Journal of
Clinical Medicine
Systematic Review
Safety and Efficacy of Vaptans in the Treatment of
Hyponatremia from Syndrome of Inappropriate Antidiuretic
Hormone Secretion (SIADH): A Systematic Review
and Meta-Analysis
Pajaree Krisanapan 1,2,3, * , Supawit Tangpanithandee 1,4 , Charat Thongprayoon 1 , Pattharawin Pattharanitima 2 ,
Andrea Kleindienst 5 , Jing Miao 1 , Iasmina M. Craici 1 , Michael A. Mao 6 and Wisit Cheungpasitporn 1, *
Citation: Krisanapan, P.;
Tangpanithandee, S.; Thongprayoon,
C.; Pattharanitima, P.; Kleindienst, A.;
Miao, J.; Craici, I.M.; Mao, M.A.;
Cheungpasitporn, W. Safety and
Efficacy of Vaptans in the Treatment
of Hyponatremia from Syndrome of
Inappropriate Antidiuretic Hormone
Secretion (SIADH): A Systematic
Review and Meta-Analysis. J. Clin.
Med. 2023, 12, 5483. https://doi.org/
10.3390/jcm12175483
Academic Editor: Jonathan Barratt
Received: 12 August 2023
Revised: 20 August 2023
Accepted: 21 August 2023
Published: 24 August 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
J. Clin. Med. 2023, 12, 5483. https://doi.org/10.3390/jcm12175483
1 Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA;
supawit_d@hotmail.com (S.T.); charat.thongprayoon@gmail.com (C.T.); miao.jing@mayo.edu (J.M.);
craici.iasmina@mayo.edu (I.M.C.)
2 Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Thammasat University,
Pathum Thani 12120, Thailand; pattharawin@hotmail.com
3 Division of Nephrology, Department of Internal Medicine, Thammasat University Hospital,
Pathum Thani 12120, Thailand
4 Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University,
Samut Prakan 10540, Thailand
5 Department of Neurosurgery, Friedrich-Alexander-University Nürnberg-Erlangen, 91054 Erlangen, Germany;
andrea.kleindienst@fau.de
6 Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic,
Jacksonville, FL 32224, USA; mao.michael@mayo.edu
* Correspondence: pajaree_fai@hotmail.com (P.K.); wcheungpasitporn@gmail.com (W.C.)
Abstract: The utilization of vasopressin receptor antagonists, known as vaptans, in the management
of hyponatremia among patients afflicted with the syndrome of inappropriate antidiuretic hormone
(SIADH) remains a contentious subject. This meta-analysis aimed to evaluate the safety and efficacy of
vaptans for treating chronic hyponatremia in adult SIADH patients. Clinical trials and observational
studies were identified by a systematic search using MEDLINE, EMBASE, and Cochrane Database
from inception through September 2022. The inclusion criteria were the studies that reported vaptans’
safety or efficacy outcomes compared to placebo or standard therapies. The study protocol was
registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD
42022357307). Five studies were identified, comprising three RCTs and two cohort studies, enrolling
a total of 1840 participants. Regarding short-term efficacy on days 4–5, vaptans exhibited a significant
increase in serum sodium concentration from the baseline in comparison to the control group, with a
weighted mean difference of 4.77 mmol/L (95% CI, 3.57, 5.96; I2 = 34%). In terms of safety outcomes,
the pooled incidence rates of overcorrection were 13.1% (95% CI 4.3, 33.6; I2 = 92%) in the vaptans
group and 3.3% (95% CI 1.6, 6.6; I2 = 27%) in the control group. Despite the higher correction rate
linked to vaptans, with an OR of 5.72 (95% CI 3.38, 9.70; I2 = 0%), no cases of osmotic demyelination
syndrome were observed. Our meta-analysis comprehensively summarizes the efficacy and effect
size of vaptans in managing SIADH. While vaptans effectively raise the serum sodium concentration
compared to placebo/fluid restriction, clinicians should exercise caution regarding the potential for
overcorrection.
Keywords: hyponatremia; SIAD; SIADH; syndrome of inappropriate antidiuresis; syndrome of
inappropriate antidiuretic hormone secretion; tolvaptan; satavaptan; vaptans; vasopressin receptor
antagonist; V2R antagonists
https://www.mdpi.com/journal/jcm
J. Clin. Med. 2023, 12, 5483 2 of 12

