Tolvaptan Response Improves Overall Survival in Patients with Refractory Ascites: A Meta-Analysis
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Liver: Systematic Review and Meta-Analysis
Dig Dis 2020;38:320–328 Received: June 2, 2019
Accepted: September 18, 2019
DOI: 10.1159/000503559 Published online: October 2, 2019
Tolvaptan Response Improves Overall
Survival in Patients with Refractory
Ascites: A Meta-Analysis
Ioannis Bellos a Konstantinos Kontzoglou b Amanda Psyrri c
Vasilios Pergialiotis a
a Laboratoryof Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School,
National and Kapodistrian University of Athens, Athens, Greece; b 2nd Department of Propedeutic Surgery,
“Laikon” General Hospital, National and Kapodistrian University of Athens, Athens, Greece; c Division of Oncology,
2nd Department of Internal Medicine, Attikon University Hospital, Athens, Greece
Keywords sodium restoration (HR 0.35, 95% CI [0.20–0.61]. Sensitivity
Tolvaptan · Response · Ascites · Cirrhosis · Meta-analysis analysis suggested that the presence of hepatocellular car-
cinoma, the sample size, and the quality of the studies did
not significantly affect the overall result of the meta-analysis.
Abstract Conclusions: The outcomes of the meta-analysis support
Background and Aims: Refractory ascites represents a sig- the prognostic role of tolvaptan response in patients with
nificant complication of decompensated cirrhosis, associat- cirrhosis and refractory ascites, as it was shown to lead to
ed with increased mortality rates. The aim of this meta-anal- significantly improved overall survival. These findings should
ysis was to evaluate whether response to treatment with be confirmed by future large-scale studies, while efficient
tolvaptan is associated with improved overall survival in cir- biomarkers should be identified in order to accurately pre-
rhotic patients with refractory ascites. Methods: Medline, dict response to tolvaptan and discriminate patients that
Scopus, Cochrane Central Register of Controlled Trials, Clini- would benefit from its administration.
caltrials.gov, and Google Scholar databases were systemati- © 2019 S. Karger AG, Basel
cally searched from inception to April 11, 2019. All studies
that assessed the overall survival of patients with ascites de-
pending on their response to tolvaptan were held eligible. Introduction
Results: Nine studies were included, with a total of 736 pa-
tients with cirrhosis and ascites. Response to tolvaptan was Ascites represents a major complication of decompen-
estimated to be linked to significantly improved overall sur- sated liver cirrhosis, associated with increased morbidity,
vival (hazard ratio [HR] 0.42, 95% CI [0.31–0.58]). Subgroup poor quality of life, and adverse long-term outcomes [1].
analysis indicated that the same outcome was present when The pathophysiology of ascites formation is multifacto-
tolvaptan responsiveness was defined either as effective rial and is based on the presence of hypoalbuminemia,
body weight loss (HR 0.44, 95% CI [0.30–0.63] or as effective portal hypertension, and splanchnic vasodilation [2].
© 2019 S. Karger AG, Basel Ioannis Bellos, MD
Laboratory of Experimental Surgery and Surgical Research N.S. Christeas
Athens University Medical School, National and Kapodistrian University of Athens
karger@karger.com
15Β, Ag. Thoma street, GR–115 27 Athens (Greece)
www.karger.com/ddi E-Mail bellosg @ windowslive.comSubsequently, sympathetic nervous system and vasocon- presumed to meet the selection criteria were retrieved as full-texts.
strictor factors, especially arginine-vasopressin and re- Finally, all observational studies (both prospective and retrospec-
tive) that reported the outcome of interest were included. Case
nin-angiotensin-aldosterone axis are homeostatically ac- reports, small case series (Color version available online
Records identified through Additional records ideitified
Identification
database searching through other sources
(n = 370) (n = 0)
Records after duplicates removed
(n = 321)
Screening
Records excluded after
Records screened reading yhr title and/or
(n = 321) abstract
(n = 308)
Full-text articles assessed Records excluded with
for eligibility ressons
(n = 13) (n = 4)
Eligibility
Studies included in
qualitative synthesis
(n = 9)
Included
Studies included in
qualitative synthesis
(meta-analysis)
(n = 9)
Fig. 1. Search plot diagram.
vival was separately calculated for patients without hepatocellular studies. The most common tolvaptan dose was 7.5 mg/day
carcinoma, as well as for studies with large sample size (> 80 pa- (range 3.5–30 mg/day). Conventional treatment included
tients) and low risk of bias, as assessed by the ROBINS-I tool.
