BETA- BLOCKERS

IN LIVER CIRRHOSIS,
DO WE NEED TO CHANGE OUR CONCEPT
?NOW

.Prof

Dr-Mohammed Emam
Zagazig university
Egypt
2014
2014
 Introduction
Beta-blockers have been
established in numerous
studies as part of the
cornerstone of the
medical management of
cirrhosis, particularly in
the primary and
secondary prevention of
The use of non-selective beta--
blocker therapy for cirrhotic
patients was first introduced by
Lebrec and colleagues in 1981 for
prevention of recurrent
.gastrointestinal bleeding

The findings from this and-

additional studies (more than 500
publications)established the role
of non-selective beta-blockers in
the secondary prevention of
 The aspirin of
hepatologists
Non selective beta- blocker is-
considered the aspirin of
hepatologists ,both due to
their hemodynamic and non-
hemodynamic effects

It's one of the most frequently-

used drug in patients with
cirrhosis over the last thirty
However, new evidence
has cautioned the use of
beta-blockers in group of
cirrhotic patients
especially those with end-
stage cirrhosis and
.refractory ascites
New data from clinical
studies presented for the
first time at the
International Liver
Congress 2013 provide
new rationale for an old
and established treatment
option for portal
Objectives
Review the beneficial effects of beta--1
.blocker therapy in cirrhotic patients

The potential harms of aggressive-2

beta-blocker therapy in cirrhotic
.patients

Provide suggestions regarding the-3

appropriate use of this class of
medications in patients with
.cirrhosis
 THE BENEFICAL
EFFECTS
OF BETA BLOCKERS
IN CIRRHOSIS
Increasing numbers of patients with-1
chronic liver disease on anti-
hypertensive for essential
hypertension, due to the co-
morbidity of hypertension, metabolic
syndrome, and NASH cirrhosis

Beta-blockers have also been well-2

established in the secondary
prevention of variceal hemorrhage in
patients with cirrhosis

Subsequent studies expanded the-3

role of non-selective beta-blockers to
include primary prevention of variceal
Beta blockers also beneficial in-4
the prevention of other
complications of cirrhosis and
portal hypertension, including
bleeding from portal
hypertensive gastropathy

Also beneficial in the-5

prevention the development of
spontaneous bacterial peritonitis

Beta-blocker therapy has been-6

NSBB, through the-7
decrease in portal
hypertension may exert a
beneficial effect by improving
the intestinal congestion and
edema and by normalizing
the intestinal transit.
increases bowel motility and
reduces the overgrowth of
enteric bacterial flora, the
migration of micro biota into
Patients who were found to have
the highest levels of
gastrointestinal permeability were
also found to be at most risk of
bleeding from esophageal varices;
a complication of cirrhosis which
.carries a high risk of mortality
These findings provide a new
rationale for the use of non-
selective beta-blockers in patients
with cirrhosis
NSBB: non-hemodynamic-8
mechanisms
The use of NSBB might also be
beneficial for other outcomes,
such as ascites, spontaneous
bacterial peritonitis (SBP),
hepatic encephalopathy and
. overall survival

A landmark study by Abraldeset-

al (2010)documented a positive
effect of NSBB in the prevention
Besides its effects in lowering-9
HVPG, NSBB markedly decreased
blood flow through gastro
esophageal collaterals and
varices in patients with cirrhosis,
as assessed from measurements
,of azygous blood flow
an effect more manifest that the
decrease in portal blood flow,
which explains why in some
patients NSBB decrease variceal
pressure more than HVPG, and in
Anti angiogenic effect-10
Recently, evidence of a potential
anti-angiogenic effect of NSBBs
has also emerged, which could
slow down the development of
. collaterals

Propranolol significantly reduces the

size of severe hemangiomas of
infancy; proposed mechanisms
include decreased expression of
vascular endothelial growth factor
 Anti angiogenic effect

All of the above suggest a

pleiotropic action of
NSBBs over and above
HVPG reduction, similar to
that of statins in
preventing cardiovascular
events
 Pleiotropic:Producing or having
multiple effects from a single gene.
For example, the Marfan gene is
pleiotropic, potentially causing such
diverse effects as long fingers and
toes (arachnodactyly), dislocation of
the lens of the eye, and dissecting
aneurysmof the aorta
Proposed mechanisms of beneficial (green) and .
deleterious
effects of nonselective beta-blockers in patients ( red)
 NEW CAUTION
FOR THE USE OF BETA-
BLOCKERS IN
PATIENTS WITH
DECOMPENSATED
CIRRHOSIS
 Hemodynamic changes in
cirrhosis
As cirrhosis advances,
portal hypertension
develops, resulting in
ascites, hepatic
encephalopathy, and
. variceal hemorrhage
Over one third of patients
diagnosed with cirrhosis
Circulatory
disturbances
Circulatory disturbances
also develop, including
increased cardiac output
and heart rate, decreased
systemic vascular
resistance, and decreased
 The peripheral arterial
vasodilatation hypothesis
Systemic vasodilatation ( from reduced systemic

