Effects and safety of oral tolvaptan in patients with congestive heart failure: A systematic review and network meta-analysis
Effects and safety of oral tolvaptan in patients with congestive heart failure: A systematic review and network meta-analysis
Mei-Yi Wu 0 1
Tzu-Ting Chen 1
Ying-Chun Chen 1
Der-Cherng Tarng 1
Yun-Chun Wu 1
Hsien-Ho Lin 1
Yu-Kang Tu 1
0 Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University , New Taipei City, Taiwan , 2 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University , New Taipei City, Taiwan , 3 Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University , Taipei, Taiwan , 4 Department of Pharmacy, Taipei Medical University±Shuang Ho Hospital , New Taipei City, Taiwan , 5 Institute of Clinical Medicine, National Yang-Ming University , Taipei, Taiwan , 6 Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital , Taipei , Taiwan
1 Editor: Yoshihiro Fukumoto, Kurume University School of Medicine , JAPAN
Several studies reported treatment benefits of tolvaptan in patients with congestive heart failure (CHF). However, the optimal dosage remains unclear. We aimed to compare different dosage of tolvaptan to determine the optimal dosage in terms of the efficacy and safety.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: Yun-Chun Wu and Yu-Kang Tu were partly funded by a grant from the Ministry of Science and Technology in Taiwan (grant no. MOST103-2314-B-002-032-MY3).
Competing interests: The authors have declared that no competing interests exist.
We searched MEDLINE, PubMed, EMBASE, Cochrane CENTRAL and ClinicalTrials.gov
through Aug 31, 2016. Randomized controlled trials (RCTs) comparing tolvaptan of different
dosages or to placebo in patients with CHF were included. We used network meta-analysis
to look for the optimal dosage in terms of effectiveness and safety. Urine output, body weight
change and change in serum sodium were the main outcomes of efficacy. Adverse effects
were the secondary outcomes. Quality was assessed by Cochrane risk-of-bias tool.
Twelve RCTs reporting 14 articles with 5793 patients (mean age, 65.7 ± 11.9 years; 73.7%
man) were included. Compared with placebo, the tolvaptan 30 mg had similar effects to
tolvaptan 45±90 mg in terms of urine output (mean difference [MD] 2.03 liter; 95% confidence
interval [CI] 1.3 to 2.71), body weight change (MD -1.12 kg; 95% CI -1.37 to -0.88) and
change in serum sodium (MD 3.06 meq/L; 95% CI 2.43 to 3.68). Compared with placebo,
tolvaptan of different dosage showed a non-significant higher risk of adverse effects.
These findings suggest that tolvaptan 30 mg and 45 mg may be the optimum dosage for
CHF patients, because of its ability to provide favourable clinical results without greater
adverse effects. However, tolvaptan is not beneficial for reducing all-cause mortality in CHF
Congestive heart failure (CHF) is a clinical condition with reduced cardiac output and tissue
hypo-perfusion, leading to morbidity and mortality. Patients with CHF typically present with
shortness of breath, fatigue, legs edema and exercise intolerance, thereby resulting in poor
quality of life, frequent admissions, and a shorter life expectancy. Epidemiologic studies
indicate that a total of 670,000 new cases of CHF are diagnosed annually and its incidence and
prevalence increase with age [
]. Treatment of CHF, aiming at adequate decongestion of the
volume overload state, consists of diuretics, beta-blocker, angiotensin converting enzyme
(ACE) inhibitors or angiotensin receptor blockers (ARBs) or angiotensin receptor±neprilysin
inhibitor (ARNI), digoxin, and aldosterone antagonists. Common adverse effects of
pharmacotherapy are abnormal water homeostasis, worsening kidney function, electrolyte
disturbances and drug-drug interactions. The resistance to diuretics and the associated morbidities
have led to the development of effective and safe treatment strategies that maximize
decongestion but minimize the adverse impact on kidney function [
Vasopressin receptor antagonists (VRA), or vaptans, have the unique ability to attain an
aquaresis, the excretion of electrolyte-free water without accompanying solutes by directly
blocking binding of arginine vasopressin (AVP) to its renal receptors. Thus, vasopressin
antagonists has been used for the treatment of CHF in the years [
]. There is also a debate over
the optimal dosage of vaptans. Several randomized controlled trials (RCTs) evaluated the
efficacy and safety of tolvaptan, a selective V2 receptor antagonist in patients with CHF. The
results demonstrate symptomatic improvement in patients with decompensated heart failure.
