Tolvaptan Improves Refractory Ascites and Overall Survival in Cirrhosis: A Meta-Analysis
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Introduction: Refractory ascites is a frequent complication associated with liver cirrhosis. Tolvaptan, a V2-receptor antagonist, has shown effectiveness in improving refractory ascites. This meta-analysis sought to assess the effectiveness of tolvaptan in patients suffering from cirrhosis and refractory ascites.
Methods: Databases including Google Scholar, Cochrane, ClinicalTrials.gov, PubMed, and PubMed Central were systematically queried to search for papers from January 1, 2020, to August 10, 2023. Eligible publications for this study included all research evaluating body weight reduction and overall survival rates in patients with refractory ascites according to their response to tolvaptan. The meta-analysis included five studies, encompassing 530 patients with cirrhosis and refractory ascites who were treated with tolvaptan. Research characteristics were documented for all included studies, and outcomes were recorded for tolvaptan responders compared to non-responders.
Results: The statistical analysis revealed a significant weight reduction in tolvaptan responders in comparison to non-responders, with a risk ratio (RR) of 1.92 and a confidence interval (CI) of 1.12 to 3.31. The results of the heterogeneity analysis performed on the two outcomes, weight reduction and overall survival in tolvaptan responders, were I²=84%, τ²=0.1328, p<0.01, and I²=86%, τ²=0.6006, respectively.
Conclusion: The clinical application of tolvaptan improves symptoms in cirrhotic patients with refractory ascites, resulting in increased survival rates. Nonetheless, additional randomized controlled trials of a larger scale are necessary to validate the findings of this study, accurately predict the benefits of tolvaptan, and identify the patients who would derive the most benefit from its use.
Highlights:
- Our meta-analysis covers the most recent studies and confirms that tolvaptan improves survival rates in cirrhotic patients with refractory ascites, hence reducing morbidity and mortality.
- Notable weight reduction is seen in patients with refractory ascites who respond to tolvaptan.
Adachi T, Takaki A, Sato S, Tobita H, Kobashi H, et al. (2020). High expression of a vascular stricture‐related marker is predictive of an early response to tolvaptan, and a low fractional excretion of sodium is predictive of a poor long‐term survival after tolvaptan administration for liver cirrhosis. Hepatology Research 50(12): 1347–1354. doi: 10.1111/hepr.13573.
Adebayo D, Neong SF, Wong F (2019). Refractory ascites in liver cirrhosis. American Journal of Gastroenterology 114(1): 40–47. doi: 10.1038/s41395-018-0185-6.
Arase Y, Kagawa T, Tsuruya K, Sato H, Teramura E, et al. (2019). Impaired renal function may not negate the efficacy of tolvaptan in the treatment of cirrhotic patients with refractory ascites. Clinical Drug Investigation 39(1): 45–54. doi: 10.1007/s40261-018-0714-5.
Bell A, Fairbrother M, Jones K (2019). Fixed and random effects models: making an informed choice. Quality & Quantity 53(2): 1051–1074. doi: 10.1007/s11135-018-0802-x.
Bellos I (2021). Safety profile of tolvaptan in the treatment of autosomal dominant polycystic kidney disease. Therapeutics and Clinical Risk Management 17: 649–656. doi: 10.2147/TCRM.S286952.
Bellos I, Kontzoglou K, Psyrri A, Pergialiotis V (2020). Tolvaptan response improves overall survival in patients with refractory ascites: A meta-analysis. Digestive Diseases 38(4): 320–328. doi: 10.1159/000503559.
Biggins SW, Angeli P, Garcia‐Tsao G, Ginès P, Ling SC, et al. (2021). Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 74(2): 1014–1048. doi: 10.1002/hep.31884.
Dettori JR, Norvell DC, Chapman JR (2021). Seeing the forest by looking at the trees: How to interpret a meta-analysis forest plot. Global Spine Journal 11(4): 614–616. doi: 10.1177/21925682211003889.
Fortune B, Cardenas A (2017). Ascites, refractory ascites and hyponatremia in cirrhosis. Gastroenterology Report 5(2): 104–112. doi: 10.1093/gastro/gox010.
