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Namba Y, Kobayashi T, Kuroda S, Hashimoto M, Takei D, Fukuhara S, Oshita K, Matsubara K, Honmyo N, Nakano R, Sakai H, Tahara H, Ohira M, Ide K, Ohdan H. Protocol to evaluate the efficacy and safety of tolvaptan in patients with refractory ascites after liver resection: an open-label, single-arm phase I/II study. Int J Surg Protoc 2024; 28:1-5. [PMID: 38433869 PMCID: PMC10905494 DOI: 10.1097/sp9.0000000000000015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 07/23/2023] [Indexed: 03/05/2024] Open
Abstract
BACKGROUND In patients with chronic liver diseases such as cirrhosis, massive ascites after hepatic resection is the cause of prolonged hospitalization and worsening prognosis. Recently, the efficacy of tolvaptan in refractory ascites has been reported; however, there are no reports on the efficacy or safety of tolvaptan for refractory ascites after hepatic resection. This study aims to evaluate the efficacy of early administration of tolvaptan in patients with refractory ascites after hepatic resection. MATERIALS AND METHODS This is an open-label, single-arm phase I/II study. This study subject will comprise patients scheduled for hepatic resection of a liver tumor. Patients with refractory ascites after hepatic resection (drainage volume on postoperative day 1 ≥5 ml/body weight 1 kg/day) will be treated with tolvaptan. The primary endpoint will include the maximum change in body weight after hepatic resection relative to the preoperative baseline. The secondary endpoints will include drainage volume, abdominal circumference, urine output, postoperative complication rate (heart failure and respiratory failure), number of days required for postoperative weight gain because of ascites to decrease to preoperative weight, change in improvement of postoperative pleural effusion, total amount of albumin or fresh frozen plasma transfusion, type and amount of diuretics used, and postoperative hospitalization days. CONCLUSION This trial will evaluate the efficacy and safety of tolvaptan prophylaxis for refractory ascites after hepatic resection. As there are no reports demonstrating the efficacy of tolvaptan prophylaxis for refractory ascites after hepatic resection, the authors expect that these findings will lead to future phase III trials and provide valuable indications for the selection of treatments for refractory postoperative ascites.
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Affiliation(s)
- Yosuke Namba
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Shintaro Kuroda
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Masakazu Hashimoto
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
- Department of Gastroenterological-Breast and Transplant Surgery, Hiroshima Prefectural Hospital
| | - Daisuke Takei
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
- Department of Surgery and Endoscopic Surgery, JA Onomichi General Hospital, Hiroshima, Japan
| | - Sotaro Fukuhara
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Ko Oshita
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Keiso Matsubara
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Naruhiko Honmyo
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Ryosuke Nakano
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Hiroshi Sakai
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Hiroyuki Tahara
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Kentaro Ide
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University
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Iida H, Maehira H, Mori H, Nitta N, Maekawa T, Takebayashi K, Kaida S, Miyake T, Tani M. Effect of early administration of tolvaptan on pleural effusion post-hepatectomy. Langenbecks Arch Surg 2023; 408:406. [PMID: 37845430 DOI: 10.1007/s00423-023-03136-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 10/04/2023] [Indexed: 10/18/2023]
Abstract
PURPOSE This study evaluated the efficacy of tolvaptan administration at the early stage after hepatectomy to control pleural effusion and improve the postoperative course. METHODS Patients were administered tolvaptan (7.5 mg) and spironolactone (25 mg) from postoperative day 1 to postoperative day 5 (tolvaptan group, n = 68) for 13 months. Early administration of tolvaptan was not provided in the control group (n = 68); however, diuretics were appropriately administered according to the patient's condition. The amount of pleural effusion on computed tomography on postoperative day 5 was compared between the two groups. RESULTS The amount of pleural effusion and increase in body weight on postoperative day 5 showed significant differences in both groups (p < 0.001 and p = 0.019, respectively). However, the rate of pleural aspiration and the duration of postoperative hospitalization were comparable between the groups. The amount of intraoperative blood loss and lack of early administration of tolvaptan were identified as independent risk factors contributing to pleural effusion on multivariate analysis. CONCLUSION Early administration of tolvaptan to patients after hepatectomy was found to be capable of controlling postoperative pleural effusion and increase in body weight, but it did not reduce the rate of pleural aspiration or the hospitalization period.
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Affiliation(s)
- Hiroya Iida
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan.
| | - Hiromitsu Maehira
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Haruki Mori
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Nobuhito Nitta
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Takeru Maekawa
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Katsushi Takebayashi
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Sachiko Kaida
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Toru Miyake
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Masaji Tani
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
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Chai L, Li Z, Wang T, Wang R, Pinyopornpanish K, Cheng G, Qi X. Efficacy and safety of tolvaptan in cirrhotic patients: a systematic review and meta-analysis of randomized controlled trials. Expert Rev Gastroenterol Hepatol 2023; 17:1041-1051. [PMID: 37794713 DOI: 10.1080/17474124.2023.2267421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 10/03/2023] [Indexed: 10/06/2023]
Abstract
BACKGROUND AND AIMS Tolvaptan has been approved for the management of cirrhosis-related complications according to the Japanese and Chinese practice guidelines, but not the European or American practice guidelines in view of FDA warning about its hepatotoxicity. This study aimed to systematically evaluate its efficacy and safety in cirrhosis. METHODS The PubMed, EMBASE, and Cochrane library databases were searched to identify randomized controlled trials (RCTs) evaluating the efficacy and/or safety of tolvaptan in cirrhosis. Risk ratios (RRs) and weight mean differences (WMDs) were calculated. The incidence of common adverse events (AEs) was pooled. RESULTS Eight RCTs were included. Tolvaptan was significantly associated with higher rates of improvement of ascites (RR = 1.49, P < 0.001) and hyponatremia (RR = 1.80, P = 0.005) and incidence of any AEs (RR = 1.18, P = 0.003), but not serious AEs (RR = 0.86, P = 0.410). Tolvaptan was significantly associated with reductions in body weight (WMD = -1.30 kg, P < 0.001) and abdominal circumference (WMD = -1.71 cm, P < 0.001), and increases in daily urine volume (WMD = 1299.84 mL, P < 0.001) and serum sodium concentration (WMD = 2.57 mmol/L, P < 0.001). The pooled incidences of dry mouth, thirst, constipation, and pollakiuria were 16%, 24%, 6%, and 17%, respectively. CONCLUSION Short-term use of tolvaptan may be considered in cirrhotic patients with ascites who have inadequate response to conventional diuretics and those with hyponatremia.
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Affiliation(s)
- Lu Chai
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- NMPA Key Laboratory for Research and Evaluation of Drug Regulatory Technology, Shenyang Pharmaceutical University, Shenyang, China
| | - Zhe Li
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- NMPA Key Laboratory for Research and Evaluation of Drug Regulatory Technology, Shenyang Pharmaceutical University, Shenyang, China
| | - Ting Wang
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- NMPA Key Laboratory for Research and Evaluation of Drug Regulatory Technology, Shenyang Pharmaceutical University, Shenyang, China
| | - Ran Wang
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
| | - Kanokwan Pinyopornpanish
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Gang Cheng
- NMPA Key Laboratory for Research and Evaluation of Drug Regulatory Technology, Shenyang Pharmaceutical University, Shenyang, China
| | - Xingshun Qi
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- NMPA Key Laboratory for Research and Evaluation of Drug Regulatory Technology, Shenyang Pharmaceutical University, Shenyang, China
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Curative Effect and Safety of Tolvaptan Combined With Traditional Diuretics in Treatment of Patients With Cirrhotic Ascites and Relevant Research on Its Dose. Am J Ther 2023; 30:158-162. [PMID: 33416254 DOI: 10.1097/mjt.0000000000001327] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Wang R, Chai L, Guo X. Diuretics in Cirrhotic Patients with Ascites. PHARMACOTHERAPY FOR LIVER CIRRHOSIS AND ITS COMPLICATIONS 2022:167-178. [DOI: 10.1007/978-981-19-2615-0_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Yoshiji H, Nagoshi S, Akahane T, Asaoka Y, Ueno Y, Ogawa K, Kawaguchi T, Kurosaki M, Sakaida I, Shimizu M, Taniai M, Terai S, Nishikawa H, Hiasa Y, Hidaka H, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for Liver Cirrhosis 2020. J Gastroenterol 2021; 56:593-619. [PMID: 34231046 PMCID: PMC8280040 DOI: 10.1007/s00535-021-01788-x] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023]
Abstract
The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.
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Affiliation(s)
- Hitoshi Yoshiji
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
| | - Sumiko Nagoshi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takemi Akahane
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshinari Asaoka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshiyuki Ueno
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Koji Ogawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takumi Kawaguchi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masayuki Kurosaki
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Isao Sakaida
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masahito Shimizu
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Makiko Taniai
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Shuji Terai
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroki Nishikawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoichi Hiasa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hisashi Hidaka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuaki Chayama
- The Japan Society of Hepatology, Kashiwaya 2 Building 5F, 3-28-10 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tetsuo Takehara
- The Japan Society of Hepatology, Kashiwaya 2 Building 5F, 3-28-10 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
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7
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Yoshiji H, Nagoshi S, Akahane T, Asaoka Y, Ueno Y, Ogawa K, Kawaguchi T, Kurosaki M, Sakaida I, Shimizu M, Taniai M, Terai S, Nishikawa H, Hiasa Y, Hidaka H, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for liver cirrhosis 2020. Hepatol Res 2021; 51:725-749. [PMID: 34231046 DOI: 10.1111/hepr.13678] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022]
Abstract
The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.
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Affiliation(s)
- Hitoshi Yoshiji
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan.,Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Sumiko Nagoshi
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Takemi Akahane
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoshinari Asaoka
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoshiyuki Ueno
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Koji Ogawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Takumi Kawaguchi
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Masayuki Kurosaki
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Isao Sakaida
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Masahito Shimizu
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Makiko Taniai
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Shuji Terai
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hiroki Nishikawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoichi Hiasa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hisashi Hidaka
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | | | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | | | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
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8
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Yatsuhashi H, Sano H, Hirano T, Shibasaki Y. Real-world hospital mortality of liver cirrhosis inpatients in Japan: a large-scale cohort study using a medical claims database: Prognosis of liver cirrhosis. Hepatol Res 2021; 51:682-693. [PMID: 33710718 DOI: 10.1111/hepr.13635] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 02/08/2021] [Accepted: 02/23/2021] [Indexed: 12/13/2022]
Abstract
AIM Prognosis of liver cirrhosis patients is poor when ascites is present and liver function is impaired, but such up-to-date information from a large-scale, real-world setting is limited in Japan. We aimed to investigate the hospital mortality of Japanese liver cirrhosis inpatients. METHODS This retrospective cohort study included data on liver cirrhosis inpatients between January 2011 and September 2018 extracted from an administrative claims database. The outcome was in-hospital mortality. The 1- and 3-year cumulative survival rates were examined for liver cirrhosis etiology, Child-Pugh classification, or ascites presence/absence using Kaplan-Meier analysis. The survival up to 1 year for tolvaptan prescription/nonprescription was examined. RESULTS We analyzed the data of 57 769 inpatients. Survival rates did not substantially differ among etiologies, with a better prognosis for alcohol etiology and poorer prognosis for hepatitis C virus. According to the Child-Pugh classification, the 1- and 3-year survival rates were 90.2% and 75.3% for grade A, 73.5% and 53.9% for grade B, and 41.9% and 28.9% for grade C, respectively. Patients without ascites had a higher survival rate (83.2% and 67.0% at 1 and 3 years, respectively) than those with ascites (51.9% and 36.3%, respectively). Based on examining matched patients with ascites using a propensity score, prognosis was poor in general but was better at 6 months (58.1%) or similar at 1 year (47.1%) in patients prescribed tolvaptan compared to those not prescribed tolvaptan (54.8% and 47.5%, respectively). CONCLUSIONS Poorer prognosis was suggested in inpatients with cirrhosis who had a worse Child-Pugh grade and ascites.