According to the American Heart Association (AHA) guideline and European Society of
Cardiology (ESC) guideline, VRA may be prescribed to improve serum sodium concentration in
hypervolemic hyponatremia states in CHF patients [
]. While the treatment efficacy of
tolvaptan with different dosage have been investigated, no single clinical trial has been
undertaken to compare the treatment effects of different dosages of tolvaptan simultaneously.
Although previous RCTs and systematic reviews [7±10] reported treatment benefits of
tolvaptan on patients with CHF, the optimal dosage remains unclear. This is because traditional
meta-analysis can only make pairwise comparisons and is not well suited to compare multiple
treatments, such as different dosages of the same drug. The aim of this systematic review was
therefore to use network meta-analysis, an emerging new methodology for multiple treatment
comparisons, to synthesize all available evidence from RCTs comparing different dosages of
tolvaptan in patients with CHF to identify the best treatment strategies.
We undertook electronic literature searches within the MEDLINE, PubMed, EMBASE and
Cochrane databases from their inceptions up to Aug 31, 2016. We also searched the World
Health Organization International Clinical Trials Registry Platform
(http://www.controlledtrials.com) and reference lists of relevant review articles. The following MeSH search headings
were used: heart or cardiac or congestive, failure, vasopressin antagonist, tolvaptan. These
terms and their combinations were also searched as text-words. The `related articles' facility in
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PubMed was used to broaden the search, and all retrieved abstracts, studies, and citations
were reviewed. The protocol for this systematic review was registered in PROSPERO
(CRD42012002061). In addition, we attempted to identify other studies by hand-searching the
reference lists of the accessed papers and by contacting known experts in the field. No language
restrictions were applied. (S1 Appendix)
Criteria for study inclusion
We included all published RCTs evaluating the effects of tolvaptan on patients with CHF,
either in acute or chronic condition. The full text of potentially relevant studies was carefully
reviewed to ensure they satisfied following criteria: (1) the studies prospectively enrolled
patients who had confirmed as CHF (2) patients were randomized to receive tolvaptan versus
placebo or at least two different dosage of tolvaptan. (3) 1 or more of the primary or secondary
outcomes were reported. The studies were excluded if the outcomes of interest were not clearly
reported; extraction or calculation of treatment effects from the published results was not
possible; or an overlap was present between patient cohorts evaluated by two or more studies.
Primary and secondary outcomes
We used the following outcomes to evaluate the efficacy and safety of tolvaptan for CHF: (1)
body weight loss; (2) urine output; (3) change of serum sodium; (4) mortality; (5) thirsty; (6)
renal failure; (7) incidence of all adverse events.
Weight loss was defined as changes in body weight between baseline and follow-up body
weights after treatment. Urine volumes were collected on the first day of treatment. Change in
serum sodium was measured before and after the first day of treatment. Reported adverse
events including mortality, thirsty, renal failure, and incidence of all adverse events were
recorded and analyzed. The incidence of renal failure is defined as an increase in serum
creatinine ( 0.3 mg/dL increase from baseline) during the period of observation [
Data extraction and risk of bias assessment
Two reviewers (Mei-Yi Wu and Ying-Chun Chen) independently screened all titles and
abstracts identified in the literature search, reviewed the full texts of eligible studies, and
extracted the following information from each study: name of the first author, year of
publication, study population characteristics, study design, inclusion and exclusion criteria, matching
criteria, experimental drugs administration, net urine output, weight loss, parameters of the
renal function, and complications using a data extraction form. The original authors of the
identified studies were contacted for additional information when deemed necessary. Two
reviewers independently assessed the risk of bias of each study for each outcome including
selection bias, performance bias, detection bias, attrition bias, reporting bias and other bias
according to the risk of bias tool developed by the Cochrane Collaboration . Any
disagreement between the 2 reviewers was resolved by consulting the senior author (Y-K Tu).