Moreover, leave-one-out analysis was performed in order to eval-
sodium restriction, administration of furosemide and spi-
uate the influence of individual studies on the overall outcome. To ronolactone, albumin infusion, or the combination of the
achieve this, one study was sequentially omitted at a time and thus above. Tolvaptan response was defined as effective body
its contribution to the meta-analytic result was assessed. weight loss in 7 studies, while in the rest 2 as effective so-
dium restoration [22, 26]. The patients’ baseline charac-
teristics (age, Child-Pugh score, presence of hepatitis C or
Results hepatocellular carcinoma, blood urea nitrogen, serum so-
dium, and albumin) are presented in Table 2. No signifi-
Included Studies cant differences were noted among the 2 groups concern-
Nine studies [19–27] were included in the analysis, with ing the majority of the examined parameters.
a total of 736 patients. Among them, 451 patients present-
ed clinical response to tolvaptan therapy, while the rest 285 Excluded Studies
were judged as nonresponders. The methodological char- Four studies [12, 28, 29, 30] were excluded after read-
acteristics of the included studies (study design, eligibility ing the full text. Specifically, one of them did not directly
criteria, tolvaptan dosage, concomitant medications, and compare the survival among tolvaptan responders and
definition of response) are described in Table 1. The anal- nonresponders [30], while 2 studies investigated predic-
ysis was based exclusively on cohort studies, with one of tive factors of response to tolvaptan without evaluating its
them presenting a prospective design. The presence of hy- effect on overall survival rates [12, 29]. In addition, one
ponatremia was a prerequisite for 2 studies [22, 26], while study was excluded as a partial duplicate of another study
cases with hepatocellular carcinoma were included in 7 already included in the analysis [28].
322 Dig Dis 2020;38:320–328 Bellos/Kontzoglou/Psyrri/Pergialiotis
DOI: 10.1159/000503559Table 1. Study characteristics
Author, year Study Inclusion criteria Exclusion criteria Tolvaptan dose Concomitant medications Response
design definition
Kida [27], RC Hepatic ascites Hepatic malignancy 3.75 mg, increased to Sodium restriction, Body weight
2019 7.5 mg/day if insufficient albumin, furosemide, loss ≥1.5 kg
effect on day 3 spironolactone within 1st week
Wang PC Hepatic ascites Age 75 years, hepatic 7.5–30 mg/day Sodium restriction, Serum sodium
et al. [26], 2018 and hyponatremia malignancy, type 1 hepatorenal furosemide, between 135
syndrome, any neurological spironolactone and 155 mEq/L
disorder, history of stroke,
uncontrolled DM, HF, anuria,
hepatic encephalopathy ≥ grade 2
Tajiri RC Refractory Temporary ascites, HF, ADPKD, 3.75–7.5 mg/day Sodium restriction, Body weight
et al. [25], 2018 hepatic ascites carcinomatous peritonitis furosemide, spironolactone loss ≥2 kg
within 1st week
Arase RC Refractory SBP, hepatic encephalopathy 7.5 mg/day Furosemide, spironolactone Body weight
et al. [24], 2018 hepatic ascites ≥ grade 2, albumin infusion loss ≥1.5 kg
within 7 days within 1st week
Tahara RC Refractory Drainage by paracentesis within 7.5 mg/day Sodium restriction, Body weight
et al. [23], 2017 hepatic ascites 7 days, warfarin use furosemide, spironolactone loss ≥2 kg
within 1st week
Kogiso RC Hepatic ascites Severe renal dysfunction, hepatic 3.75 mg/day Sodium restriction, Serum sodium
et al. [22], 2017 and hyponatremia encephalopathy ≥ grade 2 furosemide, spironolactone ≥135 mEq/L
within 1st week
Atsukawa RC Refractory hepatic Age 90 years, type 1 7.5 mg/day Sodium restriction, Body weight
et al. [21], 2018 ascites, pleural hepatorenal syndrome, hepatic furosemide, spironolactone loss ≥1.5 kg
effusion or encephalopathy ≥ grade 2, varices within 1st week
lower-limb edema requiring treatments, serum
sodium >147 mEq/L
Yamada RC Refractory hepatic Age 80 years, SBP, 3.75–7.5 mg/day Sodium restriction, Body weight
et al. [20], 2016 ascites or pleural hepatic encephalopathy, albumin, furosemide, loss ≥2 kg
effusion hemodialysis spironolactone within 1st week
Iwamoto RC Refractory NR 3.75 mg, increased to Furosemide, spironolactone Body weight
et al. [19], 2016 hepatic ascites 7.5 mg/day if insufficient loss ≥2 kg
effect on day 3 within 1st week
RC, retrospective cohort; PC, prospective cohort; DM, diabetes mellitus; HF, heart failure; ADPKD, Autosomal Dominant Polycystic Kidney Disease; SBP, spontaneous bacterial
peritonitis; NR, not reported.