1. Introduction
Hyponatremia is a widely acknowledged risk factor for increased mortality, morbidity,
and hospital length of stay [1–8]. In addition, chronic hyponatremia is linked to mental
impairment, abnormal gait, falls, osteoporosis, and a higher risk of fractures [9–13]. The
syndrome of inappropriate antidiuretic hormone secretion (SIADH) is recognized as one
of the most common causes of hyponatremia in hospitalized patients [14–16]. In a large
multinational hyponatremia registry, the prevalence of SIADH was reported to be as high
as 49% in euvolemic and hypervolemic patients [17]. The pathophysiology of SIADH is
characterized by the inappropriate reduction of free water clearance due to elevated levels of
plasma vasopressin (AVP) or gain-of-function activity of the V2 vasopressin receptor (V2R).
SIADH can be caused by various underlying disorders, such as malignancy, pulmonary
disorders, central nervous system disorders, HIV infection, or idiopathic [18–20].
Vaptans, or V2R antagonists, are a novel class of drugs that can effectively treat hy-
ponatremia by directly inhibiting V2R [21–24]. Several vaptans have been developed
for clinical use, including conivaptan, lixivaptan, satavaptan, and tolvaptan. Currently,
however, only tolvaptan and conivaptan have been approved by the Food and Drug Ad-
ministration (FDA) for the treatment of clinically significant hypervolemic and euvolemic
hyponatremia [25] and solely tolvaptan has received authorization from the European
Medicines Agency (EMA) for treating SIADH. Even though tolvaptan showed significant
short-term efficacy in increasing serum sodium in the Study of Ascending Levels of Tolvap-
tans in Hyponatremia (SALT-1 and SALT-2) [16], the use of vaptans as first-line, or even
second-line, therapy among SIADH patients remains controversial [2,26–29].
To date, two meta-analyses published in 2010 and 2011 have reported the short-term
efficacy and safety of vaptans in comparison to placebo for the treatment of hyponatremia.
These studies examined hyponatremia not specific to the etiology of SIADH [25,30]. Overall,
vaptans modestly increased the serum sodium concentration after 3–7 days, but there was
a 2.5 to 3 times increased risk of an overly rapid increase in the serum sodium concentra-
tion [2,25,30]. Thus, the European guideline recommends against the use of vaptans for
SIADH treatment due to the risk of overcorrection, where the primary concern is for the
development of osmotic demyelination syndrome (ODS) [2,31,32]. Moreover, vaptans are
expensive and their use in symptomatic patients has yet to be evaluated [21]. Nevertheless,
recently, there has been a global urea shortage, resulting in a concern related to the avail-
ability of urea treatment for SIADH in some countries. Therefore, it is worth investigating
if vaptans could become an alternative therapy for SIADH.
The safety and efficacy of vaptans in the treatment of hyponatremia from SIADH
remain undetermined. Therefore, we conducted a systematic review and meta-analysis to
evaluate the safety and short-term efficacy of vaptans versus placebo or standard treatment
for patients with SIADH.

2. Materials and Methods

2.1. Search Strategy and Study Eligibility
The protocol for this systematic review and meta-analysis was registered with the
International Prospective Register of Systematic Reviews (PROSPERO; CRD42022357307).
Two investigators (P.K. and S.T.) independently performed a systematic search of MED-
LINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Database of
Systematic Reviews from inception through September 2022. To assess the safety and effi-
cacy of vaptans in the treatment of hyponatremia from SIADH, the search terms included
“Vaptans OR tolvaptan OR conivaptan OR satavaptan OR lixivaptan” and “syndrome of
inappropriate antidiuretic hormone secretion OR SIADH”. The search strategy is provided
in the Supplementary Table S1. The search was limited to humans without language re-
strictions. A manual search of the references of the included studies for additional relevant
studies was also conducted. The reporting of this systematic review followed the standards
of the PRISMA Statement [33].
J. Clin. Med. 2023, 12, 5483 3 of 12

Studies were included in this meta-analysis if they were clinical trials or cohort studies
that reported the safety or efficacy outcomes of vaptans (any dosage regimen) in comparison
to placebo or any standard therapies (including fluid restriction, urea, salt tablet, and
furosemide) for the treatment of hyponatremia in adult SIADH patients (age ≥ 18 years),
who were either hospitalized or nonhospitalized. Eligible studies needed to provide at least
one of the following outcomes: the early change in serum sodium level from the baseline
(at day 2–7), the rate of response, or the rate of sodium level overcorrection.
Studies that primarily reported other treatment outcomes or were comprised of mixed
etiologies of hyponatremia without a subgroup analysis for SIADH alone were also ex-
cluded. Retrieved studies were independently reviewed for eligibility by the two inves-
tigators (P.K. and S.T.). Discrepancies were resolved by mutual consensus between all
authors.

2.2. Data Extraction and Quality Assessment

A standardized data collection form was used to collect the following from each
included study: study title, author names, publication year, study type, the country where
the study was conducted, number of patients, age, follow-up duration, inclusion criteria,
causes of SIADH, control, study drug, dose of vaptans, drug exposure, interested outcomes,
baseline serum sodium, efficacy outcomes, days of efficacy assessment, change of serum
sodium from the baseline, the proportion of responders, time to response, overcorrection,
need for rescue therapy, mortality, adverse events, and withdrawn due to adverse event.
The outcome of ODS was primarily defined by the original included studies.
The quality of each study was independently appraised by each investigator. The
Newcastle–Ottawa quality scale (NOS) was used for cohort studies [34] (Supplementary
Table S2), and the Cochrane risk of bias tool was used to assess the quality of RCTs
(Supplementary Figure S1) [35].

