Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

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.

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
Fig. 3

Similar content being viewed by others

References

  1. Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, Carnes CA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A, Van Wagoner DR (2001) C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 104:2886–2891

    Article  CAS  PubMed  Google Scholar 

  2. Thambidorai SK, Parakh K, Martin DO, Shah TK, Wazni O, Jasper SE, Van Wagoner DR, Chung MK, Murray RD, Klein AL (2004) Relation of C-reactive protein correlates with risk of thromboembolism in patients with atrial fibrillation. Am J Cardiol 94:805–807

    Article  CAS  PubMed  Google Scholar 

  3. Borensztajn K, Peppelenbosch MP, Spek CA (2008) Factor Xa: at the crossroads between coagulation and signaling in physiology and disease. Trends Mol Med 14:429–440

    Article  CAS  PubMed  Google Scholar 

  4. Spronk HM, de Jong AM, Crijns HJ, Schotten U, Van Gelder IC, Ten Cate H (2014) Pleiotropic effects of factor Xa and thrombin: what to expect from novel anticoagulants. Cardiovasc Res 101:344–351

    Article  CAS  PubMed  Google Scholar 

  5. Zhou Q, Bea F, Preusch M, Wang H, Isermann B, Shahzad K, Katus HA, Blessing E (2011) Evaluation of plaque stability of advanced atherosclerotic lesions in apo E-deficient mice after treatment with the oral factor Xa inhibitor rivaroxaban. Mediators Inflamm 2011:432080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hara T, Fukuda D, Tanaka K, Higashikuni Y, Hirata Y, Nishimoto S, Yagi S, Yamada H, Soeki T, Wakatsuki T, Shimabukuro M, Sata M (2015) Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. Atherosclerosis 242:639–646

    Article  CAS  PubMed  Google Scholar 

  7. Bae JS, Rezaie AR (2008) Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand. Thromb Haemost 100:101–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:883–891

    Article  CAS  Google Scholar 

  9. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151

    Article  CAS  Google Scholar 

  10. Mak KH (2012) Coronary and mortality risk of novel oral antithrombotic agents: a meta-analysis of large randomised trials. BMJ Open 2:e001592

    Article  PubMed  PubMed Central  Google Scholar 

  11. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM (2012) Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 366:9–19

    Article  CAS  PubMed  Google Scholar 

  12. Sharma A, Garg A, Borer JS, Krishnamoorthy P, Garg J, Lavie CJ, Arbab-Zadeh A, Mukherjee D, Ahmad H, Lichstein E (2014) Role of oral factor Xa inhibitors after acute coronary syndrome. Cardiology 129:224–232

    Article  CAS  PubMed  Google Scholar 

  13. Schulman S, Kearon C (2005) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 3:692–694

    Article  CAS  Google Scholar 

  14. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Katus HA, Lindahl B, Morrow DA, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasche P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S (2012) Third universal definition of myocardial infarction. Circulation 126:2020–2035

    Article  Google Scholar 

  15. Borissoff JI, Spronk HM, ten Cate H (2011) The hemostatic system as a modulator of atherosclerosis. N Engl J Med 364:1746–1760

    Article  CAS  PubMed  Google Scholar 

  16. Esmon CT (2014) Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost 111:625–633

    Article  CAS  PubMed  Google Scholar 

  17. Bukowska A, Zacharias I, Weinert S, Skopp K, Hartmann C, Huth C, Goette A (2013) Coagulation factor Xa induces an inflammatory signalling by activation of protease-activated receptors in human atrial tissue. Eur J Pharmacol 718:114–123

    Article  CAS  PubMed  Google Scholar 

  18. Christersson C, Oldgren J, Wallentin L, Siegbahn A (2011) Treatment with an oral direct thrombin inhibitor decreases platelet activity but increases markers of inflammation in patients with myocardial infarction. J Intern Med 270:215–223