Data synthesis and analysis
We estimated weighted mean difference (WMD) for weight loss, net urine output, and change
in serum sodium, and relative risk (RR) for adverse effects between different treatments. We
firstly did pair-wise meta-analyses for direct comparisons using DerSimonian and Laird
random-effect model [
]. Statistical heterogeneity was assessed using the I2 statistic, with values
greater than 50% indicating substantial heterogeneity [
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Network meta-analysis used both direct and indirect comparisons to estimate relative
efficacy of different treatments. We used the network suite of commands written by Ian White
implemented in the statistical software package STATA (version 13.0) to undertake network
meta-analysis. The probabilities of treatment ranking for each tolvaptan dosage was obtained
by simulations, and results were presented by means of rankograms, surface under the
cumulative ranking curve (SUCRA), and mean ranks [
]. All the analyses were conducted using
STATA (version 13, StataCorp, College Station, Texas, USA). The level of statistical
significance was set at 5%, and all statistical tests were 2-sided. For the potential inconsistency within
our network meta-analyses, we evaluated the loop-specific inconsistency models,
node-splitting models, and the design-by-treatment interaction models [
Fig 1 showed the flow chart for the electronic searching process. Our initial search strategy
yielded 198 citations, 137 of which were excluded based on our screening of titles and
abstracts. Full texts of 61 studies were then obtained and reviewed; eventually 14 articles of 12
RCTs were eligible for our systematic review [11, 12, 18±28], and 5793 participants in these 12
RCTs were included in our network meta-analyses.
Characteristics and baseline patient information from each of the 14 articles included in
our systematic review were shown in Table 1. The studies were published between 2003 and
2016, and their sample sizes ranged from 20 to 2085. All the trials enrolled patients with CHF
who received tolvaptan of various dosages. Mean age of patients in these trials ranged from 57
to 79 years old, and 73.7% of participants were male (in the range of 43±90.5%). NYHA classes
of CHF were reported except one. The follow-up length of the included trials ranged from 7
days to more than 1 year. The tolvaptan dosages were adjusted according to various protocols,
ranging from 7.5 to 90 mg/d. Durations of tolvaptan therapy ranged from 1 to 365 days.
Serum creatinine levels in all CHF patients were below 3 mg/dl. Diuretic therapy was
prescribed by 12 studies [
]. Five RCTs [
11, 12, 18, 19, 25
] were performed exclusively in
patients with acute decompensated heart failure (ADHF), whereas 7 RCTs [20, 21, 23, 24, 26±
28] were conducted in patients with CHF. Six trials evaluated the urine output after tolvaptan
11, 12, 18, 20, 24, 26
]. Eight trials evaluated the body weight loss after tolvaptan
treatment [11, 12, 18±21, 23, 26]. Change of serum sodium was reported in 8 trials [11, 12, 18±
20, 25, 26, 28]. The safety of tolvaptan was evaluated by the occurrence of mortality, thirsty,
renal failure, and adverse events.
Fig 2 showed the network plots for the primary and secondary outcomes. The size of each
node is proportional to the number of patients receiving the treatment, and the width of each
line is proportional to the number of studies directly comparing the two treatments connected
by the line.
Results from network meta-analysis and meta-analysis of direct comparisons and for
primary outcomes were shown in the Fig 3 and S1±S3 Figs, respectively. Results for secondary
outcomes such as mortality, thirst, renal failure, and adverse events were shown in S4 and S5
Primary outcomesÐUrine output, body weight change, change in serum
The network meta-analysis for the 3 primary outcomes included 6 to 8 trials involving 994 to
5020 CHF patients (Fig 3). For urine output, no difference was found between tolvaptan 7.5
mg and placebo. Tolvaptan 15 mg or greater dosages yielded on average 0.91 to 2.3 liter more
urine output compared to placebo (Fig 3A): tolvaptan 15 mg, 0.91 Liter (L) (95% confidence
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Fig 1. Flow diagram of literature search and trial selection. Abbreviations: HF, heart failure and VRAs,
vasopressin receptor antagonists.
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Fig 2. Network geometry for outcomes in network meta-analysis of tolvaptan dosage strategies for CHF. (A) Urine output 994
participants (6 trials). (B) Body weight change 5020 participants (8 trials). (C) Change of serum sodium 4623 participants (8 trials). (D)
Mortality 5019 participants (5 trials). (E) Thirst 5223 participants (8 trials). (F) Renal failure 5150 participants (8 trials). (G) Incidence
of all adverse effects 5336 participants (8 trials).
interval [CI], 0.22±1.60 L); tolvaptan 30 mg, 2.01 L (95% CI, 1.30±2.71 L); tolvaptan 45 mg,
2.03 L (95% CI, 1.15±2.91 L); tolvaptan 60 mg, 2.3L (95% CI, 1.60±3.0 L); and tolvaptan 90 mg,
1.97 L (95% CI, 0.98±2.96 L). Network meta-analysis also showed that tolvaptan 30 mg to 90
mg had similar effects on urine output.