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Affiliation(s)
| | - Hiromi Sano
- Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan
| | - Takahiro Hirano
- Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan
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Management of Cirrhotic Ascites under the Add-on Administration of Tolvaptan. Int J Mol Sci 2021; 22:ijms22115582. [PMID: 34070416 PMCID: PMC8197450 DOI: 10.3390/ijms22115582] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/21/2021] [Accepted: 05/22/2021] [Indexed: 12/15/2022] Open
Abstract
Tolvaptan is a recently available diuretic that blocks arginine vasopressin receptor 2 in the renal collecting duct. Its diuretic mechanism involves selective water reabsorption by affecting the water reabsorption receptor aquaporin 2. Given that liver cirrhosis patients exhibit hyponatremia due to their pseudo-aldosteronism and usage of natriuretic agents, a sodium maintaining agent, such as tolvaptan, is physiologically preferable. However, large scale studies indicating the patients for whom this would be effective and describing management under its use have been insufficient. The appropriate management of cirrhosis patients treated with tolvaptan should be investigated. In the present review, we collected articles investigating the effectiveness of tolvaptan and factors associated with survival and summarized their management reports. Earlier administration of tolvaptan before increasing the doses of natriuretic agents is recommended because this may preserve effective arterial blood volume.
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Early Administration of Tolvaptan Can Improve Survival in Patients with Cirrhotic Ascites. J Clin Med 2021; 10:jcm10020294. [PMID: 33466878 PMCID: PMC7830941 DOI: 10.3390/jcm10020294] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/04/2021] [Accepted: 01/11/2021] [Indexed: 11/17/2022] Open
Abstract
(1) Backgrounds and aim: Tolvaptan, a selective vasopressin type 2 receptor antagonist, was approved for ascites, and its short-term efficacy and safety have been confirmed. However, it is still unclear whether this novel drug may improve long-term survival rates in cirrhotic patients with ascites. (2) Patients and methods: A total of 206 patients who responded insufficiently to conventional diuretics and were hospitalized for refractory ascites for the first time were retrospectively enrolled in this study. Among them, the first 57 consecutive patients were treated with conventional diuretics (the conventional therapy group); the latter 149 consecutive patients were treated with tolvaptan in addition to the conventional therapy (the tolvaptan group). (3) Results: The exacerbation of renal function was significantly milder in the tolvaptan group than in the conventional therapy group. The prognostic factors for survival in the tolvaptan group were being male, having hyperbilirubinemia, having a high blood urea nitrogen (BUN), and receiving high-dose furosemide at the start of tolvaptan treatment. The one-year and three-year cumulative survival rates were 67.8 and 45.3%, respectively, in patients with low-dose furosemide (<40 mg/day) at the start of tolvaptan treatment. The prognosis was significantly better in the tolvaptan group with low-dose furosemide than in the conventional therapy group (p < 0.001). (4) Conclusion: Tolvaptan can improve survival in patients with cirrhotic ascites, especially when tolvaptan is started before high-dose furosemide administration.
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Tang J, Wang Y, Han T, Mao Q, Cheng J, Ding H, Shang J, Zhang Q, Niu J, Ji F, Chen C, Jia J, Jiang X, Lv N, Gao Y, Wang Z, Wei Z, Chen Y, Zeng M, Mao Y. Tolvaptan therapy of Chinese cirrhotic patients with ascites after insufficient diuretic routine medication responses: a phase III clinical trial. BMC Gastroenterol 2020; 20:391. [PMID: 33213378 PMCID: PMC7678173 DOI: 10.1186/s12876-020-01536-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 11/10/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND To determine the safety and efficacy of different doses of tolvaptan for treating Chinese cirrhotic patients with or without hyponatraemia who still had ascites after routine therapy with diuretics. METHODS In the present placebo-controlled, randomized, double-blinded, multicentre clinical trial, patients with cirrhotic ascites who failed to adequately respond to a combination of an aldosterone antagonist plus an orally administered loop diuretic were randomly placed at a 4:2:1 ratio into 3 groups [the 15 mg/day tolvaptan group (N = 301), 7.5 mg/day tolvaptan group (N = 153) and placebo group (N = 76)] for 7 days of treatment. The effects and safety were evaluated on days 4 and 7. A change in body weight from baseline on day 7 of treatment was the primary endpoint. RESULTS The administration of 7.5 or 15 mg/day tolvaptan significantly decreased body weight from baseline on day 7 of treatment compared to that with placebo treatment (P = 0.026; P = 0.001). For the secondary endpoints, changes in abdominal circumference from baseline and improvements in ascites were markedly different in the treatment groups and the placebo group on day 7 (P7.5 = 0.05, P15.0 = 0.002 and P7.5 = 0.037, P15.0 = 0.003), but there was no difference between the 7.5 mg/day and 15 mg/day dosage groups. The 24-h cumulative urine volume was higher in the 7.5 mg/day and 15 mg/day tolvaptan groups than the placebo group (P = 0.002, P < 0.001) and was greater in the 15 mg/day tolvaptan group than the 7.5 mg/day tolvaptan group (P = 0.004). Sodium serum concentrations were higher in patients with hyponatraemia after tolvaptan treatment, with no significant difference between the two dosage groups. The incidence of serious adverse drug reactions was not different between the groups (P = 0.543). CONCLUSIONS Tolvaptan treatment at 7.5 mg per day might be a good therapeutic choice for Chinese cirrhotic patients with ascites who did not achieve satisfactory clinical responses to previous treatment regimens with combination therapy with an aldosterone antagonist and an orally administered loop diuretic. TRIAL REGISTRATION NCT01349348. Retrospectively registered May 2011.
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Affiliation(s)
- Jieting Tang
- School of Medicine Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, No. 145, Middle Shandong Road, Shanghai, 200001, China
| | - Yongfeng Wang
- School of Medicine Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, No. 145, Middle Shandong Road, Shanghai, 200001, China
| | - Tao Han
- Tianjin Third Hospital, Tianjin, China
| | - Qing Mao
- Southwest Hospital, Chongqing, China
| | - Jun Cheng
- Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Huiguo Ding
- Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jia Shang
- Henan Provincial Peoples Hospital, Zhengzhou, China
| | - Qin Zhang
- Shanghai Public Health Clinical Center, Shanghai, China
| | - Junqi Niu
- The First Hospital of Jilin University, Changchun, China
| | - Feng Ji
- The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Chengwei Chen
- 85 Hospital of Peoples Liberation Army, Shanghai, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | | | - Nonghua Lv
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yueqiu Gao
- Shanghai Shuguang Hospital, Shanghai, China
| | - Zhenghua Wang
- School of Medicine Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, No. 145, Middle Shandong Road, Shanghai, 200001, China
| | - Zhong Wei
- School of Medicine Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, No. 145, Middle Shandong Road, Shanghai, 200001, China
| | - Yingxuan Chen
- School of Medicine Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, No. 145, Middle Shandong Road, Shanghai, 200001, China
| | - Minde Zeng
- School of Medicine Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, No. 145, Middle Shandong Road, Shanghai, 200001, China
| | - Yimin Mao
- School of Medicine Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, No. 145, Middle Shandong Road, Shanghai, 200001, China.
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12
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Sakaida I, Terai S, Kurosaki M, Okada M, Hirano T, Fukuta Y. Real-world effectiveness and safety of tolvaptan in liver cirrhosis patients with hepatic edema: results from a post-marketing surveillance study (START study). J Gastroenterol 2020; 55:800-810. [PMID: 32388692 PMCID: PMC7376514 DOI: 10.1007/s00535-020-01691-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND This large-scale post-marketing surveillance study (START study) evaluated the effectiveness and safety of tolvaptan in Japanese liver cirrhosis patients with hepatic edema in real-world clinical settings. Here, we present the final analysis outcomes. METHODS A prospective, multicenter, non-interventional study involving patients who received tolvaptan for the treatment of liver cirrhosis with hepatic edema with an insufficient response to conventional diuretics. The observation period was up to 6 months. Effectiveness evaluation included changes in body weight and clinical symptoms. Safety analysis included evaluation of adverse drug reactions (ADRs). RESULTS Case reports of 1111 patients were collected. Of these, 1109 were included in the safety analysis and 1098 in the effectiveness analysis. The mean age was 69.4 ± 11.5 years and 695 (62.7%) patients were male. After tolvaptan treatment, a decrease in body weight from baseline was - 2.6 ± 2.7 kg on day 7 and - 3.8 ± 4.1 kg on day 14. Moreover, clinical symptoms significantly improved over the 14-day treatment. Frequently reported ADRs were thirst (6.6%), hepatic encephalopathy (2.3%), dehydration (1.5%), and hypernatremia (1.2%). A serum sodium level of ≥ 150 mEq/L was reported in five patients (0.5%). Multivariate analyses showed that the baseline blood urea nitrogen (BUN) level (cut-off value: 22.4 mg/dL) was the predictive factor for tolvaptan treatment response. CONCLUSIONS The results suggest that tolvaptan was effective and well-tolerated in liver cirrhosis patients with hepatic edema. In the real-world clinical setting, tolvaptan provides a useful option for the treatment of hepatic edema.
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Affiliation(s)
- Isao Sakaida
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, 1-1-1, Minamikoogushi, Ube City, Yamaguchi, 755-8505, Japan.
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Japanese Red Cross Musashino Hospital, Tokyo, Japan
| | - Mitsuru Okada
- Department of Pharmacovigilance, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Takahiro Hirano
- Department of Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Yasuhiko Fukuta
- Department of Pharmacovigilance, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan
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13
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Yatsuhashi H, Sano H, Hirano T, Shibasaki Y, Yada T. Prevalence of ascites and its treatment in inpatients with liver cirrhosis: a cohort study using a Japanese medical claims database. ACTA ACUST UNITED AC 2020. [DOI: 10.2957/kanzo.61.314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
| | - Hiromi Sano
- Medical Affairs, Otsuka Pharmaceutical Co., Ltd
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14
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Iida H, Maehira H, Mori H, Maekawa T, Tani M. Post-hepatectomy tolvaptan-induced hypernatremia in a hepatocellular carcinoma patient with cirrhosis: a case report. Surg Case Rep 2020; 6:61. [PMID: 32232601 PMCID: PMC7105548 DOI: 10.1186/s40792-020-00825-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 03/19/2020] [Indexed: 12/18/2022] Open
Abstract
Background Tolvaptan is used in Japan to reduce fluid retention caused by cirrhosis. However, hypernatremia is one of the most important side effects. This report is the first case report of a patient who developed hypernatremia after tolvaptan administration in the early stages following hepatectomy. Case presentation A female patient in her 60s, who was admitted to the psychiatric department of a different hospital for bipolar disorder, developed hepatocellular carcinoma with cirrhosis. She was transferred to our hospital, and hepatectomy was performed in October 2019, after which pleural effusion and severe edema due to fluid retention were evident. Thus, the patient was started on tolvaptan (7.5 mg/day) from postoperative day (POD) 1. The patient began to experience disturbance of consciousness after POD 4. On the fifth day, the serum sodium (Na) level increased to 174 mEq/L, and hypernatremia was diagnosed. The Na level gradually improved with fluid infusion therapy, dropping to preoperative levels on the ninth day; her consciousness also gradually improved. Conclusions Tolvaptan administration must be performed under strictly controlled conditions, followed by careful observation during the early postoperative period, when the patient’s physical status is unstable.