Quality Assessment 48%) or as effective sodium restoration (HR 0.35, 95%
The outcomes of ROBINS-I tool are presented in Ta- CI [0.20–0.61], I2 = 0%; Fig. 2). More specifically, a sur-
ble 3. The overall bias was judged to be low in 5 studies vival benefit was observed when effective body weight
and moderate in the rest 4. It should be noted that risk of loss was defined either as weight loss ≥1.5 kg within 1st
bias mainly came from the domain of missing data, due week (HR 0.36, 95% CI [0.15–0.85], Ι2 = 78%) or as
to lack of firm evidence that no discrepancies of the fol- weight loss ≥2 kg within 1st week (HR 0.44, 95% CI
low-up periods existed depending on tolvaptan response. [0.31–0.63], I2 = 0%). Sensitivity analysis revealed that
Furthermore, confounding may have contributed to the tolvaptan response also lead to better overall survival
overall bias in studies where nonresponders presented when patients without hepatocellular carcinoma were
higher Child-Pugh scores or impaired renal function. separately examined (HR 0.25, 95% CI [0.11–0.55], 3
studies). Moreover, the same outcome was evident in
Outcomes studies with large (>80 patients) sample size (HR 0.37,
Response to tolvaptan treatment was associated with 95% CI [0.21–0.66], 4 studies), as well as in studies with
improved overall survival (HR 0.42, 95% CI [0.31–0.58], low risk of bias (HR 0.38, 95% CI [0.25–0.57], 5 studies).
I2 = 39%). Subgroup analysis indicated that the same ef- Leave-one-out analysis suggested that the results remain
fect was present when response was defined as effective stable, since the overall outcome was significantly af-
body weight loss (HR 0.44, 95% CI [0.30–0.63], I2 = fected by no single study (Table 4).
Tolvaptan Response in Refractory Ascites Dig Dis 2020;38:320–328 323
DOI: 10.1159/000503559Table 2. Patients’ baseline characteristics
Author, Patients Age, years Child-Pugh HCC HCV BUN, mg/dL Serum Serum
year number score sodium, mEq/L albumin, g/dL
Responders vs. non-responders
Kida [27], 53 vs. 33 75.2±14.1 vs. 10.2±1.7 vs. – 11 vs. 20.2±13.5 vs. 137±6 vs. 2.6±0.6 vs.
2019 78±14.1 10±1.2 7 37.3±29.3 135±6 2.5±0.6
Wang et al. 44 vs. 25 54.6±8.58 NR – 4 14.8±2.2 130±4 NR
[26], 2018
Tajiri et al. 37 vs. 37 68 (35–90) A: 0, B: 29, 25 20 23.5 (6–150) 135 (118–142) 2.35 (1.2–3.7)
[25], 2018 C: 45
Arase et al. 27 vs. 16 68 (39–84) A: 0, B: 20, 9 21 23 (7–92) 137 (118–145) 2.2 (1.4–3.1)
[24], 2018 C: 23
Tahara et al. 45 vs. 20 71.5±9.1 A: 0, B: 28, 28 40 NR 137.0±4.7 2.3±0.5
[23], 2017 C: 37
Kogiso et al. 65 vs. 18 64 (22–90) vs. 10 (7–14) vs. 22 vs. NR 23.1 (5.5–78.7) vs. NR 2.5 (1.9–4.2) vs.
