Etilefrine Could Improve Response to Standard Medical Therapy in Chronic Hepatitis C Egyptian Patients with Cirrhotic Refractory Ascites: A Randomized Pilot Study-Juniper Publishers
JUNIPER PUBLISHERS-OPEN ACCESS JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES
Ascites is the most common of the three major
complications of cirrhosis; the other complications are hepatic
encephalopathy and variceal hemorrhage [1]. Approximately 50% of patients with "compensated" cirrhosis develop ascites during 10 years of observation [1]. Ascites is the most common complication of cirrhosis that leads to hospital admission [2].
Development of fluid retention in the setting of cirrhosis is an
important landmark in the natural history of chronic liver disease:
approximately 15% of patients with ascites succumb in 1 year and 44%
succumb in 5 years [3].
Many patients are referred for liver transplantation after development
of ascites. Refractory ascites develops in approximately 5-10% of all
cases of cirrhosis- related ascites and carries a high mortality rate [4].
The available therapies for patients with refractory ascites are
repeated large volume paracentesis, trans jugular intra hepatic
portosystemic shunts, peritoneovenous shunts, and liver transplantation [5,6].
The mechanism by which refractory ascites develops in
cirrhosis is related to splanchnic vasodilatation followed by maximal
activation of the sympathetic nervous system (SNS) and the renin -
angiotensin- aldosterone system (RAAS) [7-10].
Splanchnic and peripheral vasoconstrictors (octreotide, midodrine, and
terlipressin) increase effective arterial volume and decrease activation
of the renin-angiotensin system with resultant increase in renal sodium
excretion [6]. Vasopressors causing splanchnic vasoconstriction have been used in hepatorenal syndrome [11-13] for the prevention of post-paracentesis circulatory dysfunction [14-16], improving circulatory and renal function in patients with cirrhotic ascites [17,18] and for control of ascites in patients with refractory ascites [19].
Combined use of midodrine with standard medical therapy (SMT) was found
to improve the systemic hemodynamics without any renal or hepatic
dysfunction and is superior to SMT alone for the control of refractory
cirrhotic ascites [20]. Clonidine, a centrally-acting presynaptic É‘2-
adrenergic receptor agonist, when given with spironolactone has been
shown to cause rapid mobilization of ascites by significantly decreasing
the sympathetic activity and renin- aldosterone levels [21,22]. Synthetic vasopressin-V2 receptor antagonists are being evaluated for mobilization of ascites by increasing the excretion of solute-free water [23-25].
Etilefrine is a sympathomimetic agent with a potent stimulating effect
on peripheral ɑ-adrenoceptors and a mild agonist effects on β1- and β2-adrenoceptors.
It has a potent vasoconstrictor effect. It has a stimulant effect on
the cardiovascular system where it raises blood pressure to normal,
improves cardiac performance and tissue perfusion. Etilefrine is
indicated in hypotension and, hypotensive circulatory disorders [26-28].
There are no published reports on the combined use of etilefrine and
SMT in patients with refractory cirrhotic ascites. Therefore, this study
is designed to investigate whether the long-term use of etilefrine
would improve systemic hemodynamics and control of ascites in patients
with cirrhosis and refractory ascites.
Methods
The study protocol was approved by the local ethics
committee and was conducted in accordance with the principles of
Helsinki declaration. Written informed consent was obtained from all
patients before enrollment in the study. A total of 58 chronic hepatitis
C patients with refractory cirrhotic ascites were evaluated for
inclusion in the study between November 2015 and May 2016. Eight of the
enrolled patients were lost during the study period for different
personal unidentified reasons. Accordingly, 50 CHC patients with
cirrhosis and refractory ascites with stable renal function (creatinine
level <1.5 for at least 7days), attending Gastroenterology and
Hepatology Department of a specialized hospital were prospectively
included in the study. Diagnosis of cirrhosis was based on clinical,
biochemical and ultrasonography findings with or without liver biopsy [29,30].
Inclusion criteria were as follows: presence of refractory ascites;
patients less than 60 years of age and no treatment with drugs known to
affect systemic or renal hemodynamics within one week before initiation
of the study.