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Affiliation(s)
- Hiroya Iida
- Department of Surgery, Shiga University of Medical Science, Seta Tsukiniwa-Cho, Otsu, Shiga, 520-2192, Japan.
| | - Hiromitsu Maehira
- Department of Surgery, Shiga University of Medical Science, Seta Tsukiniwa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Haruki Mori
- Department of Surgery, Shiga University of Medical Science, Seta Tsukiniwa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Tsuyoshi Maekawa
- Department of Surgery, Shiga University of Medical Science, Seta Tsukiniwa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Masaji Tani
- Department of Surgery, Shiga University of Medical Science, Seta Tsukiniwa-Cho, Otsu, Shiga, 520-2192, Japan
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Kanayama K, Chiba T, Kobayashi K, Koroki K, Maruta S, Kanzaki H, Kusakabe Y, Saito T, Kiyono S, Nakamura M, Ogasawara S, Suzuki E, Ooka Y, Nakamoto S, Yasui S, Kanda T, Maruyama H, Kato J, Kato N. Long-term administration of Tolvaptan to patients with decompensated cirrhosis. Int J Med Sci 2020; 17:874-880. [PMID: 32308540 PMCID: PMC7163362 DOI: 10.7150/ijms.41454] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 02/20/2020] [Indexed: 12/20/2022] Open
Abstract
Aim: Tolvaptan, an oral vasopressin-2 antagonist, sometimes improves hepatic edema including ascites in patients with decompensated cirrhosis. In this study, we examined the effectiveness and survival advantage in patients with the long-term administration of tolvaptan. Methods: A total of 115 patients with refractory ascites who were treated with tolvaptan were retrospectively analyzed based on their clinical records. Patients with a decrease in body weight of ≥1.5 kg from the baseline on day 7 were determined as responders. Re-exacerbation was defined as a return to the baseline BW, dose escalation of conventional diuretics, or abdominal drainage. Results: Of the 115 patients, 84 were included in this analysis. Response to tolvaptan treatment was observed in 55 out of the 84 patients (65.5%), with a mean weight reduction of 2.52 kg. Multivariate analyses demonstrated that body mass index (≥24) and urinary specific gravity (≥1.018) were significant predictors of the response to tolvaptan. However, cumulative re-exacerbation rates in responders at 6 and 12 months were 42.4 and 60.1%, respectively. Child-Pugh (classification C), HCC complication, and serum sodium levels (≥133 mEq/L) were determined as independent prognostic factors impacting overall survival (OS). Although there were no significant differences in OS between tolvaptan responders and non-responders, the responders without re-exacerbation within 3 months showed significantly longer OS than those with re-exacerbation within 3 months. Conclusion: A persistent therapeutic response, but not early response to tolvaptan, was associated with favorable survival of decompensated cirrhotic patients.
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Affiliation(s)
- Kengo Kanayama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Susumu Maruta
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Yuko Kusakabe
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Eiichiro Suzuki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Yoshihiko Ooka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Shin Yasui
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hitoshi Maruyama
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
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Li M, Bi Z, Huang Z. Impact of Vaptans on Clinical Outcomes in Cirrhosis Patients: A Meta-Analysis of Randomized Controlled Trials. Front Pharmacol 2019; 10:1365. [PMID: 31824315 PMCID: PMC6880191 DOI: 10.3389/fphar.2019.01365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 10/28/2019] [Indexed: 12/21/2022] Open
Abstract
Background: Vaptans have been confirmed to mobilize ascites and improve hyponatremia in cirrhosis patients. However, the effects of vaptans on all-cause mortality, ascites-related complications, and adverse events in cirrhosis patients have not been fully determined. Objectives: To systematically evaluate the impact of vaptans on the clinical outcomes in patients with cirrhosis. Materials and Methods: A systematic review and meta-analysis was performed. The PubMed, Embase, and Cochrane’s Library electronic databases were systematically searched for randomized controlled trials (RCTs) investigating the clinical efficacy of vaptans in cirrhosis patients. The results were pooled with a random-effect model. Results: Eighteen RCTs containing 3,059 cirrhosis patients with ascites and/or hyponatremia were included. Meta-analysis showed that vaptans did not significantly affect the risk of all-cause mortality (RR: 1.02, 95% CI: 0.87 to 1.08, p = 0.83; I2 = 2%), consistent with studies with short-term (< 26 weeks) and long-term (≥ 26 weeks) follow-up durations. Additionally, vaptans did not affect the incidence of variceal bleeding (RR: 0.96, p = 0.86), showed a trend of reduced incidence of hepatic encephalopathy (RR: 0.86, p = 0.09), significantly reduced the incidence of spontaneous bacterial peritonitis (RR: 0.75, p = 0.03), but did not significantly affect the risk of hepatorenal syndrome or renal failure (RR: 1.09, p = 0.36). Vaptans did not affect the incidence of adverse events in cirrhosis patients. Discussion: Treatment with vaptans is not associated with improved survival in cirrhosis patients, although it may reduce the risk of hepatic encephalopathy and spontaneous bacterial peritonitis in these patients. The limitations of the current study include limited number of available studies, small sample sizes of the included studies, variations of baseline patient characteristics, and differences in the dose and duration of vaptans.
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Affiliation(s)
- Miao Li
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhuofang Bi
- Department of Ultrasonography, the Sihui People's Hospital, Zhaoqing, China
| | - Zicheng Huang
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Kiritani S, Kaneko J, Miyata Y, Matsumura M, Akamatsu N, Ishizawa T, Arita J, Tamura S, Kokudo N, Hasegawa K. A selective oral vasopressin V2-receptor antagonist for patients with end-stage liver disease awaiting liver transplantation: a preliminary study. Biosci Trends 2019; 13:189-196. [PMID: 31019162 DOI: 10.5582/bst.2019.01072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Administration of the selective arginine vasopressin V2 receptor antagonist tolvaptan to cirrhotic patients is controversial. There are no reports of tolvaptan use for patients with far-advanced end-stage liver disease (ESLD) and refractory ascites awaiting liver transplantation. Between 2013 and 2016, 64 patients awaiting adult-to-adult living donor liver transplantation (LDLT) were screened for enrollment. Patients with refractory ascites and on dual conventional diuretics (≥ 50 mg/day of spironolactone and ≥ 20 mg/day of a loop diuretic) were enrolled and assigned to the tolvaptan (TOL) group (n = 10), and low-dose tolvaptan, 3.75 mg/day, was started. The remaining patients who had no or little ascites on conventional diuretic therapy (CDT) were assigned to the CDT group (n = 23). The median model for end-stage liver disease and Child-Pugh scores were 16 (range 7-41) and 10 (7-15), respectively. The median dose of spironolactone in the TOL group was 88 mg (range 50-200) vs. 50 (0-100) in the CDT group (p < 0.01). The median dose of loop diuretics in the TOL group was 70 mg (20-120) vs. 20 (0-80) in the CDT group (p = 0.03). No significant liver damage was detected during tolvaptan therapy. Tolvaptan demonstrated favorable effects in 60% (6/10) of the patients, decreasing the body weight by at least 1.5 kg during the 7 day treatment. These findings suggest that low-dose of tolvaptan may be safe for patients having far-advanced ESLD patients with apparent and refractory ascites taking dual conventional diuretics for a short period before LDLT.
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Affiliation(s)
- Sho Kiritani
- Hepato-Biliary-Pancreatic Surgery Division, and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Junichi Kaneko
- Hepato-Biliary-Pancreatic Surgery Division, and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Yoichi Miyata
- Hepato-Biliary-Pancreatic Surgery Division, and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Masaru Matsumura
- Hepato-Biliary-Pancreatic Surgery Division, and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Nobuhisa Akamatsu
- Hepato-Biliary-Pancreatic Surgery Division, and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Takeaki Ishizawa
- Hepato-Biliary-Pancreatic Surgery Division, and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Junichi Arita
- Hepato-Biliary-Pancreatic Surgery Division, and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | - Sumihito Tamura
- Hepato-Biliary-Pancreatic Surgery Division, and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
| | | | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo
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Kamimura K, Sakamaki A, Kamimura H, Setsu T, Yokoo T, Takamura M, Terai S. Considerations of elderly factors to manage the complication of liver cirrhosis in elderly patients. World J Gastroenterol 2019; 25:1817-1827. [PMID: 31057296 PMCID: PMC6478616 DOI: 10.3748/wjg.v25.i15.1817] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 03/12/2019] [Accepted: 03/16/2019] [Indexed: 02/06/2023] Open
Abstract
The aging of the organ function causes sensitivity to the disease progression and need careful consideration for the medical treatment. With the increase of aging population, the opportunity to provide medical treatment for people in very old age is rapidly increasing therefore, the understanding of the various physiological changes of cellular function, size and function of organs are essential for the decision of therapeutic options. Among the various chronic conditions seen in elderly people, we have focused on liver cirrhosis, since despite specific therapeutic options for many of liver diseases including direct acting antivirals for hepatitis C virus, nucleoside analogs for hepatitis B, and corticosteroids for autoimmune hepatitis, there is currently no standard therapy to treat liver cirrhosis, which is the final stage of these liver diseases. Therefore, management of the various symptoms of liver cirrhosis is essential, and aging-related parameters must be considered in the decision making for therapeutic strategies and dosage of the available medicine. In this mini-review, we have summarized the therapeutic options to manage various symptoms of liver cirrhosis, carefully considering the physiological changes of various organs associated with aging.
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Affiliation(s)
- Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Toru Setsu
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Masaaki Takamura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
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Sagawa E, Okubo H, Ando H, Sorin Y, Kanazawa R, Nakadera E, Fukada H, Kokubu S, Miyazaki A. Plasma concentration and efficacy of tolvaptan in cirrhotic patients with refractory ascites. J Pharmacol Sci 2019; 139:373-376. [DOI: 10.1016/j.jphs.2019.01.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 01/18/2019] [Indexed: 01/14/2023] Open
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Segawa M, Sakaida I. Treatment of Refractory Ascites. CLINICAL INVESTIGATION OF PORTAL HYPERTENSION 2019:501-508. [DOI: 10.1007/978-981-10-7425-7_51] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Fukui H, Kawaratani H, Kaji K, Takaya H, Yoshiji H. Management of refractory cirrhotic ascites: challenges and solutions. Hepat Med 2018; 10:55-71. [PMID: 30013405 PMCID: PMC6039068 DOI: 10.2147/hmer.s136578] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Among the various risky complications of liver cirrhosis, refractory ascites is associated with poor survival of cirrhotics and persistently worsens their quality of life (QOL). Major clinical guidelines worldwide define refractory ascites as ascites that cannot be managed by medical therapy either because of a lack of response to maximum doses of diuretics or because patients develop complications related to diuretic therapy that preclude the use of an effective dose of diuretics. Due to the difficulty in receiving a liver transplantation (LT), the ultimate solution for refractory ascites, most cirrhotic patients have selected the palliative therapy such as repeated serial paracentesis, transjugular intrahepatic portosystemic shunt, or peritoneovenous shunt to improve their QOL. During the past several decades, new interventions and methodologies, such as indwelling peritoneal catheter, peritoneal-urinary drainage, and cell-free and concentrated ascites reinfusion therapy, have been introduced. In addition, new medical treatments with vasoconstrictors or vasopressin V2 receptor antagonists have been proposed. Both the benefits and risks of these old and new modalities have been extensively studied in relation to the pathophysiological changes in ascites formation. Although the best solution for refractory ascites is to eliminate hepatic failure either by LT or by causal treatment, the selection of the best palliative therapy for individual patients is of utmost importance, aiming at achieving the longest possible, comfortable life. This review briefly summarizes the changing landscape of variable treatment modalities for cirrhotic patients with refractory ascites, aiming at clarifying their possibilities and limitations. Evolving issues with regard to the impact of gut-derived systemic and local infection on the clinical course of cirrhotic patients have paved the way for the development of a new gut microbiome-based therapeutics. Thus, it should be further investigated whether the early therapeutic approach to gut dysbiosis provides a better solution for the management of cirrhotic ascites.