[22], 2017 61 (31–84) 11 (8–13) 6 22.5 (5.8–64.3) 2.4 (1.8–3.2)
Atsukawa et al. 116 vs. 94 67 (41–85) vs. A: 1 vs. 4, 34 vs. NR 18.8 (6.0–94.0) vs. 136 (118–146) vs. 2.6 (1.7–4.0) vs.
[21], 2018 65 (40–89) B: 49 vs. 41, 30 21.9 (5.4–81.8)* 136 (115–147) 2.6 (1.6–4.2)
C: 66 vs. 49
Yamada et al. 48 vs. 32 73 (62–79) vs. C: 15 vs. 24* 31 vs. 31 vs. NR 136 (132–139) vs. 2.8 (2.5–3.2) vs.
[20], 2016 68 (63–75) 24 14 133 (130–136) 2.8 (2.4–3.0)
Iwamoto et al. 16 vs. 10 71.6±9 vs. 9.8±1.9 vs. 17 20 24.2±14.4 vs. 136.6±3.6 vs. 2.6±0.5 vs.
[19], 2016 71.9±6.2 9.7±1.1 36.1±11.4* 134.4±5.7 2.5±0.4
* p value < 0.05.
HCC, hepatocellular carcinoma; HCV, hepatitis C virus; BUN, blood urea nitrogen; NR, not reported.
Discussion hepatocellular carcinoma or the definition of tolvaptan
response, suggesting its long-term prognostic value in di-
Refractory ascites and hyponatremia constitute ma- uretic-resistant ascites. Interestingly, extended survival
jor complications of liver cirrhosis, since they are asso- was even observed in responders with severe chronic kid-
ciated with increased morbidity and mortality, as well ney disease, as tolvaptan was able to increase urine vol-
as with poor quality of life [31]. Vaptans have been pro- ume without compromising renal function [24]. Much
posed as promising tools for the management of cir- research interest has been devoted to identify potential
rhotic patients, since they are able to promote free-wa- markers in order to predict which patients would benefit
ter excretion, alleviate edema, and restore serum sodi- from the administration of tolvaptan. Specifically, the
um levels. Although no clinical benefit was shown from most promising results exist regarding the use of urine
the use of satavaptan [32], growing evidence supports osmolality, sodium excretion [35], and aquaporin 2 levels
that treatment with tolvaptan represents a safe and ef- [36], although the optimal predictive model remains still
ficient option for patients with refractory ascites. Spe- under investigation.
cifically, tolvaptan has been suggested to effectively re-
duce body weight, limit the required doses of diuretics, Strengths and Limitations of the Study
and elevate serum sodium concentration, without sig- The present study accumulated for the first time cur-
nificantly increasing the rate of serious adverse effects rent literature knowledge regarding the possible prog-
[33, 34]. nostic role of tolvaptan response in patients with refrac-
The findings of the present meta-analysis indicate that tory ascites. This was accomplished by systematically
short-term response to tolvaptan administration is asso- searching 5 independent literature databases and by ap-
ciated with significantly improved overall survival in pa- plying no date or language restriction. In contrast to pre-
tients with liver cirrhosis and refractory ascites or hypo- vious meta-analyses in the field [37, 38], the present me-
natremia. This effect was independent of the presence of ta-analysis focused on survival outcomes and examined
324 Dig Dis 2020;38:320–328 Bellos/Kontzoglou/Psyrri/Pergialiotis
DOI: 10.1159/000503559Table 3. Outcomes of the quality assessment. The overall risk of bias was evaluated to be low to moderate
ROBINS-I tool
Author, year Bias due to Bias in selection Bias due to Bias in Bias in selection Overall
confounding of participants into missing data measurement of the reported bias
the study of outcomes result
Kida [27], 2019 Low Low Moderate Low Low Low
Wang Moderate Moderate Moderate Low Low Moderate
et al. [26], 2018
Tajiri Low Low Moderate Low Low Low
et al. [25], 2018
Arase Low Low Moderate Low Low Low
et al. [24], 2018
Tahara Low Low Moderate Low Low Low
et al. [23], 2017
Kogiso Moderate Moderate Moderate Low Low Moderate
et al. [22], 2017
Atsukawa Moderate Low Moderate Low Low Moderate
et al. [21], 2018
Yamada Low Low Moderate Low Low Low
et al. [20], 2016
Iwamoto Moderate Moderate Moderate Low Low Moderate
et al. [19], 2019
ROBINS-I, Risk Of Bias In Non-randomized Studies of Interventions.
