Comparison of anti-inflammatory effects of rivaroxaban vs. dabigatran in patients with non-valvular atrial fibrillation (RIVAL-AF study): multicenter randomized study

  • Shinnosuke Kikuchi
  • Kengo TsukaharaEmail author
  • Kentaro Sakamaki
  • Yukiko Morita
  • Takeshi Takamura
  • Kazuki Fukui
  • Tsutomu Endo
  • Makoto Shimizu
  • Reimin Sawada
  • Teruyasu Sugano
  • Hideo Himeno
  • Syunichi Kobayashi
  • Kentaro Arakawa
  • Yasuyuki Mochida
  • Takashi Tsunematsu
  • Tomohiko Shigemasa
  • Jun Okuda
  • Toshiyuki Ishikawa
  • Kazuo Kimura
  • Kouichi Tamura
Original Article


Some experimental studies have shown that direct oral anticoagulants (DOACs) have anti-inflammatory effects. However, the interval changes in inflammatory markers in patients with non-valvular atrial fibrillation (AF) who receive DOACs remain unknown. Between July 2013 and April 2014, a total of 187 AF patients randomly assigned to receive rivaroxaban (n = 91) or dabigatran (n = 96) were assessed for eligibility. The levels of the following inflammatory markers were serially evaluated: high-sensitivity C-reactive protein, pentraxin-3, interleukin (IL)-1β, IL-6, IL-18, tumor necrosis factor-α, monocyte chemotactic protein-1, growth and differentiation factor-15, and soluble thrombomodulin (sTM). The aim in this study was to evaluate the anti-inflammatory effects of rivaroxaban and dabigatran in patients with AF, in addition to the impact of markers on bleeding events. Finally, 117 patients (rivaroxaban: n = 55, dabigatran: n = 62) were included in the analysis at 12 months. Although the interval changes in sTM levels tended to be greater in the dabigatran group [0.3 (0–0.7) vs. 0.5 (0–1.0) FU/ml, p = 0.061], there were no significant differences in the interval changes in any inflammatory marker between 2 groups. There were no significant differences in bleeding events between 2 groups. The interval changes in sTM levels were significantly greater in patients with bleeding compared with those without [0.8 (0.5–1.3) vs. 0.4 (− 0.1–0.8) FU/ml, p = 0.017]. There were no significant differences in the interval changes in any inflammatory marker between rivaroxaban and dabigatran treatments in patients with AF. The increased levels of sTM after DOACs treatment might be related to bleeding events.


Inflammation Direct oral anticoagulation Atrial fibrillation Bleeding Thrombomodulin 



The authors would like to express their gratitude to the physicians and paramedics participating in the RIVAL-AF study.


This study was financially supported by Bayer Yakuhin, Ltd., Osaka, Japan.

Compliance with ethical standards

Conflicts of interest

Dr. Tsukahara has received research grants from AstraZeneca K.K. and Daiichi-Sankyo Company, Limited and speakers’ Bureau/Honorarium from Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Inc., Eisai Co Ltd., and Daiichi-Sankyo Company, Limited. Dr. Kimura has received research grants from Sanofi K.K., Bayer Yakuhin Ltd., Kowa Pharmaceutical Co. LTD., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company, Eisai Co., Ltd. and Mitsubishi Tanabe Pharma Corporation, and honoraria from Daiichi-Sankyo Company, Bayer Yakuhin Ltd., AstraZeneca K.K., MSD K.K. Dr. Tamura has received research grants from AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Tsumura, Daiichi-Sankyo Company, Novartis, Astellas Pharma, Inc., MSD K.K., Pfizer Japan Inc. Research Institute for Production Development, Takeda Pharmaceutical Company, Kyowa Hakko Kirin Co. LTD., Chugai Pharmaceutical Co. LTD., Mochida Pharmaceutical Co. LTD. and Mitsubishi Tanabe Pharma Corporation., and honoraria from Mochida Pharmaceutical Co. LTD., Pfizer Japan Inc. Research Institute for Production Development, Sumitomo Dainippon Pharma and Kyowa Hakko Kirin Co. LTD. .

Supplementary material

380_2018_1324_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 14 kb)


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Copyright information

© Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  • Shinnosuke Kikuchi
    • 1
    • 3
  • Kengo Tsukahara
    • 1
    Email author return OK on get
  • Kentaro Sakamaki
    • 2
  • Yukiko Morita
    • 3
  • Takeshi Takamura
    • 4
  • Kazuki Fukui
    • 5
  • Tsutomu Endo
    • 6
  • Makoto Shimizu
    • 7
  • Reimin Sawada
    • 8
  • Teruyasu Sugano
    • 9
  • Hideo Himeno
    • 10
  • Syunichi Kobayashi
    • 11
  • Kentaro Arakawa
    • 12
  • Yasuyuki Mochida
    • 13
  • Takashi Tsunematsu
    • 14
  • Tomohiko Shigemasa
    • 15
  • Jun Okuda
    • 16
  • Toshiyuki Ishikawa
    • 9
  • Kazuo Kimura
    • 1
  • Kouichi Tamura
    • 17
  1. 1.Division of CardiologyYokohama City University Medical CenterYokohamaJapan
  2. 2.Department of BiostatisticsYokohama City University HospitalYokohamaJapan
  3. 3.Division of CardiologyNational Hospital Organization Sagamihara National HospitalSagamiharaJapan
  4. 4.Division of CardiologyNagatsuda Kousei General HospitalYokohamaJapan
  5. 5.Division of CardiologyKanagawa Cardiovascular and Respiratory CenterYokohamaJapan
  6. 6.Division of CardiologySaiseikai Yokohama City Southern HospitalYokohamaJapan
  7. 7.Division of CardiologyInternational Goodwill HospitalYokohamaJapan
  8. 8.Division of CardiologyHadano Red Cross HospitalHadanoJapan
  9. 9.Division of CardiologyYokohama City University HospitalYokohamaJapan
  10. 10.Division of CardiologyFujisawa City HospitalFujisawaJapan
  11. 11.Division of CardiologyYokohama Hodogaya Central HospitalYokohamaJapan
  12. 12.Division of CardiologyFujisawa Shounandai HospitalFujisawaJapan
  13. 13.Division of CardiologyOmori Red Cross HospitalTokyoJapan
  14. 14.Division of CardiologyAshigarakami HospitalAshigaraJapan
  15. 15.Division of CardiologyInternational University of Health and Welfare Atami HospitalAtamiJapan
  16. 16.Division of CardiologyYokosuka City HospitalYokosukaJapan
  17. 17.Department of Medical Science and Cardiorenal MedicineYokohama City University Graduate School of MedicineYokohamaJapan

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