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Affiliation(s)
- Hiroshi Fukui
- Department of Gastroenterology, Endocrinology and Metabolism, Nara Medical University, Nara, Japan,
| | - Hideto Kawaratani
- Department of Gastroenterology, Endocrinology and Metabolism, Nara Medical University, Nara, Japan,
| | - Kosuke Kaji
- Department of Gastroenterology, Endocrinology and Metabolism, Nara Medical University, Nara, Japan,
| | - Hiroaki Takaya
- Department of Gastroenterology, Endocrinology and Metabolism, Nara Medical University, Nara, Japan,
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Endocrinology and Metabolism, Nara Medical University, Nara, Japan,
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Nagler EV, Haller MC, Van Biesen W, Vanholder R, Craig JC, Webster AC. Interventions for chronic non-hypovolaemic hypotonic hyponatraemia. Cochrane Database Syst Rev 2018; 6:CD010965. [PMID: 29953167 PMCID: PMC6513194 DOI: 10.1002/14651858.cd010965.pub2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Chronic (present > 48 hours) non-hypovolaemic hyponatraemia occurs frequently, can be caused by various conditions, and is associated with shorter survival and longer hospital stays. Many treatments, such as fluid restriction or vasopressin receptor antagonists can be used to improve the hyponatraemia, but whether that translates into improved patient-important outcomes is less certain. OBJECTIVES This review aimed to 1) look at the benefits and harms of interventions for chronic non-hypovolaemic hypotonic hyponatraemia when compared with placebo, no treatment or head-to-head; and 2) determine if benefits and harms vary in absolute or relative terms dependent on the specific compound within a drug class, on the dosage used, or the underlying disorder causing the hyponatraemia. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 1 December 2017 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. We also screened the reference lists of potentially relevant studies, contacted authors, and screened the websites of regulatory agencies. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs that compared the effects of any intervention with placebo, no treatment, standard care, or any other intervention in patients with chronic non-hypovolaemic hypotonic hyponatraemia. We also included subgroups with hyponatraemia from studies with broader inclusion criteria (e.g. people with chronic heart failure or people with cirrhosis with or without hyponatraemia), provided we could obtain outcomes for participants with hyponatraemia from the report or the study authors. DATA COLLECTION AND ANALYSIS Two authors independently extracted data and assessed risk of bias. We expressed treatment effects as mean difference (MD) for continuous outcomes (health-related quality of life, length of hospital stay, change from baseline in serum sodium concentration, cognitive function), and risk ratio (RR) for dichotomous outcomes (death, response and rapid increase in serum sodium concentration, hypernatraemia, polyuria, hypotension, acute kidney injury, liver function abnormalities) together with 95% confidence intervals (CI). MAIN RESULTS We identified 35 studies, enrolling 3429 participants. Twenty-eight studies (3189 participants) compared a vasopressin receptor antagonist versus placebo, usual care, no treatment, or fluid restriction. In adults with chronic, non-hypovolaemic hypotonic hyponatraemia, vasopressin receptor antagonists have uncertain effects on death at six months (15 studies, 2330 participants: RR 1.11, 95% CI 0.92 to 1.33) due to risk of selective reporting and serious imprecision; and on health-related quality of life because results are at serious risk of performance, selective reporting and attrition bias, and suffer from indirectness related to the validity of the Short Form Health Survey (SF-12) in the setting of hyponatraemia. Vasopressin receptor antagonists may reduce hospital stay (low certainty evidence due to risk of performance bias and imprecision) (3 studies, 610 participants: MD -1.63 days, 95% CI -2.96 to -0.30), and may make little or no difference to cognitive function (low certainty evidence due to indirectness and imprecision). Vasopressin receptor antagonists probably increase the intermediate outcome of serum sodium concentration (21 studies, 2641 participants: MD 4.17 mmol/L, 95% CI 3.18 to 5.16), corresponding to two and a half as many people having a 5 to 6 mmol/L increase in sodium concentration compared with placebo at 4 to 180 days (moderate certainty evidence due to risk of attrition bias) (18 studies, 2014 participants: RR 2.49, 95% CI 1.95 to 3.18). But they probably also increase the risk of rapid serum sodium correction - most commonly defined as > 12 mmol/L/d (moderate certainty evidence due to indirectness) (14 studies, 2058 participants: RR 1.67, 95% CI 1.16 to 2.40) and commonly cause side-effects such as thirst (13 studies, 1666 participants: OR 2.77, 95% CI 1.80 to 4.27) and polyuria (6 studies, 1272 participants): RR 4.69, 95% CI 1.59 to 13.85) (high certainty evidence). The potential for liver toxicity remains uncertain due to large imprecision. Effects were generally consistent across the different agents, suggesting class effect.Data for other interventions such as fluid restriction, urea, mannitol, loop diuretics, corticosteroids, demeclocycline, lithium and phenytoin were largely absent. AUTHORS' CONCLUSIONS In people with chronic hyponatraemia, vasopressin receptor antagonists modestly raise serum sodium concentration at the cost of a 3% increased risk of it being rapid. To date there is very low certainty evidence for patient-important outcomes; the effects on mortality and health-related quality of life are unclear and do not rule out appreciable benefit or harm; there does not appear to be an important effect on cognitive function, but hospital stay may be slightly shorter, although available data are limited. Treatment decisions must weigh the value of an increase in serum sodium concentration against its short-term risks and unknown effects on patient-important outcomes. Evidence for other treatments is largely absent.Further studies assessing standard treatments such as fluid restriction or urea against placebo and one-another would inform practice and are warranted. Given the limited available evidence for patient-important outcomes, any study should include these outcomes in a standardised manner.
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Affiliation(s)
- Evi V Nagler
- Ghent University HospitalRenal Division, Sector Metabolic and Cardiovascular ConditionsDe Pintelaan 185GhentBelgium9000
- Guidance Body of the European Renal Association – European Dialysis and Transplant Association (ERA‐EDTA)European Renal Best Practice (ERBP)LondonUK
| | - Maria C Haller
- Guidance Body of the European Renal Association – European Dialysis and Transplant Association (ERA‐EDTA)European Renal Best Practice (ERBP)LondonUK
- Medical University ViennaSection for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent SystemsSpitalgasse 23ViennaAustriaA‐1090
- Ordensklinikum Linz ElisabethinenDepartment of NephrologyFadingerstraße 1LinzAustria4020
| | - Wim Van Biesen
- Ghent University HospitalRenal Division, Sector Metabolic and Cardiovascular ConditionsDe Pintelaan 185GhentBelgium9000
- Guidance Body of the European Renal Association – European Dialysis and Transplant Association (ERA‐EDTA)European Renal Best Practice (ERBP)LondonUK
| | - Raymond Vanholder
- Ghent University HospitalRenal Division, Sector Metabolic and Cardiovascular ConditionsDe Pintelaan 185GhentBelgium9000
- Guidance Body of the European Renal Association – European Dialysis and Transplant Association (ERA‐EDTA)European Renal Best Practice (ERBP)LondonUK
| | - Jonathan C Craig
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchWestmeadNSWAustralia2145
- The University of SydneySydney School of Public HealthEdward Ford Building A27SydneyNSWAustralia2006
- Flinders UniversityCollege of Medicine and Public HealthAdelaideSAAustralia5001
| | - Angela C Webster
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchWestmeadNSWAustralia2145
- The University of SydneySydney School of Public HealthEdward Ford Building A27SydneyNSWAustralia2006
- The University of Sydney at WestmeadCentre for Transplant and Renal Research, Westmead Millennium InstituteWestmeadNSWAustralia2145
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Tajiri K, Tokimitsu Y, Ito H, Atarashi Y, Kawai K, Minemura M, Yasumura S, Takahara T, Shimizu Y, Sugiyama T. Survival Benefit of Tolvaptan for Refractory Ascites in Patients with Advanced Cirrhosis. Dig Dis 2018; 36:314-321. [PMID: 29852495 DOI: 10.1159/000489258] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 04/11/2018] [Indexed: 02/05/2023]
Abstract
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.
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Affiliation(s)
- Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
| | | | - Hiroyuki Ito
- Department of Gastroenterology, Takaoka Municipal Hospital, Toyama, Japan
| | | | - Kengo Kawai
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
- Department of Gastroenterology, Nanto Municipal Hospital, Nanto, Japan
| | - Masami Minemura
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
| | - Satoshi Yasumura
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
| | - Terumi Takahara
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
| | - Yukihiro Shimizu
- Department of Gastroenterology, Nanto Municipal Hospital, Nanto, Japan
| | - Toshiro Sugiyama
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
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Validation trial for efficacy of ultrasonographic measurement method to predict ascitic volume using virtual ultrasonography. J Med Ultrason (2001) 2018; 45:555-564. [PMID: 29671146 DOI: 10.1007/s10396-018-0879-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 03/22/2018] [Indexed: 01/15/2023]
Abstract
PURPOSE The aim of this study was to clarify whether ultrasound quantitative methods were positively correlated with volume of ascites evaluated by whole abdominopelvic CT. METHODS Sixty-eight patients with cirrhotic ascites were retrospectively analyzed. First, to confirm that virtual ultrasonography (VUS) is an alternative method to conventional ultrasound, 22 patients underwent both conventional ultrasonography and VUS. Second, the efficacy of US quantitative methods (3-point method, 4-point method, 5-point method, and Matsumoto's method) was confirmed by VUS in 68 patients. We assessed whether the ascites volume predicted by VUS corresponded with that calculated by 3D-CT. Of the 68 patients, 23 patients were analyzed before and after administration of tolvaptan. RESULTS The predictive volumes calculated by VUS were remarkably relative to those yielded by conventional US. Correlations between exact volume and those measured by VUS were significantly high (3-point method: r = 0.882, p < 0.001; 4-point method: r = 0.797, p < 0.001; 5-point method: r = 0.836, p < 0.001; Matsumoto's method: r = 0.453, p < 0.001). Correlations between decreasing volume on 3D-CT and that measured by VUS were also significantly high in patients with administration of tolvaptan. CONCLUSION Ascites volume measured by ultrasound was effective, especially the 3-point and 5-point methods. It was useful to assess the efficacy of diuretics in cirrhotic patients.
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Wang YF, Tang JT, Han T, Ding HG, Ye WJ, Wang MR, Cheng J, Yang YP, Chen CW, Xie Q, Mao Q, Niu JQ, Wang ZH, Wei Z, Chen YX, Zeng MD, Mao YM. Tolvaptan in Chinese cirrhotic patients with ascites: A randomized, placebo-controlled phase 2 trial. J Dig Dis 2018; 19:144-154. [PMID: 29389068 DOI: 10.1111/1751-2980.12583] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 01/25/2018] [Accepted: 01/29/2018] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To evaluate tolvaptan as a novel therapeutic option for Chinese patients with liver cirrhosis-associated ascites in a phase 2 clinical trial. METHODS This randomized, double-blind, placebo-controlled, multicenter trial was conducted in patients with insufficient responses to combination therapies of an oral loop diuretic and an aldosterone antagonist. Reduction in body weight and abdominal circumference, increase in 24-h cumulative urine volume and improvement in serum sodium level from baseline to the end of treatment in the tolvaptan groups (15 mg/day or 30 mg/day orally) were compared with those in the placebo group. Drug safety was also assessed. RESULTS Sixty-two patients were allocated to the placebo group, 56 to the tolvaptan 15-mg group and 63 to the tolvaptan 30-mg group. Their mean changes in body weight were -0.5 ± 1.6 kg, -2.1 ± 2.0 kg and -1.9 ± 2.0 kg, respectively. Body weight reductions in both tolvaptan groups were significantly greater than that in the placebo group (difference -1.6, 95% confidence interval [CI] -2.5 to -0.8, and difference -1.4, 95% CI, -2.2 to -0.7, both P < 0.0001). The administration of tolvaptan also significantly reduced the abdominal circumference, increased 24-h cumulative urine volume and serum sodium level compared with placebo. The most common adverse events in the tolvaptan groups were constipation, diarrhea, dry mouth and thirst, with no severe adverse events observed. CONCLUSION Tolvaptan at 15 mg/day significantly reduced the body weight and abdominal circumference in patients with liver cirrhosis-associated ascites, which needs to be confirmed in a phase 3 trial.
