Original article

Comparative study of spironolactone and

eplerenone in management of ascites in patients of
cirrhosis of liver
Rishabh Sehgala, Harsimranjit Singhb and Inder Pal Singhc

Introduction: The present study was conducted to compare the efficacy and side effects of Spironolactone and
Eplerenone in management of ascites due to liver cirrhosis.
Materials and methods: 105 patients of ascites with liver cirrhosis were randomized into three groups of 35 patients each.
Group I was given Spironolactone 100 mg, group II was given Eplerenone 100 mg and group III was given Eplerenone 50 mg.
All patients were put on salt-restricted diet (less than or equal to 2 g of sodium) and no loop diuretics were used. Patients
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were followed after 7 days from the baseline and then biweekly for the period of three months and serial measurements
of weight, abdominal girth and incidence of side effects especially gynecomastia, mastalgia, hyperkalemia were recorded.
Results were compared. Patients having Child–Turcotte–Pugh score-C, massive ascites, hepatic encephalopathy, Hepatorenal
syndrome and ascites due to cardiac, renal, malignant causes were excluded.
Observations: Difference in mean weight reduction was non significant (P = 0.964) in group I and group II whereas
the difference was significant when comparison was made between Group I and III; and Group II and III (P = <0.001,
<0.001, respectively). In group I, the incidence of gynecomastia was 14.28% whereas in group II and group III no case of
gynecomastia was observed (P <0.001, <0.001). Hyperkalemia was present in one patient (2.8%) in group I whereas no
patient developed hyperkalemia in group II and group III (P = >0.05, >0.05).
Conclusion: Eplerenone and spironolactone are equally effective in management of ascites due to liver cirrhosis but side
effect profile of eplerenone scores over Spironolactone. Eur J Gastroenterol Hepatol 2020: 535–539
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Introduction at blocking dihydrotestosterone activation of androgen

Ascites are one of the common complications of cirrhosis
[1]. Diuretics like aldosterone antagonist and loop diu-
retics are mainstay of treatment of these patients. These
drugs are associated with side effects like gynecomastia,
mastodynia, impotency and abnormal vaginal bleeding.
Eplerenone (EP) is a newer, highly selective mineralocor-
ticoid receptor antagonist which in contrast to spirono-
lactone (SP) is not associated with an increased risk of
gynecomastia and rather has been associated with res-
olution of gynecomastia [2]. Treatment with EP is also
associated with low incidence of mastodynia and abnor-
mal vaginal bleeding. SP is approximately 40-fold more
potent than EP in blocking aldosterone activation of the
mineralocorticoid receptor; however, the selectivity of EP
is significantly greater than SP at androgen, progesterone
and glucocorticoid receptors and it is 370-fold less potent
European Journal of Gastroenterology & Hepatology 2020, 32:535–539
Keywords: ascites, eplerenone, cirrhosis, portal hypertension,
spironolactone
a
Department of Gastroenterology, DMC&H LDH, Punjab,  bDepartment of
Cardiology, Shri Jayadeva Institute of Cardiology, Banglore and  cDepartment of
Medicine, GMC Patiala, Punjab, India
Correspondence to Inder Pal Singh, MD, Government Medical College Patiala,
Patiala 147001, Punjab, India
Tel: + 9815550138; fax: 01614065250; e-mail: drinderpal@gmail.com
Received 19 October 2019 Accepted 16 December 2019
receptors leading to less side effects [3]. This difference in
mechanism of action convinced us to compare the efficacy
and side effects of both these drugs in patients of ascites
due to cirrhosis.
Material and method
The present study was conducted in Government Medical
College, Amritsar with ethical clearance from the ethi-
cal committee. One hundred five patients were enrolled
into the study after their informed consent and they were
randomized into three groups of 35 patients each. First
group was given SP 100 mg, second group was given EP
100 mg and third group was given EP 50 mg. Comparison
was done of 50 mg/100 mg of EP with 100 mg of SP. All
patients were put on salt-restricted diet (less than or equal
to 2 g of sodium) and no loop diuretics were used. Dose of
the drugs was kept static and strict monitoring of weight
and side effects (gynecomastia, abnormal vaginal bleed-
ing, hyperkalemia, hyponatremia, precipitation of hepatic
encephalopathy and renal dysfunction) was done. Patients
were followed 1 week after the start of treatment and then
biweekly for the total period of 3 months.
Inclusion criteria
(1) Patients with ascites due to cirrhosis; (2) patient with
mild to moderate ascites.