Vascular resistance) Arterial under filling

the sequestration of fluid into the peritoneal cavity ,

Activates
z

Neuro hormonal systems salt-retaining mechanisms

such as the sympathetic nervous system and the rennin-

angiotensin -aldosterone system to counteract low arterial blood
pressuresvolume
In this path
physiological
context that
beta-adrenergic
blockade has
both theoretical
 Hemodynamic effects of NSBB and
current guidelines

Patients with portal hypertension have a

hyperdynamic circulation characterized
: by
Increased cardiac output and splanchnic-1
blood inflow
Reduced peripheral and splanchnic-2
vascular resistance, associated with an
.expanded plasma volume
The increase in the intra-hepatic-3
resistance
NSBB act on this hyperdynamic
circulatory state which plays a major
Hemodynamic effects of NSBB in
:prevention of variceal bleeding
The most important-1
hemodynamic effect of NSBB is a
decrease in cardiac output via 1
receptors
Splanchnic vasoconstriction-2
through 2 receptors, leading to
a reduction in portal inflow
A direct reduction in variceal- 3
flow, due to the increase in
Porto-collateral resistance
 selective beta-1 antagonists

such as metoprolol and

atenolol have been shown
to be less effective and
are not recommended for
the prophylaxis of variceal
hemorrhage
Key studies supporting beta-
blocker usage
Common Adverse
Adverse effects of beta-blocker
the Adverse effects of beta-
effects of beta-
blocker therapy

blocker therapy
Despite the proven clinical-1-
effectiveness of beta-
blocker therapy, its success
is limited by potential
adverse effects and
suboptimal treatment
.adherence
Patient adherence to beta--2
blocker therapy decline
substantially over
Despite well established-3
guidelines and
recommendations, as few as
622% of patients with known
medium or large varices
received primary prophylaxis
with beta-blockers

Side effects led to treatment-4

discontinuation in
The acute withdrawal of beta-blocker-5
therapy can lead to serious morbidity
.and potential mortality
Abrupt cessation of beta-blocker-6
therapy can result in accelerated
angina, myocardial infarction, and
sudden death, even in patients who do
not previously have coronary artery
.disease
These symptoms are presumably due to
rebound sympathetic activity resulting
in a hyper adrenergic state, which is
more likely to occur with shorter-acting
.medications such as propranolol
 Adverse effects of
Adverse effects of beta-blocker
the Adverse effects of beta-
beta-blocker
blocker therapy
therapy
In cirrhotic patients
 The differential effect of beta-
blockers in cirrhosis
The window hypothesis
Recent studies suggest that
beta-blockers may be
effective only within a
particular clinical window of
liver disease
Outside of this window, beta-
blockers may be ineffective
in early cirrhosis with some
 Fig. 1

The differential effect of beta-blockers in cirrhosis. Modified with permission from: Krag A,
Widest R, Lapillus A, Gluud LL. The window hypothesis: hemodynamic and non-hemodynamic
Source: Journal of Hematology 2014; 60:643-653 (DOI:10.1016/j.jhep.2013.09.016 )
effects of beta-blockers improve survival of patients with cirrhosis during a window in the
Terms and Conditions Copyright 2014 European Association for the Study of the Liver
 Circulatory changes in early
,cirrhosis
The beta-blocker therapy is ineffective in patients
with early cirrhosis this can be attributed to a milder
splanchnic and systemic hyperdynamic circulatory
.state

The non-selective beta-blocker was proven to be

ineffective in preventing the development of varices
in those patients with cirrhosis and portal
.hypertension

Also there was a significant increase in the number of

adverse events which included bradycardia, fatigue,
shortness of breath, syncope, claudication, and
. impotence was reported in those group of patients
 circulatory change In advanced
cirrhosis
There is an up-regulation of the sympathetic
nervous systemand of the renin- angiotensin-
.aldosterone system

These circulatory changes, along with the

development of sodium and water retention and
the formation of ascites, are aimed at maintaining
. adequate cardiac output and organ perfusion

They reflect an adaptive response to the peripheral

vasodilatation, effective hypovolemia, and arterial
. hypotension that accompanies advanced cirrhosis
 As cirrhosis progresses
However, as cirrhosis progresses,.
the cardiovascular system
eventually loses its
compensatory ability. It is at this
stage that the maintenance of
blood pressure and cardiac
output is in prolonging overall
survival, and there is evidence
essential that the hemodynamic
effects of beta-blockers in
 NEW
RECOMMENDATION
FOR NSBB
IN PORTAL
HYPERTESION
Patients with large/medium
varices should receive primary
prophylaxis either with NSBB or
, with endoscopic band ligation