Exclusion criteria were as follows: presence of
marked hepatic encephalopathy, GIT bleeding, hepatorenal syndrome,
hepatocellular carcinoma, bacterial peritonitis, portal vein thrombosis,
arterial hypertension, diabetes, intrinsic renal or cardiovascular
disease. Refractory ascites is defined as
A. fluid overload that is unresponsive to sodium-
restricted diet and high-dose diuretic treatment (400mg/d of
spironolactone and 160mg/d furosemide),
B. buildup of fluid that recurs rapidly after therapeutic paracentesis or
C. development of diuretic-related complications
that exclude the use of an effective diuretic dosage. Patients were
randomized to either SMT alone (n=25) or SMT plus oral etilefrine
(n=25). Etilefrine is active ingredient of EffortilR produced by
Chemical Industries Development, Egypt under license of Boehringer
Ingelheim International, Germany. Etilefrine was blindly given orally at
a dose of 5 mg/8h. SMT was defined by dietary restriction of sodium
(≤2g/day, starting at least 7 days before the start of the study),
treatment with a combination of a loop diuretic (furosemide 160mg/d) and
a distally-acting aldosterone antagonist (spironolactone 400mg/d) and
repeated large volume paracentesis (LVP) along with intravenous albumin
(8g/L of ascitic fluid removed).
During the study period, diuretic doses were reduced
by a 40mg for furosemide and100 mg for spironolactone for a mean weight
loss >0.8kg over 4 days from the previous weight. Large- volume
paracentesis was performed when ascites is tense and symptomatic.
Frequency of paracentesis sessions over the 4 weeks preceding the study
was obtained from patient files. All patients were subjected to baseline
clinical and biochemical workup including, body weight, mean arterial
blood pressure, 24-h urinary output, 24-h urinary sodium excretion,
liver function tests and renal function tests. These parameters were
assessed at baseline and at weekly intervals for 1 month. Measurement of
mean arterial blood pressure (MAP) was calculated as diastolic blood
pressure+((systolic blood pressure-diastolic blood pressure)/3). Three
measurements were taken each 1-hour apart and the mean was calculated.
Plasma renin activity and plasma aldosterone concentration were
evaluated at baseline and after 1 month (endpoint). Plasma renin
activity (PRA) was measured by radioimmunoassay using RIA plasma renin
activity kit (Diasorin, Stillwater, MN, USA). Plasma aldosterone
concentration (PAC) was measured by radioimmunoassay using ALDO-RIACT
aldosterone kit (Cisbio, Parc Marcel Boiteux, France). Diuretic
requirements were assessed at baseline, at weekly intervals and at
endpoint. Patients were instructed to undergo tapping when become
symptomatic.
Outcome measures
The primary endpoints of the study were partial or
complete control of ascites. Complete response was defined as the
elimination of ascites (as assessed by clinical examination and
abdominal ultrasonography); a partial response was defined as the
presence of ascites not requiring paracentesis; and absence of a
response was defined as the persistence of ascites requiring
paracentesis [31].
Secondary endpoints include alteration of diuretic requirements,
changes in the scores of end-stage liver disease, liver and renal
function, and frequency of other complications of cirrhosis (e.g.,
encephalopathy, upper GIT hemorrhage or development of hepatorenal
syndrome) after 1 month of therapy.
Statistical analysis
Data were analyzed using SPSS for MS-Windows (version
17.0, SPSS, Chicago, IL, USA). The baseline patient characteristics
(clinical as well as biochemical) were compared between two groups (SMT
or SMT plus etilefrine) by using Kruskal-Wallis ANOVA, Chi-square test
or Fisher's exact test as appropriate. Intra-group comparisons were done
using multiple repeated- measures analysis of variance. The paired
t-test was performed to detect mean and standard deviation of prevalues
(baseline) and post values (endpoint at 1 month) of the same variable of
the same patients. The results were reported as mean values ±SD. A
p-value of ≤ 0.05 was taken as significant.
Results
SMT, standard medical therapy, MAP, mean arterial
pressure; MELD, model for end-stage liver disease; INR, international
normalized ratio. *Baseline values between groups 1, and 2 are not
significantly different (P> 0.05). Data are expressed as mean ± SD.