2.3. Statistical Analysis

A comprehensive meta-analysis version 3.3.070 (Biostat Inc., Englewood, NJ, USA) was
used to perform this meta-analysis. The differences in effects were expressed as odds ratios
with 95% confidence intervals (CIs) for dichotomous outcomes and the weighted mean
difference (WMD) with 95% confidence intervals for continuous outcomes. If those data
were unavailable in the original articles, we calculated them by using data obtained from
investigators or figures. For RCTs, participants were analyzed in the groups of intention to
treat.
Heterogeneity was assessed using χ2 and/or the I2 statistic, with I2 values above 50%
or a p-value below 0.1, indicating significant heterogeneity. In the presence of significant
heterogeneity, a random-effect model was applied for meta-analysis. To evaluate the
presence of publication bias, a funnel plot and the Egger test [36] were utilized. A subgroup
analysis for primary outcomes based on the types of control was planned but could not be
performed due to the limited data availability. A sensitivity analysis of overcorrection was
performed by excluding a study by Kleindienst et al. [37] given that this study included
solely patients with SIADH following postoperative pituitary surgery. A p-value < 0.05
was considered statistically significant for all analyses.

3. Results
3.1. Study Characteristics
A total of 919 potential articles were retrieved by our search strategy (Figure 1), of
which 222 were duplicated articles. We excluded 651 articles because they did not meet
the inclusion criteria due to article type, methodology, or lack of relevance to both vaptans
and SIADH. Therefore, 46 articles underwent full-length review. Forty-one articles were
further excluded because of duplicated population, lack of controls, lack of outcome of
interest, no subgroup analysis of SIADH patients, or it included a population with severe
symptomatic hyponatremia. Only five studies with a total of 1840 patients were included in
J. Clin. Med. 2023, 12, x FOR PEER REVIEW 4 of 12

J. Clin. Med. 2023, 12, 5483 4 of 12

symptomatic hyponatremia. Only five studies with a total of 1840 patients were included
in this systematic review and meta-analysis, consisting of three RCTs [37,38]. and two co-
this studies
hort systematic review and meta-analysis, consisting of three RCTs [37,38]. and two cohort
[37,38].
studies [37,38].

Figure 1. PRISMA flow diagram.

Figure 1. PRISMA flow diagram.
Tolvaptan was used in most of the studies with a dose ranging from 3.75 to 60 mg once
dailyTolvaptan was used
[37–40], whereas in one
only most of the
study studies with
investigated a dose ranging
satavaptan from
[41] (Table 1). 3.75
The to 60 mg
control or
once daily [37–40], whereas only one study investigated satavaptan [41] (Table
standard treatment group consisted of a placebo in three RCTs [39–41] and fluid restriction 1). The
control
in two or standard
cohort treatment
studies [37,38].group consistedfollow-up
The median of a placebo in was
time three22.5
RCTs [39–41]
days (IQRand
7.5,fluid
201),
ranging from
restriction 7 days
in two to 1studies
cohort year. The median
[37,38]. Thedrug exposure
median time was
follow-up time17.5
wasdays
22.5 (IQR
days 4, 29),
(IQR
ranging
7.5, 201), from 1 day
ranging to 30
from days. to 1 year. The median drug exposure time was 17.5 days
7 days
(IQR 4, 29), ranging from 1 day to 30 days.
J. Clin. Med. 2023, 12, 5483 5 of 12

Table 1. Characteristics of the included studies.

Baseline Serum Study

Study Age Control(s) Dose of Drug
Study (Year) Site Total N F/U Time Population Sodium Drug
Type (Years) (n) Vaptans Exposure
(mmol/L) (n)
Multicenter
(Belgium, 25 or 50 mg
Soupart SIADH patients with stable 68.0 Placebo Satavaptan
RCT Germany, 35 12 months 125.9 ± 5.1 oral once 28 days
et al. (2006) [41] hyponatremia a ± 14.3 (n = 9) (n = 26)
Hungary, and daily
France)
Subgroup analysis of
30–60 mg
Verbalis patients with a diagnosis of 64.5 54% < 130 mmol/L, Tolvaptan
RCT Multicenter (US) 110 37 days Placebo (n = 58) oral once 30 days
et al. (2011) [40] SIADH from the SALT-1 ± 14.5 46% ≥ 130 mmol/L (n = 52)
daily
and SALT-2 trials
Chinese SIADH patients
30–60 mg
Chen Multicenter who hospitalized with 62.1 Tolvaptan
RCT 45 7 days 126.1 ± 5.6 Placebo (n = 24) oral once 7 days
et al. (2014) [39] (China) nonhypovolemic and ± 13.5 (n = 21)
daily
nonacute hyponatremia
no active therapy,
fluid restriction,
Prospective salt tablets,
Burst multina- Multinational SIADH patients with 88% of patients FR + NSS, Tolvaptan
1524 N/A N/A N/A N/A
et al. (2017) [38] tional register (US, EU) significant hyponatremia b aged > 50 years demeclocycline, (n = 122) c
registry NSS, hypertonic
saline
(n = 1,402) c
43% of
Prospective Post-operative SIADH 3.75 or 7.5
tolvaptan
Kleindienst et al. observa- Single center patients after pituitary 51.5 Fluid restriction Tolvaptan mg oral once
126 8 days 127.9 ± 3.4 group got
(2020) [37] tional (Germany) surgery, excluding TSH ± 16.4 (n = 40) (n = 86) daily until
a single
study and ACTH deficiency resolution
dose
Abbreviations: ACTH: adrenocorticotropic hormone; FR: fluid restriction; F/U: follow-up; NSS: normal saline; SIADH: syndrome of inappropriate secretion of antidiuretic hormone;
TSH: thyroid-stimulating hormone. a Stable hyponatremia was defined as serum Na+ increase ≤ 4 mmol/L between two measurements of 24 h apart and serum Na+ between
115–132 mmol/L. b Significant hyponatremia was defined as serum Na ≤ 130 mmol/L. c Calculated based on the use of tolvaptan by 8% of all patients.
J. Clin. Med. 2023, 12, 5483 6 of 12