High risk patients(child grad B-C)

with small varices the main
treatment is represented by
.NSBB

Regarding low risk patients with

small varices, these may be
The use of NSBB
in pre-primary
prophylaxis of
variceal bleeding
is currently not
. indicated
A French study of the.
prevention of varices
showed that, in patients
without varices or with
small varices, the
development of large
varices was more frequent
among propranolol-
treated patients than
among patients who
 NSBB AND
MEAN ARTERIAL
BLOOD PRESSURE
 Blood pressure and
survival
The correlation between blood
pressure and survival in
patients with cirrhosis was
suggested that mean arterial
pressure was found to be an
independent predictor of
.survival
Mean arterial pressure of
82mmHg was the single
 Blood pressure and
survival
The increased activity of the
renin- angiotensin-aldosterone
and sympathetic nervous
systems in patients with
cirrhosis with ascites is a
homeostatic response to
maintain arterial pressures near
or within normal range, and that
mean arterial pressure is
possibly itself a reflection of the
degree of alteration of the
the survival probability
rate of cirrhotic patients
with mean arterial
pressure 82mmHg was
approximately 20% at
24months and 0% at
48months, in contrast
with approximately 70%
at 24months and 50% at
48months among patients
 MAP, or mean arterial
pressure
Defined as the average pressure
in a patients arteries during one
.cardiac cycle
It is considered a better indicator
of perfusion to vital organs than
. systolic blood pressure (SBP)
True MAP can only be determined
by invasive monitoring and
complex calculations; however it
can also be calculated using a
 Mean arterial blood
pressure
Equation: MAP = [(2 x diastolic)
+systolic] / 3

Diastole counts twice as much as

systole because 2/3 of the cardiac
cycle is spent in diastole. An MAP of
about 60 is necessary to perfuse
coronary arteries, brain, kidneys.
Usual range: 70-110
Another way to calculate the MAP is
to first calculate the pulse
pressure (subtract the DBP from
the SBP) and divide that by 3,
:then add the DBP
MAP = 1/3 (SBP DBP) + DBP
MAP = 1/3 (83-50) + 50
MAP = 1/3 (33) + 50
MAP = 11 + 50
MAP = 61 mm Hg
 low cardiac output and
development of hepatorenal
syndrome
In the patients with low
cardiac indices and
ascites, beta-blockers
and/or other methods of
decreasing systemic
pressures may worsen
hemodynamic, resulting in
the development of
 Midodrine
Evidence confirming the importance of
maintaining cardiac output in patients with
advanced cirrhosis has been suggested
among studies of midodrine, an alpha-1
adrenergic agonist
Midodrine has a preferential effect on the
, splanchnic circulation
Its acute administration overall improves
systemic hemodynamics, renal function, and
sodium excretion in non-azotemic patients
with ascites
Many studies introduced the combination of
octreotide and midodrine as a treatment for
type 1 hepatorenal syndrome
 Carvedilol

Studies of newer-generation beta-

blockers such as carvedilol
concluded that while carvedilol
has a potent portal hypotensive
effect that may be superior to
propranolol, it has greater
potential to cause systemic
hypotension, especially in
patients with cirrhosis and
ascites
 ACE inhibitors

Studies investigating the effects of angiotensin-

converting enzyme (ACE) inhibitors and angiotensin
receptor blockers (ARBs) in patients with cirrhosis have
likewise shown that reducing cardiac index and mean
arterial pressures results in worsened outcomes in
.patients with advanced cirrhosis and ascites

The latest clinical practice guidelines from both the

American Association for the Study of Liver
Diseases and the European Association for the
Study of the Liver on the management of adult
patients with ascites due to cirrhosis recommend
against the use of ACE inhibitors and ARBs in
patients with ascites due to concerns of
hypotension and renal failure
 BETA-BLOCKERS
IN
PORTO PULMONARY
HYPERTENSION
 Porto- pulmonary
hypertension
In patients with moderate to severe
Porto- pulmonary hypertension, -
blockers are associated with
significant worsening in exercise
capacity and pulmonary
. hemodynamic
These deleterious effects support the
contraindication of -blockers in
patients with port pulmonary
.hypertension
BETA-BLOCKERS
IN
REFRACTORY
ASCITES
Is this really the end
of beta-blockers in
patients with
cirrhosis and
?refractory ascites
 Beta-blockers in
refractory ascites
In 2010, almost 30years following
their landmark article on the use
of propranolol for the prevention
of recurrent variceal
bleedingLebrec and colleagues
(Sersteet al.) showed in a
prospective observational study
that the use of beta-blockers in
patients with refractory ascites
may be associated with poor
survival, suggesting that beta-
Cirrhosis and refractory ascites

