Aims: The study aimed to evaluate the effects of tolvaptan treatment on survival of patients with decompensated liver cirrhosis with refractory ascites. Methods: This multicenter, retrospective, observational study included patients with cirrhosis who were treated with tolvaptan for hepatic ascites refractory to conventional diuretics. Patients who could and could not decrease accompanying diuretics within 1 month after tolvaptan administration were defined as the “Decreased” and “Not-decreased” groups, respectively. Results: Median body weight change 1 week after tolvaptan treatment was –1.95 kg, with the 50% of patients experiencing a 2 kg/week reduction. Spot urinary sodium was found to be a better predictor of tolvaptan response than liver function and liver fibrosis markers. Median survival was significantly longer (not reached versus 116 days, p = 0.005) and serum creatinine concentrations 12 weeks after tolvaptan administration significantly lower (0.99 vs. 1.55 mg/dL, p < 0.05) in the Decreased than in the Not-decreased group. Multivariate analysis showed that the presence of viable hepatocellular carcinoma (hazards ratio [HR] 2.14, p = 0.02) and a decrease in diuretics were independently prognostic of survival (HR 0.36, p < 0.01). Conclusions: The maintenance of renal function is essential in enhancing survival of patients with cirrhosis. Doses of diuretics should be adjusted appropriately during tolvaptan treatment.

1.
Castello L, Pirisi M, Sainaghi PP, Bartoli E: Hyponatremia in liver cirrhosis: pathophysiological principles of management. Dig Liver Dis 2005; 37: 73–81.
2.
Gines P, Guevara M: Hyponatremia in -cirrhosis: pathogenesis, clinical significance, and management. Hepatology 2008; 48: 1002–1010.
3.
Salerno F, Guevara M, Bernardi M, Moreau R, Wong F, Angeli P, Garcia-Tsao G, Lee SS: Refractory ascites: pathogenesis, definition and therapy of a severe complication in patients with cirrhosis. Liver Int 2010; 30: 937–947.
4.
Planas R, Montoliu S, Balleste B, Rivera M, Miquel M, Masnou H, Galeras JA, Gimenez MD, Santos J, Cirera I, Morillas RM, Coll S, Sola R: Natural history of patients hospitalized for management of cirrhotic ascites. Clin Gastroenterol Hepatol 2006; 4: 1385–1394.
5.
Bernardi M, De Palma R, Trevisani F, Santini C, Servadei D, Gasbarrini G: Comparative pharmacodynamics of furosemide and muzolimine in cirrhosis. Study on renal sodium and potassium handling and renin-aldosterone axis. Z Kardiol 1985; 74(suppl 2): 129–134.
6.
Gines P, Arroyo V, Quintero E, Planas R, Bory F, Cabrera J, Rimola A, Viver J, Camps J, Jimenez W, et al: Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study. Gastroenterology 1987; 93: 234–241.
7.
Okita K, Sakaida I, Okada M, Kaneko A, Chayama K, Kato M, Sata M, Yoshihara H, Ono N, Murawaki Y: 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: 979–987.
8.
Sakaida I, Kawazoe S, Kajimura K, Saito T, Okuse C, Takaguchi K, Okada M, Okita K; Ascites-Doubleblind Study Group: Tolvaptan for improvement of hepatic edema: A phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Res 2014; 44: 73–82.
9.
Okita K, Kawazoe S, Hasebe C, Kajimura K, Kaneko A, Okada M, Sakaida I; ASCITES Dose-Finding Trial Group: Dose-finding trial of tolvaptan in liver cirrhosis patients with hepatic edema: a randomized, double-blind, placebo-controlled trial. Hepatol Res 2014; 44: 83–91.
10.
Yan L, Xie F, Lu J, Ni Q, Shi C, Tang C, Yang J: The treatment of vasopressin V2-receptor antagonists in cirrhosis patients with ascites: a meta-analysis of randomized controlled trials. BMC Gastroenterol 2015; 15: 65.
11.
Akiyama S, Ikeda K, Sezaki H, Fukushima T, Sorin Y, Kawamura Y, Saitoh S, Hosaka T, Akuta N, Kobayashi M, Suzuki F, Suzuki Y, Arase Y, Kumada H: Therapeutic effects of short- and intermediate-term tolvaptan administration for refractory ascites in patients with advanced liver cirrhosis. Hepatol Res 2015; 45: 1062–1070.
12.
Zhang X, Wang SZ, Zheng JF, Zhao WM, Li P, Fan CL, Li B, Dong PL, Li L, Ding HG: Clinical efficacy of tolvaptan for treatment of refractory ascites in liver cirrhosis patients. World J Gastroenterol 2014; 20: 11400–11405.
13.
Chishina H, Hagiwara S, Nishida N, Ueshima K, Sakurai T, Ida H, Minami Y, Takita M, Kono M, Minami T, Iwanishi M, Umehara Y, Watanabe T, Komeda Y, Arisumi T, Kudo M: Clinical factors predicting the effect of tolvaptan for refractory ascites in patients with decompensated liver cirrhosis. Dig Dis 2016; 34: 659–664.
14.
Kawaratani H, Fukui H, Moriya K, Noguchi R, Namisaki T, Uejima M, Kitade M, Takeda K, Okura Y, Kaji K, Nishimura N, Takaya H, Aihara Y, Sawada Y, Sato S, Seki K, Mitoro A, Yamao J, Yoshiji H: Predictive parameter of tolvaptan effectiveness in cirrhotic ascites. Hepatol Res 2017; 47: 854–861.