The demographic characteristics and baseline clinical
and biochemical parameters were similar between SMT and SMT/ etilefrine
groups (Table 1).
Baseline body weight did not differ significantly between the two
groups (p>0.05). There was a significant decrease in mean body weight
in SMT/etilefrine group at 1-month as compared to baseline (p<0.05)
however; it did not change in the SMT group (Table 2) (Figure 1).
SMT, standard medical therapy, MAP, mean arterial pressure; MELD, model for end-stage liver disease.
*1-month values are significantly different from
baseline (P<0.05) in the etilefrine group but not in the SMT group.
Data are expressed as mean ±SD.
Baseline MAP did not differ between SMT and
SMT/etilefrine groups (p>0.05). There was a significant increase in
mean arterial pressure in SMT/etilefrine group at 1-month as compared to
baseline (p<0.05) and a significant decrease (p<0.05) in the SMT
group (Table 2) (Figure 2).
Baseline urine output did not differ between SMT and etilefrine groups
(p>0.05). The urine output was significantly higher in the
SMT/etilefrine group (p<0.05) but not the SMT after 1 month of
treatment as compared to baseline (Table 2) (Figure 3).
Baseline urinary sodium excretion was comparable in the SMT and
SMT/etilefrine groups (p>0.05). Urinary sodium excretion
significantly increased in the SMT/ etilefrine group after treatment at
1-month as compared to baseline (p<0.05); however, it did not change
in the SMT group (Figure 4).
Baseline values for plasma renin activity (Table 1)
were similar in both treatment groups (p>0.05). Plasma renin
activity significantly decreased at 1-month (p<0.05) only in the
SMT/etilefrine group with no change in the SMT group compared to
baseline (Figure 5).
Baseline plasma aldosterone concentrations did not differ between the
two groups (p>0.05). Plasma aldosterone concentrations decreased
significantly in the SMT/etilefrine group at 1-month as compared to
baseline (p<0.05); however, it did not change in the SMT group (Figure 6). Baseline values for serum creatinine in both SMT and SMT/ etilefrine groups were similar (p>0.05, (Table 1).
There was no significant change in serum creatinine in both groups
after 1-month treatment as compared to baseline (p>0.05, (Table 2).
Baseline serum bilirubin and INR were similar in both groups (p>0.05, (Table 1) but there were significant increase in their values at 1 month only in the SMT group (p<0.05, (Table 2). Baseline MELD score was similar in both treatment groups (p>0.05; (Table 1).
There was a significant deterioration in MELD score in SMT group at 1
month (p<0.05) with no change in the SMT/etilefrine group as compared
to baseline (p>0.05. The need for LVP (≥5L) was significantly
reduced in the SMT/etilefrine group (p<0.05; (Figure 7)
at lmonth compared to baseline value. No significant change was noted
in the SMT group. Fifteen patients from the SMT group required LVP
compared to only six in the SMT/etilefrine group over the 1-month period
of therapy.
SMT, standard medical therapy.
As depicted in Table 2,
diuretic requirements were significantly declined from baseline in the
SMT/etilefrine group (p<0.05) with no change in the SMT group. There
was higher rate of partial response to treatment and better control of
ascites in the SMT/etilefrine group (p<0.05; (Table 3) (Figure 8)
compared to SMT group at 1 month of treatment. Mild abdominal pain that
subsided on its own was noted in three patients in the SMT group. In
the SMT/etilefrine group, mild headache was developed in two patients,
which disappeared with time without discontinuation of therapy.
Follow-up
The 1-month morbidity and mortality of the study is depicted in Table 4.
In SMT group, encephalopathy developed in two patients, upper
gastrointestinal bleeding, spontaneous bacterial peritonitis (SBP) and
renal failure developed in one patient each. One case of SBP was
recorded in the SMT/etilefrine group. The 1-month mortality was two in
the SMT group and was related to sepsis during the follow-up period. No
mortalities were recorded in the SMT/etilefrine group.