the effect of tolvaptan response on patients’ long-term ducted in Asian populations, a fact that although enhanc-
prognosis. In order to properly analyze time-to-event es their comparability, may limit the generalizability of
data, HRs were estimated for each study and were pooled the results.
together to provide the meta-analytic estimate. More-
over, subgroup and sensitivity analyses were conducted, Implications for Current Clinical Practice and Future
taking into account the most important confounding Research
factors that may have remarkably altered the outcomes The outcomes of the present meta-analysis suggest that
of the analysis. patients with refractory ascites responding to tolvaptan
Nevertheless, the findings of the meta-analysis were treatment present significantly improved overall survival
based on 9 studies, including a moderate number of pa- rates. As a result, short-term clinical response, defined ei-
tients. More specifically, the interpretation of the study ther as effective body weight loss or sodium elevation, rep-
outcomes may be complicated by the existing interstudy resents an important prognostic factor, as it is associated
heterogeneity. Definition of tolvaptan response was rec- with better long-term outcomes. However, it should be
ognized as the most important confounding factor; there- noted that these findings are derived from observational
fore, subgroup analysis was performed, indicating that studies and thus warrant confirmation by large-scale ran-
overall survival was improved irrespective of whether re- domized controlled trials, in order to limit the possibility
sponse was defined as sodium normalization, weight loss of bias due to confounding and patient selection. Specifi-
≥1.5 or ≥2 kg during the 1st week of treatment. Further- cally, future studies evaluating the potency of tolvaptan
more, the design of the majority of the studies was retro- should not only assess its diuretic effects but they should
spective and thus bias due to missing data could not be also focus on hard outcomes, such as hospitalization stay
safely excluded. However, sensitivity analysis indicated and mortality rates. Quality of life should also be taken into
that the outcomes of the meta-analysis were not affected consideration, as it constitutes a significant aspect of cir-
when studies with low risk of bias were separately exam- rhotic patients’ management. Finally, since hepatotoxicity
ined. It is also important to state that all studies were con- represents the main concern about the wide use of tolvap-
Tolvaptan Response in Refractory Ascites Dig Dis 2020;38:320–328 325
DOI: 10.1159/000503559Color version available online
HR HR
Study or subgroup log (HR) SE Weight IV, random, 95% CI IV, random, 95% CI
1.1.1 Effective body weight reduction
Iwamoto, 2016 –0.77 1.28 1.4% 0.46 [0.04, 5.69]
Yamada, 2016 –1.02 0.29 15.1% 0.36 [0.20, 0.64]
Atsukawa, 2017 –0.4 0.18 22.3% 0.67 [0.47, 0.95]
Tahara, 2017 –1.04 0.36 11.8% 0.35 [0.17, 0.72]
Arase, 2018 –1.04 0.38 11.0% 0.35 [0.17, 0.74]
Tajiri, 2018 –0.39 0.33 13.1% 0.68 [0.35, 1.29]
Kida, 2019 –2.12 0.64 5.0% 0.12 [0.03, 0.42]
Subtotal (95% CI) 79.8% 0.44 [0.30, 0.63]
Heterogeneity: Tau2 = 0.11; Chi2 = 11.50, df = 6 (p = 0.07); I2 = 48%
Test for overall effect: Z = 4.38 (p < 0.0001)
1.1.2 Effective sodium elevation
Kogiso, 2017 –1.14 0.33 13.1% 0.32 [0.17, 0.61]
Wang, 2018 –0.82 0.52 7.0% 0.44 [0.16, 1.22]
Subtotal (95% CI) 20.2% 0.35 [0.20, 0.61]
Heterogeneity: Tau2 = 0.00; Chi2 = 0.27, df = 1 (p = 0.60); I2 = 0%
Test for overall effect: Z = 3.76 (p = 0.0002)
Total (95% CI) 100.0% 0.42 [0.31, 0.58]
Heterogeneity: Tau2 = 0.08; Chi2 = 13.06, df = 8 (p = 0.11); I2 = 39%
Test for overall effect: Z = 5.48 (p < 0.00001) 0.01 0.1 1 10 100
Test for subgroup differences: Chi2 = 0.41, df = 1 (p = 0.52); I2 = 0% Favours (responders) Favours (non-responders)
Fig. 2. Forest plot illustrating the overall survival benefit of tolvaptan responders compared to nonresponders. HR, hazard ratio.