Hirooka M, Koizumi Y, Yano R, Nakamura Y, Sunago K, et al. (2022). Cisterna chyli as an optimal marker of tolvaptan response in severe cirrhotic ascites. Scientific Reports 12(1): 8124. doi: 10.1038/s41598-022-11889-z.
Hosui A, Tanimoto T, Okahara T, Ashida M, Ohnishi K, et al. (2021). Early administration of tolvaptan can improve survival in patients with cirrhotic ascites. Journal of Clinical Medicine 10(2): 294. doi: 10.3390/jcm10020294.
Imai M, Ishikawa T, Kojima Y, Azumi M, Nozawa Y, et al. (2021). Prediction factors of tolvaptan effectiveness in patients with refractory ascites complicated with hepatocellular carcinoma. European Journal of Gastroenterology & Hepatology 33(1S): e161–e166. doi: 10.1097/MEG.0000000000001985.
John S, Thuluvath PJ (2015). Hyponatremia in cirrhosis: Pathophysiology and management. World Journal of Gastroenterology 21(11): 3197–3205. doi: 10.3748/wjg.v21.i11.3197.
Kanayama K, Chiba T, Kobayashi K, Koroki K, Maruta T, et al. (2020). Long-term administration of tolvaptan to patients with decompensated cirrhosis. International Journal of Medical Sciences 17(7): 874–880. doi: 10.7150/ijms.41454.
Kasztelan-Szczerbinska B, Cichoz-Lach H (2019). Refractory ascites—The contemporary view on pathogenesis and therapy. PeerJ 7: e7855. doi: 10.7717/peerj.7855.
Kawaratani H, Moriya K, Namisaki T, Shimozato N, Kaji K, et al. (2020). Ascites symptom inventory-7 is a valuable tool for evaluating the effectiveness of tolvaptan in patients with cirrhotic ascites. Experimental and Therapeutic Medicine 21(1): 30. doi: 10.3892/etm.2020.9462.
Kudo T, Murai Y, Kojima Y, Uehara K, Satoh T (2021). Efficacy and safety of tolvaptan in patients with malignant ascites: A phase 2, multicenter, open-label, dose-escalation study. Japanese Journal of Clinical Oncology 51(3): 354–362. doi: 10.1093/jjco/hyaa196.
Kulkarni AV, Kumar P, Sharma M, Sowmya TR, Talukdar R, et al. (2020). Pathophysiology and prevention of paracentesis-induced circulatory dysfunction: A concise review. Journal of Clinical and Translational Hepatology 8(X): 1–7. doi: 10.14218/JCTH.2019.00048.
Lan T, Chen M, Tang C, Deltenre P (2024). Recent developments in the management of ascites in cirrhosis. United European Gastroenterology Journal 12(2): 261–272. doi: 10.1002/ueg2.12539.
Larrue H, Vinel JP, Bureau C (2021). Management of severe and refractory ascites. Clinics in Liver Disease 25(2): 431–440. doi: 10.1016/j.cld.2021.01.010.
Li B, Fang D, Qian C, Feng H, Wang Y (2017). The efficacy and safety of tolvaptan in patients with hyponatremia: A meta-analysis of randomized controlled trials. Clinical Drug Investigation 37(4): 327–342. doi: 10.1007/s40261-016-0470-3.
Macken L, Corrigan M, Prentice W, Finlay F, McDonagh J, et al. (2022). Palliative long-term abdominal drains for the management of refractory ascites due to cirrhosis: A consensus document. Frontline Gastroenterology 13(e1): e116–e125. doi: 10.1136/flgastro-2022-102128.
Muka T, Glisic M, Milic J, Verhoog S, Bohlius J, et al. (2020). A 24-step guide on how to design, conduct, and successfully publish a systematic review and meta-analysis in medical research. European Journal of Epidemiology 35(1): 49–60. doi: 10.1007/s10654-019-00576-5.
Osawa L, Nakanishi H, Kurosaki M, Kirino S, Inada K, et al. (2022). Plasma renin activity predicts prognosis and liver disease-related events in liver cirrhosis patients with ascites treated by tolvaptan. Digestive Diseases 40(4): 479–488. doi: 10.1159/000518099.