0954-691X Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000001678   535

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536   European Journal of Gastroenterology & Hepatology
Exclusion criteria
(1) Patients with Child–Turcotte–Pugh (CTP-C) score. (2)
Patients with massive ascites (grade 3 – ascites accord-
ing to EASL-2018 guidelines which means gross or large
ascites which provokes marked abdominal distension) [4].
(3) Prior treatment with aldosterone antagonist or loop
diuretic. (4) Current medication interacting with aldoster-
one antagonists. (5) Patients in hepatic encephalopathy. (6)
Patients having deranged renal function tests or Hepatic
Renal Syndrome or deranged electrolytes. (7) Patient with
SBP. (8) Patients with tubercular ascites. (9) Ascities due to
cardiac abnormality. (10) Uncontrolled heart disease. (11)
Current malignancy.
Statistical analysis
Data were described in terms of mean ± SD and relative
frequencies (percentages) as appropriate. Comparison of
quantitative variables in a study group and between the
study groups was done using t-test. For comparing cate-
gorical data, chi-square (χ2) test was performed. A P-value
less than 0.05 was considered statistically significant. All
statistical calculations were done using Statistical Package
for the Social Science SPSS 21.
Observations
All patients completed the study. Patients were followed 1
week after the start of treatment and then biweekly for the
total period of 3 months. Serial measurements of weight,
abdominal girth and incidence of side effects like gyneco-
mastia, abnormal vaginal bleeding, hyperkalemia, hypon-
atremia, precipitation of hepatic encephalopathy and
renal dysfunction were recorded. Out of total 105 patients
included in the study, 80 were males and 25 were females.
Group I (SP100) had 28 males and seven females, group
II (EP100) had 26 males and nine females and group III
(EP50) had 26 males and nine females.
The mean age of group I (SP100) patients was 50.86 ±
15.008 years, group II (EP100) patients had a mean age of
45.80 ± 10.518 years and in group III (EP50) patients had
mean age of 48.74 ± 11.239 years.
Mean weight distribution in groups at various stages
during study
Baseline mean CTP score of group I, II and III was 7.80
± 1.05, 8.00 ± 1.00 and 7.60 ± 1.20, respectively, and
the difference was non-significant. Alcohol was the most
common etiology in all the three groups (group I = 60%,
group II = 57.14%, group III = 65.71%). Baseline mean
Table 1. Mean weight distribution in groups at various stages during study
Groups Group I (mean ± SD) Group II (mean ± SD)
Baseline 73.714 ± 9.0475 72.943 ± 10.465
1 week 72.322 ± 8.82 71.58 ± 10.21
2 weeks 70.75 ± 8.53 69.83 ± 9.87
4 weeks 69.57 ± 8.33 68.55 ± 9.60
6 weeks 68.63 ± 8.19 67.65 ± 9.42
8 weeks 67.96 ± 8.02 67.18 ± 9.30
10 weeks 67.79 ± 7.96 67.11 ± 9.21
3 months 67.79 ± 7.96 67.11 ± 9.21
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April 2020 • Volume 32 • Number 4
weight of patients in Group I was 73.714 ± 9.04  kg, in
group II it was 72.943 ± 10.465 kg and in group III it was
67.714 ± 7.964 kg and the difference between them was
statistically non-significant (P = 0.93, 0.061, 0.051). Over
the period of three months mean weight of the patients
decreased significantly in all three groups (P = <0.05 in all
the three groups) as shown in Table 1.
Comparison of absolute weight reduction among all
groups from start till end
Mean weight reduction in group I, group II, group III was
5.92 ± 1.58  kg, 5.83 ± 1.63  kg, 3.91 ± 1.19  kg, respec-
tively. Mean weight reduction in group I (SP100) when
compared to mean weight reduction in group II (EP100),
was found to be statistically non-significant (P = 0.964).
When mean weight reduction in group I (SP100) was
compared to mean weight reduction in group III (EP50)
the difference was found to be statistically significant (P
< 0.001). Similarly when mean weight reduction in group
II (EP100) was compared to mean weight reduction in
group III (EP50) the difference was found to be statisti-
cally significant (P < 0.001); as shown in Fig. 1.