For body weight loss, no difference was found between tolvaptan 7.5 mg and placebo.
Tolvaptan 15 mg to 90 mg yielded significantly greater body weight loss than placebo (Fig 3B):
tolvaptan 15 mg, -0.57 kg (95% CI, -0.83, -0.31 kg); tolvaptan 30 mg, -0.82 kg (95% CI, -0.96,
-0.67 kg); tolvaptan 45 mg, -1.12 kg (95% CI, -1.37, -0.88 kg); tolvaptan 60 mg, -1.11 kg (95%
CI, -1.33, -0.9 kg); and tolvaptan 90 mg, -1.27 kg (95% CI, -1.74, -0.8 kg). Network
meta-analysis also showed that tolvaptan 45 mg to 90 mg seemed to attain greater body weight loss than
smaller doses of tolvaptan.
Tolvaptan yielded greater increases in serum sodium than placebo (Fig 3C): tolvaptan 7.5
mg, 2.94 meq/L (95% CI: 0.0±5.88 meq/L); 15 mg, 1.28 meq/L (95% CI, 0.46±2.1 meq/L);
tolvaptan 30 mg, 3.06 meq/L (95% CI, 2.43±3.68 meq/L); tolvaptan 45 mg, 3.80 meq/L (95% CI,
2.45±5.15 meq/L); tolvaptan 60 mg, 3.96 meq/L (95% CI, 3.02±4.91 meq/L); and tolvaptan 90
mg, 3.83 meq/L (95% CI, 2.55±5.11 meq/L). Network meta-analysis also suggested that
tolvaptan 30 mg to 90 mg had similar effects on increase of serum sodium. Four trials reported the
incidence of hypernatremia, ranging from 0.5±8% in the tolvaptan group [
12, 19, 22, 25
Secondary outcomesÐMortality, thirsty, renal failure, incidence of all
The network meta-analysis for the 4 secondary outcomes included 5 to 8 trials involving 5019
to 5336 CHF patients. In network meta-analysis, there was no significant difference in the risk
of the secondary outcome-mortality between interventions. Tolvaptan with dosage 15 mg or
above with an increased RR of being thirsty compared with placebo. There was no significant
difference in the risk of being thirsty among different dosages of tolvaptan. Details of the
comparisons between various dosages of tolvaptan and placebo in mortality, thirst, renal failure,
and all incidence of adverse effect are shown in the S5 Fig.
Ranking probability. We summarize the rankings of the 7 different dosage strategies with
SUCRA probabilities in terms of body weight change, urine output, change of serum sodium,
mortality, thirst, renal failure, and adverse effectsÐwith detailed provided in the S6 Fig.
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Fig 3. Results from network meta-analysis of primary outcomes. (A) Urine output. (B) Body weight
change. (C) Change of serum sodium.
Risk of bias of included studies
The methodological quality of the 12 included RCTs (14 articles) is assessed by the tool for risk
of bias [
]. Overall, studies were considered to be at a low risk of bias. Overall and study-level
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risks of bias assessments are summarized in S7 Fig in the supplement. Seven studies described
whether or how patient allocation to different treatment groups was concealed from the
participants (50%). Reporting on blinding was inadequately addressed by most included studies but
all were considered at low risk of bias because the outcome of interest were laboratory outcome
and unlikely to be influenced by a lack of blinding. All studies were at a low risk of attrition
bias. Four studies did not report relevant information so the risk of incomplete data bias was
low. Eleven studies were funded by pharmaceutical companies and were judged to be at high
risk of bias. Other potential biases included small study group, short follow-up time, and
industrial sponsor on authorship. We found no evidence of inconsistency.
Our network meta-analysis of 12 RCTs with 5793 CHF patients showed that CHF patients
treated with different dosages of tolvaptan yielded greater body weight loss, increased urine
output and greater change in serum sodium compared with placebo. We also found that doses
of 30 mg or greater appeared to show similar treatment effects in terms of urine output. Doses
of 45 mg or greater appeared to show similar treatment effects on body weight change.
