89
Prevention and Management of Variceal Hemorrhage
Guadalupe Garcia-Tsao
Section of Digestive Diseases, Yale University School of Medicine, and Connecticut Veterans Administration
Healthcare System, New Haven, Connecticut
Varices and variceal hemorrhage are a direct consequence of portal
hypertension. Gastroesophageal varices are present in approximately
50% of cirrhotic patients when endoscopy is performed at the time
of the diagnosis of cirrhosis. Their presence correlates with the sever-
ity of liver disease; while only 40% of Child A patients have varices,
they are present in 85% of Child C patients.1 Patients with varices
almost invariably have a portal pressure (as determined by the hepat-
ic venous pressure gradient [HVPG]) of at least 12 mm Hg, while
normal HVPG is 3–5 mm Hg.2,3
NATURAL HISTORY OF VARICES
The natural history of varices in cirrhotic patients with portal hyper-
tension evolves from a patient without varices to the patient that
develops varices to the patient that develops variceal hemorrhage
(Figure 1). Initially varices are small, but they enlarge with increasing
blood flow. When a varix enlarges and the tension in its wall exceeds
the expanding force, rupture occurs, leading to the most deadly com-
plication of cirrhosis, variceal hemorrhage. This complication has a
high risk of recurrence (Figure 1).
In patients without them, varices develop at a rate of 8% per
year.4,5 No clinical predictors of variceal development had been
trolled trial of timolol, a nonselective β-blocker, in the preven-
identified until 2005 when the results of a randomized con-
tion of varices was published.5 In this study, which included 213
Figure 1. Natural history of varices and variceal hemorrhage in patients with
cirrhosis. The patient with cirrhosis evolves from having no varices (either
because the patient has not yet developed portal hypertension or has not
reached the threshold portal pressure necessary for the formation of varices)
to a patient with small varices that, with time and as flow increases through
them (contributed by the hyperdynamic circulation), will enlarge, increasing
the tension in the wall of the varix. Rupture of the varix occurs when the
expanding force exceeds its maximal wall tension. Once rupture (variceal
hemorrhage) has occurred there will be a high risk of recurrence if there is
no modification in the tension of the wall (determined by size and pressure).
patients with cirrhosis and portal hypertension (HVPG >5 mm
Hg) who did not have varices upon enrollment into the trial, the
strongest predictor of variceal development, by Cox regression
analysis, was the baseline HVPG. The 1-, 3-, and 5-year cumula-
HVPG ≥10 mm Hg (n = 134) was 93%, 75%, and 53%, respec-
tive probability of being free of varices in patients with an
tively, while in patients with a baseline HVPG between 6–10
mm Hg (n = 79) these rates were significantly lower at 99%,
86%, and 70%, respectively (P = .006) (Figure 2).
Patients with small varices develop large varices also at a rate of
8% per year and factors associated with this progression are the
presence of decompensated cirrhosis (Child B/C), alcoholic etiology,
and presence of red wale marks at the time of baseline endoscopy.4
Variceal hemorrhage occurs at a rate of 5%–15% per year
and the most important predictor of hemorrhage is the size of
varices, with the highest risk of first hemorrhage (15% per year)
occurring in patients with large varices. Other predictors of
hemorrhage are decompensated cirrhosis (Child B/C) and the
presence of red wale marks on endoscopy.6 Although bleeding
from esophageal varices ceases spontaneously in up to 40% of
patients, the mortality of an episode of variceal hemorrhage is of
at least 20% at 6 weeks, and it occurs mostly in patients with
severe liver disease and in those with early re-bleeding. Late re-
bleeding occurs in approximately 60% of untreated patients
within 1–2 years of the index hemorrhage.7,8
Figure 2. HVPG predicts variceal development. In a prospective trial of 213
cirrhotic patients with portal hypertension (HVPG >5 mm Hg) but without
varices, baseline HVPG at a cutoff of 10 mm Hg was the strongest predictor
of variceal development. The 1-, 3- and 5-year probability of remaining free
of varices in patients with an HVPG ≥ 10 mm Hg (n = 134) was 93%, 75%,
and 53%, respectively, while in patients with a baseline HVPG between
6–10 mm Hg (n = 79) these rates were significantly lower at 99%, 86%,
and 70%, respectively. From Groszmann et al.5
90 GARCIA-TSAO

