Journal of Gastroenterology

, Volume 53, Issue 2, pp 258–268 | Cite as

Response criteria of tolvaptan for the treatment of hepatic edema

  • Yasunari HiramineEmail author
  • Haruki Uojima
  • Hiroyuki Nakanishi
  • Akira Hiramatsu
  • Takuya Iwamoto
  • Mutsuumi Kimura
  • Hideto Kawaratani
  • Shuji Terai
  • Hitoshi Yoshiji
  • Hirofumi Uto
  • Isao Sakaida
  • Namiki Izumi
  • Kiwamu Okita
  • Kazuhiko Koike
Original Article—Liver, Pancreas, and Biliary Tract



Although tolvaptan is an effective treatment for hepatic edema, there are no established criteria for assessment of the therapeutic effect. The present study evaluates the association between body weight change and clinical symptoms to identify an effective indicator of tolvaptan response.


The study comprised 460 patients. The first data set contained 147 patients with hepatic edema who received tolvaptan in Kagoshima Kouseiren Hospital, a representative institution of this study. From these data, an optimal cutoff value of body weight change, which accurately indicated symptom reduction, was identified. The response rates obtained based on the cutoff value were evaluated by receiver-operating characteristic (ROC) analysis and kappa coefficients. The kappa coefficient was then validated internally using the bootstrap method and externally using the validation data set of 313 patients from four other hospitals.


A cutoff value for body weight loss of 1.5 kg/week produced the largest area under the ROC curve (0.961; sensitivity, 89.8%; specificity, 92.0%) and a high kappa coefficient (0.831). The correlation between symptom reduction and body weight loss of 1.5 kg/week was evaluated internally and externally, and the cutoff value was validated.


The cutoff value of body weight change that most accurately reflected symptom reduction was 1.5 kg/week; this value is expected to be an effective indicator of response to tolvaptan in clinical practice.


Tolvaptan Hepatic edema Body weight loss Cutoff value Clinical findings 



Receiver-operating characteristic


Aquaporin 2


Area under the ROC curve


Ascites Symptom Inventory-7


Chronic Liver Disease Questionnaire


Author contributions

YH, HU, HN, AH, TI, MK, ST, HY, KO, and KK conceived of the study and participated in its design and coordination. YH, HU, HN, AH, MK, HK, and TI conducted the data analysis. YH interpreted the findings and drafted the original manuscript. HU, HY, ST, KO, and KK edited the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

HN, ST, IS, NI, KO and KK have received honoraria from Otsuka Pharmaceutical Co., Ltd. The other authors declare that they have no conflict of interest.