The majority of the patients included in this systematic review were from Europe [37,38,41]
and the United States [38,40], while only a few were from China [39]. SIADH etiologies,
which were reported in three studies [37,38,41], included idiopathic, malignancy related,
drug induced, and postoperative. The latter was highlighted only in Kleindienst et al. since
they exclusively evaluated SIADH patients following pituitary tumor surgery [37]. Overall,
the mean age of patients was 59.3 ± 15.1 years old in four studies [37,39–41]. The mean
baseline serum sodium was 127.2 ± 4.3 mmol/L [37,39,41] in three studies and a separate
RCT reported that half of the patients had a baseline serum sodium < 130 mmol/L [40].

3.2. Efficacy of Vaptans on the Changes in Serum Sodium Levels from Baseline
Four studies assessed the changes in serum sodium levels from the baseline, with
three studies reporting changes on day 4 [37,39,40] and one study reporting changes on day
5 [41]. The reported changes in serum sodium were presented as either absolute values or
J. Clin. Med. 2023, 12, x FOR PEER REVIEW
average daily area under the curve (AUC) (Supplementary Table S3). In the meta-analysis, 6 of 12
the use of vaptans demonstrated a significant increase in the change of serum sodium levels
from baseline compared to the control group (placebo/fluid restriction), with a WMD of
4.77 mmol/L
significant (95% CI,
increase in 3.57, 5.96; I2 of
the change = 34%)
serum(Figure
sodium2A). Additionally,
levels a sensitivity
from the baseline analysis
compared to
was
the control group remained significant, with a WMD of 5.24 mmol/L (95% CI, 3.88, 6.60;ofI2
additionally performed including only RCTs. A significant increase in the change
serum
= 18%)sodium
(Figurelevels
2B). from the baseline compared to the control group remained significant,
with a WMD of 5.24 mmol/L (95% CI, 3.88, 6.60; I2 = 18%) (Figure 2B).

Figure 2. Alterations in Serum Sodium Levels from the Baseline. (A) Early change in serum sodium
Figure 2. Alterations in Serum Sodium Levels from the Baseline. (A) Early change in serum sodium
concentration from the baseline contrasting vaptans to the control, based on meta-analysis results;
concentration from the baseline contrasting vaptans to the control, based on meta-analysis results;
Soupart
Soupart et et al.
al.[41];
[41];Verbalis
Verbalisetetalal[40];
[40];Chen
Chenetetal.
al.[39]
[39]and
andKleindienst
Kleindienstetetal.
al.[37].
[37]. (B)
(B)Sensitivity
Sensitivity
analysis
analysis considering only RCTs, still indicating significant change from the baseline whencompared
considering only RCTs, still indicating significant change from the baseline when compared
to
tothe
thecontrol.
control.ForForboth
bothanalyses,
analyses,studies
studiesarearereferenced
referencedby bythe
theinitial
initialauthor’s
author’sname
nameand andpublication
publication
year. Soupart
year. Soupart et et al.
al. [41];
[41]; Verbalis
Verbalisetetalal[40]
[40]and
andChen
Chenetetal.al.[39].
[39].Weighted
Weightedmeanmeandifferences
differenceswere were
consolidatedutilizing
consolidated utilizingthetherandom-effects
random-effectsmodel,model,depicted
depictedonona ascale
scaleranging
rangingfrom
from−−1515 toto15
15mEq/L.
mEq/L.
Abbreviation:CI-confidence
Abbreviation: CI-confidence interval
interval [39–41].
[39–41]. Squares:
Squares: Represent
Represent the point
the point estimate
estimate of theofeffect
the from
effect
from individual studies. The size of the square often reflects the weight of the study
individual studies. The size of the square often reflects the weight of the study in the meta-analysis, in the meta-
analysis, with larger squares indicating greater weight. Diamond: Represents the summarized effect
with larger squares indicating greater weight. Diamond: Represents the summarized effect estimate
estimate from the combined studies. The width of the diamond provides an idea about the precision
from the combined studies. The width of the diamond provides an idea about the precision of
of the estimate; a wider diamond suggests less precision, while a narrower diamond indicates more
the estimate; a wider diamond suggests less precision, while a narrower diamond indicates more
precision.
precision.
3.3. Efficacy of Vaptans on the Response of Treatment
The early response after vaptan treatment at days 4–5 was assessed in three studies
[38–40]. The responders were defined as patients whose serum sodium normalized (135
mmol/L) or increased by at least 5 mmol/L from the baseline. Overall, there were greater
numbers of responders in the vaptans with a pooled odds ratio (OR) of 12.80 (95% CI 5.78,
28.28; I2 = 0%) (Figure 3A).
J. Clin. Med. 2023, 12, 5483 7 of 12