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Affiliation(s)
- Yong Feng Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jie Ting Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Tao Han
- Division of Hepatology, Tianjin Third Hospital, Tianjin, China
| | - Hui Guo Ding
- Division of Gastroenterology and Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Wei Jiang Ye
- Department of Infectious Diseases, Xixi Hospital of Hangzhou, Hangzhou, Zhejiang Province, China
| | - Mao Rong Wang
- Department of Infectious Diseases, Nanjing Bayi Hospital, Nanjing, Jiangsu Province, China
| | - Jun Cheng
- Department of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yong Ping Yang
- Department of Infectious Diseases, 302 Military Hospital of China, Beijing, China
| | - Cheng Wei Chen
- Division of Hepatology, 85 Hospital of People's Liberation Army, Shanghai, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Mao
- Department of Infectious Diseases, Southwest Hospital, Chongqing, China
| | - Jun Qi Niu
- Department of Infectious Diseases, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Zheng Hua Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Zhong Wei
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ying Xuan Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Min De Zeng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yi Min Mao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
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Sbardella E, Isidori AM, Arnaldi G, Arosio M, Barone C, Benso A, Berardi R, Capasso G, Caprio M, Ceccato F, Corona G, Della Casa S, De Nicola L, Faustini-Fustini M, Fiaccadori E, Gesualdo L, Gori S, Lania A, Mantovani G, Menè P, Parenti G, Pinto C, Pivonello R, Razzore P, Regolisti G, Scaroni C, Trepiccione F, Lenzi A, Peri A. Approach to hyponatremia according to the clinical setting: Consensus statement from the Italian Society of Endocrinology (SIE), Italian Society of Nephrology (SIN), and Italian Association of Medical Oncology (AIOM). J Endocrinol Invest 2018; 41:3-19. [PMID: 29152673 DOI: 10.1007/s40618-017-0776-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 10/13/2017] [Indexed: 12/17/2022]
Affiliation(s)
- E Sbardella
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - A M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - G Arnaldi
- Clinica di Endocrinologia e Malattie del Metabolismo, Università Politecnica delle Marche Azienda Ospedaliero-Universitaria, Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Ancona, Italy
| | - M Arosio
- Endocrinology and Diabetology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - C Barone
- UOC di Oncologia Medica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - A Benso
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - R Berardi
- Clinica Oncologica, Università Politecnica delle Marche Azienda Ospedaliero-Universitaria; Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Ancona, Italy
| | - G Capasso
- Dipartimento di Scienze Cardio-Toraciche e Respiratorie, Università della Campania "Luigi Vanvitelli", Caserta, Italy
| | - M Caprio
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy
| | - F Ceccato
- Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Padua, Italy
| | - G Corona
- Endocrinology Unit, Medical Department, Azienda Usl Bologna Maggiore-Bellaria Hospital, Bologna, Italy
| | - S Della Casa
- Endocrinology and Metabolic Diseases Unit, Catholic University of the Sacred Heart, Rome, Italy
| | - L De Nicola
- Nephrology, Medical School, University of Campania Luigi Vanvitelli, Naples, Italy
| | - M Faustini-Fustini
- Pituitary Unit, IRCCS Institute of Neurological Sciences, Bellaria Hospital, Bologna, Italy
| | - E Fiaccadori
- Renal Unit, Parma University Medical School, Parma, Italy
| | - L Gesualdo
- Nephrology Dialysis and Transplantation, Bari University Medical School, Bari, Italy
| | - S Gori
- UOC Oncologia Medica, Ospedale Sacro Cuore Don Calabria, Negrar, Verona, Italy
| | - A Lania
- Endocrine Unit, Department of Biomedical Sciences, Humanitas Research Hospital, Humanitas University, Rozzano (MI), Italy
| | - G Mantovani
- Endocrinology and Diabetology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - P Menè
- Nephrology, Sapienza University of Rome, Rome, Italy
| | - G Parenti
- Endocrine Unit, Careggi Hospital, Florence, Italy
| | - C Pinto
- Oncologia Medica IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, Italy
| | - R Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università "Federico II" di Napoli, Naples, Italy
| | - P Razzore
- Endocrine Unit, AO Ordine Mauriziano, Turin, Italy
| | - G Regolisti
- Renal Unit, Parma University Medical School, Parma, Italy
| | - C Scaroni
- Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Padua, Italy
| | - F Trepiccione
- Dipartimento di Scienze Cardio-Toraciche e Respiratorie, Università della Campania "Luigi Vanvitelli", Caserta, Italy
| | - A Lenzi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - A Peri
- Endocrine Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", AOU Careggi, University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy.
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27
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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. [PMID: 27958663 DOI: 10.1111/hepr.12852] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 12/08/2016] [Accepted: 12/09/2016] [Indexed: 02/08/2023]
Abstract
AIM Loop diuretics and spironolactone are used in patients with hepatic edema, but they are sometimes associated with insufficient responses as well as adverse events. Tolvaptan, a vasopressin type 2 receptor antagonist, was approved for hepatic edema in 2013. A large-scale post-marketing surveillance study has been carried out to evaluate the effectiveness and safety of tolvaptan in real-world clinical settings. METHODS Patients with hepatic cirrhosis with insufficient response to conventional diuretics were enrolled. The observational period was up to 6 months. Changes in body weight and clinical symptoms were measured to evaluate effectiveness. The incidence of adverse drug reactions was summarized as a safety measure. RESULTS Of 970 patients enrolled, 463 were included in the safety analysis. Of this group, 340 were included in the effectiveness analysis. Decreases in body weight from baseline were -2.38 kg on day 7 and -3.52 kg on day 14. Ascites and bloated feeling was significantly improved within 14 days. The mean change in body weight depended on estimated glomerular filtration rate levels. The most frequently reported adverse drug reaction was thirst (6.9% of patients). Serum sodium level of ≥146 mEq/L was observed in 12 patients (2.7%). CONCLUSIONS In the real-world clinical setting, tolvaptan showed aquaretic effectiveness in patients with cirrhosis. The mean change in body weight depended on renal function. We recommend tolvaptan use for hepatic cirrhosis at a stage in which the renal function is maintained.
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Affiliation(s)
- Isao Sakaida
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan
| | - Shuji Terai
- Department of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan
| | - Moriyoshi Yasuda
- Department of Pharmacovigilance, Otsuka Pharmaceutical Co.Ltd., Osaka, Japan
| | - Mitsuru Okada
- Department of Pharmacovigilance, Otsuka Pharmaceutical Co.Ltd., Osaka, Japan
| | - Kosuke Bando
- Department of Pharmacovigilance, Otsuka Pharmaceutical Co.Ltd., Osaka, Japan
| | - Yasuhiko Fukuta
- Department of Pharmacovigilance, Otsuka Pharmaceutical Co.Ltd., Osaka, Japan
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28
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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. [PMID: 27704665 DOI: 10.1111/hepr.12826] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 09/28/2016] [Accepted: 10/02/2016] [Indexed: 02/06/2023]
Abstract
AIMS The efficacy of the vasopressin V2 receptor antagonist tolvaptan for difficult-to-treat cirrhotic ascites has recently been reported. However, its effect is variable among patients. This study aimed to clarify the predictive factors for obtaining a good response to tolvaptan in patients with difficult-to-treat ascites. METHODS Data were collected from 50 patients with liver cirrhosis having ascites (hepatitis B, n = 1; hepatitis C, n = 22; alcoholism, n = 11; and others, n = 16) after treatment with tolvaptan (3.75-7.5 mg/day) in addition to conventional diuretics. A follow-up assessment was carried out after 7-day tolvaptan treatment for all patients. RESULTS After an uneventful 7-day tolvaptan treatment, 18 patients (36.0%) lost more than 2 kg of their body weight (responders). Twenty-six patients (52.0%) showed an increase in urine volume (>300 mL) on day 2. Tolvaptan was also effective for patients with pleural effusion, portal vein thrombosis, and hepatocellular carcinoma. Basal blood urea nitrogen (BUN) levels, plasma renin activity, and aldosterone levels were significantly higher in the poor responders (<2 kg weight loss), who were considered to be in the relative vascular underfilling state, than in the responders. Basal BUN was extracted as a predictive factor of responsiveness by multivariate logistic regression analysis. CONCLUSIONS Tolvaptan is useful and safe for the treatment of cirrhotic ascites. This report showed that BUN will predict the response of tolvaptan even when measured before tolvaptan treatment.
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Affiliation(s)
- Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Hiroshi Fukui
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Ryuichi Noguchi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Masakazu Uejima
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Kosuke Takeda
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Yasushi Okura
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Norihisa Nishimura
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Yousuke Aihara
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Yasuhiko Sawada
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Kenichiro Seki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Junichi Yamao
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
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29
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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. [PMID: 27059410 DOI: 10.1111/hepr.12716] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Revised: 03/18/2016] [Accepted: 03/29/2016] [Indexed: 02/08/2023]
Abstract
AIM To assess the correlation between response to tolvaptan and treatment-related factors in liver cirrhosis patients. METHODS This single-center retrospective study was carried out at Shonan Kamakura General Hospital in Kanagawa, Japan, between October 2013 and September 2015. Forty-three liver cirrhosis patients (mean age, 65.7 years) with insufficient responses to conventional diuretics for at least 7 days were enrolled. All patients received oral tolvaptan (7.5 mg/day for 7 days) and guideline-directed medical therapy including sodium intake restrictions. A responder to tolvaptan was defined as a patient having a ≥2-kg decrease in body weight 1 week after commencing drug treatment, and a non-responder was defined as a patient not losing ≥2 kg in body weight 1 week after commencing treatment. We investigated the correlation of change in body weight for 1 week after drug administration compared to baseline clinical characteristics. RESULTS The mean body weight change from the baseline on the final dosing day was -2.47 ± 3.34 kg (P < 0.0001). There were 20 (46.5%) responders to tolvaptan. Urinary sodium and volume excretion was higher in responders than in non-responders (108.2 ± 70.5 vs 42.6 ± 36.7, P = 0.0003; 1462.8 ± 625.7 vs 960.9 ± 600.6, P = 0.0073). Logistic regression analyses for responders to tolvaptan were carried out, and independent correlation of the responders was urinary sodium excretion (P = 0.0114; hazard ratio, 0.9418; 95% confidence interval, 0.8768-0.9896) in the multivariate analyses. CONCLUSION In decompensated liver cirrhosis patients, urinary excretion sodium showed good correlation with tolvaptan response.