    Article  CAS  PubMed  Google Scholar 

  19. Herbert J, Bono F, Herault J, Avril C, Dol F, Mares A, Schaeffer P (1998) Effector protease receptor 1 mediates the mitogenic activity of factor Xa for vascular smooth muscle cells in vitro and in vivo. J Clin Invest 101:993–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cirino G, Cicala C, Bucci M, Sorrentino L, Ambrosini G, DeDominicis G, Altieri DC (1997) Factor Xa as an interface between coagulation and inflammation. Molecular mimicry of factor Xa association with effector cell protease receptor-1 induces acute inflammation in vivo. J Clin Invest 99:2446–2451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ishibashi Y, Matsui T, Fukami K, Ueda S, Okuda S, Yamagishi S (2015) Rivaroxaban inhibits oxidative and inflammatory reactions in advanced glycation end product-exposed tubular cells by blocking thrombin/protease-activated receptor-2 system. Thromb Res 135:770–773

    Article  CAS  PubMed  Google Scholar 

  22. Lee IO, Kratz MT, Schirmer SH, Baumhakel M, Bohm M (2012) The effects of direct thrombin inhibition with dabigatran on plaque formation and endothelial function in apolipoprotein E-deficient mice. J Pharmacol Exp Ther 343:253–257

    Article  CAS  PubMed  Google Scholar 

  23. Borissoff JI, Otten JJ, Heeneman S, Leenders P, van Oerle R, Soehnlein O, Loubele ST, Hamulyak K, Hackeng TM, Daemen MJ, Degen JL, Weiler H, Esmon CT, van Ryn J, Biessen EA, Spronk HM, ten Cate H (2013) Genetic and pharmacological modifications of thrombin formation in apolipoprotein e-deficient mice determine atherosclerosis severity and atherothrombosis onset in a neutrophil-dependent manner. PLoS One 8:e55784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chan YH, Kuo CT, Yeh YH, Chang SH, Wu LS, Lee HF, Tu HT, See LC (2016) Thromboembolic, bleeding, and mortality risks of rivaroxaban and dabigatran in asians with nonvalvular atrial fibrillation. J Am Coll Cardiol 68:1389–1401

    Article  CAS  PubMed  Google Scholar 

  25. Espinola-Klein C, Rupprecht HJ, Bickel C, Lackner K, Genth-Zotz S, Post F, Munzel T, Blankenberg S (2008) Impact of inflammatory markers on cardiovascular mortality in patients with metabolic syndrome. Eur J Cardiovasc Prev Rehabil 15:278–284

    Article  PubMed  Google Scholar 

  26. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101:1767–1772

    Article  CAS  Google Scholar 

  27. Zemer-Wassercug N, Haim M, Leshem-Lev D, Orvin KL, Vaduganathan M, Gutstein A, Kadmon E, Mager A, Kornowski R, Lev EI (2015) The effect of dabigatran and rivaroxaban on platelet reactivity and inflammatory markers. J Thromb Thrombolysis 40:340–346

    Article  CAS  PubMed  Google Scholar 

  28. Gibson CM, Pinto DS, Chi G, Arbetter D, Yee M, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, Burton P, van Eickels M, Korjian S, Daaboul Y, Jain P, Lip GY, Cohen M, Peterson ED, Fox KA (2017) Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stenting treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin k antagonist treatment strategy. Circulation 135:323–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chan MY, Lin M, Lucas J, Moseley A, Thompson JW, Cyr D, Ueda H, Kajikawa M, Ortel TL, Becker RC (2012) Plasma proteomics of patients with non-valvular atrial fibrillation on chronic anti-coagulation with warfarin or a direct factor Xa inhibitor. Thromb Haemost 108:1180–1191

    Article  PubMed  Google Scholar 

  30. Jansson JH, Boman K, Brannstrom M, Nilsson TK (1996) Increased levels of plasma thrombomodulin are associated with vascular and all-cause mortality in patients on long-term anticoagulant treatment. Eur Heart J 17:1503–1505

    Article  CAS  PubMed  Google Scholar 

  31. Lind M, Boman K, Johansson L, Nilsson TK, Ohlin AK, Birgander LS, Jansson JH (2009) Thrombomodulin as a marker for bleeding complications during warfarin treatment. Arch Intern Med 169:1210–1215

