Randomized Clinical Trial
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2017; 23(45): 8062-8072
Published online Dec 7, 2017. doi: 10.3748/wjg.v23.i45.8062
Efficacy of combination therapy with natriuretic and aquaretic drugs in cirrhotic ascites patients: A randomized study
Haruki Uojima, Hisashi Hidaka, Tsuyoshi Nakayama, Ji Hyun Sung, Chikamasa Ichita, Shinnosuke Tokoro, Sakue Masuda, Akiko Sasaki, Kazuya Koizumi, Hideto Egashira, Makoto Kako
Haruki Uojima, Ji Hyun Sung, Chikamasa Ichita, Shinnosuke Tokoro, Sakue Masuda, Akiko Sasaki, Kazuya Koizumi, Hideto Egashira, Makoto Kako, Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura 247-8533, Japan
Haruki Uojima, Hisashi Hidaka, Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kanagawa 252-0375, Japan
Tsuyoshi Nakayama, Department of Gastroenterology, Shonan Atsugi Hospital, Kanagawa 243-8551, Japan
Author contributions: Uojima H, Hidaka H, Nakayama T, Sung JH, Ichita C, Tokoro S, Masuda S, Sasaki A, Koizumi K, Egashira H and Kako M contributed equally to this work; Uojima H and Nakayama T collected and analyzed the data; Uojima H drafted the manuscript; Kako M designed and supervised the study; Sung JH, Ichita C, Tokoro S, Masuda S, Sasaki A, Koizumi K and Egashira H offered technical or material support; all authors have read and approved the final version to be published.
Institutional review board statement: The study was reviewed and approved by the Tokushukai Group Ethical Committee’s institutional review board.
Clinical trial registration statement: This study is registered at https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017694. The registration identification number is UMIN000015218.
Informed consent statement: This prospective study was conducted at Shonan Kamakura General Hospital and Shonan Atsugi Hospital. Informed consent was obtained from patients and their families before study participation commenced.
Conflict-of-interest statement: We declare no conflicts of interest.
Data sharing statement: The technical appendix, statistical code, and dataset are available from the corresponding author (email: kiruha@kitasato-u.ac.jp). No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Haruki Uojima, MD, Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0375, Japan. kiruha555@yahoo.co.jp
Telephone: +81-42-7788111 Fax: +81-42-7788390
Received: September 13, 2017
Peer-review started: September 14, 2017
First decision: October 10, 2017
Revised: October 25, 2017
Accepted: November 8, 2017
Article in press: November 8, 2017
Published online: December 7, 2017
Processing time: 81 Days and 21.8 Hours
ARTICLE HIGHLIGHTS
Research background

Recently, several studies have evaluated the effects of aquaretic drugs such as tolvaptan for treating ascites resistant to conventional therapies.

Research motivation

Whether a combination therapy with natriuretic and aquaretic drugs is more effective than conventional therapy with natriuretic for liver cirrhosis patients with ascites remains unclear.

Research objectives

We assessed the effects of a combination therapy with natriuretic and aquaretic drugs in cirrhotic ascites patients.

Research methods

A two-center, randomized, open-label, prospective study was conducted. Japanese patients who met the criteria were randomized to trial groups and they received an aquaretic drug (7.5 mg of tolvaptan) or a natriuretic drug (40 mg of furosemide) for 7 d in addition to the natriuretic drug which was used prior to enrolment in this study. The primary endpoint was the change in body weight from the baseline. Vital signs, fluid intake, and laboratory and urinary data were assessed to determine the pharmacological effects of tolvaptan and furosemide.

Research results

A total of 56 patients were randomized to receive either tolvaptan (n = 28) or furosemide (n = 28). In the tolvaptan and furosemide groups, the average decrease in body weight from the baseline was 3.21 ± 3.17 kg (P < 0.0001) and 1.75 ± 2.36 kg (P = 0.0006), respectively, when measured on the final dosing day. Following 1 wk of treatment, a significantly greater reduction in body weight was observed in the tolvaptan group compared to that in the furosemide group (P = 0.0412).

Research conclusions

Compared to a conventional therapy with only natriuretic drugs, a combination therapy with natriuretic and aquaretic drugs is more effective for patients with cirrhotic ascites. Following 1 wk of treatment, a significantly greater reduction in body weight was observed in the combination therapy compared to that in the conventional therapy. Combination therapy that involves the blocking of sodium and water reabsorption may be more effective in treating liver cirrhosis with ascites than conventional therapy, which only blocks sodium reabsorption. Combination therapy including tolvaptan and conventional diuretics reduced the occurrence of diuretic-related severe side effects. A two-center, randomized, open-label, prospective study was conducted. The criteria were randomized to a trial group and the combination diuretic group (natriuretic and aquaretic drugs) or the conventional diuretic group (a natriuretic drug only). A combination diuretic therapy including an aquaretic drug resulted in a greater decrease in body weight compared to conventional diuretic with only a natriuretic drug for cirrhotic ascites patients. Moreover, compared to conventional diuretic therapy, combination diuretic therapy reduced the occurrence of diuretic-related severe side effects. Compared to a conventional diuretic therapy with only a natriuretic drug, a combination diuretic therapy with natriuretic and aquaretic drugs proved to be more effective for patients with cirrhotic ascites. Combination therapy may establish a strategy to treat ascites refractory to the standard diuretic therapy.

Research perspectives

The study compared to a conventional diuretic therapy with only a natriuretic drug, a combination diuretic therapy with natriuretic and aquaretic drugs is more effective for patients with cirrhotic ascites. It is not clear whether or not the combination therapy improved the long-term prognosis of these patients. Therefore, future long-term observational studies are warranted. The future research should assess the influence of renal function after the administration of tolvaptan and furosemide in liver cirrhosis patients with ascites for at least 24 wk.