Many prospective
observational studies
showed that patients with
cirrhosis and refractory
ascites who were treated
with beta-blockers had a
significantly higher mortality
rate than those who were
not. In addition, the median
There is no clear
explanation for the
finding of deleterious
effects of beta-blocker
treatment on mortality in
patients with cirrhosis
.. and refractory ascites
Low mean arterial pressure
in patients with refractory
ascites treated with beta-
blockers was reported in
many studies contrast to
observations in most
patients with cirrhosis, in
whom beta-blockers have
no effect on arterial
 NSBB
AND
PARACENTESIS-INDUCED
CIRCULATORY
DYSFUNCTION (PICD)
Beta-blocker administration may contribute
to the development of post Paracentesis-
,induced circulatory dysfunction

Large-volume Paracentesis in patients with

cirrhosis and ascites induces arterial
vasodilatation and decreases effective
arterial blood volume, termed
Paracentesis-induced circulatory
,dysfunction (PICD)

a syndrome associated with low survival in

.patients with cirrhosis and tense ascites
After discontinuation of beta- _
blockers, patients experienced a
significant increase in heart rate with
no significant change in mean arterial
pressure following Paracentesis, with
the development of Paracentesis-
. induced circulatory dysfunction

Paracentesis-induced circulatory-
dysfunction, which although may be
clinically silent in itself, is associated
.with shortened survival
Key studies suggesting potential harm from beta-blocker
usage
 Ligation or beta blockers
Beta-blocker therapy needs to be given for a -1
prolonged period, possibly for life, and non
compliance raises the risk of bleeding to pre
.-treatment levels

In contrast, with ligation, varices can be -2

obliterated within about a month, or
possibly earlier, and therefore ligation
offers a distinct advantage over lifelong
. propranolol therapy

No patient in ligation group had to be- 3

excluded, whereas in the propranolol group
 Hemodynamic
responders
and non-
responders:
utility of assessing
HVPG response
Advantages of NSBB include not
only their low
cost and ease of administration,
but also the fact that further
endoscopic follow up is not
necessary once treatment has
. been started

On other hand, the main

inconvenience of NSBB is
that15% of patients may have
absolute or relative
longitudinal studies in patients treated
with NSBB both in primary and
secondary prophylaxis have
suggested a very low residual risk of
bleeding if there is a decrease of
HVPG by at least 20% of baseline or
to values 12 mmHg .Patients
achieving such a target reduction in
portal pressure have been defined
hemodynamic responders. However,
concerns have been raised in relation
to the feasibility, the clinical
appropriateness, the risks and the
This problem could partially be
solved by re-measuring the
HVPG after a shorter interval
(even less than 1 month) ,Some
studies investigated the role of
acute HVPG response to i.v.
propranolol in predicting The
risk of bleeding and survival . It
is possible that the assessment
of such an acute hemodynamic
response may have clinical
utility, possibly even with a
In addition, there are a substantial number of
patients who
find themselves in what has been termed a
grey area, in which
clinical benefit from NSBB is not explained by
changes in portal
pressure. This could be explained by the non
hemodynamic
. mechanisms of NSBB described earlier

The protective effect of -blockers may

not only be due to a reduction in
portal pressure but also to a
reduction in bacterial infections and,
through this, to a reduction in the
As a result, it currently
seems reasonable to
aim for the maximum
tolerated dose of NSBB
in all patients who have
no contraindications to
this treatment, without
the need for routine
assessment of
Concluding remarks
Despite some debate about the-
relative benefit of NSBB in patients
with refractory ascites, they are still
considered the aspirin of
hepatologists both due to their
Hemodynamic and non-hemodynamic
. effects
The distinction Of hemodynamic-
responders and non-responders does
not Fully take into account the
complexity of the effects of this class
of drugs, which represents one of the
Concluding remarks
It appears that the controversy
regarding NSBB use in advanced
, cirrhosis might continue
NSBBs should continue to be used
. to prevent variceal bleeding

However, the risk/benefit ratio of

such treatment may vary
according to the stage of the
cirrhosis, perhaps becoming
Concluding remarks
New studies are necessary to-
establish if NSBBs exert different
effects in different subsets of
patients with cirrhosis, although
it is unlikely that such studies
. are currently under way
Awaiting the results of such-
studies, patients with ascites
who are on NSBBs should be
monitored closely, and
 Fig. 2

Source: Journal of Hematology 2014; 60:643-653 (DOI:10.1016/j.jhep.2013.09.016 )

Terms and Conditions Copyright 2014 European Association for the Study of the Liver
Summary of recommendations for beta-adrenergic
.antagonists in patients with cirrhosis