Conversely, tolvaptan was associated with higher risk of thirsty compared with placebo, but no
significant differences were found between different dosages of tolvaptan. These findings suggest
that tolvaptan 30 mg to 45 mg might be considered the optimal dosage for CHF patients,
because of its favorable clinical results and similar risks for adverse effects.
In patients with CHF, there is an increased level of AVP, contributing to symptoms such as
edema, congestion, and dyspnea. Treatment goals of CHF are to decrease congestion,
afterload, and neurohormonal activation in order to improve hemodynamics and symptoms and,
perhaps, reduce in-hospital events, re-hospitalizations, and mortality while avoiding toxicities
of therapy [
]. Patients with CHF related hyponatremia are associated with increase in
]. Diuretics is a convenient and low-cost treatment in acute decompensated heart
failure. However, the shortcoming of conventional diuretics is the development of resistance and
side effects (electrolyte abnormalities, activation of the sympathetic nerve system and the
renin-angiotensin-aldosterone system, worsening renal function and ototoxicity) [
Tolvaptan, a selective V2 receptor antagonist, reduced cardiac preload resulting in decreased body
weight and improved edema and serum sodium without affecting blood pressure or renal
function in patients with CHF. It promotes free-water excretion without electrolyte imbalance
but has no effect on long-term outcome [
19, 20, 22
]. In 2009, United States Food and Drug
Administration (FDA) approved tolvaptan in the treatment of hypervolemic or normovolemic
hyponatremia including patients with heart failure, liver cirrhosis and syndrome of
inappropriate anti-diuretic hormone (SIADH) [
]. Hypernatremia was seldom reported in the
tolvaptan-treated groups, but it should be closely monitored for safety concern. The principal
finding of our network meta-analysis is that tolvaptan treatment has efficacy for CHF patients
with few adverse effects and dosage recommendation is 30±45 mg for clinical usage.
Renal insufficiency and CHF are frequently co-existed, which is called organ cross-talk and
led to well-known definition of cardiorenal syndrome (CRS). Loop diuretics are frequently
used for CKD patients to ameliorate congestion in those with CRS. The studies included in the
network meta-analysis were conducted in subjects with near-normal kidney function or mildly
impaired kidney function (serum creatinine < 3 mg/dl). Future study should focus on whether
tolvaptan is also safe and effective on urine volume and serum sodium excretions in CHF
patients with late stage CKD.
Although adverse events were observed more frequently in the tolvaptan-treated groups
than in the placebo group, our results indicated that the incidences of renal failure and all
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adverse effects and mortality were similar. Only the incidence of thirsty was significantly
higher in tolvaptan treatment group compared with placebo group.
Although null effects in morbidity and mortality were found in our network meta-analysis,
some studies showed potentially benefit in certain populations. There have been few studies
conducted to investigate the tolvaptan effect on mortality in CHF patients [
18, 22, 24, 27, 29
In a post hoc analysis study, total mortality was lower in the tolvaptan groups compared with
placebo in patients with elevated BUN levels and severe systemic congestion at randomization
]. Because this is a post hoc analysis, these conclusions need to be interpreted cautiously
due to high drop-out rate. Matsue et al. also reported short-term, early tolvaptan treatment in
ADHF with renal dysfunction showed a neutral effect on prognosis but potential benefit
among the patients with relatively preserved renal function [
]. The long-term beneficial
effect of tolvaptan on mortality should be validated in large-scale, randomized controlled trials
with a longitudinal follow-up. No benefit of tolvaptan on reducing all-cause mortality in CHF
patients was found in the network meta-analysis.
It is unclear in the previous literature about optimal dosage of tolvaptan in terms of the
safety and adverse effects. Matsuzaki et al. reported that tolvaptan at doses of 15±45 mg/day
exhibited dose-dependency in urine volume, but not in body weight change [
]. Our network
meta-analysis compared tolvaptan of different dosages in the same model and found that
30mg of tolvaptan improved urine output, whereas increasing dosage adds little urine output
but possible increase in adverse effects. Our results suggest that tolvaptan 45 mg increased
body weight loss, whereas increasing dosage provides little further benefit. This network
metaanalysis is the first to assess efficacy, safety and optimal dosage of vasopressin antagonist
tolvaptan. Our results show that increasing dosage beyond tolvaptan 45 mg provides little
additional benefit to body weight change and urine output, and therefore future trials with dosage
above 45 mg are probably unwarranted. Taking into account the cost-effectiveness, tolvaptan
30 mg is recommended.