Table 4. Outcomes of the leave-one-out analysis
Omitted study HR 95% CI p value Heterogeneity
I2, % p value
Kida [27], 2019 0.47 0.36–0.61order to construct a combined model effectively discrimi- • This association was independent of response definition and
nating the population in which the benefits of tolvaptan presence of hepatocellular carcinoma.
• Future studies should identify efficient markers to predict
therapy would outweigh the risks of liver toxicity. tolvaptan response.
Conclusions Acknowledgment
The present meta-analysis supports the prognostic None.
role of tolvaptan response, since it is associated with sig-
nificantly improved overall survival in cirrhotic patients
with refractory ascites. This effect was independent of re- Statement of Ethics
sponse definition or presence of hepatocellular carcino-
ma. Future large-scale trials should verify these outcomes, No ethical approval was required. The present systematic re-
as well as to identify the optimal markers to predict the view and meta-analysis is based on aggregated data that were re-
trieved from studies already retrieved. We did not collect individ-
effectiveness of tolvaptan. Patients’ comorbidities and ual patient data and did not have direct contact with patients in-
concomitant medications should be taken into account in cluded.
order to limit the possibility of confounding.
Disclosure Statement
Key Points
The authors have no conflicts of interest to declare.
• Refractory ascites represents a major complication of cirrhosis
leading to increased morbidity and mortality.
• Tolvaptan has been proposed as an add-on treatment in order
to alleviate edema and decrease body weight. Funding Sources
• The present meta-analysis suggests that response to tolvaptan
is linked to improved overall survival. There is no funding source to declare.
References
1 Ginés P, Quintero E, Arroyo V, Terés J, Bru- cokinetic and Pharmacodynamic Properties 13 Liberati A, Altman DG, Tetzlaff J, Mulrow C,
guera M, Rimola A, et al.: Compensated cir- and Drug Interactions. J Clin Med. 2014 Nov; Gøtzsche PC, Ioannidis JP, et al. The PRISMA
rhosis: natural history and prognostic factors. 3(4):1276–90. statement for reporting systematic reviews
Hepatology. 1987 Jan-Feb;7(1):122–8. 8 Li B, Fang D, Qian C, Feng H, Wang Y. The and meta-analyses of studies that evaluate
2 Di Pascoli M, Sacerdoti D, Pontisso P, Angeli Efficacy and Safety of Tolvaptan in Patients health care interventions: explanation and
P, Bolognesi M. Molecular Mechanisms with Hyponatremia: A Meta-Analysis of Ran- elaboration. J Clin Epidemiol. 2009 Oct;
Leading to Splanchnic Vasodilation in Liver domized Controlled Trials. Clin Drug Inves- 62(10):e1–34.
Cirrhosis. J Vasc Res. 2017;54(2):92–9. tig. 2017 Apr;37(4):327–42. 14 Sterne JA, Hernán MA, Reeves BC, Savović J,
3 Pose E, Cardenas A. Translating Our Current 9 Wang C, Xiong B, Cai L. Effects of Tolvaptan Berkman ND, Viswanathan M, et al. ROB-
Understanding of Ascites Management into in patients with acute heart failure: a system- INS-I: a tool for assessing risk of bias in non-
New Therapies for Patients with Cirrhosis atic review and meta-analysis. BMC Cardio- randomised studies of interventions. BMJ.
and Fluid Retention. Dig Dis. 2017; 35(4): vasc Disord. 2017 Jun;17(1):164. 2016 Oct;355:i4919.
402–10. 10 Bellos I, Iliopoulos DC, Perrea DN. The Role 15 Higgins JP, Thompson SG, Deeks JJ, Altman
4 Ginès P, Cárdenas A, Arroyo V, Rodés J. of Tolvaptan Administration After Cardiac DG. Measuring inconsistency in meta-analy-
Management of cirrhosis and ascites. N Engl Surgery: A Meta-Analysis. J Cardiothorac ses. BMJ. 2003 Sep;327(7414):557–60.
