Gastroentérologie Clinique et Biologique (2008) 32, 532—540

Disponible en ligne sur www.sciencedirect.com

CURRENT TREND

Primary prophylaxis of esophageal variceal

bleeding in cirrhosis
Prévention primaire de la rupture de varices
œsophagiennes au cours de la cirrhose
P. Bellot, J.C. García-Pagán, J.G. Abraldes, J. Bosch ∗

Hepatic Hemodynamic Laboratory and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
(Ciberehd), Liver Unit, IMD, Hospital Clinic, IDIBAPS, University of Barcelona, C. Villarroel 170, 08036 Barcelona, Spain

Available online 5 May 2008

Summary Variceal bleeding is a common and severe complication of liver cirrhosis. The risk of
bleeding increases with the size of varices, red wheal marks and disease severity. Noninvasive
tests are not accurate enough for the diagnosis of varices, so all patients with cirrhosis should
be screened by endoscopy. Nonselective beta-blockers (propranolol, nadolol) are indicated for
primary prophylaxis in patients with medium/large varices, and for those with small varices
and red signs or advanced liver failure (Child C). In such patients, beta-blockers have been
shown to reduce the risk of bleeding from 25 to 15%. There is no evidence to support using
beta-blockers with nitrates or spironolactone. In patients with contraindication or intolerance
to beta-blockers, endoscopic band ligations are indicated.
© 2008 Elsevier Masson SAS. All rights reserved.

Résumé L’hémorragie digestive par rupture de varices œsophagiennes est une complication
fréquente et grave au cours de la cirrhose. Le risque d’hémorragie est d’autant plus impor-
tant que les varices sont de grande taille, qu’il existe des signes rouges endoscopiques et que
l’insuffisance hépatique est sévère. Aucune méthode non invasive n’est aujourd’hui suffisante
pour le diagnostic de varices et tous les patients atteints de cirrhose doivent bénéficier d’une
surveillance endoscopique. Les bêtabloquants non cardiosélectifs (propranolol et nadolol) sont
indiqués en prévention primaire chez les patients ayant des varices de stade II ou III et chez
ceux ayant des varices de stade I avec signes rouges ou une insuffisance hépatique sévère (Child
C). Chez ces malades, ils permettent de réduire le risque hémorragique de 25 à 15 % à deux
ans. L’intérêt de l’association des bêtabloquants avec les dérivés nitrés ou la spironolactone
n’est pas montré. En cas de contre-indication ou d’intolérance aux bêtabloquants le traitement
endoscopique par ligature élastique est recommandé.
© 2008 Elsevier Masson SAS. All rights reserved.

∗ Corresponding author.
E-mail address: jbosch@clinic.ub.es (J. Bosch).