Comparison of abdominal girth reduction among all
groups from start till end
In all the three groups there was significant reduction in
abdominal girth after 3 months of treatment. Mean abdom-
inal girth reduction in group I (SP100) was 8.41 ± 2.06 cm
(P = <0.001), in group II (EP100) it was 8.47 ± 2.38 cm (P =
<0.001) and it was 5.64 ± 1.64 cm (P = <0.001) in group III
(EP50). Mean abdominal girth reduction in group I (SP100)
when compared to mean abdominal girth reduction (total)
in group II (EP100), was found to be statistically non-sig-
nificant (P = 0.993). Mean abdominal girth reduction in
group I (SP100) when compared to mean abdominal girth
reduction in group III (EP50) was found to be statistically
significant (P = < 0.001). Similarly, mean abdominal girth
reduction in group II (EP100) when compared to mean
abdominal girth reduction in group III (EP50) was found to
be statistically significant (P = < 0.001) as shown in Fig. 2.
Comparison of gynecomastia in three groups
In group I with patients on SP 100  mg, out of total 28
male patients, four (14.28%) patients developed gyneco-
mastia. None of the male patients developed gynecomas-
tia in group II and group III, so no patient on EP 50 or
100  mg developed gynecomastia (P = <0.001, <0.001).
None of the female patient developed any breast pain.
Group III (mean ± SD) Gp I vs. II Gp I vs. III Gp II vs. III
67.714 ± 7.964 0.935 0.061 0.051
66.92 ± 7.84 0.937 0.056 0.082
65.97 ± 7.719 0.892 0.063 0.166
65.15 ± 7.56 0.870 0.082 0.225
64.514 ± 7.44 0.877 0.105 0.266
64.02 ± 7.28 0.916 0.118 0.250
63.82 ± 7.30 0.936 0.112 0.220
63.80 ± 7.28 0.936 0.109 0.214
Comparative study of spironolactone and eplerenone Sehgal et al.
Fig. 1. Absolute weight reduction and percentage of weight reduction in all groups from start till end.
Fig. 2. Comparison of abdominal girth reduction and percentage of
abdominal girth reduction in all groups from start till end.
Comparison of menstrual irregularities in three
groups
Only one patient in group I (14.2%) experienced men-
strual irregularities (abnormal vaginal bleed) while none
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www.eurojgh.com  537
of the patient in group II or group III experienced men-
strual irregularities (P = <0.001, <0.001).
Comparison of electrolyte derangement in three
groups
Baseline mean potassium levels of three groups are shown
in Table  2 and the difference between them was statisti-
cally non-significant. Only one (2.8%) patient in group I
developed hyperkalemia. No patient in group II or group
III developed hyperkalemia over a period of 3 months (P
= >0.05, >0.05). No patient developed hyponatremia in
any of the group.
Discussion
This study was conducted to compare the efficacy and side
effects of two aldosterone receptor blockers, that is, SP
and EP in management of ascites in liver cirrhosis. Both
these drugs are potassium-sparing diuretics; however, EP
is 40 times less potent than SP as aldosterone receptor
blocker and 370 times less potent in blocking dihydrotes-
tosterone activation of androgen receptors [3]. To the best
of our knowledge at present no study has been done to
compare the efficacy of SP and EP in patients of ascites
due to cirrhosis.
In this study in all the three groups mean reduction
of weight and abdominal girth after 3 months of treat-
ment came out to be statistically significant (P = <0.001 in
all three groups). Thus this indicates that in all the three
groups the drugs in their respective doses were effective
in causing significant weight and girth reduction, indi-
cating that the drugs were effective in reducing ascites
by inducing effective diuresis and natriuresis. There was
538   European Journal of Gastroenterology & Hepatology
Table 2. Potassium levels in all groups at various stages
Groups Group I (mean ± SD) Group II (mean ± SD)
Baseline 3.91 ± 0.25 3.96 ± 0.23
1 month 3.97 ± 0.24 4.02 ± 0.19
2 months 4.05 ± 0.25 4.16 ± 0.19
3 months 4.35 ± 0.26 4.28 ± 0.22
Similarly, no patient developed renal derangement and precipitation of hepatic encephalopathy.
no statistically significant difference in mean weight and
abdominal girth reduction between group I and group II
indicating that both SP and EP are equally efficacious at
equal doses (100  mg each). Group II (EP)100 was more
effective than group III (EP)50 in terms of weight loss
or reduction of ascites by diuresis. The difference noted
above is particularly due to the difference in dose of the
drugs in the two groups with increase in dose leading
to increase in effect in terms of weight loss. It was also
observed that majority of weight reduction occurred in
the first 2 months, with weight remaining almost stable in
the last month. This indicates that maximum effect with
a fixed-dose occurred till the end of 2 months after which
the weight remained almost stable.