R Core Team (2023). R Statistical Software for Windows, version 4.3.0. Retrieved from https://cran.r-project.org/bin/windows/base/old/4.3.0/.
Schiavo JH (2019). PROSPERO: An international register of systematic review protocols. Medical Reference Services Quarterly 38(2): 171–180. doi: 10.1080/02763869.2019.1588072.
Singh V, De A, Mehtani R, Angeli P, Maiwall R, et al. (2023). Asia–Pacific association for study of liver guidelines on management of ascites in liver disease. Hepatology International 17(4): 792–826. doi: 10.1007/s12072-023-10536-7.
Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, et al. (2016). ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ 355: i4919. doi: 10.1136/bmj.i4919.
Sterns RH (2018). Treatment of severe hyponatremia. Clinical Journal of the American Society of Nephrology 13(4): 641–649. doi: 10.2215/CJN.10440917.
Suzuki Y, Naganuma A, Hoshino T, Hatanaka T, Ueno T, et al. (2021). Tolvaptan reduces the required amount of albumin infusion in patients with decompensated cirrhosis with uncontrolled ascites: A multicenter retrospective propensity score-matched cohort study. Acta Gastro Enterologica Belgica 84(1): 57–63. doi: 10.51821/84.1.357.
Tang J, Wang Y, Han T, Mao Q, Cheng J, et al. (2020). Tolvaptan therapy of Chinese cirrhotic patients with ascites after insufficient diuretic routine medication responses: A phase III clinical trial. BMC Gastroenterology 20(1): 391. doi: 10.1186/s12876-020-01536-0.
Tawfik GM, Dila KAS, Mohamed MYF, Tam DNH, Kien ND, et al. (2019). A step by step guide for conducting a systematic review and meta-analysis with simulation data. Tropical Medicine and Health 47(1): 46. doi: 10.1186/s41182-019-0165-6.
Téllez L, Albillos A (2022). Non‐selective beta‐blockers in patients with ascites: The complex interplay among the liver, kidney and heart. Liver International 42(4): 749–761. doi: 10.1111/liv.15166.
Téllez L, Ibáñez-Samaniego L, Pérez del Villar C, Yotti R, Martínez J, et al. (2020). Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites. Journal of Hepatology 73(6): 1404–1414. doi: 10.1016/j.jhep.2020.05.011.
Tripathi D, Stanley AJ, Hayes PC, Travis S, Armstrong MJ, et al. (2020). Transjugular intrahepatic portosystemic stent-shunt in the management of portal hypertension. Gut 69(7): 1173–1192. doi: 10.1136/gutjnl-2019-320221.
Tsuzuki N, Usui M, Itoh A, Futamura A, Imai K (2023). Efficacy and safety of tolvaptan for refractory fluid collection and edema in the terminal cancer patients. Fujita Medical Journal 9(1): 8–11. doi: 10.20407/fmj.2021-005.
Vidal-González D, Pérez-López KP, Vera-Nungaray SA, Moreno-Madrigal LG (2022). Treatment of refractory ascites: Current strategies and new landscape of non-selective beta-blockers. Gastroenterología y Hepatología 45(9): 715–723. doi: 10.1016/j.gastrohep.2022.02.004.
Wang R, Chai L, Guo X (2022). Diuretics in cirrhotic patients with ascites. In: Pharmacotherapy for Liver Cirrhosis and Its Complications. Singapore: Springer Nature Singapore. doi: 10.1007/978-981-19-2615-0_11.
Will V, Rodrigues SG, Berzigotti A (2022). Current treatment options of refractory ascites in liver cirrhosis – A systematic review and meta-analysis. Digestive and Liver Disease 54(8): 1007–1014. doi: 10.1016/j.dld.2021.12.007.
Wong F, Bendel E, Sniderman K, Frederick T, Haskal ZJ, et al. (2020). Improvement in quality of life and decrease in large-volume paracentesis requirements with the automated low-flow ascites pump. Liver Transplantation 26(5): 651–661. doi: 10.1002/lt.25724.
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