3.3. Efficacy of Vaptans on the Response of Treatment

J. Clin. Med. 2023, 12, x FOR PEER REVIEW 7 of
The early response after vaptan treatment at days 4–5 was assessed in three studies [38–40].
The responders were defined as patients whose serum sodium normalized (135 mmol/L)
or increased by at least 5 mmol/L from the baseline. Overall, there were greater numbers
of responders in the vaptans with a pooled odds ratio (OR) of 12.80 (95% CI 5.78, 28.28;
I2 = 0%) (Figure 3A).

Figure 3. Pooled odds ratio of early response (A) (Soupart et al. [41]; Verbalis et al [40]; Chen et al. [39–41]
and mortality (B) (Verbalis et al [40]; Chen et al. [39–41] comparing vaptans with the control. Studies
were identified by the name of the first author and the year of publication. Odds ratios were pooled
using the random-effects
Figure 3. Pooled model
oddsandratioshown onresponse
of early a scale of(A)
0.01–100.
(SoupartAbbreviation: CI: confidence
et al. [41]; Verbalis et al [40]; Chen et
interval. Squares:
[39–41] Represent the (B)
and mortality point estimate
(Verbalis of[40];
et al the effect
Chen etfrom individual
al. [39–41] studies.vaptans
comparing The size of the contr
with
Studies
the square often werethe
reflects identified
weight by name of
of the study in the first author andwith
meta-analysis, the year
largerof squares
publication. Odds ratios we
indicating
pooled
greater weight. using the
Diamond: random-effects
Represents model and
the summarized shown
effect on afrom
estimate scaletheofcombined
0.01–100.studies.
Abbreviation: C
The width of the diamond provides an idea about the precision of the estimate; a wider diamondstudies. T
confidence interval. Squares: Represent the point estimate of the effect from individual
size of the square often reflects the weight of the study in the meta-analysis, with larger squar
suggests less precision, while a narrower diamond indicates more precision.
indicating greater weight. Diamond: Represents the summarized effect estimate from the combin
3.4. Efficacystudies. The on
of Vaptans width of the diamond provides an idea about the precision of the estimate; a wid
Mortality
diamond suggests less precision, while a narrower diamond indicates more precision.
Mortality was reported in two RCTs consisting of 154 patients [39,40]. Overall, five
deaths were reported without a significant difference between the two treatment groups
3.4. Efficacy of Vaptans on Mortality
(OR 0.85; 95% CI 0.10, 7.29; I2 = 20%) (Figure 3B).
Mortality was reported in two RCTs consisting of 154 patients [39,40]. Overall, fiv
3.5. Safety of Vaptans
deaths wereon reported
Overcorrection
without a significant difference between the two treatment group
(OR 0.85; 95% CI
There were four studies that0.10, 7.29; I2 = 20%)
assessed (Figure
serum 3B). overcorrection [37,38,40,41].
sodium
Mostly, overcorrection was defined as an increase in the serum sodium level > 12 mmol/L
3.5.24
over the first Safety
h and of >18
Vaptans on Overcorrection
mmol/L over the first 48 h in three studies [38,40,41], whereas
another study had a lower
There werethreshold for overcorrection
four studies that assessed defined as an increase
serum sodium in the serum
overcorrection [37,38,40,41
sodium level >10 mmol/L
Mostly, over the
overcorrection first
was 24 h [37]
defined as an(Supplementary
increase in the Table
serumS4). In this
sodium meta-
level > 12 mmol
analysis, the pooled incidence rates of overcorrection were 13.1% (95% CI 4.3, 33.6; I 2 = 92%)
over the first 24 h and >18 mmol/L over the first 48 h in three studies [38,40,41], where
in the vaptans group
another study(Supplementary Figure S2)
had a lower threshold for and 3.3% (95%defined
overcorrection CI 1.6, 6.6;
as anI2increase
= 27%) in the seru
the controlsodium
group (Supplementary
level >10 mmol/L Figure
over S3). Overall,
the first 24 h there was a statistically
[37] (Supplementary significant
Table S4). In this met
increased rate of overcorrection
analysis, with vaptans
the pooled incidence rateswith a pooled OR ofwere
of overcorrection 5.72 13.1%
(95% CI 3.38,CI9.70;
(95% 4.3, 33.6; I2
I2 = 0%) (Figure
92%) in4).the
Meta-analyses,
vaptans group based on the type of Figure
(Supplementary study, were additionally
S2) and 3.3% (95%performed.
CI 1.6, 6.6; I2 = 27%
Subgroup in analysis by study
the control design
group revealed a statistically
(Supplementary significant
Figure S3). Overall,increased
there was ratea ofstatistical
overcorrection
significant increased rate of overcorrection with vaptans with a pooled OR10.20;
with vaptans in cohort studies with a pooled OR of 5.92 (95% CI 3.44, of 5.72 (95% C
I2 = 0%). However,
3.38, 9.70;when solely
I2 = 0%) including
(Figure RCTs, this statistically
4). Meta-analyses, significant
based on the increased
type of study, were risk
additional
performed. Subgroup analysis by study design revealed a statistically significa
increased rate of overcorrection with vaptans in cohort studies with a pooled OR of 5.9
(95% CI 3.44, 10.20; I2 = 0%). However, when solely including RCTs, this statistical
J. Clin. Med. 2023, 12, x FOR PEER REVIEW 8 of 12
J. Clin. Med. 2023, 12, 5483 8 of 12