Compared to previous meta-analyses, our network meta-analysis has several strengths:
first, we considered relevant outcomes (that is, urine output, weight loss, change of serum
sodium, thirsty, renal failure, incidence of all adverse effects and all-cause mortality). Also,
we used a comprehensive search in multiple databases and all languages and are unlikely to
have missed important numbers of relevant paper. Finally, we did a network meta-analysis
to evaluate the optimal dosage. Rather than grouping various dosages into one treatment
group, our network meta-analysis evaluated the efficacy of different dosages separately
within a single statistical model. Network meta-analysis also allowed us to compare different
dosages indirectly when no head-to-head trial was available. Our findings need to be
considered as average effects because we did not have individual patient data which would allow us
to identify potential differential effects of available dosage of tolvaptan in subgroup of CHF
Our network meta-analysis has also several limitations: First, detailed dosages of
diuretic and inotropic agents were not available. Diuretic may cause electrolyte
abnormalities, such as hypokalemia and hyponatremia. Second, population characteristics, tolvaptan
dosage, renal function status, concurrent medications in included studies would contribute
to the observed heterogenicity. The applied analysis is based on relative treatment effect
and the analysis accounts for these differences by preserving randomization. Third, the
length of follow-up varied across studies, resulting in potential variations in event rates in
the adverse effects. Our analysis does not incorporate costs, future studies need to be
conducted to determine the treatment period and the most cost-effective management
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In summary, patients treated with tolvaptan showed greater weight loss and urine output than
placebo group. The adverse effects were similar between the two groups except for thirsty. Our
study has several implications for clinical practice. Clinicians can consider more widespread
use of tolvaptan for the patients with CHF which might result in more appropriate treatment
and symptom relief. From a clinical perspective, tolvaptan is a promising decongestive
treatment to achieve symptomatic improvement and favorable clinical outcomes. Taking all
evidence into account, tolvaptan 30-45mg is the most effective dosage.
S1 Fig. Forest plot of direct comparison: Tolvaptan versus Control. Efficacy outcome: body
weight change at 24-hr.
S2 Fig. Forest plot of direct comparison: Tolvaptan versus Control. Efficacy outcome: urine
output at 24-hr.
S3 Fig. Forest plot of direct comparison: Tolvaptan versus Control. Efficacy outcome:
change of serum sodium at 24-hr.
S4 Fig. Forest plot of direct comparison: Tolvaptan versus Control. Main secondary
outcomes: 4.1.1 Thirst/ 4.1.2 Renal failure/ 4.1.3 Incidence of all adverse effects/ 4.1.4 Mortality.
S5 Fig. Main secondary outcomes of thirst, renal failure, incidence of all adverse effects
(C) Renal failure
(D) Incidence of all adverse effects
(A) Urine output
(B) Body weight change
(C) Change of serum sodium
(F) Renal failure
(G) Incidence of all adverse effects
S6 Fig. Ranking Probability of Strategies and Surface under the Cumulative Curve in the
Network Meta-analysis of tolvaptan dosage strategies for CHF patients.
S7 Fig. (A) Risk of bias graph: Review authors' judgements about each risk of bias item
presented as percentages across all included studies (B) Risk of bias summary: Review authors'
judgements about each risk of bias item for each included study.
S1 Appendix. Literature search strategy details.
Conceptualization: Mei-Yi Wu, Tzu-Ting Chen, Ying-Chun Chen, Der-Cherng Tarng,
Hsien-Ho Lin, Yu-Kang Tu.
Data curation: Mei-Yi Wu, Ying-Chun Chen.
Formal analysis: Tzu-Ting Chen, Yun-Chun Wu.
Methodology: Mei-Yi Wu, Hsien-Ho Lin, Yu-Kang Tu.
Software: Tzu-Ting Chen, Yun-Chun Wu.
Supervision: Der-Cherng Tarng, Hsien-Ho Lin, Yu-Kang Tu.
Writing ± original draft: Mei-Yi Wu, Tzu-Ting Chen, Yu-Kang Tu.
Writing ± review & editing: Mei-Yi Wu, Ying-Chun Chen, Der-Cherng Tarng, Hsien-Ho
Lin, Yu-Kang Tu.
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