0399-8320/$ – see front matter © 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.gcb.2008.03.012
Primary prophylaxis of esophageal variceal bleeding in cirrhosis
Variceal bleeding is one of the most common and severe
complications of liver cirrhosis. Even with the best med-
ical care currently available, mortality from variceal
bleeding remains around 15—20% [1]. Moreover, variceal
bleeding often leads to deterioration of liver function,
and may trigger other complications of cirrhosis such
as bacterial infections and hepatorenal syndrome. The
high morbidity—mortality associated with variceal bleed-
ing emphasizes the need of effective preventative therapy
[1,2]. The present report reviews the established strategies
for prevention of the first variceal bleeding.
Risk factors of first variceal bleeding
The probability of bleeding from esophageal varices is vari-
able, but can be estimated according to clinical, endoscopic
and hemodynamic parameters.
Clinical and endoscopic risk indicators
In patients with no varices on the initial endoscopy, the risk
of bleeding is extremely low (1—2% at two years). The risk
increases to 10% at two years for those with small varices,
and to 30% for those with medium or large varices at diag-
nosis [2—4]. The risk of variceal bleeding also increases
with the severity of liver dysfunction, according to the
Child—Pugh classification, and the presence of red wheal
marks in the varix wall [5]. The prognostic value of variceal
size, the presence of red wheals and the Child—Pugh score
have been combined in the North Italian Endoscopic Club
(NIEC) index, which allows the classification of patients into
different categories according to their predicted one-year
bleeding risk (ranging from 6 to 76%) [5,6]. Although this
index has been validated, its overall predictive accuracy is
far from satisfactory, having only 74% sensitivity and 64%
specificity in predicting the risk of variceal bleeding [6].
Moreover, among patients presenting with a first variceal
bleeding episode, less than 50% would have been classified
a priori as being high-risk patients by the NIEC index [7].
This suggests that decisions for prophylactic therapy based
on components of the NIEC index would most likely result in
no therapy for around half of the patients who would benefit
from it.
Hemodynamic risk indicators
Cross-sectional and prospective studies have found that
varices and ascites do not develop until the hepatic venous-
pressure gradient (HVPG) increases to greater than or equal
to 10 mmHg [4,8], and that the HVPG has to be at least
12 mmHg for variceal bleeding to occur [8—10]. Implicit in
these findings is that preventing the HVPG from surpass-
ing these values would prevent the development of these
complications of portal hypertension. It is also a well-known
development following drastic reductions in portal pressure
through the use of surgical shunts or transjugular intrahep-
atic portosystemic shunt. Recent studies have further shown
that if HVPG is reduced to below these thresholds by phar-
macological treatments [11,12] or due to an improvement in
liver disease [13], variceal bleeding can be completely pre-
533
vented and the varices decreased in size. In fact, even if this
target is not achieved, reducing the HVPG to greater than
or equal to 20% from baseline is associated with a marked
reduction in the risk of variceal bleeding [12,14—20].
Screening for esophageal varices
Noninvasive tests such as platelet count, the presence of
splenomegaly, the ratio of both [21] or the data obtained
from abdominal ultrasonography have all been suggested as
useful for selecting patients who have a high risk of devel-
oping large esophageal varices. More recently, transient
elastography has been proposed to be a sensitive noninva-
sive method to predict the presence of large varices [22,23],
although it is less sensitive for varices of other sizes [24].
However, none of these tests, either alone or in combina-
tion, is accurate enough to completely exclude the presence
of esophageal varices when noninvasive indicators are nega-
tive. This is important because, although the risk of bleeding
in patients with small varices is lower than in those with
moderate/large varices, almost 50% of all variceal bleedings
occur in patients who originally had small varices. Thus, the
current recommendation is that all patients with cirrhosis
should be screened for the presence of esophageal varices at
the time of initial diagnosis [25]. In patients without varices
on the initial endoscopy, a follow-up evaluation should be
performed after two to three years to detect the develop-
ment of varices before they bleed. This interval should be
shorter in patients who have an initial HVPG greater than
10 mmHg. Once they develop, varices may increase in size.
Reported progression rates in prospective studies range from
5 to 20% per year, with a median rate of 12% [26]. Accord-
ingly, in patients with small varices for whom no decision to
initiate prophylactic treatment has been made, endoscopy
should be repeated every one to two years to detect any
progression to larger varices [2,3,27,28].
Patients eligible for primary prophylaxis
In clinical practice, patients with medium or large varices,
as well as those who have small varices and advanced liver
failure (Child—Pugh C) or red signs in the varix wall, are
considered to be at considerable risk of bleeding and so
should receive therapy to prevent variceal bleeding [28,29].
Patients with small varices and no other risk indicator can be
treated pharmacologically if there are no contraindications.
Prevention of the development and
progression in size of varices
The observation that it is possible to attenuate or delay the
development of collaterals in experimental models of por-
tal hypertension using nonselective beta-blockers [30,31]
prompted studies to investigate whether these agents could
prevent the development of esophageal varices in patients
with cirrhosis. Unfortunately, this has not been confirmed in
a recent study [32]. However, the study did find that a base-
line HVPG less than 10 mmHg, or a decrease in HVPG greater
than 10% of baseline or less than 10 mmHg, were the only
independent predictors of being free of esophageal varices.
534 P. Bellot et al.

Table 1 Meta-analysis of randomized controlled trials comparing endoscopic band ligation (EBL) and nonselective beta-blockers
for the prevention of first variceal bleeding shows that EBL significantly reduced the risk of first variceal bleeding in patients
with medium and large esophageal varices compared with the drugs.
Méta-analyse des études contrôlées randomisées comparant la ligature endoscopique aux bêtabloquants non sélectifs dans la
prévention primaire de la rupture de varices œsophagiennes. Impact sur l’incidence du premier épisode hémorragique. Chez
les patients ayant des varices de taille moyenne ou grande, la ligature réduit significativement le risque du premier épisode de
rupture de varices œsophagiennes par rapport aux bêtabloquants non sélectifs. EBL : ligature endoscopique, BB : bêtabloquants ;
n/N : nombre d’événements/nombre de malades ; RR : risque relatif ; CI : intervalle de confiance.