At present, there is only one study in which EP is used
in patients of ascites because of cirrhosis which was con-
ducted by Dimitriadis et al. [2] in which they replaced SP
with EP in 19 patients who developed gynecomastia and
in all these patients gynecomastia resolved; however, they
did not compare the efficacy of both drugs. Rest all studies
of EP and its comparison with SP has been done in the
setting of hypertension or heart failure.
Karagiannis et al. [5] conducted a study involving 34
patients with IHA in which they were assigned to receive
either SP 25  mg b.i.d. (n = 17) or EP 25  mg b.i.d. (n =
17) for 24 weeks. It was concluded that EP was as effec-
tive as SP in reducing BP in patients with Idiopathic
Hyperaldosteronism (IHA). In EP post-acute myocar-
dial infarction heart failure efficacy and survival study
the incidence of gynecomastia in men was 0.5% which
was comparable with placebo whereas in the randomized
Aldactone evaluation study 9% of patients treated with
SP developed gynecomastia as compare to 1% in placebo
group [6,7].
Bloch and Basile [8] conducted a multicenter, rand-
omized, double-blind, noninferiority study to compare
the efficacy and tolerability of SP (75–225 mg daily) with
EP (100–300 mg daily) in patients with idiopathic adre-
nal hyperplasia (IAH). In the EP group, the most com-
mon reported adverse effects were headache (17.1%) and
upper respiratory infection (5.7%). In the SP group, the
most common reported adverse effects were gynecomastia
(21.2%), breast pain (21.1%). However in our study, no
patient had headache, upper respiratory infection, gyne-
comastia or menstrual irregularity who was given EP
whether 50 or 100  mg; whereas 14.8% of patients had
gynecomastia and 14.2% had developed menstrual irreg-
ularity who were given SP 100 mg.
In our study, incidence of hyperkalemia at the doses
used was found to be non-significant. Only one patient
who received SP 100  mg developed hyperkalemia as
compare to a study conducted by Karagiannis et al. [5]
involving 34 patients with idiopatic hyperaldosteronism
(IHA) in which mild hyperkalemia was observed in two
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April 2020 • Volume 32 • Number 4
Group III (mean ± SD) Gp I vs. II Gp I vs. III Gp II vs. III
3.96 ± 0.20 0.71 0.68 0.99
4.00 ± 0.12 0.64 0.82 0.95
4.06 ± 0.19 0.09 0.96 0.17
4.35 ± 0.26 0.49 1 0.49
patients receiving 400  mg of SP and in three patients
receiving 150 mg of EP. There was no incidence of hypon-
atremia, renal dysfunction and precipitation of hepatic
encephalopathy.
Our study does have some limitations. Dosage of diu-
retics was kept static over 3 months and no loop diuretic
was added. As only patients of mild to moderate ascites
were included; it was done to compare the efficacy (dose
wise) and side effects of drugs and to avoid confounding
factors; however despite that patients in all three groups
achieved significant weight loss. Another limitation is
that patients with CTP C were excluded as many of these
patients have deranged renal parameters which would had
contraindicated the use of diuretics. Also hormones were
not measured.
Conclusion
In patients of liver cirrhosis with ascites, Renin Angiotensin
Aldosterone System and the sympathetic system are over-
active leading to a state of hyperaldosteronism which
cause sodium and water retention. SP and EP are aldoster-
one antagonists and causes natriuresis [9]. In the present
study, the two drugs were found to be equally effective
in terms of weight reduction and abdominal girth reduc-
tion, indicating equal efficacy in diuretic and natriuretic
effect. Those patients who were given EP 50 mg achieved
significantly less weight and girth reduction than those
who were given 100 mg of EP and SP. Incidence of hyper-
kalemia as side effect when compared between the groups
over a period of 3 months was found to be statistically
nonsignificant. Incidence of gynecomastia as a side effect
was found to be more with SP 100 mg when compared to
EP 50 and 100  mg and this was statistically significant.
Incidence of menstrual irregularities was more with SP,
but this was statistically non-significant.
Thus aldosterone receptor blockers EP and SP are
equally effective in management of ascites due to liver
cirrhosis but side effect profile of EP scores over SP. SP
is much more cost-effective than EP, so patients must be
started on SP and if potentially disturbing side effects sur-
face, patient should be shifted to EP. Both EP and SP are
efficacious and safe in the treatment of ascites due to liver
cirrhosis, although EP’s selectivity yields a superior tolera-
bility profile in terms of sexual side effects.
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