significant increased
of overcorrection risk
with of overcorrection
vaptans with vaptans
was not observed with awas not observed
pooled OR of 3.22with
(95%a pooled
CI 0.35,
OR of 3.22
29.46; 2 (95% CI 0.35, 29.46; I = 0%).
I = 0%).
2

Figure 4. Pooled odds ratio of overcorrection with vaptans compared to the control. Studies were
Figure 4. Pooled odds ratio of overcorrection with vaptans compared to the control. Studies were
identified by the name of the first author, year of publication, and type of study. Odds ratios
identified by the name of the first author, year of publication, and type of study. Odds ratios were
were pooled using the random-effects model and shown on a scale of 0.01–100. Abbreviation: CI:
pooled using the random-effects model and shown on a scale of 0.01–100. Abbreviation: CI:
confidence interval
confidence interval(Burst
(Burstetetalal[38];
[38];Soupart
Soupartetetal.al.[41];
[41];Verbalis
Verbalisetetalal[40];
[40];Kleindienst
Kleindienstetetal.al.[37]).
[37]).
Squares: Represent the point estimate of the effect from individual studies. The
Squares: Represent the point estimate of the effect from individual studies. The size of the squaresize of the square
often reflects
often reflects the
the weight
weight of
of the
the study
study in
in the
the meta-analysis,
meta-analysis, with
with larger
larger squares
squares indicating
indicating greater
greater
weight.
weight. Diamond:
Diamond:Represents
Representsthethesummarized
summarized effect
effect estimate
estimate from
from the
thecombined
combined studies.
studies. The
Thewidth
width
of
ofthe
thediamond
diamondprovides
provides an
anidea
ideaabout
aboutthe
theprecision
precision ofofthe
theestimate;
estimate;aawider
widerdiamond
diamondsuggests
suggestsless
less
precision,
precision, while
while aa narrower
narrower diamond
diamond indicates
indicates more
more precision.
precision.

Sensitivity
Sensitivity analysis of ofovercorrection
overcorrectionwas was performed
performed by excluding
by excluding a study
a study by
by Klein-
Kleindienst
dienst et al.et[37]al. [37] given
given thatthat
thisthis study
study includedsolely
included solelypatients
patientswith
with SIADH following
following
postoperative
postoperative pituitary surgerysurgeryand andhadhada adifferent
different definition
definition of of overcorrection
overcorrection among
among the
restrest
the of the studies.
of the studies.The
Thepooled
pooledincidence
incidencerates
ratesof
ofovercorrection
overcorrection were
were 9.2% (95%
(95% CICI4.9,
4.9,
16.9; II22==34%)
16.9; 34%)in inthe
thevaptans
vaptansgroup
group(Supplementary
(SupplementaryFigure
FigureS4)
S4)and
and2.5%
2.5%(95%
(95%CI CI1.6,
1.6,3.9;
3.9;
2
II ==0%)
2 0%)ininthe thecontrol
controlgroup
group(Supplementary
(SupplementaryFigure FigureS5).
S5). Overall,
Overall,there
therewas
wasaastatistically
statistically
significant increased
significant increased rate
rate of
of overcorrection
overcorrection withwith vaptans
vaptans with
with aa pooled
pooled OROR of
of 5.26
5.26 (95%
(95% CICI
2.94, 9.41; II22==0%)
2.94, 9.41; 0%)(Supplementary
(SupplementaryFigureFigureS6).
S6).