Discussion
Splanchnic arterial vasodilatation induced by nitric oxide [32] and glucagons [33]
leads to disturbance of systemic hemodynamics reflected as reduced
arterial blood pressure, reduced vascular resistance, and decreased
effective blood volume with activation of potent vasoconstricting
systems such as the sympathetic nervous system, the renin-angiotensin-
aldosterone system, in addition to nonosmotic release of vasopressin [34-36]. This results in renal vasoconstriction, avid sodium and fluid retention with development of ascites [37].
The administration of arterial vasoconstrictors has been associated
with improvement in systemic hemodynamics and renal function in
cirrhotic patients with ascites [38].
The efficacy of vasoconstrictors in advanced cirrhotic ascites might be
related to failure of the activated endogenous vasopressor systems to
counteract the arterial vasodilatation [39], probably due to reduced arterial reactivity to vasopressors [40]. Administration of intravenous arterial vasoconstrictors such as metaraminol [41], norepinephrine [42,43], angiotensin II [44] and terlipressin [45]
in cirrhotic ascitic patients has been associated with improvement of
systemic hemodynamics without harmful effects on renal function.
Midodrine, a potent peripherally acting oral a-adrenergic receptor
agonist, either alone [19,20,46] or in combination with octreotide and albumin [47]
has been used to improve renal hemodynamics in cirrhotic patients with
ascites. In these studies, midodrine-induced splanchnic vasoconstriction
improved systemic hemodynamics with better control of ascites without
any renal or hepatic dysfunction.
Combined use of midodrine with tolvaptan, an
aquaretic vasopressin V2 receptor antagonist, has been found to control
ascites and improve response to diuretic therapy. Rai et al. [48],
reported that midodrine (by causing splanchnic vasoconstriction,
increasing effective arterial blood volume and improving renal
perfusion) and tolvaptan (by increasing free water clearance) acting at
different sites in combination were more effective in combating
increased renal sodium retention and refractoriness to diuretic therapy
and better controlled ascites. There are no studies in literature on the
short- or longterm use of combination of etilefrine and standard
medical therapy in patients with cirrhotic refractory ascites, therefore
the results of the present study will be compared to previous studies
in which different vasopressor agents were used for the control of
refractory ascites.
In our study, we compared the changes in systemic
hemodynamics (MAP), renal excretory function (24-hour urinary sodium
excretion, 24-hour urinary output), plasma renin activity and plasma
aldosterone concentration in patients with cirrhotic refractory ascites
after 1-month treatment with SMT alone or in combination with
etilefrine. Changes in models for end-stage liver disease scores, the
need for paracentesis and diuretic requirements were also compared in
both groups.In the current study, there was a significant increase in
the mean arterial pressure (MAP) with etilefrine while there was no
change in the SMT group. Etilefrine-induced increase in MAP may be
related to reducing venous pooling and counteracting reflex arteriolar
vasodilatation [28].
In agreement with our results, Kalambokis et al. [17,38]
reported an improvement in circulatory function manifested as a
significant increase in MAP after short-term use of midodrine [17] and chronic combined use of midodrine with octreotide [38] in patients with nonazotemic cirrhotic ascites. Similar results were reported after long-term use of midodrine with SMT [19,20,48], and combined use of midodrine with SMT and clonidine [20]. On contrary, Oda et al. [49]
reported that a 3-month course of midodrine produced no change in MAP
in cirrhotic patients with refractory ascites. In comparison to baseline
values, our results showed a meaningful improvement in renal
hemodynamics and function reflected as a significant increase in
twenty-four-hour urine output and urinary sodium excretion in the
etilefrine/SMT group but not in the SMT group. These findings agree with
those observed with previous studies employing midodrine plus SMT [19,20,48] , combined use of midodrine with SMT and clonidine [20], and combined use of midodrine with SMT and tolvaptan [48].
In another study, a single dose of terlipressin (vasopressin V1
receptor agonist) showed marked increase in urinary sodium excretion in
patients with and without refractory ascites [18]. The results of our study disagreed with a previous study [50] that found no change in 24-h urine volume after two-week midodrine therapy.