although 10 patients bled on withdrawal of β-blockers (with 2 fatal

The management of the cirrhotic patient depends on the breath) resolved after discontinuation of the medication and

outcomes), one could argue that deaths related to β-blockers could

“stage” of portal hypertension, from the patient with cirrhosis
and portal hypertension who has not yet developed varices to
the therapy of the patient with acute variceal hemorrhage in
whom the objective is to control the active episode and to pre-
vent re-bleeding. In 2005, the fourth Baveno consensus confer-
ence reuniting experts in the field of portal hypertension took
place and an important document summarizing the recommen-
dations from this meeting was published.9
PREVENTING THE DEVELOPMENT OF VARICES
The reduction in portal pressure induced by β-adrenergic blockers
has been shown experimentally to prevent the development of por-
have been prevented if EVL had been started prior to discontinuing
them, while deaths from the EVL procedure itself were unavoidable
and required hospitalization.
One of the studies included in abstract form in the first meta-
analysis was published in full in 2005,15 the results of which have
been controversial.16,17 This multicenter, randomized trial included
62 patients (31 in each of the EVL and propranolol groups) and
had to be stopped before the 104 planned number of patients had
been enrolled and after a mean follow-up of only 18 months
because interim analysis showed a significant higher number of

placebo-controlled trial of timolol (a potent nonselective β-blocker)

tosystemic collaterals.10 This led to the performance of a multicenter treatment “failures” (bleeding or a severe side effect) in the propra-
nolol group (6/31 or 19%) compared to the EVL group (0/31).
in the prevention of varices. Prior to the publication of this study, Using this combined endpoint, there was a statistically significant

universal empiric β-blocker therapy for the primary prophylaxis of

decision analysis studies with Markov modeling had suggested that
variceal hemorrhage was a cost-effective measure, as the use of
screening endoscopy to guide therapy added significant cost with
only marginal increase in effectiveness.11 Results from randomized
clinical trials supersede conclusions derived from cost-analysis stud-
ies, as is the case of this multicenter study in which 213 patients with
cirrhosis and portal hypertension (minimal HVPG of 6 mm Hg) but
without varices were randomized to receive timolol (n = 108) or
placebo (n = 105).5 While the rate of varices did not differ between
the timolol and the placebo groups (39% vs. 40%, respectively, in a
median follow-up of 54.9 months), serious adverse events were more
common among patients in the timolol group than among those in
the placebo group (18% vs. 6%, P = .006). Based on this study,
difference between groups (P = .024 by two-sided Fisher’s exact
test; P = .012 by log rank test). When using a combined endpoint,
the weight of each endpoint should be roughly equivalent; a
variceal bleed cannot be considered equivalent to symptomatic
hypotension. In fact, regarding the most important outcome, first
variceal hemorrhage, differences between groups (4/31 with EVL
and 0/31 with propranolol) were not statistically significant (P =
.113 by two-sided Fisher’s exact test) (Figure 3). Additionally, it is
uncertain why a P value of <.02 was chosen in the decision to stop
the trial as this value is usually of insufficient strength to stop a
trial for benefit and more stringent levels should be used (e.g., P <
.001).18 Therefore, from these data one can infer a possible, but
inconclusive, superiority of EVL.
Conversely, another trial published in 2005 compared EVL ver-

with cirrhosis and, in those patients without varices, β-blockers are cations to β-blockers showing opposite results but experiencing
endoscopic screening for varices should be performed in all patients sus no therapy in cirrhotic patients with intolerance or contraindi-

not recommended.9 In these patients, endoscopy should be repeated

in 2–3 years, sooner if there is evidence of hepatic decompensation.