BB: beta-blockers; n/N: number of events/number of patients in the treatment arm; RR: relative risk; CI: confidence interval.

Although this occurred more frequently with beta-blockers
than with a placebo, overall the study was negative, so
beta-blockers cannot be recommended for the prevention
of the development of esophageal varices in patients with
cirrhosis.
Two controlled studies have evaluated the role of non-
selective beta-blockers in preventing the increase in size
of small varices. Cales et al. [33] showed no benefit with
long-acting propranolol versus placebo in preventing the
development of large varices in 206 cirrhotic patients who
either had no or small varices. This study has been criticized
because, although the risk of developing large varices in the
propranolol group was greater than in the placebo group
(31% versus 14%), this was not matched by an increased
risk of bleeding. This unexpected finding may be due to
an undetected bias, perhaps in part attributable to the
large proportion (one-third) of patients lost to follow-up. In
contrast, in the study by Merkel et al. [34], including 161 cir-
rhotic patients with small varices, there was a significantly
lower rate of variceal size increase in patients receiving
nadolol compared with a placebo. In addition, the bleed-
ing risk at the end of follow-up was significantly lower in the
nadolol group (12%) compared with the placebo group (22%).
Based on these data, the last Baveno consensus conference
concluded that: ‘‘Prophylactic treatment with nonselective
beta-blockers could be considered in patients with small
esophageal varices with the primary aim to reduce variceal
growth. However, further studies are required before this
suggestion can be accepted as a formal recommendation’’.
Treatments for the prevention of the first
bleeding
Pharmacological therapy
A total of 12 trials has assessed nonselective beta-adrenergic
blockers for the prevention of first bleeding. Meta-analysis
of these studies shows that continued propranolol or nadolol
therapy reduces the risk of a first variceal bleeding episode
from approximately 25% with nonactive treatment to 15%
with beta-adrenergic blockers, over a median follow-up of
two years [35]. Mortality was not significantly reduced (from
27 to 23%). The benefit of therapy extends to patients with
medium or large varices, with or without ascites, or with
good or poor liver function [35,36]. Once initiated, therapy
with beta-adrenergic blockers should be maintained indefi-
nitely, as the bleeding risk reverts to baseline if treatment
is withdrawn [37].
Propranolol and nadolol are the two most widely used
nonselective beta-blockers [35]. Nadolol is easier to admin-
ister because it has a longer half-life, thereby allowing
once-a-day dosing. In addition, its low lipid solubility means
that it does not cross the blood—brain barrier and, for this
reason, may have a lower likelihood of causing central side-
effects [38].
Beta-adrenergic blockers are titrated in stepwise
increases until the maximum tolerated dose is reached—
–around 160 mg bid for propranolol and 240 mg/day for
Primary prophylaxis of esophageal variceal bleeding in cirrhosis 535

Table 2 Meta-analysis of randomized controlled trials comparing endoscopic band ligation (EBL) and nonselective beta-blockers
in the prevention of first variceal bleeding shows no significant differences in mortality between the two.
Méta-analyse des études contrôlées randomisées comparant la ligature endoscopique aux bêtabloquants non sélectifs dans la
prévention primaire de la rupture de varices œsophagiennes. Impact sur la mortalité. Aucune différence significative sur la
mortalité n’a été mise en évidence. EBL : ligature endoscopique ; n/N : nombre d’événements/nombre de malades ; OR : odds
ratio ; CI : intervalle de confiance.

n/N: number of events/number of patients in the treatment arm; OR: odds ratio; CI: confidence interval.