3.6.Adverse
3.6. AdverseEvents
Eventswith
withVaptans
Vaptans
Overall, adverse
Overall, adverseevents
eventsrequiring drug drug
requiring discontinuation were notwere
discontinuation significantly different be-
not significantly
tween the two groups (OR 0.90; 95% CI 0.32, 2.53; 3 studies; I2 = 0%) (Supplementary Figure S7).
different between the two groups (OR 0.90; 95% CI 0.32, 2.53; 3 studies; I2 = 0%)
However, vaptans
(Supplementary were S7).
Figure significantly
However, associated
vaptans withwereansignificantly
increased risk of thirst (OR
associated with2.38;
an
95% CI 1.03, 5.53; three studies; I 2 = 0%) (Supplementary Figure S8). There was only one
increased risk of thirst (OR 2.38; 95% CI 1.03, 5.53; three studies; I = 0%) (Supplementary
2
RCT that reported hypernatremia with an incidence of 7.69% (2/26) in the vaptan group
Figure S8). There was only one RCT that reported hypernatremia with an incidence of
(satavaptan) and 0% (0/9) in the control group [41].
7.69% (2/26) in the vaptan group (satavaptan) and 0% (0/9) in the control group [41].
Interestingly, vaptans were not significantly associated with urinary frequency/polyuria
Interestingly, vaptans were not significantly associated with urinary
(1.41; 95% CI 0.40, 5.00; two studies; I2 = 0%) (Supplementary Figure S9), dry mouth (OR
frequency/polyuria (1.41; 95% CI 0.40, 5.00; two studies; I2 = 0%) (Supplementary Figure
2.06; 95% CI 0.87, 4.85; two studies; I2 = 0%) (Supplementary Figure S10), or hypotension
S9), dry mouth (OR 2.06; 95% CI 0.87, 4.85; 2 two studies; I2 = 0%) (Supplementary Figure
(OR 0.73; 95% CI 0.17, 3.06; two studies; I = 19%) (Supplementary Figure S11), as compared
S10), or hypotension (OR 0.73; 95% CI 0.17, 3.06; two studies; I2 = 19%) (Supplementary
to the control. Furthermore, across four studies, there were no reported cases of osmotic
Figure S11), as compared to the control. Furthermore, across four studies, there were no
demyelination syndrome (ODS) [37,38,40,41].
reported cases of osmotic demyelination syndrome (ODS) [37,38,40,41].
3.7. Evaluation of Publication Bias
3.7. Evaluation of Publication Bias
A funnel plot to assess for publication bias in the difference of mean change in serum
sodiumA funnel
from plot to assessisfor
the baseline publication
shown bias in the difference
in Supplementary of mean
Figure S12 change
and for in serum
log odds ratio
sodium from the baseline is shown in Supplementary Figure S12 and for log odds
of overcorrection in Supplementary Figure S13. Egger’s regression asymmetry test was ratio of
overcorrection in Supplementary Figure S13. Egger’s regression asymmetry
utilized and this showed no publication bias with p > 0.05 for all analyses. test was
utilized and this showed no publication bias with p > 0.05 for all analyses.
J. Clin. Med. 2023, 12, 5483 9 of 12

4. Discussion
Our systematic review/meta-analysis is the first study that evaluates the safety and
efficacy of vaptans for the treatment of hyponatremia caused exclusively by SIADH. This
study demonstrated that vaptans significantly increase serum sodium from the baseline
and also increase the rate of early response compared to control groups. There was an
increased risk of overcorrection in the vaptan group; however, there were no reported cases
of osmotic demyelination syndrome or increased mortality.
The efficacy outcomes in our analysis were consistent with two previous meta-analyses
that evaluated vaptans for the treatment of euvolemic and hypervolemic hyponatremia not
specific to SIADH. Rozen-Zvi et al. and Jaber et al. reported that vaptans significantly in-
creased the serum sodium level compared to the placebo with a WMD of 5.27 mmol/L (95%
CI 4.27, 6.26) at 3–7 days and 5.70 mmol/L (95% CI 4.10, 7.40) at 5 days, respectively [30,42].
Since vaptans directly antagonize the V2R, and SIADH is characterized by inappropriate
elevations of AVP or gain-of-function of the V2R, it is not unexpected that vaptans have the
highest efficacy in increasing serum sodium compared to the other available therapies for
SIADH treatment [38]. These meta-analyses, in sum, reveal that vaptans are effective in
both SIADH and other etiologies of hyponatremia.
Although there is evidence that hyponatremia increases the risk of death [1,7,8],
our meta-analysis, as well as prior meta-analyses [30,42], did not find that correction of
hyponatremia with vaptans reduces mortality. The lack of mortality benefit could be
due to a lack of power to detect outcomes, as only 5 deaths out of 154 participants were
reported in our eligible studies. Another possible explanation is that SIADH is frequently a
consequence of other chronic illnesses, particularly several types of cancers. Malignancy has
been reported to be the cause of SIADH in up to 21% of a hyponatremia registry [38]. Thus,
the primary disease causing SIADH may override any mortality benefit of hyponatremia
correction with vaptans.
It is noted that the rate of overcorrection in our review is significantly higher than
in prior meta-analyses, as we found that the risk of overcorrection with vaptan treatment
for SIADH patients was 5.7 times higher than with traditional therapy. Even after exclud-
ing SIADH from postoperative pituitary surgery in the sensitivity analysis, the risk of
overcorrection with vaptan still remained 5.3 times higher than with traditional therapy.
Meanwhile, the risk of overcorrection in euvolemic/hypervolemic hyponatremic individu-
als treated with vaptans was only 2.5 and 3.0 times higher than the placebo [30,42]. Despite
the increased risk of overcorrection associated with vaptans, neither our study nor prior
meta-analyses found any cases of ODS [30,42].
This increased risk of overcorrection with hyponatremia due to SIADH compared
to other hyponatremic etiologies may reflect the greater efficacy of vaptan therapy in
SIADH. Jaber et al. reported that significantly greater increases in net serum sodium
levels occurred on day 1 with vaptan treatment in euvolemic hyponatremia (i.e., SIADH)
compared to those with hypervolemic hyponatremia (i.e., heart failure or cirrhosis) [30].
Our hypothesis for the higher rate of overcorrection in our study could be due to the
vaptan dosage. It has been suggested that the approved standard doses of tolvaptan may
be excessive for the treatment of SIADH, particularly in patients with very low serum
sodium concentrations [43–47]. There is evidence that tolvaptan, at a dose of 7.5 mg/day,
is as effective as 15 mg in increasing serum sodium and has a lower rate of overly rapid
sodium correction in SIADH patients [43,45,48]. However, most of the included studies in
our review evaluated a standard higher dose of vaptan, including tolvaptan at the dose of
30–60 mg/day and satavaptan at the dose of 25–50 mg/day [39–41]. There was only one
study that evaluated a lower dose of tolvaptan at 3.75–7.5 mg/day [37]. Therefore, future
studies are required to assess the appropriate starting dose of vaptans in SIADH patients.
Apart from the risk of sodium overcorrection, vaptans did not increase adverse events
that required drug discontinuation in our analysis. Thirst was only found to be significantly
associated with vaptans, which is consistent with prior meta-analyses [30,42]. Our study
thus showed that vaptans did not increase the risk of other adverse events, including dry
J. Clin. Med. 2023, 12, 5483 10 of 12