    Article  CAS  PubMed  Google Scholar 

  32. Salomaa V, Matei C, Aleksic N, Sansores-Garcia L, Folsom AR, Juneja H, Chambless LE, Wu KK (1999) Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atheroscierosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case-cohort study. Lancet 353:1729–1734

    Article  CAS  PubMed  Google Scholar 

  33. Ishii H, Uchiyama H, Kazama M (1991) Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb Haemost 65:618–623

    Article  CAS  PubMed  Google Scholar 

  34. Seigneur M, Dufourcq P, Conri C, Constans J, Mercie P, Pruvost A, Amiral J, Midy D, Baste JC, Boisseau MR (1993) Levels of plasma thrombomodulin are increased in atheromatous arterial disease. Thromb Res 71:423–431

    Article  CAS  PubMed  Google Scholar 

  35. Hijazi Z, Oldgren J, Andersson U, Connolly SJ, Eikelboom JW, Ezekowitz MD, Reilly PA, Yusuf S, Siegbahn A, Wallentin L (2017) Growth-differentiation factor 15 and risk of major bleeding in atrial fibrillation: insights from the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Am Heart J 190:94–103

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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

Funding

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

Author information

Authors and Affiliations

  1. Division of Cardiology, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan

    Shinnosuke Kikuchi, Kengo Tsukahara & Kazuo Kimura

  2. Department of Biostatistics, Yokohama City University Hospital, Yokohama, Japan

    Kentaro Sakamaki

  3. Division of Cardiology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Japan

    Shinnosuke Kikuchi & Yukiko Morita

  4. Division of Cardiology, Nagatsuda Kousei General Hospital, Yokohama, Japan

    Takeshi Takamura

  5. Division of Cardiology, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan

    Kazuki Fukui

  6. Division of Cardiology, Saiseikai Yokohama City Southern Hospital, Yokohama, Japan

    Tsutomu Endo

  7. Division of Cardiology, International Goodwill Hospital, Yokohama, Japan

    Makoto Shimizu

  8. Division of Cardiology, Hadano Red Cross Hospital, Hadano, Japan

    Reimin Sawada

  9. Division of Cardiology, Yokohama City University Hospital, Yokohama, Japan

    Teruyasu Sugano & Toshiyuki Ishikawa

  10. Division of Cardiology, Fujisawa City Hospital, Fujisawa, Japan

    Hideo Himeno

  11. Division of Cardiology, Yokohama Hodogaya Central Hospital, Yokohama, Japan

    Syunichi Kobayashi

  12. Division of Cardiology, Fujisawa Shounandai Hospital, Fujisawa, Japan

    Kentaro Arakawa

  13. Division of Cardiology, Omori Red Cross Hospital, Tokyo, Japan

    Yasuyuki Mochida

  14. Division of Cardiology, Ashigarakami Hospital, Ashigara, Japan

    Takashi Tsunematsu

  15. Division of Cardiology, International University of Health and Welfare Atami Hospital, Atami, Japan

    Tomohiko Shigemasa

  16. Division of Cardiology, Yokosuka City Hospital, Yokosuka, Japan

    Jun Okuda

  17. Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Kouichi Tamura

Authors
  1. Shinnosuke Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kengo Tsukahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kentaro Sakamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yukiko Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takeshi Takamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuki Fukui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tsutomu Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Makoto Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Reimin Sawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Teruyasu Sugano
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hideo Himeno
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Syunichi Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kentaro Arakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yasuyuki Mochida
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Takashi Tsunematsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Tomohiko Shigemasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jun Okuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Toshiyuki Ishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Kazuo Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Kouichi Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kengo Tsukahara.

Ethics declarations

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. .

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 (DOCX 14 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kikuchi, S., Tsukahara, K., Sakamaki, K. et al. Comparison of anti-inflammatory effects of rivaroxaban vs. dabigatran in patients with non-valvular atrial fibrillation (RIVAL-AF study): multicenter randomized study. Heart Vessels 34, 1002–1013 (2019). https://doi.org/10.1007/s00380-018-01324-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-018-01324-7

Keywords

Search

Navigation