nadolol. Propranolol is commonly initiated at a dose of
40 mg bid, while nadolol is usually begun at a dose
of 40 mg/day. The most common side-effects are light-
headedness, fatigue, shortness of breath, impotence and
sleep disorders. Although these are usually not severe, they
may require a dose-reduction or result in noncompliance.
Around 10—15% of side-effects result in treatment discontin-
uation [39]. In addition, approximately 15% of patients have
contraindications to the use of beta-blockers [40]. Absolute
contraindications include congestive heart failure, asthma,
severe chronic obstructive pulmonary disease, second- or
third-degree heart block, severe aortic stenosis and periph-
eral vascular disease. Insulin-dependent diabetes and sinus
bradycardia are relative contraindications.
The role of nonselective beta-blockers in the preven-
tion of first bleeding in patients with cirrhosis and gastric
or ectopic varices has not been properly evaluated, as
is the case for noncirrhotic (including prehepatic) portal
hypertension. However, because the effect of nonselective
beta-blockers in decreasing portal pressure has also been
well established in noncirrhotic portal hypertension, it is
assumed that they are likely to be useful in cirrhotic patients
with varices as well.
The addition of isosorbide mononitrate enhances the
portal pressure reduction achieved with beta-adrenergic
blockers [41,42]. However, it is not clear whether or not
this translates into greater clinical efficacy. A clinical trial
comparing nadolol with nadolol plus isosorbide mononitrate
demonstrated a significantly lower rate of first bleeding
in the combination group, but no improvement in survival
rate [43,44]. However, a larger randomized double-blind
study failed to confirm the advantage of the combination
treatment. Furthermore, more side-effects were observed
with the combination [39]. Therefore, the combination of
isosorbide mononitrate with nonselective beta-blockers is
not recommended as a standard therapy for the primary
prophylaxis of variceal bleeding [25]. The same limitations
apply to the combination of propranolol or nadolol with
other vasodilators. Spironolactone and a low-sodium diet
have been shown to reduce portal pressure in patients with
compensated cirrhosis by diminishing the increased plasma
volume and splanchnic blood flow [45]. However, nadolol
plus spironolactone has not been shown to improve the clin-
ical efficacy of nadolol alone as primary prophylaxis [46].
Isosorbide mononitrate on its own does not prevent variceal
bleeding [40] and may increase morbidity, especially in
patients with advanced cirrhosis and ascites [47].
In conclusion, nonselective beta-blockers are the only
pharmacological treatment with proven efficacy for primary
prophylaxis of esophageal variceal bleeding. They are also
among the safest and cheapest drugs in Europe. However,
around 20—30% of cirrhotic patients with medium/large
esophageal varices may either have contraindications for
nonselective beta-blockers or simply cannot tolerate these
drugs, and the degree of protection afforded (about 40%
reduction in relative risk) is far from ideal, which has stim-
ulated the search for alternatives.
Endoscopic therapy
The introduction of endoscopic band ligation (EBL), and
the demonstration that its use is more effective and asso-
ciated with fewer side-effects than endoscopic injection
536 P. Bellot et al.

Table 3 Side-effects of endoscopic band ligation (EBL) compared with nonselective beta-blockers (BB) as the primary prophy-
laxis for esophageal variceal bleeding.
Effets indésirables de la ligature endoscopique (EBL) et des bêtabloquants (BB) dans la prévention primaire de la rupture de
varices œsophagiennes.

Study EBL Beta-blockersa

Severe side-effects EBL-related Severe side-effects Bleeding after

(n/N) deaths (n) (n/N)a withdrawal of BB
(n/N)

De et al., 1999 0/15 0 0/15 0

Sarin et al., 1999 2/45 Ulcer-related 0 2/44 Hypotension, —–
bleeding weakness, altered
sensations
Lui et al., 2002 2/44 Ulcer-related 0 20/66 Breathlessness, 3/24b (6, 8 and 18
bleeding. Overtube tiredness, dizziness, months after
perforation wheezing, nausea, withdrawal)
insomnia,
nightmares, poor
memory
Lo et al., 2004 0/50 0 2/50 Hypotension, —–
breathlessness
Schepke et al., 2004 5/75 Ulcer-related 2 12/77 Arterial 6/19c (13 ± 10 months
bleeding hypotension, after withdrawal)
peripheral vascular
disease, exanthema
Jutabha et al., 2005 1/31 Melena post-EBL 0 2/31 Hypotension (2 1/2 (6 months after
patients) withdrawal)
Thuluvath et al., 2005 1/16 EBL-related 0 0/15 0
bleeding
Psilopoulos et al., 2005 0/30 0 4/30 Bradycardia, —–d
hypotension, prerenal
azotemia
Lay et al., 2006 0/50 0 0 25/50 Hypotension, 2/10 (6.2 ± 3.2
gastrointestinal months after
discomfort, dizziness, withdrawal)
peripheral edema
a No beta-blocker-related fatalities.
b Four further patients were not compliant.
c Seven further patients were not compliant.
d Four patients were not compliant; n/N: number of patients with complication/total number of patients.