PREVENTING FIRST VARICEAL HEMORRHAGE IN

PATIENTS WITH VARICES

tive β-blockers (propranolol, nadolol) to prevent first variceal hemor-

Current guidelines recommend prophylactic therapy with nonselec-

rhage in cirrhotic patients with medium- to large-sized esophageal

rhage with β-blocker therapy is significantly decreased, it is not elim-

varices on screening endoscopy. Although the risk of first hemor-

inated. Furthermore, β-blockers cause side effects in ~20% of cases,

Alternatives to β-blockers have therefore been explored. Endoscopic

leading to discontinuation of treatment in ~12% of patients.12

variceal ligation (EVL) has been compared to β-blockers in several

randomized trials. Two meta-analyses of these trials were published

with EVL, 311 with β-blockers)13 and the second included 12 studies
in 2005, the first included 8 trials and comprised 596 subjects (285

comprising 839 subjects (410 with EVL, 429 with β-blockers).14

Both show that EVL is associated with a slightly significant lower
incidence of first gastrointestinal bleed and no differences in mortali-
ty (Figure 3). The results are the same when only fully published tri-
als or high-quality trials are analyzed. Although the rate of severe
adverse events is significantly lower in the EVL group (4% vs. 13%),
the severity of the events is different. Severe adverse events in EVL-
treated patients included ligation-induced esophageal ulcer bleeds in
perforation in 1 patient. In the β-blocker group, severe adverse
10 patients with 2 fatal outcomes and overtube-induced esophageal
events necessitating withdrawal (hypotension, fatigue, shortness of
Figure 3. Meta-analysis of 12 trials comparing variceal ligation (EVL) versus
nonselective β-blockers (BB) in the prevention of first variceal hemorrhage.
Relative risks (squares) with 95% confidence intervals (horizontal lines) for
variceal hemorrhage (left panel) and death (right panel) are shown for each
of the trials. Studies with large confidence intervals are less reliable. Relative
risks to the left of the equivalence line indicate a benefit for EVL, while rela-
tive risks to the right of the equivalence line indicate benefit for β-blockers.
The pooled odds ratios are indicated with the green diamonds. The larger
diamond for the survival pooled odds ratio reflects a greater reliability of the
result. From Garcia-Pagan & Bosch.14z
 PREVENTION AND MANAGEMENT OF VARICEAL HEMORRHAGE
the same problems.19 The trial was also stopped early after only
19.5 months of follow-up when only 52 of the 214 planned
patients had been enrolled because of an unexpected higher rate
of bleeding in the EVL group that led to an unplanned interim
analysis with recalculation of sample size and realization that a
larger (unfeasible) sample size would be required to test for differ-
ences. Bleeding occurred in 5/25 (20%) patients randomized to
EVL (2 considered possibly related to the EVL procedure) and in
2/27 (7%) of patients randomized to no treatment (P = .241 by
Fisher’s exact test; P = .18 by log rank test). This study had the
additional problem of having included patients with small varices,
which constituted 60% of the study population and for whom no
specific therapy is recommended given the low risk of bleeding
and the low efficacy of EVL.
In a recent systematic review of randomized controlled trials
stopped early for benefit,20 it is concluded that clinicians should
view the results of such trials with skepticism. These trials, each
time more common, often fail to adequately report relevant infor-
mation about the decision to stop early and show implausibly large
treatment effects, particularly when the number of events is small,
as in the two studies described above. Neither of them had an
independent data and safety monitoring board as a body accessing
and interpreting interim data, which would have prevented their
early discontinuation. Having such a body is considered an essen-
In summary, EVL is slightly better than β-blockers for preven-
tial part of good practice for randomized trials.18
tion of a first variceal bleed. However, given controversial results
ence still stand, that is, that nonselective β-blockers are first line
from incomplete trials, the recommendations of the Baveno confer-
therapy in the prevention of first variceal hemorrhage and EVL
dates for long-term β-blocker therapy.9 An additional recommenda-
should be offered to patients with large varices who are not candi-
ation of β-blockers in those who cannot tolerate these drugs.