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Affiliation(s)
- Haruki Uojima
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan.,Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takeshi Kinbara
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Hisashi Hidaka
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Ji Hyun Sung
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Masachika Ichida
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Shinnosuke Tokoro
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Sakue Masuda
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Satoshi Takizawa
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Akiko Sasaki
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Kazuya Koizumi
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Hideto Egashira
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Makoto Kako
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
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30
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Kawaratani H, Fukui H, Yoshiji H. Treatment for cirrhotic ascites. Hepatol Res 2017; 47:166-177. [PMID: 27363974 DOI: 10.1111/hepr.12769] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Revised: 06/23/2016] [Accepted: 06/27/2016] [Indexed: 12/11/2022]
Abstract
Common complications of decompensated liver cirrhosis are esophageal varices, hepatic encephalopathy and ascites. After the onset of complications, the prognosis worsens. In patients with ascites, the 5-year mortality rate is 44%. Furthermore, hyponatremia, spontaneous bacterial translocation and hepatorenal syndrome also greatly worsen the prognosis. Effective treatment of cirrhotic ascites improves the quality of life and survival rate. Recently, the newly produced diuretic, tolvaptan (vasopressin V2 receptor antagonist), was reported to be effective in the treatment of refractory ascites in liver cirrhosis; however, there has not been an associated positive effect on the prognosis. There are various types of treatment for ascites, such as large-volume paracenteses, a cell-free and concentrated ascites reinfusion therapy, a transjugular intrahepatic portosystemic shunt, and a peritoneo-venous shunt. Although they improve the prognosis, liver transplantation remains the ultimate form of treatment. The present article discusses the therapeutic management of cirrhotic ascites.
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Affiliation(s)
- Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hiroshi Fukui
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
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31
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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. [PMID: 26990144 DOI: 10.1111/hepr.12700] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Revised: 03/09/2016] [Accepted: 03/10/2016] [Indexed: 02/08/2023]
Abstract
Volume overload is common in liver cirrhosis, heart failure, and chronic kidney disease, being an independent risk factor for mortality. Loop diuretics have been widely used for treating volume overload in these patients. However, there is a tendency to increase the dose of loop diuretics partly because of diuresis resistance. Neurohormonal factors are also enhanced in these patients, which play a role in volume overload and organ ischemia. Loop diuretics cannot improve neurohormonal factors and could result in end-organ damage. The water diuretic tolvaptan has been approved for use for volume overload in heart failure and liver cirrhosis. Despite causing similar increases in urine volume, its characteristics differ from those of loop diuretics. Renal blood flow is maintained with tolvaptan but decreased with furosemide in heart failure patients. Neurohormonal factors and blood pressure are not markedly altered by tolvaptan administration. It is expected that these mechanisms of tolvaptan can protect against worsening renal function by volume overload diseases compared with loop diuretics. It has also been reported that some patients do not respond well to tolvaptan. Loop diuretics and tolvaptan share the same mechanism with regard to decreasing renal interstitial osmolality, which plays a fundamental role in water diuresis. Thus, a high dose of loop diuretics could result in resistance to tolvaptan, so tolvaptan should be administered before increasing the loop diuretic dose. Therefore, volume control without enhancing end-organ damage can be achieved by adding tolvaptan to a tolerable dose of Na-sparing diuretics.
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Affiliation(s)
- Takefumi Mori
- Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Integrative Renal Replacement Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Yusuke Ohsaki
- Division of Integrative Renal Replacement Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Ikuko Oba-Yabana
- Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Integrative Renal Replacement Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Sadayoshi Ito
- Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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32
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Jia JD, Xie W, Ding HG, Mao H, Guo H, Li Y, Wang X, Wang JF, Lu W, Li CZ, Mao Y, Wang GQ, Gao YQ, Wang B, Zhang Q, Ge Y, Wong VWS. Utility and safety of tolvaptan in cirrhotic patients with hyponatremia: A prospective cohort study. Ann Hepatol 2017; 16:123-132. [PMID: 28051801 DOI: 10.5604/16652681.1226823] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
UNLABELLED Introduction and aim. Hyponatremia is common in patients with decompensated cirrhosis and is associated with increased mortality. Tolvaptan, a vasopressor V2 receptor antagonist, can increase free water excretion, but its efficacy and safety in cirrhotic patients remain unclear. MATERIAL AND METHODS We studied the usage and safety of tolvaptan in cirrhotic patients in a real-life, non-randomized, multicenter prospective cohort study. Forty-nine cirrhotic patients with hyponatremia were treated with tolvaptan 15 mg daily, and 48 patients not treated with tolvaptan in the same period served as controls. Improvement in serum sodium level was defined as an increase in serum sodium from < 125 to ≥ 125 mmol/L or from 125-134 to ≥ 135 mmol/L on day 7. RESULTS Twenty-three (47%) patients in the tolvaptan group and 17 (35%) in the control group had normal serum sodium on day 7 (p = 0.25). Serum sodium improved in 30 (61%) patients in the tolvaptan group and 17 (35%) patients in the control group (p = 0.011). Adverse events occurred in 46-47% of patients in both groups, and tolvaptan was not associated with worsened liver function. No patient with normal serum sodium on day 7 died within 30 days of treatment, whereas 16% of those with persistent hyponatremia died (p = 0.0019). CONCLUSION In conclusion, short-term tolvaptan treatment is safe and can improve serum sodium level in cirrhotic patients with hyponatremia. Normalization of serum sodium level is associated with better survival.
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Affiliation(s)
- Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wen Xie
- Beijing Di Tan Hospital, Capital Medical University, Beijing, China
| | - Hui-Guo Ding
- Department of Gastroenterology and Hepatology, Beijing You'an Hospital affiliated with Capital Medical University, Beijing, China
| | - Hua Mao
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Hui Guo
- 5 First Teaching Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yonggang Li
- Department of Integrative Medical Center, 302 Military Hospital of People's Liberation Army, Beijing, China
| | - Xiaojin Wang
- Hospital 85 People's Liberation Army of China, Shanghai, China
| | - Jie-Fei Wang
- Shanghai Public Health Clinical Center Affiliated to Fudan University, Shanghai, China
| | - Wei Lu
- Tianjin Second People-s Hospital, Tianjin First Center Hospital, Tianjin, China
| | - Cheng-Zhong Li
- Renji Hospital Shanghai, Jiao Tong University School of Medicine, Shanghai, China
| | - Yimin Mao
- Peking University First Hospital, Beijing, China
| | - Gui-Qiang Wang
- Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue-Qiu Gao
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China
| | - Bangmao Wang
- Tongren Hospital Shanghai, Jiaotong University School of Medicine, Shanghai, China
| | - Qin Zhang
- Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou, China
| | - Yan Ge
- Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Vincent Wai-Sun Wong
- Changhai Hospital, The Second Military Medical University, Shanghai, China
- Renji Hospital Shanghai, Jiao Tong University School of Medicine, Shanghai, China
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Ogihara Y, Yamada N, Dohi K, Matsuda A, Ota S, Ishikura K, Nakamura M, Ito M. Effects of low-dose tolvaptan on electrolyte abnormality and hemodynamic parameters in a liver cirrhosis-associated portopulmonary hypertension patient: A case report. Exp Ther Med 2016; 13:269-272. [PMID: 28123500 DOI: 10.3892/etm.2016.3945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 10/27/2015] [Indexed: 12/14/2022] Open
Abstract
The present study reported a case of portopulmonary hypertension (POPH) that was secondary to underlying liver cirrhosis in a 58-year-old woman, who was successfully treated with low-dose tolvaptan. The patient had suffered from refractory peripheral edema and electrolyte abnormalities, including severe hypokalemia, under the combination therapy of sildenafil, ambrisentan, furosemide and spironolactone. Subsequent to the initiation of low-dose tolvaptan at 3.75 mg/day with concurrent de-escalation of the dose of furosemide, the daily urine volume increased, peripheral edema improved and the serum potassium level increased immediately. In addition, plasma renin activity, plasma aldosterone concentration and plasma brain natriuretic peptide level decreased within 1 week after the initiation of tolvaptan therapy. Hemodynamic assessments using a right heart catheter revealed that the pulmonary vascular resistance decreased by ~20%. Finally, chronic combination therapy with spironolactone and low-dose tolvaptan without loop diuretics achieved adequate fluid management. In conclusion, the findings of the present study suggest that low-dose tolvaptan may be a promising therapeutic option for liver cirrhosis-associated POPH in patients with an electrolyte abnormality due to liver cirrhosis and conventional diuretics.
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Affiliation(s)
- Yoshito Ogihara
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Norikazu Yamada
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Kaoru Dohi
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Akimasa Matsuda
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Satoshi Ota
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Ken Ishikura
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Mashio Nakamura
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Masaaki Ito
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
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Hirai K, Shimomura T, Moriwaki H, Ishii H, Shimoshikiryo T, Tsuji D, Inoue K, Kadoiri T, Itoh K. Risk factors for hypernatremia in patients with short- and long-term tolvaptan treatment. Eur J Clin Pharmacol 2016; 72:1177-1183. [PMID: 27395406 DOI: 10.1007/s00228-016-2091-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 07/01/2016] [Indexed: 12/14/2022]
Abstract
PURPOSE The long-term efficacy of tolvaptan, a vasopressin V2 receptor antagonist, has been reported. However, the safety of long-term treatment remains to be fully elucidated. We assessed the safety profile of tolvaptan with respect to hypernatremia. METHODS This retrospective study included 371 patients treated with tolvaptan. Risk factors for hypernatremia (serum sodium concentration ≥147 mEq/L) were determined. RESULTS Hypernatremia occurred in 95 patients (25.6 %), of whom 71 (19.1 %) developed hypernatremia within 7 days of tolvaptan treatment (early onset). Stepwise logistic regression analysis demonstrated that baseline serum sodium ≥140 mEq/L, an initial tolvaptan dosage >7.5 mg, and a BUN/serum creatinine ratio ≥20 were independent risk factors for early onset of hypernatremia. Tolvaptan was prescribed for more than 7 days to 233 patients, of whom 123 were administrated tolvaptan for more than 1 month. Hypernatremia occurred in 24 of these patients (10.3 %) (late onset). Predictive factors for late onset of hypernatremia were an average daily dosage of tolvaptan >7.5 mg and age ≥75 years. CONCLUSIONS A daily dosage of 7.5 mg or less was recommended to prevent hypernatremia in short- as well as long-term tolvaptan treatment, and mainly elderly patients were at risk for hypernatremia.
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Affiliation(s)
- Keita Hirai
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan.,Laboratory of Clinical Pharmacogenomics, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Tatsuki Shimomura
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Hideaki Moriwaki
- Department of Cardiology, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Hidetoshi Ishii
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan.,Department of Pharmacy, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Takayuki Shimoshikiryo
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Daiki Tsuji
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan.,Laboratory of Clinical Pharmacogenomics, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Kazuyuki Inoue
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan.,Laboratory of Clinical Pharmacogenomics, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Toshihiko Kadoiri
- Department of Pharmacy, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Kunihiko Itoh
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan. .,Laboratory of Clinical Pharmacogenomics, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan.
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35
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Evidence-based clinical practice guidelines for liver cirrhosis 2015. J Gastroenterol 2016; 51:629-50. [PMID: 27246107 DOI: 10.1007/s00535-016-1216-y] [Citation(s) in RCA: 231] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 04/12/2016] [Indexed: 02/04/2023]
Abstract
The Japanese Society of Gastroenterology revised the evidence-based clinical practice guidelines for liver cirrhosis in 2015. Eighty-three clinical questions were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases for the period between 1983 and June 2012. Manual searching of the latest important literature was added until August 2015. The guidelines were developed with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. This digest version in English introduces selected clinical questions and statements related to the management of liver cirrhosis and its complications. Branched-chain amino acids relieve hypoalbuminemia and hepatic encephalopathy and improve quality of life. Nucleoside analogues and peginterferon plus ribavirin combination therapy improve the prognosis of patients with hepatitis B virus related liver cirrhosis and hepatitis C related compensated liver cirrhosis, respectively, although the latter therapy may be replaced by direct-acting antivirals. For liver cirrhosis caused by primary biliary cirrhosis and active autoimmune hepatitis, urosodeoxycholic acid and steroid are recommended, respectively. The most adequate modalities for the management of variceal bleeding are the endoscopic injection sclerotherapy for esophageal varices and the balloon-occluded retrograde transvenous obliteration following endoscopic obturation with cyanoacrylate for gastric varices. Beta-blockers are useful for primary prophylaxis of esophageal variceal bleeding. The V2 receptor antagonist tolvaptan is a useful add-on therapy in careful diuretic therapy for ascites. Albumin infusion is useful for the prevention of paracentesis-induced circulatory disturbance and renal failure. In addition to disaccharides, the nonabsorbable antibiotic rifaximin is useful for the management of encephalopathy. Anticoagulation therapy is proposed for patients with acute-onset or progressive portal vein thrombosis.