J Med. 2004 Apr;350(16):1646–54. Vasc Anesth. 2019 Aug;33(8):2170–9. 16 Tierney JF, Stewart LA, Ghersi D, Burdett S,
5 Cárdenas A, Ginès P. Management of refrac- 11 Hayashi M, Abe K, Fujita M, Okai K, Taka- Sydes MR. Practical methods for incorporat-
tory ascites. Clin Gastroenterol Hepatol. 2005 hashi A, Ohira H. Association between the Se- ing summary time-to-event data into meta-
Dec;3(12):1187–91. rum Sodium Levels and the Response to analysis. Trials. 2007 Jun;8(1):16.
6 Taki Y, Kanazawa H, Narahara Y, Itokawa N, Tolvaptan in Liver Cirrhosis Patients with As- 17 Parmar MK, Torri V, Stewart L. Extracting
Kondo C, Fukuda T, et al. Predictive factors cites and Hyponatremia. Intern Med. 2018 summary statistics to perform meta-analyses
for improvement of ascites after transjugular Sep;57(17):2451–8. of the published literature for survival end-
intrahepatic portosystemic shunt in patients 12 Kawaratani H, Fukui H, Moriya K, Noguchi points. Stat Med. 1998 Dec;17(24):2815–34.
with refractory ascites. Hepatol Res. 2014 R, Namisaki T, Uejima M, et al. Predictive 18 Williamson PR, Smith CT, Hutton JL, Mar-
Aug;44(8):871–7. parameter of tolvaptan effectiveness in cir- son AG. Aggregate data meta-analysis with
7 Bhatt PR, McNeely EB, Lin TE, Adams KF Jr, rhotic ascites. Hepatol Res. 2017 Aug; 47(9): time-to-event outcomes. Stat Med. 2002 Nov;
Patterson JH. Review of Tolvaptan’s Pharma- 854–61. 21(22):3337–51.
Tolvaptan Response in Refractory Ascites Dig Dis 2020;38:320–328 327
DOI: 10.1159/00050355919 Iwamoto T, Maeda M, Hisanaga T, Saeki I, of cirrhotic patients with ascites and hypona- hyponatremia in cirrhosis. J Hepatol. 2012
Fujisawa K, Matsumoto T, et al. Predictors of tremia. BMC Gastroenterol. 2018 Sep; 18(1): Mar;56(3):571–8.
the Effect of Tolvaptan on the Prognosis of 137. 35 Uojima H, Kinbara T, Hidaka H, Sung JH,
Cirrhosis. Intern Med. 2016;55(20):2911–6. 27 Kida Y. Positive Response to Tolvaptan Treat- Ichida M, Tokoro S, et al. Close correlation
20 Yamada T, Ohki T, Hayata Y, Karasawa Y, ment Would Be a Good Prognostic Factor for between urinary sodium excretion and re-
Kawamura S, Ito D, et al. Potential Effective- Cirrhotic Patients with Ascites. Dig Dis. 2019; sponse to tolvaptan in liver cirrhosis patients
ness of Tolvaptan to Improve Ascites Unre- 37(3):239–46. with ascites. Hepatol Res. 2017 Mar; 47(3):
sponsive to Standard Diuretics and Overall 28 Kogiso T, Yamamoto K, Kobayashi M, E14–21.
Survival in Patients with Decompensated Liv- Ikarashi Y, Kodama K, Taniai M, et al. Re- 36 Nakanishi H, Kurosaki M, Hosokawa T,
er Cirrhosis. Clin Drug Investig. 2016 Oct; sponse to tolvaptan and its effect on prognosis Takahashi Y, Itakura J, Suzuki S, et al. Urinary
36(10):829–35. in cirrhotic patients with ascites. Hepatol Res. excretion of the water channel aquaporin 2
21 Atsukawa M, Tsubota A, Kato K, Abe H, Shi- 2017 Aug;47(9):835–44. correlated with the pharmacological effect of
mada N, Asano T, et al. Analysis of factors 29 Nakai M, Ogawa K, Takeda R, Ohara M, tolvaptan in cirrhotic patients with ascites. J
predicting the response to tolvaptan in pa- Kawagishi N, Izumi T, et al. Increased serum Gastroenterol. 2016 Jun;51(6):620–7.
tients with liver cirrhosis and hepatic edema. C-reactive protein and decreased urinary 37 Yan L, Xie F, Lu J, Ni Q, Shi C, Tang C, et al.