tion should be to initiate EVL before or promptly after discontinu-
TREATING ACUTE VARICEAL HEMORRHAGE
Regarding non-specific management, current guidelines recommend
prophylactic antibiotic therapy for cirrhotic patients admitted with
acute variceal hemorrhage and should be instituted from admission.9
The recommended specific management consists of the combina-
tion of endoscopic therapy plus a safe vasoactive drug (terlipressin
or analogues, somatostatin or analogues).9 The advantage of these
drugs is that they can be started at admission and before diagnos-
tic/therapeutic endoscopy and continued for 2–5 days to prevent
early variceal re-bleeding. Two hemodynamic studies published in
2005 suggest that terlipressin may be of greater benefit than
somatostatin and its analogues. In one of these studies,21 patients
with variceal hemorrhage were randomized to terlipressin, 2 mg IV
bolus (n = 21), or the somatostatin analogue, octreotide, 100 mcg
IV bolus followed by a continuous infusion at 250 mcg/hour (n =
21). Although both drugs decreased HVPG significantly, the effect
of terlipressin was sustained over the 25-minute duration of the
study while the effect of octreotide was transient having shown a
maximal effect at the first minute (decrease of 45% from baseline);
however, the HVPG had returned to baseline as of the 5-minute
time point (Figure 4). In the other study,22 patients in whom HVPG
did not decrease by at least 10% after 10 minutes on a standard
dose of somatostatin (250 mcg bolus followed by an infusion of
250 mcg/hour), were randomized to a control group (n = 7) in
which they received a placebo bolus and continued the infusion of
91
somatostatin at 250 mcg/hour, a terlipressin group (n = 20) in
which they received an IV bolus of 2 mg of terlipressin followed by
a placebo infusion, and a high-dose somatostatin group (n = 22) in
which they received a placebo bolus followed by infusion of
somatostatin at a dose of 500 mcg/hour. HVPG was measured 30
minutes after randomization. While HVPG in the control group
did not decrease after randomization, it decreased significantly in
the other two groups. The decrease was larger in the terlipressin
group (15% vs. 10%, P = .05) and more patients on terlipressin
decreased HVPG >20% (36% vs. 5%) compared to those random-
ized to high-dose somatostatin.22 A major issue with both these
studies is that the effects were only analyzed over a short period of
time (25 and 30 minutes, respectively). Whether these short-term
hemodynamic effects can be translated into clinical results remains
to be determined. In fact, a meta-analysis looking at clinical out-
comes failed to show any significant differences between terli-
pressin versus somatostatin (3 studies, 2 of them high quality), or
between terlipressin versus octreotide (3 low-quality studies).23
Since octreotide is the only drug available in the United States and
given the acute decrease in HVPG after its bolus administration,21
it would appear reasonable to recommend bolus injections before
initiating octreotide infusion and perhaps before endoscopic thera-
py or any evidence of re-bleed.
Regarding the best endoscopic therapy for the control of acute
variceal hemorrhage, a meta-analysis of 10 randomized controlled
trials including 404 patients shows an almost significant benefit of
EVL in the initial control of bleeding compared to sclerotherapy
(pooled relative risk of 0.53 with a confidence interval of 0.28 to
1.01).14 In addition, a study reported that sclerotherapy is associat-
ed with an increase in HVPG that was maintained throughout the
5-day period of the study, while EVL was associated with only a
transient increase in HVPG that returned to pretreatment values
within 48 hours.24 Therefore, in the Baveno consensus report, EVL
is the recommended form of endoscopic therapy for acute
esophageal variceal bleeding although sclerotherapy is recommend-
ed if EVL is technically difficult.9
Figure 4. Decrease in HVPG after octreotide and terlipressin. Patients with
acute variceal hemorrhage were randomized to octreotide (n = 21; 100 mcg
IV bolus followed by a continuous infusion at 250 mcg/hour) or terlipressin
(n = 21; 2 mg IV bolus). Octreotide (left panel) significantly decreased HVPG
at minute 1; however, HVPG returned promptly toward baseline and from
5–25 minutes it was no different from baseline. Terlipressin (right panel) sig-
nificantly decreased HVPG over the 25-minute duration of the study. From
Baik et al.21
92 GARCIA-TSAO

