Heart and Vessels

, Volume 34, Issue 10, pp 1684–1691 | Cite as

Clinical safety and efficacy of tolvaptan for acute phase therapy in patients with low-flow and normal-flow severe aortic stenosis

  • Miho Mitsui
  • Akihisa KataokaEmail author
  • Yugo Nara
  • Fukuko Nagura
  • Hideyuki Kawashima
  • Hirofumi Hioki
  • Makoto Nakashima
  • Yusuke Watanabe
  • Naoyuki Yokoyama
  • Ken Kozuma
Original Article


Conventional diuretic therapy for low-flow (LF) severe aortic stenosis (SAS) often has an inadequate effect or causes hemodynamic instability. Tolvaptan is used for acute heart failure in addition to conventional diuretics, and it does not cause intravascular dehydration. This study aimed to retrospectively investigate the safety and efficacy of tolvaptan in the acute phase in 56 consecutive patients with SAS and compared LF-SAS with normal-flow (NF) SAS. The primary endpoints were adverse clinical events (death, worsening heart failure, worsening renal failure, fatal arrhythmia, cardiogenic or hypovolemic shock, and use of inotropic agents) and the volume of urine within 48 h of tolvaptan administration. Among 56 patients, 16 had LF-SAS (29%), and 40 had NF-SAS (71%). Severe adverse clinical events were not observed 48 h after tolvaptan administration. In both groups, the urine volume significantly increased after tolvaptan administration in comparison to 24 h before tolvaptan administration (both, p < 0.01). There were no changes in the urine volume during the initial 24 and 48 h. In the LF-SAS group, tolvaptan resulted in a significant decrease in fluid balance during the initial 24 and 48 h compared to 24 h before tolvaptan administration (p < 0.05). Adding tolvaptan to conventional treatment is safe and effective without renal dysfunction and hypotension in patients with SAS, including those with LF.


Tolvaptan Severe aortic stenosis Low-flow severe aortic stenosis Normal-flow severe aortic stenosis 



The authors thank Mr. Miyoshi Sakai, MPH for providing statistical assistance.



Compliance with ethical standards

Conflict of interest

The author(s) declare that they have no competing interests.

Ethical approval

The ethics committee of our institution approved the study protocol (number TEIRIN 17-111). The study protocols were developed in accordance with the ethical guidelines of the Declaration of Helsinki. This observational trial was registered with the University Hospital Medical Information Network (number UMIN R000036168).

Informed consent

The need for informed consent was waived because of the retrospective study design.