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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. [PMID: 26610908 DOI: 10.1007/s00535-015-1143-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 10/28/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND The water channel aquaporin 2 (AQP2) at the apical membrane of renal collecting duct cells mediates water reabsorption. The expression of AQP2 at the apical membrane is tightly regulated by vasopressin and was quantitated by measurement of the urinary form by a recently developed ELISA. Tolvaptan, an antagonist of vasopressin type 2 receptor, inhibits water reabsorption in cirrhosis. The aim of this study was to determine the correlation between the pharmacological effect of tolvaptan and the dynamics of urinary AQP2 levels. METHODS Tolvaptan was administered to 41 cirrhotic patients with ascites unresponsive to standard diuretic therapy. Urinary excretion of AQP2 and urinary osmolarity were measured at the baseline and at 4, 8, and 24 h after administration of tolvaptan. RESULTS At the baseline, urinary AQP2/creatinine ratios were significantly higher in cirrhotic patients with ascites than in healthy controls (P < 0.0001). After administration of tolvaptan, urinary AQP2/creatinine ratios decreased by 45.0 % at 4 h and 77.0 % at 8 h. Similarly, urinary osmolarity decreased by 42.0 % at 4 h and 41.5 % at 8 h. Urinary AQP2 levels and urinary osmolarity significantly correlated at the baseline and at all time points after tolvaptan administration. The degree of the decrease in urinary AQP2 levels and degree of the decrease in urinary osmolarity correlated significantly at 4 h (r = 0.452, P = 0.009) and 8 h (r = 0.384, P = 0.030) after tolvaptan administration. CONCLUSIONS These results indicate that the vasopressin-AQP2 system plays a major role in fluid retention in cirrhosis and that the pharmacological effect of tolvaptan to inhibit water reabsorption can be monitored by measurement of the dynamics of urinary AQP2 levels.
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Shigeto K, Kawaguchi T, Niizeki T, Kunitake Y, Takedatsu H, Tonan T, Fujimoto K, Tanaka M, Abe T, Naito H, Torimura T. Efficacy of peritoneovenous shunt for treating tolvaptan-resistant refractory ascites in a cirrhotic patient with portal vein thrombosis: A case report. Oncol Lett 2016; 11:3205-3209. [PMID: 27123091 DOI: 10.3892/ol.2016.4357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 02/08/2016] [Indexed: 12/16/2022] Open
Abstract
Peritoneovenous shunt is normally used for the treatment of refractory ascites. However, its efficacy in treating tolvaptan-resistant refractory ascites has not been reported thus far. In addition, the impact of peritoneovenous shunt on the prognosis of cirrhotic patients remains controversial. In the present report, a case of tolvaptan-resistant refractory ascites associated with liver cirrhosis and portal vein thrombosis is described. The male patient was diagnosed with hepatitis C virus-related liver cirrhosis at the age of 51 years. At the age of 56 years, the patient developed portal vein thrombosis, resulting in the development of refractory ascites. Since the ascites was resistant to treatment with a low-sodium diet and diuretics such as tolvaptan, a peritoneovenous shunt was implanted upon obtaining consent. The shunt immediately increased the urine volume, and the ascites was markedly decreased. The patient's body weight decreased from 62.7 to 57.1 kg in 2 days, and his ascites symptom inventory-7 score decreased from 23 to 0 points in 31 days. Although the patient succumbed to sepsis on day 486 following the shunt implant, his activities of daily living were preserved until 8 days prior to mortality. Thus, the present case supports the efficacy of peritoneovenous shunt for the treatment of tolvaptan-resistant refractory ascites associated with liver cirrhosis and portal vein thrombosis. Furthermore, the present case suggests that peritoneovenous shunt may prolong the survival of cirrhotic patents with refractory ascites.
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Affiliation(s)
- Kota Shigeto
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Takumi Kawaguchi
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Takashi Niizeki
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Yasushi Kunitake
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Hidetoshi Takedatsu
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Tatsuyuki Tonan
- Department of Radiology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Kiminori Fujimoto
- Department of Radiology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | | | - Toshi Abe
- Department of Radiology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | | | - Takuji Torimura
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
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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:E194-200. [PMID: 26123753 DOI: 10.1111/hepr.12547] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/14/2015] [Accepted: 06/20/2015] [Indexed: 12/11/2022]
Abstract
AIM Recently, the short-term efficacy of the vasopressin V2 receptor antagonist tolvaptan for the treatment of ascites in cirrhosis was reported. However, the long-term effects remain unknown. Here, we report the clinical features of decompensated cirrhosis treated using long-term tolvaptan therapy, and evaluate its safety and efficacy. METHODS Fifty-five cirrhotic patients hospitalized due to ascites, despite receiving appropriate diuretic treatment, were treated with tolvaptan. We excluded 35 patients due to liver transplant (20.0%), death (28.6%), poor general status (14.3%), improved ascites (5.7%) or other reasons (31.4%). In 20 cases treated with tolvaptan for 6 months, total body water (TBW) and extracellular fluids (ECW) were measured using bioelectric impedance analysis (BIA) with an InBody720. RESULTS The median age of the 20 patients was 64 years (range, 48-90), and 60% were male. The etiology of cirrhosis included hepatitis C (45%), alcohol-induced (20%) and other (35%). The percentage of patients with Child-Pugh class A, B and C was 0%, 40% and 60%, respectively. Biochemical findings revealed that serum creatinine levels and estimated glomerular filtration rate were not affected during 6 months of treatment with tolvaptan, and there was no renal disturbance. The median serum sodium levels were increased from 138 to 139 mEq/L, but serious adverse events related to renal and liver function were not observed. Data also revealed that long-term treatment reduced the BIA-estimated ECW/TBW ratio. CONCLUSION Long-term tolvaptan treatment was a safe and effective treatment for decompensated cirrhosis.
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Affiliation(s)
- Tomomi Kogiso
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Katsutoshi Tokushige
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Etsuko Hashimoto
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Yuichi Ikarashi
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazuhisa Kodama
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Makiko Taniai
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Nobuyuki Torii
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Keiko Shiratori
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
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Guo H, Wu LJ, Jin Z, Li XZ, Jin JJ. Vasopressin V2-receptor antagonist tolvaptan for treating cirrhotic patients with hyponatremia and hepatic edema: A systemic review. Shijie Huaren Xiaohua Zazhi 2016; 24:938-946. [DOI: 10.11569/wcjd.v24.i6.938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy and safety of vasopressin V2-receptor antagonist tolvaptan in treating cirrhotic patients with hyponatremia and hepatic edema.
METHODS: Randomized controlled trials (RCTs) about tolvaptan in treating cirrhotic patients with hyponatremia and hepatic edema were searched from the following databases: Embase, PubMed, Medline, Cochrane Library, Google Scholar, China National Knowledge Infrastructure (CNKI), VIP and Wanfang Database. The related research data were extracted, and RevMan5.3 was used for systemic review and meta-analysis.
RESULTS: Eight RCTs including 725 patients met the inclusion criteria. Meta-analysis showed that compared with placebo, tolvaptan could significantly increase serum sodium concentration [weighted mean difference (WMD) = 7.36 mmol/L, 95%CI: 4.15-10.57, P < 0.001] and 24-h urine volume (WMD = 1060.98 mL/24 h, 95%CI: 529.43-1592.52, P < 0.001), and reduce the body weight and abdominal circumference (body weight: WMD = -1.14 kg, 95%CI: -1.34--0.94, P < 0.001; abdominal circumference: WMD = -2.18 cm, 95%CI: -3.02--1.34, P < 0.001). The effects of tolvaptan on serum potassium, serum creatinine, heart rate, systolic pressure and diastolic pressure were not statistically different from those of the placebo (P > 0.05). The incidence of adverse reactions were not statistically different between the tolvaptan and placebo groups (RR = 1.43, 95%CI: 0.73-2.80, P = 0.300).
CONCLUSION: Tolvaptan could provide a new drug option for cirrhotic patients with hyponatremia and hepatic edema.
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Iwamoto T, Maeda M, Hisanaga T, Saeki I, Fujisawa K, Matsumoto T, Hidaka I, Ishikawa T, Takami T, Sakaida I. Predictors of the Effect of Tolvaptan on the Prognosis of Cirrhosis. Intern Med 2016; 55:2911-2916. [PMID: 27746425 PMCID: PMC5109555 DOI: 10.2169/internalmedicine.55.6819] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Objective Tolvaptan was first approved for use for cirrhosis in Japan in September 2013. The aim of the study was to examine the effect of tolvaptan, a vasopressin V2 receptor antagonist, on the prognosis of cirrhosis. Methods The effect of tolvaptan was evaluated in 26 patients with cirrhosis treated at our hospital from September 2013 to April 2015. Results The primary disease was hepatitis C in 20 patients, hepatitis B in 2, nonalcoholic steatohepatitis in 2 and others in 2; and 12 had hepatocellular carcinoma. The Child-Pugh score was 9.7±1.6 and the serum albumin level was 2.53±0.44 g/dL. Body weight decreased from 55.5±11.8 kg before administration to 52.1±14.7 kg after 7 days of tolvaptan treatment. After 7 days, patients with weight loss ≥2 kg (n=16, mean decrease of 4.3±2.3 kg) had significantly lower blood urea nitrogen (24.2±14.4 vs. 36.1±11.4 mg/dL) and serum creatinine (1.1±0.5 vs. 1.5±0.7 mg/dL) levels and decreased urine osmolality 4 h after the administration of tolvaptan (236±96 vs. 364±122 mOsm/kg) compared with patients with weight loss <2 kg (n=10, mean increase of +0.7±2.1 kg) (all p<0.05). The prognosis was significantly better in the group with weight loss ≥2 kg. Conclusion The effect of tolvaptan on the renal function is likely to improve the prognosis of patients with cirrhosis if the drug is started at a stage in which the renal function is maintained.
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Affiliation(s)
- Takuya Iwamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Japan
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Fukui H. Do vasopressin V2 receptor antagonists benefit cirrhotics with refractory ascites? World J Gastroenterol 2015; 21:11584-11596. [PMID: 26556988 PMCID: PMC4631962 DOI: 10.3748/wjg.v21.i41.11584] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 08/08/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
Hyponatremia is a frequent complication of advanced cirrhosis with ascites associated with increased morbidity and mortality. It is caused by an impairment in the renal capacity to eliminate solute-free water and is considered to be related to persistent secretion of vasopressin despite low serum osmolality. This nonosmotic release of vasopressin is mediated by the autonomic nervous system, which senses the underfilling of arterial vascular component. This reduction of effective arterial blood volume is closely related to the development of ascites. Although the short-time effects of vasopressin V2 receptor antagonists (vaptans) on hyponatremia and ascites have been repeatedly reported, their effects on the long-term management of cirrhotic ascites have not been established yet. Considering that their effects on water diuresis and their safety are limited by severe underfilling state of patients, cautious approaches with adequate monitoring are needed to advanced cirrhosis. Proper indication, adequate doses and new possibility of combination therapy should be explored in the future controlled study. As hyponatremia is frequent obstacle to ascites management, judicious combination with low-dose diuretics may decrease the incidence of refractory ascites. Although vaptans show much promise in the treatment of advanced cirrhosis, the problem of high cost should be solved for the future.