  1. 1.
    Matsuzaki M, Hori M, Izumi T, Tolvaptan Investigators, et al. 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;25:33–45.CrossRefGoogle Scholar
  2. 2.
    Okita K, Sakaida I, Okada M, et al. A multicenter, open-label, dose-ranging study to exploratively evaluate the efficacy, safety, and dose-response of tolvaptan in patients with decompensated liver cirrhosis. J Gastroenterol. 2010;45:979–87.CrossRefPubMedGoogle Scholar
  3. 3.
    Jujo K, Saito K, Ishida I, et al. Randomized pilot trial comparing tolvaptan with furosemide on renal and neurohumoral effects in acute heart failure. ESC Heart Fail. 2016;3:177–88.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Matsue Y, Suzuki M, Torii S, et al. Prognostic impact of early treatment with tolvaptan in patients with acute heart failure and renal dysfunction. Int J Cardiol. 2016;221:188–93.CrossRefPubMedGoogle Scholar
  5. 5.
    Hanatani A, Shibata A, Kitada R, et al. Administration of tolvaptan with reduction of loop diuretics ameliorates congestion with improving renal dysfunction in patients with congestive heart failure and renal dysfunction. Heart Vessels. 2016;32:287–94 (Epub ahead of print).CrossRefPubMedGoogle Scholar
  6. 6.
    Sakaida I, Kawazoe S, Kajimura K, et al. Tolvaptan for improvement of hepatic edema: a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Res. 2014;44:73–82.CrossRefPubMedGoogle Scholar
  7. 7.
    Sakaida I, Yamashita S, Kobayashi T, et al. Efficacy and safety of a14-day administration of tolvaptan in the treatment of patients with ascites in hepatic oedema. J Int Med Res. 2013;41:835–47.CrossRefPubMedGoogle Scholar
  8. 8.
    Hiramine Y, Uto H. Imamura Y, al. Efficacy of vasopressin V2 receptor antagonist tolvaptan in treatment of hepatic edema. Hepatol Res. 2016;. doi: 10.1111/hepr.12778 (Epub ahead of print).PubMedGoogle Scholar
  9. 9.
    Uojima H, Kinbara T, Hidaka H, et al. Close correlation between urinary sodium excretion and response to tolvaptan in liver cirrhosis patients with ascites. Hepatol Res. 2016;. doi: 10.1111/hepr.12716 (Epub ahead of print).PubMedGoogle Scholar
  10. 10.
    Sakaida I, Terai S, Nakajima K, et al. Predictive factors of the pharmacological action of tolvaptan in patients with liver cirrhosis: a post hoc analysis. J Gastroenterol. 2017;52:229–36.CrossRefPubMedGoogle Scholar
  11. 11.
    Imamura T, Kinugawa K, Fujino T, et al. Increased urine aquaporin-2 relative to plasma arginine vasopressin is a novel marker of response to tolvaptan in patients with decompensated heart failure. Circ J. 2014;78:2240–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Sakaida I, Nakajima K, Okita K, et al. Can serum albumin level affect the pharmacological action of tolvaptan in patients with liver cirrhosis? A post hoc analysis of previous clinical trials in Japan. J Gastroenterol. 2015;50:1047–53.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Yan L, Xie F, Lu J, et al. The treatment of vasopressin V2-receptor antagonists in cirrhosis patients with ascites: a meta-analysis of randomized controlled trials. BMC Gastroenterol. 2015;15:65.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Santos J, Planas R, Pardo A, et al. Spironolactone alone or in combination with furosemide in the treatment of moderate ascites in nonazotemic cirrhosis. A randomized comparative study of efficacy and safety. J Hepatol. 2003;39:187–92.CrossRefPubMedGoogle Scholar
  15. 15.
    Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55:1–12.CrossRefGoogle Scholar
  16. 16.
    European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010;53:397–417.CrossRefGoogle Scholar
  17. 17.
    Angeli P, Fasolato S, Mazza E, et al. Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial. Gut. 2010;59:98–104.CrossRefPubMedGoogle Scholar
  18. 18.
    Wong F, Watson H, Gerbes A, Satavaptan Investigators Group, et al. Satavaptan for the management of ascites in cirrhosis: efficacy and safety across the spectrum of ascites severity. Gut. 2012;61:108–16.CrossRefPubMedGoogle Scholar
  19. 19.
    Izumi Y, Miura K, Iwao H. Therapeutic potential of vasopressin-receptor antagonists in heart failure. J Pharmacol Sci. 2014;124:1–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Imamura T, Kinugawa K, Shiga T, et al. Novel criteria of urine osmolality effectively predict response to tolvaptan in decompensated heart failure patients-association between non-responders and chronic kidney disease. Circ J. 2013;77:397–404.CrossRefPubMedGoogle Scholar
  21. 21.
    Iwamoto T, Maeda M, Hisanaga T, et al. Predictors of the effect of tolvaptan on the prognosis of cirrhosis. Intern Med. 2016;55:2911–6.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kawaratani H, Fukui H, Moriya K, et al. Predictive parameter of tolvaptan effectiveness in cirrhotic ascites. Hepatol Res. 2016;. doi: 10.1111/hepr.12826 (Epub ahead of print).Google Scholar
  23. 23.
    Nakanishi H, Kurosaki M, Hosokawa T, et al. Urinary excretion of the water channel aquaporin 2 correlated with the pharmacological effect of tolvaptan in cirrhotic patients with ascites. J Gastroenterol. 2016;51:620–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhang X, Wang SZ, Zheng JF, et al. Clinical efficacy of tolvaptan for treatment of refractory ascites in liver cirrhosis patients. World J Gastroenterol. 2014;20:11400–5.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Imamura T, Kinugawa K, Ohtani T, et al. Assessment of quality of life during long-term treatment of tolvaptan in refractory heart failure: design and rationale of the AQUA-TLV study. Int Heart J. 2014;55:264–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367:2407–18.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    O’Brien A, China L, Gant V. The potential danger of empiric antimicrobial therapy for nosocomial SBP. Hepatology. 2016;64:2267–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55.CrossRefPubMedGoogle Scholar
  29. 29.
    National Cancer Institute. Common terminology criteria for adverse events. Bethesda: National Institutes of Health; 2009.Google Scholar
  30. 30.
    Fukuhara S, Ware JE Jr, Kosinski M, et al. Psychometric and clinical tests of validity of the Japanese SF-36 health survey. J Clin Epidemiol. 1998;51:1045–53.CrossRefPubMedGoogle Scholar
  31. 31.
    Dimenäs E, Glise H, Hallerbäck B, et al. Quality of life in patients with upper gastrointestinal symptoms. An improved evaluation of treatment regimens? Scand J Gastroenterol. 1993;28:681–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Morita T, Fujimoto K, Namba M, et al. Palliative care needs of cancer outpatients receiving chemotherapy: an audit of a clinical screening project. Support Care Cancer. 2008;16:101–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Fukazawa R, Koyama S, Kanetaka H, et al. Leg edema detected on comprehensive geriatric assessment for elderly outpatients and its associated risk factors. Nihon Ronen Igakkai Zasshi. 2013;50:384–91.CrossRefPubMedGoogle Scholar
  34. 34.
    National Collaborating Centre for Chronic Conditions. Chronic obstructive pulmonary disease. National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax. 2004;59:1–232.Google Scholar
  35. 35.
    Kundel HL, Polansky M. Measurement of observer agreement. Radiology. 2003;228:303–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Hesterberg TC. What teachers should know about the bootstrap: resampling in the undergraduate statistics curriculum. Am Stat. 2015;69:371–86.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Sakaida I, Terai S, Kurosaki M, et al. Effectiveness and safety of tolvaptan in liver cirrhosis patients with edema: interim results of post-marketing surveillance of tolvaptan in liver cirrhosis (START study). Hepatol Res. 2016;. doi: 10.1111/hepr.12852 (Epub ahead of print).Google Scholar
  38. 38.
    Sakaida I, Okita K. Correlation between changes in bodyweight and changes in ascites volume in liver cirrhosis patients with hepatic edema in short-term diuretic therapy. Hepatol Res. 2014;44:735–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology. 1996;23:164–76.CrossRefPubMedGoogle Scholar
  40. 40.
    Higginson IJ, McCarthy M. Validity of the support team assessment schedule: do staffs’ ratings reflect those made by patients or their families? Palliat Med. 1993;7:219–28.CrossRefPubMedGoogle Scholar
  41. 41.
    Onishi Y, Wakita T, Fukuhara S, et al. Development and validation of a symptom scale specific for ascites accompanied with cirrhosis: the ASI-7. Clin Transl Gastroenterol. 2014;5:e48.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Younossi ZM, Guyatt G, Kiwi M, et al. Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease. Gut. 1999;45:295–300.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Nakamura T, Sata M, Hiroishi K, et al. Contribution of diuretic therapy with human serum albumin to the management of ascites in patients with advanced liver cirrhosis: a prospective cohort study. Mol Clin Oncol. 2014;2:349–55.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Felker GM, Mentz RJ, Cole R, et al. Efficacy and safety of tolvaptan in patients hospitalized with acute heart failure. J Am Coll Cardiol. 2016;. doi: 10.1016/j.jacc.2016.09.004 (Epub ahead of print).Google Scholar

