Clinic (Masaharu OZAKI), NHO Kumamoto Saishusou Hospital (Ikuo MISUMI), Kansai Rosai Hospital (Masaaki UEMATSU), Hatayama Clinic (Toru HATAYAMA), SATO Internal Medicine Pediatrics clinic (Atsushi SATO), Narita Medical Clinic (Hidetoshi NARITA), Toyamori Internal Medicine pediatrics clinic (Hiroshi TOYAMORI), St.Mary's Heart Clinic (Kazuhiro YOSHIDA), Furukawa Medical Clinic (Kayoko FURUKAWA), Iwate Medical University (Takashi KOMATSU), Yamaguchi University Graduate School of Medicine (Akihiko SHIMIZU), Shizuoka City Shizuoka Hospital (Tomoya ONODERA), Igarashi Clinic, Cardiology and Internal Medicine (Morio IGARASHI), Fujino Circulation Clinic (Takao FUJINO), Japan Community Health Care Organization Osaka Hospital (Shinji HASEGAWA), Suzuki Internal Medicine Clinic (Tomomi SUZUKI), Odawara municipal hospital (Masaru YUGE), Inoue Cardiology and Internal Medicine Clinic (Takeshi INOUE), Okidate Heart Clinic (Takeshi KUDO), Saien Heart Medical Clinic (Toshihiko KOEDA), Japanese Red Cross Society Fukushima Hospital (Takayuki OHWADA), Sumi Cardiovascular Clinic (Hirokuni SUMI), Takei Clinic (Jinko YAMABE), Iwate Prefectural Kamaishi Hospital (Mahito OZAWA), Medical Corporation Association Koukeikai Sugiura Clinic (Toshiyuki SUGIURA), Hirosaki University Graduate School of Medicine (Ken OKUMURA and Hirofumi TOMITA), Kondo Internal Medicine Clinic (Kazuhiko KONDO), Chiba Surgical Hospital (Yasuhide MORIKAWA), Tokyo Women's Medical University, Yachiyo Medical Center (Shoji HARUTA), ISHIDA Medical Clinic (Shuji ISHIDA), Kindai University Nara Hospital (Manabu SHIROTANI), Nara Prefecture General Medical Center (Fumitaka INOUE), Kumamoto City Hospital (Koji SATO), National Hospital Organization Kumamoto Medical Center (Kazuteru FUJIMOTO), Tohoku Medical and Pharmaceutical University Hospital (Yoshiaki KATAHIRA), Awa Regional Medical Center (Akira MIZUKAMI), Horii Clinic (Norihiko MATSUMURA), JCHO Kumamoto General Hospital (Shinji TAYAMA), Japanese Red Cross Kumamoto Hospital (Ryusuke TSUNODA), Shiga General Hospital Cardiology division (Shigeru IKEGUCHI).


This study was conducted by the Cardiovascular Institute Academic Research Organization (CVI ARO), Tokyo, Japan, subsidized and funded by pharmaceutical and medical device companies. Bristol-Myers Squibb K.K. provided monetary support for this study. This study was partially supported by the Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus from Japan Agency for Medical Research and Development, AMED (JP19ek0210082h0003). The present study was funded by Bristol Myers Squibb, which had no role in the design, performing and reporting of the study.

Author information




Corresponding author

Correspondence to Masaharu Akao.

Ethics declarations

Conflict of interest

MA received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare and Daiichi-Sankyo. 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. SS received research funding from Daiichi-Sankyo and Mitsubishi-Tanabe. 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.

J-ELD AF investigators members are listed in the Acknowledgement section.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Akao, M., Yamashita, T., Suzuki, S. et al. Clinical outcomes according to dose reduction criteria of apixaban in Japanese elderly patients with atrial fibrillation: J-ELD AF Registry subanalysis. Heart Vessels (2021).

Download citation


  • Anticoagulant
  • Apixaban
  • Atrial fibrillation
  • Elderly
  • Dose reduction