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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. [PMID: 25429910 DOI: 10.1111/hepr.12455] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 10/26/2014] [Accepted: 11/21/2014] [Indexed: 12/25/2022]
Abstract
AIM Tolvaptan, an oral arginine vasopressin V2 receptor antagonist, became available for hepatic ascites. We evaluated the therapeutic efficacy and safety of tolvaptan administration to treat refractory ascites. METHODS Data were collected from 15 hospitalized patients with cirrhosis (hepatitis C, 10; alcoholism, five) after adding tolvaptan (3.75-11.25 mg/day) to conventional diuretics. Bodyweights and serum sodium and creatinine concentrations were measured. Tolvaptan was continued for 4 weeks or longer for a median follow-up period of 42 days (range, 28-56). RESULTS In the first week (introduction phase), tolvaptan significantly reduced median weight (66.6, 65.9 and 63.1 kg on days 0, 1 and 7, respectively; P < 0.004). The numbers of good responders (≥3 kg reduction in 4 days), responders (<3 kg weight reduction) and non-responders (no weight reduction) were seven (46.7%), six (40.0%) and two of the 15 (13.3%), respectively. The two non-responders had concomitant chylous pleural effusion or spontaneous bacterial peritonitis. All patients continued tolvaptan for 2 weeks or longer and six (40%, three good responders and three responders) were treated for a median of 42 days without additional intervention. During this intermediate-term administration of tolvaptan, the median weight reduction was statistically significant (65.4, 61.9 and 56.9 kg on days 0, 7 and 42, respectively; P < 0.030) and there was no serum sodium imbalance or renal dysfunction; but two of these six developed hepatic coma. CONCLUSION Tolvaptan safely alleviated fluid retention caused by hepatic cirrhosis. Intermediate-term administration of tolvaptan apparently helped maintain weight reduction achieved during the introduction phase.
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Affiliation(s)
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Taito Fukushima
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Yushi Sorin
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Yusuke Kawamura
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Masahiro Kobayashi
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan
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Suzuki E, Chiba T, Ogasawara S, Saito T, Kanogawa N, Motoyama T, Ooka Y, Tawada A, Maruyama H, Ogawa M, Yokosuka O. Tolvaptan treatment for patients with decompensated cirrhosis and advanced hepatocellular carcinoma. Hepatol Res 2015; 45:E161-2. [PMID: 26510648 DOI: 10.1111/hepr.12465] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Eiichiro Suzuki
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tomoko Saito
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tenyu Motoyama
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshihiko Ooka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Akinobu Tawada
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hitoshi Maruyama
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Makoto Ogawa
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
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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. [PMID: 26054761 PMCID: PMC4460759 DOI: 10.1186/s12876-015-0297-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 05/29/2015] [Indexed: 12/15/2022] Open
Abstract
Background Ascites is the most common complication of cirrhosis. It may lead to the consequence of poor prognosis and the deterioration of quality of life. Asopressin V2 receptor antagonists is a kind of vaptans, and it has been proved to be effective in hyponatremia patients. We conducted a meta-analysis about treatment of vaptans in cirrhosis patients with ascites. Methods Following our selection criteria, we collected a total of 14 studies containing 16 randomized controlled trials (2620 patients) from a series of database about the treatment with vaptans for cirrhosis with ascites patients. The included studies compared the treatment effect of lixivaptan (VPA 985), or RMJ-351647, or satavaptan, or tolvaptan with placebo. Results The included vaptans (asopressin V2 receptor antagonists) showed significant effect of increasing the serum sodium concentration for cirrhosis patients (WMD = 2.11 mmol/L, p < 0.00001). Patients also could acquire significant improvement of ascites, as this kind of aquaretics can significantly reduce ascites patients’ weight (WMD = −1.53, p < 0.00001), abdominal girth (WMD = −2.04, p < 0.00001), and the ratio of worsening ascites (RR = 0.51, p = 0.001). Though the drug did not produce more total adverse events (RR = 1.04, p = 0.09) and the total serious events (RR = 1.04, p = 0.42), the emergence of excessive correction of serum sodium concentrations (>145 mmol/L) was more frequently noted in patients under the employment of vaptans (RR = 2.14, 95 % CI [1.45, 3.16], p = 0.0001). Whether with the administration of vaptans for short-term or long-term, no survival benefit was detected from the selected studies. Conclusions Asopressin V2 receptor antagonists could play an effective and safe role in symptomatic treatment for cirrhosis patients with ascites, especially for refractory ascites patients who presented insufficient response to conventional diuretics.
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Affiliation(s)
- Long Yan
- Department of Special Treatment and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
| | - Feng Xie
- Department of Special Treatment and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
| | - Jiongjiong Lu
- Department of Special Treatment and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
| | - Qingqiang Ni
- Department of Special Treatment and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
| | - Changying Shi
- Department of Special Treatment and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
| | - Caixi Tang
- Hepatobiliary and pancreatic surgery center, Zhuzhou Central Hospital, Zhuzhou, 412007, China.
| | - Jiamei Yang
- Department of Special Treatment and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
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Affiliation(s)
- Nadia K Bozanich
- Medicine, Indiana University School of Medicine, 975 West Walnut, IB 327, Indianapolis, IN 46202, USA
| | - Paul Y Kwo
- Medicine, Indiana University School of Medicine, 975 West Walnut, IB 327, Indianapolis, IN 46202, USA.
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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. [PMID: 25689936 PMCID: PMC4592499 DOI: 10.1007/s00535-015-1052-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 02/03/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Patients with hypoalbuminemia often fail to respond to increased doses of loop diuretics. We therefore performed a post hoc analysis to investigate the pharmacological action of tolvaptan and whether it is dependent on the serum albumin level. METHODS This analysis was based on four previous clinical trials of tolvaptan in patients with liver cirrhosis who exhibited insufficient response to conventional diuretics. We analyzed the correlation between the change in the initial 24-h cumulative urine volume from baseline and the serum albumin level at baseline, and assessed potential predictive factors of response to tolvaptan. RESULTS The correlation coefficient was 0.029 in the placebo group and -0.112 in the 7.5 mg tolvaptan group of patients with liver cirrhosis. Administration of tolvaptan provoked a stable response regardless of the serum albumin level. Tolvaptan use was identified as a significant predictor of pharmacological action, and was shown to change the initial urine volume by 885 mL (P < 0.0001) in liver cirrhosis patients. CONCLUSIONS In this post hoc analysis, tolvaptan increased the initial urine volume from baseline regardless of serum albumin levels. Use of tolvaptan as an add-on therapy to loop diuretics can be considered an optimal therapeutic option in patients with insufficient response to loop diuretics.
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Re-response to tolvaptan after furosemide dose reduction in a patient with refractory ascites. Clin J Gastroenterol 2014; 8:47-51. [PMID: 25475138 PMCID: PMC4331598 DOI: 10.1007/s12328-014-0545-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 11/20/2014] [Indexed: 10/26/2022]
Abstract
Tolvaptan is a new drug used for treating ascites induced by liver cirrhosis, and it is covered by health insurance in Japan. In the present report, we describe the case of a 74-year-old man with type C liver cirrhosis and refractory ascites. He was receiving furosemide and spironolactone daily, but still required repeat puncture for ascites removal. Administration of tolvaptan (3.75 mg/day) was started in addition to his existing medications, and was subsequently increased to 7.5 mg/day. However, after 2 months, the ascites again exacerbated. Nevertheless, after we discontinued the administration of furosemide, the tolvaptan became effective. This may be because furosemide administration decreases urine osmolality, resulting in a non-response to tolvaptan.
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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. [PMID: 25170228 PMCID: PMC4145782 DOI: 10.3748/wjg.v20.i32.11400] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 04/11/2014] [Accepted: 05/12/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the efficacy and safety of tolvaptan to treat refractory ascites in decompensated liver cirrhosis patients with or without further complications, such as hepatorenal syndrome and/or hepatocellular carcinoma. METHODS Thirty-nine patients (mean age 55 years, males: 32) with decompensated liver cirrhosis and refractory ascites were enrolled. All patients received a combination of tolvaptan (15 mg/d for 5-14 d) and diuretics (40-80 mg/d of furosemide and 80-160 mg/d of spironolactone). The etiology of cirrhosis included hepatitis B (69.2%), hepatitis C (7.7%) and alcohol-induced (23.1%). Changes in the urine excretion volume, abdominal circumference and edema were assessed. The serum sodium levels were also measured, and adverse events were recorded. A follow-up assessment was conducted 1 mo after treatment with tolvaptan. RESULTS Tolvaptan increased the mean urine excretion volume (1969.2 ± 355.55 mL vs 3410.3 ± 974.1 mL, P < 0.001), and 89.7% of patients showed improvements in their ascites, 46.2% of whom showed significant improvements. The overall efficacy of tolvaptan in all patients was 89.7%; the efficacies in patients with hepatocellular carcinoma and hepatorenal syndrome were 84.2% and 77.8%, respectively. The incidence of hyponatremia was 53.8%. In patients with hyponatremia, the serum sodium levels increased after tolvaptan treatment (from 128.1 ± 4.22 mEq/L vs 133.1 ± 3.8 mEq/L, P < 0.001). Only mild drug-related adverse events, including thirst and dry mouth, were observed. CONCLUSION Tolvaptan is a promising aquaretic for the treatment of refractory ascites in patients with decompensated liver cirrhosis.
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Abstract
No alternative therapeutic option exists if liver cirrhosis patients have insufficient response to conventional diuretics and/or experience conventional diuretic-related adverse events. In 2013, tolvaptan (7.5 mg/day), an arginine vasopressin V2 receptor antagonist, was approved in Japan for the treatment of liver cirrhosis with oedema. Short-term use of tolvaptan produced decreases in body weight, reduction in ascites volume and increases in urine volume when compared to placebo, despite the use of conventional diuretics. Additionally, approximately 60% of patients with oedema-related symptoms improved. Low-dose tolvaptan, 3.75 mg, was also efficacious. Even in patients with low serum albumin (<2.5 g/dL), decrease in body weight was greater with tolvaptan than with placebo. For future research, the efficacy and safety of lower tolvaptan doses for the treatment of liver cirrhosis patients with oedema should be confirmed in Japan. The results of this research could be used as an indicator or a guideline for physicians around the world.
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Affiliation(s)
- Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi 755-8505, Japan
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Abstract
The burden of liver disease continues to increase in the United States, with the epidemics of hepatitis C, alcoholic liver disease, and the coming wave of nonalcoholic fatty liver disease patients all contributing to a high burden of individuals with end-stage liver disease. The complications of cirrhosis have been related to portal hypertension or synthetic dysfunction with variceal bleeding, ascites, hepatic encephalopathy, jaundice, hepatorenal syndrome, and the pulmonary complications of cirrhosis being described classically. Over the past decade, a body of evidence has now been assembled demonstrating that hyponatremia is also an important complication in patients with decompensated cirrhosis, with recent data demonstrating that hyponatremia is an important prognostic indicator in those with cirrhosis [1••]. Seminal research has demonstrated the pathophysiologic role of the hyperdynamic circulation and vasodilation in those with decompensated cirrhosis that leads to many of the complications, including hyponatremia [2•]. Moreover, a new class of drugs, the vaptans, have provided important insights into the pathophysiology and potential therapy of those with hyponatremia and possibly in those with hyponatremia and cirrhotic ascites [3]. However, there are safety concerns with some drugs in this class. In this article, the pathophysiology of hyponatremia, clinical relevance to patients with decompensated cirrhosis, and management options will be addressed.
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Affiliation(s)
- Paul Y Kwo
- Gastroenterology/Hepatology Division, Indiana University School of Medicine, 975 W. Walnut, IB 327, Indianapolis, IN, 46202-5121, USA,
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