  1. 1.
    Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M (2006) Burden of valvular heart diseases: a population-based study. Lancet 368:1005–1011CrossRefGoogle Scholar
  2. 2.
    Takasu K, Miyazaki T, Negoro K, Yatsu S, Shimizu M, Murata A, Kato T, Suda S, Hiki M, Kasai T, Miyauchi K, Daida H (2017) Successful treatment of congestive heart failure due to severe aortic valve stenosis with low dose tolvaptan in elderly patients. Int Heart J 58:378–384CrossRefGoogle Scholar
  3. 3.
    Herrmann HC, Pibarot P, Hueter I, Gertz ZM, Stewart WJ, Kapadia S, Tuzcu EM, Babaliaros V, Thourani V, Szeto WY, Bavaria JE, Kodali S, Hahn RT, Williams M, Miller DC, Douglas PS, Leon MB (2013) Predictors of mortality and outcomes of therapy in low-flow severe aortic stenosis: a Placement of Aortic Transcatheter Valves (PARTNER) trial analysis. Circulation 127:2316–2326CrossRefGoogle Scholar
  4. 4.
    Kataoka A, Watanabe Y, Kozuma K, Nara Y, Nagura F, Kawashima H, Hioki H, Nakashima M, Yamamoto M, Takagi K, Araki M, Tada N, Shirai S, Yamanaka F, Hayashida K (2018) Prognostic impact of low-flow severe aortic stenosis in small-body patients undergoing TAVR: the OCEAN-TAVI Registry. JACC Cardiovasc Imaging 11:659–669CrossRefGoogle Scholar
  5. 5.
    Le Ven F, Freeman M, Webb J, Clavel MA, Wheeler M, Dumont É, Thompson C, De Larochellière R, Moss R, Doyle D, Ribeiro HB, Urena M, Nombela-Franco L, Rodés-Cabau J, Pibarot P (2013) Impact of low flow on the outcome of high-risk patients undergoing transcatheter aortic valve replacement. J Am Coll Cardiol 62:782–788CrossRefGoogle Scholar
  6. 6.
    Gheorghiade M, Konstam MA, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C (2007) Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST clinical status trials. JAMA 297:1332–1343CrossRefGoogle Scholar
  7. 7.
    Matsuzaki M, Hori M, Izumi T, Fukunami M (2011) Efficacy and safety of tolvaptan in heart failure patients with volume overload despite the standard treatment with conventional diuretics: a phase III, randomized, double-blind, placebo-controlled study (QUEST study). Cardiovasc Drugs Ther 25:S33–45CrossRefGoogle Scholar
  8. 8.
    Goldsmith SR, Bart BA, Burnett J (2014) Decongestive therapy and renal function in acute heart failure: time for a new approach? Circ Heart Fail 7:531–535CrossRefGoogle Scholar
  9. 9.
    Nomoto H, Satoh Y, Kamiyama M, Yabe K, Masumura M, Sakakibara A, Yamashita S, Suzuki M, Sugiyama T, Oumi T, Ohno M, Takahashi Y, Isobe M (2017) Mechanisms of diuresis for acute decompensated heart failure by tolvaptan. Int Heart 58:593–600CrossRefGoogle Scholar
  10. 10.
    Inomata T, Ikeda Y, Kida K, Shibagaki Y, Sato N, Kumagai Y, Shinagawa H, Ako J, Izumi T (2017) Effects of additive tolvaptan vs. increased furosemide on heart failure with diuretic resistance and renal impairment -results from the K-STAR study. Circ J 82:159–167CrossRefGoogle Scholar
  11. 11.
    Masuda T, Murakami T, Igarashi Y, Okabe K, Kobayashi T, Takeda SI, Saito T, Sekiguchi C, Miyazawa Y, Akimoto T, Saito O, Muto S, Nagata D (2016) Dual impact of tolvaptan on intracellular and extracellular water in chronic kidney disease patients with fluid retention. Intern Med 55:2759–2764CrossRefGoogle Scholar
  12. 12.
    Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O'Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM 3rd, Thomas JD (2014) 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 63:e57–185CrossRefGoogle Scholar
  13. 13.
    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL (2013) 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 128:1810–1852CrossRefGoogle Scholar
  14. 14.
    Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 28:1–39CrossRefGoogle Scholar
  15. 15.
    Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, Iung B, Otto CM, Pellikka PA, Quiñones M (2009) Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr 22:1–23 (quiz 101–102) CrossRefGoogle Scholar
  16. 16.
    Hachicha Z, Dumesnil JG, Pibarot P (2009) Usefulness of the valvuloarterial impedance to predict adverse outcome in asymptomatic aortic stenosis. J Am Coll Cardiol 54:1003–1011CrossRefGoogle Scholar
  17. 17.
    Cramariuc D, Cioffi G, Rieck AE, Devereux RB, Staal EM, Ray S, Wachtell K, Gerdts E (2009) Low-flow aortic stenosis in asymptomatic patients. JACC Cardiovasc Imaging 2:390–399CrossRefGoogle Scholar
  18. 18.
    Herrmann S, Störk S, Niemann M, Lange V, Strotmann JM, Frantz S, Beer M, Gattenlöhner S, Voelker W, Ertl G, Weidemann F (2011) Low-gradient aortic valve stenosis myocardial fibrosis and its influence on function and outcome. J Am Coll Cardiol 58:402–412CrossRefGoogle Scholar
  19. 19.
    Ambrosy A, Goldsmith SR, Gheorghiade M (2011) Tolvaptan for the treatment of heart failure: a review of the literature. Expert Opin Pharmacother 12:961–976CrossRefGoogle Scholar
  20. 20.
    Dohi K, Ito M (2014) Novel diuretic strategies for the treatment of heart failure in Japan. Circ J 78:1816–1823CrossRefGoogle Scholar
  21. 21.
    Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, Simmons CA, Masters KS, Mathieu P, O'Brien KD, Schoen FJ, Towler DA, Yoganathan AP, Otto CM (2011) Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease-2011 update. Circulation 124:1783–1791CrossRefGoogle Scholar
  22. 22.
    Kinugawa K, Inomata T, Sato N, Yasuda M, Shimakawa T, Bando K, Mizuguchi K (2015) Effectiveness and adverse events of tolvaptan in octogenarians with heart failure. Interim analyses of Samsca Post-Marketing Surveillance In Heart faiLurE (SMILE study). Int Heart J 56:137–143CrossRefGoogle Scholar
  23. 23.
    Belziti CA, Bagnati R, Ledesma P, Vulcano N, Fernández S (2010) Worsening renal function in patients admitted with acute decompensated heart failure: incidence, risk factors and prognostic implications. Rev Esp Cardiol 63:294–302CrossRefGoogle Scholar
  24. 24.
    Shirakabe A, Hata N, Yamamoto M, Kobayashi N, Shinada T, Tomita K, Tsurumi M, Matsushita M, Okazaki H, Yamamoto Y, Yokoyama S, Asai K, Shimizu W (2014) Immediate administration of tolvaptan prevents the exacerbation of acute kidney injury and improves the mid-term prognosis of patients with severely decompensated acute heart failure. Circ J 78:911–921CrossRefGoogle Scholar
  25. 25.
    Matsue Y, Suzuki M, Torii S, Yamaguchi S, Fukamizu S, Ono Y, Fujii H, Kitai T, Nishioka T, Sugi K, Onishi Y, Noda M, Kagiyama N, Satoh Y, Yoshida K, Goldsmith SR (2016) Clinical effectiveness of tolvaptan in patients with acute heart failure and renal dysfunction. J Card Fail 22:423–432CrossRefGoogle Scholar
  26. 26.
    Testani JM, Cappola TP, Brensinger CM, Shannon RP, Kimmel SE (2011) Interaction between loop diuretic-associated mortality and blood urea nitrogen concentration in chronic heart failure. J Am Coll Cardiol 58:375–382CrossRefGoogle Scholar
  27. 27.
    Kajimoto K, Sato N, Takano T (2016) eGFR and outcomes in patients with acute decompensated heart failure with or without elevated BUN. Clin J Am Soc Nephrol 11:405–412CrossRefGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  • Miho Mitsui
    • 1
  • Akihisa Kataoka
    • 1
    Email author
  • Yugo Nara
    • 1
  • Fukuko Nagura
    • 1
  • Hideyuki Kawashima
    • 1
  • Hirofumi Hioki
    • 1
  • Makoto Nakashima
    • 1
  • Yusuke Watanabe
    • 1
  • Naoyuki Yokoyama
    • 1
  • Ken Kozuma
    • 1
  1. 1.Division of Cardiology, Department of Internal MedicineTeikyo UniversityTokyoJapan

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