lips, polyuria/urinary frequency, or hypotension. However, it is noted that there were

only a few studies with a small number of participants included in this meta-analysis that
evaluated those adverse side effects.
Our systematic review/meta-analysis has some limitations. First, due to the limited
number of included studies, we were unable to conduct subgroup analysis regarding vaptan
types (tolvaptan vs. satavaptan), or vaptan doses (low dose vs. standard dose). While
the observation regarding the potential differences between tolvaptan and satavaptan is
crucial, the scarcity of studies directly comparing these agents within the context of SIADH
treatment constrained our ability to undertake a separate assessment of their effects and
side effects. Nevertheless, the heterogeneity within the findings of our meta-analysis is
not notably high. Second, there was variation in the definition of sodium overcorrection
among the eligible studies in our meta-analysis. While the European clinical practice
guideline on diagnosis and treatment of hyponatremia defines overcorrection as a rapid
increase of serum sodium > 10 mmol/L during the first 24 h or >8 mmol/L in any 24 h
thereafter [2], only one of four included studies applied that definition in their studies [37].
The three remaining studies [38,40,41] utilized a higher cut-off for the definition of sodium
overcorrection; they defined it as an increase in the serum sodium level > 12 mmol/L over
the first 24 h, which might have led to an underestimation of the incidence of overcorrection.
In order to mitigate this potential imprecision in outcomes, we conducted a sensitivity
analysis by excluding the study conducted by Kleindienst et al. [37]. Third, when solely
focusing on RCTs, the statistically significant increased risk of overcorrection with vaptans
was not found. This, however, may arise from the controlled environmental parameters
intrinsic to clinical trials, in contrast to the varied factors prevalent in real-world data.
Furthermore, the lack of statistical significance may be attributed to the power inadequacy,
highlighted by the broad confidence interval. Fourth, the majority of studies included in our
analysis reported only short-term outcomes ranging from a week to a month. Since SIADH
is regarded to be a chronic condition, long-term outcomes are needed to assess long-term
efficacy, tolerability, and safety. Fifth, the absence of ODS in our review could potentially
be attributed to the restricted number of studies included. Therefore, the imperative for
a comprehensive large-scale RCT primarily focusing on the safety assessment of vaptans
remains evident. Last, all of the studies in our analysis included patients with mild to
moderate hyponatremia but patients with severe hyponatremia or those with significant
symptoms were excluded. Thus, this study should be applied cautiously to patients with
symptomatic or severe hyponatremia.

5. Conclusions
Our research provides a comprehensive analysis of the therapeutic potency and
magnitude of the effect of vaptans in managing SIADH. Although vaptans demonstrate a
notable enhancement in serum sodium concentrations when contrasted with placebo/FR,
there is a pronounced likelihood of an excessive correction. However, the risk associated
with osmotic demyelination syndrome is not evident.

Supplementary Materials: The following supporting information can be downloaded at: https://
www.mdpi.com/article/10.3390/jcm12175483/s1.
Author Contributions: Conceptualization, P.K. and W.C.; search and screening, P.K. and S.T.; data
extraction and quality assessment, P.K. and S.T.; statistical analysis, W.C.; writing—original draft
preparation, P.K.; writing—review and editing, S.T., C.T., P.P., A.K., J.M., I.M.C., M.A.M. and W.C.;
visualization, P.K. and W.C.; supervision, W.C. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki and approved by the Ethics Board of the Mayo Clinic (IRB ID: 23-001042).
Informed Consent Statement: Not applicable.
J. Clin. Med. 2023, 12, 5483 11 of 12

Data Availability Statement: Data are available upon reasonable request to the corresponding
author.
Conflicts of Interest: The authors declare no conflict of interest.

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