J Gastroenterol Hepatol. 2018 Jun; 33(6): aquaporin 2 levels are predictive of the effi- The treatment of vasopressin V2-receptor an-
1256–63. cacy of tolvaptan in patients with liver cirrho- tagonists in cirrhosis patients with ascites: a
22 Kogiso T, Kobayashi M, Yamamoto K, sis. Hepatol Res. 2018 Feb;48(3):E311–9. meta-analysis of randomized controlled tri-
Ikarashi Y, Kodama K, Taniai M, et al. The 30 Hiramine Y, Uto H, Mawatari S, Kanmura S, als. BMC Gastroenterol. 2015 Jun;15(1):65.
Outcome of Cirrhotic Patients with Ascites Is Imamura Y, Hiwaki T, et al.: ffect of Tolvap- 38 Dahl E, Gluud LL, Kimer N, Krag A. Meta-
Improved by the Normalization of the Serum tan on the Prognosis in Patients with Hepat- analysis: the safety and efficacy of vaptans
Sodium Level by Tolvaptan. Intern Med. 2017 ic Ascites. Hepatol Res. 2019 Jul; 49(7): 765– (tolvaptan, satavaptan and lixivaptan) in cir-
Nov;56(22):2993–3001. 77. rhosis with ascites or hyponatraemia. Aliment
23 Tahara T, Mori K, Mochizuki M, Ishiyama R, 31 Fortune B, Cardenas A. Ascites, refractory as- Pharmacol Ther. 2012 Oct;36(7):619–26.
Noda M, Hoshi H, et al. Tolvaptan is effective cites and hyponatremia in cirrhosis. Gastro- 39 Torres VE, Chapman AB, Devuyst O, Gan-
in treating patients with refractory ascites due enterol Rep (Oxf). 2017 May;5(2):104–12. sevoort RT, Grantham JJ, Higashihara E, et
to cirrhosis. Biomed Rep. 2017 Dec;7(6):558– 32 Wong F, Watson H, Gerbes A, Vilstrup H, al.; TEMPO 3:4 Trial Investigators. Tolvaptan
62. Badalamenti S, Bernardi M, et al.; Satavaptan in patients with autosomal dominant polycys-
24 Arase Y, Kagawa T, Tsuruya K, Sato H, Tera- Investigators Group. Satavaptan for the man- tic kidney disease. N Engl J Med. 2012 Dec;
mura E, Anzai K, et al. Impaired Renal Func- agement of ascites in cirrhosis: efficacy and 367(25):2407–18.
tion May Not Negate the Efficacy of Tolvap- safety across the spectrum of ascites severity. 40 Bellos I, Kontzoglou K, Perrea DN. Predictors
tan in the Treatment of Cirrhotic Patients Gut. 2012 Jan;61(1):108–16. of tolvaptan short-term response in patients
with Refractory Ascites. Clin Drug Investig. 33 Akiyama S, Ikeda K, Sezaki H, Fukushima T, with refractory ascites: A meta-analysis. J
2019 Jan;39(1):45–54. Sorin Y, Kawamura Y, et al. Therapeutic ef- Gastroenterol Hepatol. 2019 Jul;jgh.14784.;
25 Tajiri K, Tokimitsu Y, Ito H, Atarashi Y, fects of short- and intermediate-term tolvap- Epub ahead of print.
Kawai K, Minemura M, et al. Survival Benefit tan administration for refractory ascites in pa- 41 Hinz M, Wree A, Jochum C, Bechmann LP,
of Tolvaptan for Refractory Ascites in Pa- tients with advanced liver cirrhosis. Hepatol Saner F, Gerbes AL, et al.: High age and low
tients with Advanced Cirrhosis. Dig Dis. Res. 2015 Nov;45(11):1062–70. sodium urine concentration are associated
2018;36(4):314–21. 34 Cárdenas A, Ginès P, Marotta P, Czerwiec F, with poor survival in patients with hepatore-
26 Wang S, Zhang X, Han T, Xie W, Li Y, Ma H, Oyuang J, Guevara M, et al. Tolvaptan, an oral nal syndrome. Ann Hepatol. 2013 Jan-Feb;
et al. Tolvaptan treatment improves survival vasopressin antagonist, in the treatment of 12(1):92–9.
328 Dig Dis 2020;38:320–328 Bellos/Kontzoglou/Psyrri/Pergialiotis
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