In the present study a significant decrease in plasma
renin activity (PRA) and plasma aldosterone concentration was noted
only in the etilefrine/SMT group after one-month therapy compared to
baseline. This effect is possibly related to etilefrine-induced
suppression of the renin-angiotensin- aldosterone system. Similar
results with other vasoconstrictors were reported by Singh et al. [19,
20] and Rai et al. [48] after long-term use of SMT/midodrine regimen [19,20,48], combined SMT/midodrine/clonidine therapy [20] or combined SMT/ midodrine/tolvaptan therapy [48].
In an earlier study, no change in PRA was noted in patients with
refractory ascites maintained on a 3-month course of midodrine therapy [49].
In the current study, significant reduction in mean body weight was
observed in patients receiving etilefrine plus SMT compared to those
treated with SMT alone. This comes in concordance with previous findings
of decreased body weight by midodrine [38,50].
The reduction in body weight may be related to a drop in fluid
accumulation by etilefrine-induced vasoconstriction with reflex
inactivation of the renin-angiotensin-aldosterone system (RAAS). Similar
explanation were reported in previous studies in which the authors
observed a sig-nificant reduction in plasma renin and aldosterone
con-centration and a trend toward a reduction in the volume of ascitic
fluid removed by paracentesis following the administration of midodrine [38,50].
No change in body weight was reported in a number of previous studies
utilizing different vasoconstrictors including midodrine [19,20,48].
Rate of response to treatment, measured as need for
large- volume paracentesis (≥5L) and reduction of ascites with SMT alone
or combined SMT/etilefrine therapy was measured. There was higher rate
of response to treatment, reflected as a significant decrease in the
number of times of paracentesis in the combined SMT/ etilefrine therapy
at 1 month. There was no significant change in rate of response to
treatment in the SMT group. These results come in harmony with some
previous studies in which the vasoconstrictor midodrine was used with
various daily doses [20,48,50].
In another study, midodrine along with octreotide and albumin given for
1 month showed lesser requirement of paracentesis in eight patients
with refractory ascites [47]. In agreement with previous studies evaluating midodrine [17,19,20,48], midodrine and clonidine [20], midodrine plus octreotide [38] or midodrine plus tolvaptan [48]
in cirrhotic patients with ascites, our results did not show
significant change in hepatic function or MELD score in the combined
SMT/etilefrine group. A significant deterioration in MELD score was
noted in the SMT group at 1 month. In one previous study [38],
combined use of SMT with midodrine and tolvaptan showed significant
improvement in MELD score at 1 and 3 month of therapy. In another pilot
study, significant deterioration in the MELD score was observed during
treatment with midodrine at 1 month of therapy [47].
Diuretic needs for furosemide and spironolactone were significantly
reduced in the SMT/etilefrine group at 1 month compared to baseline.
Diuretic doses were reduced by increments of 40 mg (furosemide) /100mg
(spironolactone) for each ≥0.8kg mean decrease in body weight from the
previous weight over 4 days of therapy according to the criteria of
International Ascites Club [51].
The reduction of diuretic requirements and subsequent
enhancement in diuretic response may be related to etilefrine- induced
improvement in renal perfusion and/or its inhibitory effect on RAAS. No
significant change in diuretic needs was noted in patients receiving SMT
alone. Reduction in diuretic needs with better control of ascites was
reported in one earlier pilot study [20].
There was higher rate of partial response to treatment (defined as
ascites requiring no paracentesis) and better control of ascites in the
SMT/etilefrine group compared to SMT group at 1 month of treatment (76
versus 40%). Etilefrine use was well tolerated by the majority of
patients. Only two patients developed mild headache that resolved
spontaneously within few days without discontinuation of treatment.
Conclusion
To our knowledge, this is the first study of
long-term use of combined SMT/etilefrine therapy in patients with
cirrhotic refractory ascites. In patients receiving combined SMT/
etilefrine therapy, we observed a significant increase in MAP, 24-h
urinary output, 24-h urinary sodium excretion and a significant
reduction in body weight, plasma renin activity and aldosterone
concentration. There was a considerable reduction in the need for large
volume paracentesis and diuretic therapy. Large multicentre,
randomized-controlled trials are required before combined SMT/etilefrine
therapy can be routinely recommended.
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