sclerotherapy, has prompted its use in the prevention of
first variceal bleeding [48,49]. Fifteen trials have compared
EBL with beta-adrenergic blockers as the first-line option for
primary prophylaxis of variceal bleeding [50—62]. A meta-
analysis of these trials shows an advantage of EBL over
beta-adrenergic blockers in preventing a first bleeding, but
with no difference in mortality (Tables 1 and 2). However,
most of these trials were underpowered (10 involved fewer
than 90 patients), of low quality, reported only as abstracts
and had short follow-ups. This has led to considerable con-
troversy as to whether or not beta-blockers should remain
the first-line treatment option to prevent first variceal
bleeding. The relative impact of both treatments in terms of
adverse effects was analyzed by Khuroo et al. in a systematic
review of nine of the 15 randomized controlled trials [63].
An updated meta-analysis confirmed that adverse events
requiring treatment discontinuation were significantly more
frequent in patients treated with nonselective beta-blockers
than in those treated with EBL (Table 3). However, the type
and severity of the side-effects were different. Most of
the side-effects with beta-blockers (hypotension, tiredness,
breathlessness, poor memory, insomnia) were subjective,
easily managed by adjusting the dose or discontinuing the
drug, did not require hospitalization and led to no fatal-
ities. In contrast, the side-effects with EBL included 10
bleeding episodes and one esophageal perforation. In most
cases, these complications required hospitalization and
blood transfusions, and two patients died. Furthermore,
because of the short duration of follow-up in most studies,
the long-term safety and benefits of prophylactic EBL remain
uncertain.
Indeed, a recent study has questioned the efficacy of EBL
as the primary prophylaxis in cirrhotic patients with con-
traindications or intolerance to beta-blockers [64]. On the
Primary prophylaxis of esophageal variceal bleeding in cirrhosis
Figure 1 The current recommendations for primary prophylaxis in cases of portal hypertensive bleeding. EBL, endoscopic band
ligation.
Recommandations actuelles pour la prévention primaire de la rupture de varices œsophagiennes. EBL : ligature endoscopique.
other hand, the long-term safety and efficacy of prophy-
lactic nonselective beta-adrenergic blockers has been well
established [37,65]. Nevertheless, bleeding episodes after
discontinuing beta-blockers because of side-effects have
also been considered an argument against its use as the first
prophylaxis. However, as shown in Table 3, bleeding usually
occurred months after beta-blockers were withdrawn, sug-
gesting that if EBL were used in patients with intolerance or
contraindications to beta-blockers, some of these bleeding
episodes might have been prevented.
Evaluation of the cost-benefits of EBL versus beta-
blockers for primary prophylaxis has been done using the
Markov model. However, depending on the use of different
assumptions of the incidence of variceal bleeding, mortality
or other portal hypertensive complications leads to different
conclusions [66—68]. Until further large-scale studies are
available, the recommendation made at the 2005 Baveno
consensus conference is that nonselective beta-blockers
should be considered the first-choice treatment to pre-
vent first variceal bleeding, while EBL should be offered to
patients with medium/large varices and contraindications
or intolerance to beta-blockers.
Combined endoscopic and pharmacological therapy
Recently, a study has examined the possible role of com-
bining beta-blockers and EBL. The combination of both
procedures appears to offer no greater benefit in terms of
prevention of first bleeding when compared with EBL alone,
and was associated with more side-effects [69]. More studies
are required to assess the true potential of such a combina-
tion therapy.
537
Conclusion
The evidence from prophylactic trials indicates that endo-
scopic screening for varices should be a routine clinical
practice in patients with cirrhosis. If varices are found, pro-
phylactic treatment to prevent the first variceal bleeding
episode should be given to those who have one or more risk
factors for variceal bleeding (large varices, presence of red
wheals and advanced liver dysfunction) (Fig. 1).
Nonselective beta-blockers remain the recommended
first-line therapeutic choice. Nitrates alone should not be
prescribed, and there is insufficient evidence to recommend
the combination of beta-blockers with either nitrates or
spironolactone. Endoscopic band ligation is recommended
for patients who cannot tolerate or have contraindications
to beta-blockers.
Acknowledgments
The Ciberehd is funded by the Instituto de Salud Carlos III.
This work was supported in part by grants from the Instituto
de Salud Carlos III (PI 04/0655, PI 06/0623) and Ministerio
de Educación y Ciencia (SAF n◦ 04/04783).
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