15.
Kogiso T, Tokushige K, Hashimoto E, Ikarashi Y, Kodama K, Taniai M, Torii N, Shiratori K: Safety and efficacy of long-term tolvaptan therapy for decompensated liver cirrhosis. Hepatol Res 2016; 46:E194–E200.
16.
Kogiso T, Yamamoto K, Kobayashi M, Ikarashi Y, Kodama K, Taniai M, Torii N, Hashimoto E, Tokushige K: Response to tolvaptan and its effect on prognosis in cirrhotic patients with ascites. Hepatol Res 2017; 47: 835–844.
17.
Komiyama Y, Kurosaki M, Nakanishi H, Takahashi Y, Itakura J, Yasui Y, Tamaki N, Takada H, Higuchi M, Gotou T, Kubota Y, Takaura K, Hayashi T, Oh W, Okada M, Enomoto N, Izumi N: Prediction of diuretic response to tolvaptan by a simple, readily available spot urine Na/K ratio. PLoS One 2017; 12:e0174649.
18.
Uojima H, Kinbara T, Hidaka H, Sung JH, Ichida M, Tokoro S, Masuda S, Takizawa S, Sasaki A, Koizumi K, Egashira H, Kako M: Close correlation between urinary sodium excretion and response to tolvaptan in liver cirrhosis patients with ascites. Hepatol Res 2017; 47:E14–E21.
19.
Sakaida I, Terai S, Kurosaki M, Yasuda M, Okada M, Bando K, Fukuta Y: 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 2017; 47: 1137–1146.
20.
Fukui H: Do vasopressin V2 receptor antagonists benefit cirrhotics with refractory ascites? World J Gastroenterol 2015; 21: 11584–11596.
21.
Hiramine Y, Uto H, Imamura Y, Hiwaki T, Kure T, Ijuin S, Oda K, Mawatari S, Kumagai K, Tokunaga K, Higashi H, Kanetsuki I, Kubozono O, Maenohara S, Ido A: Efficacy of vasopressin V2 receptor antagonist tolvaptan in treatment of hepatic edema. Hepatol Res 2017; 47: 542–557.
22.
Cholongitas E, Papatheodoridis GV, Vangeli M, Terreni N, Patch D, Burroughs AK: Systematic review: the model for end-stage liver disease – should it replace Child-Pugh’s classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther 2005; 22: 1079–1089.
23.
Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC: A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000; 31: 864–871.
24.
Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS: A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003; 38: 518–526.
25.
Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, S Sulkowski M, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M; APRICOT Clinical Investigators: Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006; 43: 1317–1325.
26.
Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y, Makuuchi M: Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg 2007; 245: 909–922.
27.
Kokudo N, Hasegawa K, Akahane M, Igaki H, Izumi N, Ichida T, Uemoto S, Kaneko S, Kawasaki S, Ku Y, Kudo M, Kubo S, Takayama T, Tateishi R, Fukuda T, Matsui O, Matsuyama Y, Murakami T, Arii S, Okazaki M, Makuuchi M: Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines). Hepatol Res 2015; 45: 123–127.
28.
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.
29.
Alexander WD, Branch RA, Levine DF, Hartog M: The urinary sodium: potassium ratio and response to diuretics in resistant oedema. Postgrad Med J 1977; 53: 117–121.
30.
Mohii el SM, El Mansy IM, Salah M, Khedr MA: Diagnostic usefulness of the random urine Na/K ratio in predicting therapeutic response for diuretics in cirrhotic patients with ascites. J Egypt Soc Parasitol 2013; 43: 767–776.
31.
Thomas JP, Bartter FC: Relation between diuretic agents and aldosterone in cardiac and cirrhotic patients with sodium retention. Br Med J 1961; 1: 1134–1139.
32.
Adamson AR, Jamieson SW: Urinary excretion of sodium and potassium in relation to plasma aldosterone concentration. J Endocrinol 1972; 53: 425–431.
33.
Hinz M, Wree A, Jochum C, Bechmann LP, Saner F, Gerbes AL, Gerken G, Canbay A: High age and low sodium urine concentration are associated with poor survival in patients with hepatorenal syndrome. Ann Hepatol 2013; 12: 92–99.
34.
Kogiso T, Kobayashi M, Yamamoto K, Ikarashi Y, Kodama K, Taniai M, Torii N, Hashimoto E, Tokushige K: The outcome of cirrhotic patients with ascites Is improved by the normalization of the serum sodium level by Tolvaptan. Intern Med 2017; 56: 2993–3001.
35.
Mori T, Ohsaki Y, Oba-Yabana I, Ito S: Diuretic usage for protection against end-organ damage in liver cirrhosis and heart failure. Hepatol Res 2017; 47: 11–22.
36.
Yamamura Y, Nakamura S, Itoh S, Hirano T, Onogawa T, Yamashita T, Yamada Y, Tsujimae K, Aoyama M, Kotosai K, Ogawa H, Yamashita H, Kondo K, Tominaga M, Tsujimoto G, Mori T: OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther 1998; 287: 860–867.
37.
Costello-Boerrigter LC, Smith WB, Boerrigter G, Ouyang J, Zimmer CA, Orlandi C, Burnett JC: Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure. Am J Physiol Renal Physiol 2006; 290:F273–F278.
38.
Tsien CD, Rabie R, Wong F: Acute kidney injury in decompensated cirrhosis. Gut 2013; 62: 131–137.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.