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Clinical Effectiveness of Tolvaptan in Patients with Acute Decompensated Heart Failure and Renal Failure: Design and Rationale of the AQUAMARINE Study

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Abstract

Purpose

Over half of all admitted acute decompensated heart failure (ADHF) patients have renal failure. Although diuretics represent the mainstay of treatment strategy even in this population, there are unmet needs for safer and more effective treatment. Tolvaptan is a vasopressin-2 receptor antagonist, and we hypothesized that adding tolvaptan to standard diuretic therapy would be more effective in ADHF patients with renal function impairment.

Methods

The Answering question on tolvaptan’s efficacy for patients with acute decompensated heart failure and renal failure (AQUAMARINE) is a multicenter, randomized controlled clinical trial, which will enroll 220 patients from 17 hospitals in Japan. ADHF patients whose estimated glomerular filtration rate is above 15 and below 60 mL/min/1.72 m2 will be randomly assigned within 6 h after admission to usual care with furosemide or tolvaptan add-on therapy. Primary endpoint is achieved urine output within 48 h. Secondary endpoints include dyspnea relief measured by 7-points Likert scale, incidence of worsening renal function, dose of furosemide used within 48 h, and changes of brain natriuretic peptide.

Conclusion

This study is the first multicenter study in Japan to evaluate clinical effectiveness of tolvaptan add-on therapy in ADHF patients with renal failure. The results of this study address the treatment strategy of this high-risk population (UMIN Clinical Trial Registry Number: UMIN000007109).

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References

  1. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69–e171.

    Article  PubMed  Google Scholar 

  2. Sato N, Kajimoto K, Keida T, et al. Clinical features and outcome in hospitalized heart failure in Japan (from the ATTEND Registry). Circ J. 2013;77:944–51.

    Article  CAS  PubMed  Google Scholar 

  3. Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52:1527–39.

    Article  PubMed  Google Scholar 

  4. Sarraf M, Masoumi A, Schrier RW. Cardiorenal syndrome in acute decompensated heart failure. Clin J Am Soc Nephrol. 2009;4:2013–26.

    Article  CAS  PubMed  Google Scholar 

  5. Thomson MR, Nappi JM, Dunn SP, Hollis IB, Rodgers JE, Van Bakel AB. Continuous versus intermittent infusion of furosemide in acute decompensated heart failure. J Card Fail. 2010;16:188–93.

    Article  CAS  PubMed  Google Scholar 

  6. Wang DJ, Gottlieb SS. Diuretics: still the mainstay of treatment. Crit Care Med. 2008;36:S89–94.

    Article  CAS  PubMed  Google Scholar 

  7. Kon V, Yared A, Ichikawa I. Role of renal sympathetic nerves in mediating hypoperfusion of renal cortical microcirculation in experimental congestive heart failure and acute extracellular fluid volume depletion. J Clin Invest. 1985;76:1913–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Miyazaki T, Fujiki H, Yamamura Y, Nakamura S, Mori T. Tolvaptan, an orally active vasopressin V(2)-receptor antagonist—pharmacology and clinical trials. Cardiovasc Drug Rev. 2007;25:1–13.

    Article  CAS  PubMed  Google Scholar 

  9. Costello-Boerrigter LC, Smith WB, Boerrigter G, et al. Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure. Am J Physiol Ren Physiol. 2006;290:F273–8.

    Article  CAS  Google Scholar 

  10. Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.

    Article  CAS  PubMed  Google Scholar 

  11. Matsue Y, Suzuki M, Seya M, et al. Tolvaptan reduces the risk of worsening renal function in patients with acute decompensated heart failure in high-risk population. J Cardiol. 2013;61:169–74.

    Article  PubMed  Google Scholar 

  12. Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J. 2004;147:331–8.

    Article  PubMed  Google Scholar 

  13. Forman DE, Butler J, Wang Y, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol. 2004;43:61–7.

    Article  PubMed  Google Scholar 

  14. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Secular trends in renal dysfunction and outcomes in hospitalized heart failure patients. J Card Fail. 2006;12:257–62.

    Article  PubMed  Google Scholar 

  15. Matsuzaki M, Hori M, Izumi T, Fukunami M. 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. 2011;25 Suppl 1:S33–45.

    Article  PubMed  Google Scholar 

  16. Watanabe K, Dohi K, Sugimoto T, et al. Short-term effects of low-dose tolvaptan on hemodynamic parameters in patients with chronic heart failure. J Cardiol. 2012;60:462–9.