Copyright information

© Japanese Society of Gastroenterology 2017

Authors and Affiliations

  • Yasunari Hiramine
    • 1
    Email author
  • Haruki Uojima
    • 2
  • Hiroyuki Nakanishi
    • 3
  • Akira Hiramatsu
    • 4
  • Takuya Iwamoto
    • 5
  • Mutsuumi Kimura
    • 6
  • Hideto Kawaratani
    • 7
  • Shuji Terai
    • 8
  • Hitoshi Yoshiji
    • 7
  • Hirofumi Uto
    • 9
  • Isao Sakaida
    • 5
  • Namiki Izumi
    • 3
  • Kiwamu Okita
    • 10
  • Kazuhiko Koike
    • 11
  1. 1.Department of Internal MedicineKagoshima Kouseiren HospitalKagoshimaJapan
  2. 2.Department of Gastroenterology, Internal MedicineKitasato University School of MedicineSagamiharaJapan
  3. 3.Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
  4. 4.Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
  5. 5.Department of Gastroenterology and HepatologyYamaguchi University Graduate School of MedicineYamaguchiJapan
  6. 6.Department of HepatologySapporo Kosei General HospitalSapporoJapan
  7. 7.Third Department of Internal MedicineNara Medical UniversityNaraJapan
  8. 8.Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental SciencesNiigata UniversityNiigataJapan
  9. 9.Center for Digestive and Liver DiseasesMiyazaki Medical Center HospitalMiyazakiJapan
  10. 10.Shunan Memorial HospitalYamaguchiJapan
  11. 11.Department of GastroenterologyThe University of TokyoTokyoJapan

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