    Article  PubMed  Google Scholar 

  17. Gheorghiade M, Konstam MA, Burnett Jr JC, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. 2007;297:1332–43.

    Article  CAS  PubMed  Google Scholar 

  18. Konstam MA, Gheorghiade M, Burnett Jr JC, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297:1319–31.

    Article  CAS  PubMed  Google Scholar 

  19. Cuffe MS, Califf RM, Adams Jr KF, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002;287:1541–7.

    Article  CAS  PubMed  Google Scholar 

  20. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2007;297:1883–91.

    Article  CAS  PubMed  Google Scholar 

  21. Mebazaa A, Pang PS, Tavares M, et al. The impact of early standard therapy on dyspnoea in patients with acute heart failure: the URGENT-dyspnoea study. Eur Heart J. 2010;31:832–41.

    Article  PubMed  Google Scholar 

  22. Weintraub NL, Collins SP, Pang PS, et al. Acute heart failure syndromes: emergency department presentation, treatment, and disposition: current approaches and future aims: a scientific statement from the American Heart Association. Circulation. 2010;122:1975–96.

    Article  PubMed  Google Scholar 

  23. Matsuzaki M, Hori M, Izumi T, et al. Effects of tolvaptan on volume overload in Japanese patients with heart failure: results of a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Cardiovasc Drugs Ther. 2011;23 suppl 1:S19–31.

    Article  Google Scholar 

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Acknowledgments

AQUAMARINE is supported by a Multicenter Clinical Research Grant from the Japan Heart Foundation. Clinical trial registration ID assigned by the University hospital Medical Information Network (UMIN) as UMIN000007109.

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Authors and Affiliations

  1. Department of Cardiology, Kameda Medical Center, 929 Higashi-chou, Kamogawa-City, Chiba, 296-8602, Japan

    Yuya Matsue & Makoto Suzuki

  2. Department of Cardiology, Awa Regional Medical Center, Chiba, Japan

    Wataru Nagahori

  3. Harvard School of Public Health, Boston, MA, USA

    Kazuki Yoshida

  4. Department of Rhumatology, Kameda Medical Center, Chiba, Japan

    Kazuki Yoshida

  5. Department of Cardiology, Hiratsuka Kyosai Hospital, Kanagawa, Japan

    Yuko Onishi

  6. Department of Cardiology, National Disaster Medical Center, Tokyo, Japan

    Yasuhiro Satoh

  7. Department of Cardiology, Ome Municipal General Hospital, Tokyo, Japan

    Yuichi Ono

  8. Department of Cardiology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

    Toshihiko Nishioka

  9. Department of Cardiology, Social Insurance Central General Hospital, Tokyo, Japan

    Makoto Noda

  10. Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan

    Kaoru Sugi

  11. Department of Cardiology, Tokai University School of Medicine, Kanagawa, Japan

    Sho Torii

  12. Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan

    Tamotsu Tejima

  13. Department of Cardiology, Tokyo Metropolitan Health and Medical Treatment Corporation, Ohkubo Hospital, Tokyo, Japan

    Harumizu Sakurada

  14. Department of Cardiology, Tomishiro Central Hospital, Okinawa, Japan

    Satoshi Yamaguchi

  15. Heart Center, Yokohama-City Minato Red Cross Hospital, Kanagawa, Japan

    Kaoru Okishige

  16. Department of Cardiology, Yokohama Minami Kyosai Hospital, Kanagawa, Japan

    Hiroyuki Fujii

  17. Cardiovascular Center, Yokosuka Kyousai Hospital, Kanagawa, Japan

    Atsushi Takahashi

Authors
  1. Yuya Matsue
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  2. Makoto Suzuki
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  3. Wataru Nagahori
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  4. Kazuki Yoshida
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  5. Yuko Onishi
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  6. Yasuhiro Satoh
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  7. Yuichi Ono
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  8. Toshihiko Nishioka
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  9. Makoto Noda
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  10. Kaoru Sugi
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  11. Sho Torii
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  12. Tamotsu Tejima
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  13. Harumizu Sakurada
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  14. Satoshi Yamaguchi
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  15. Kaoru Okishige
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  16. Hiroyuki Fujii
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  17. Atsushi Takahashi
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Corresponding author

Correspondence to Yuya Matsue.

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Matsue, Y., Suzuki, M., Nagahori, W. et al. Clinical Effectiveness of Tolvaptan in Patients with Acute Decompensated Heart Failure and Renal Failure: Design and Rationale of the AQUAMARINE Study. Cardiovasc Drugs Ther 28, 73–77 (2014). https://doi.org/10.1007/s10557-013-6491-8

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  • DOI: https://doi.org/10.1007/s10557-013-6491-8

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