Failures of initial therapy with combined pharmacological and

endoscopic therapy are best managed by a second attempt at endo-
scopic therapy or, in the case of fundal gastric varices, by the tran-
sjugular intrahepatic portosystemic shunt (TIPS).9

PREVENTING RECURRENT VARICEAL HEMORRHAGE

Either combination pharmacological therapy (nonselective β-blockers
plus nitrates) or EVL are considered the therapy of choice in the pre-
vention of variceal re-bleeding. The choice depends on tolerance and

rates are still quite high (30%–42% in studies of β-blockers plus

local expertise. However, with either of these therapies, re-bleeding

nitrates; 20%–43% with EVL).8 The lowest re-bleeding rates of

7%–13% have been described in studies on pharmacological therapy
in which HVPG decreases by >20% from baseline or to levels below
12 mm Hg;8 however, HVPG monitoring is not yet widely applied or

been explored. Combining EVL and β-blockers had been previously

standardized and other more widely applicable alternatives have

examined in a randomized controlled trial showing a significant ben- Figure 5. Probability of being free of variceal rebleeding in EVL vs. EVL +
efit for combination therapy, with re-bleeding rates of 23% (14/60) nadolol. Patients randomized to EVL + nadolol (n = 43) had a significantly
higher probability of remaining free of re-bleeding compared to those ran-
in the EVL + nadolol group versus 47% (29/62) in the EVL-alone
domized to EVL alone (n = 37). From Lo et al.25
group.25 A second smaller randomized trial comparing EVL plus
nadolol (n = 43) versus EVL alone (n = 37) was published in 2005
and confirmed the findings from the previous study, that is, in a
median follow-up period of 16 months, there was a significantly
lower rate of recurrent variceal bleed in the EVL + nadolol group
(14% vs. 38%) with no differences in mortality (Figure 5).26
Additionally, 1-year variceal recurrence was lower in the EVL +
nadolol group (54%) than in the EVL group (77%). Major issues
with both of the studies were that they were unblinded, not placebo-
controlled and included small numbers of patients, particularly the

use EVL or β-blocker + nitrates as first line therapy, recognizing that

most recent study. Therefore the current recommendation is still to

combination EVL+ β-blocker may be a more effective therapy.9

Side effects of EVL include hemorrhage from ulcers, chest
pain, dysphagia, and odynophagia. Because gastric acid may
exacerbate post-EVL ulcers, acid suppressors may reduce EVL-
related side effects. In a randomized trial of pantoprazole (40 mg
IV after EVL followed by 40 mg oral every day for 9 days, n =
22) versus placebo (n = 20), the number of post-EVL ulcers at
day 10 after EVL was the same in both groups (2.25 placebo vs. Figure 6. First line management recommendations for cirrhotic patients at
2.18 pantoprazole); however, ulcers were significantly smaller in each stage in the natural history of varices.
the pantoprazole group and, although not statistically signifi-
cant, all 3 post-EVL bleeding episodes occurred in the placebo
group.27 The results of this small study suggest that in patients quent, the search for surrogate indicators of a beneficial effect
subjected to EVL, the use of proton pump inhibitors may be of will be important.
some benefit.
In patients who fail combined endoscopic and pharmacological REFERENCES

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are not candidates for shunt therapy and should be evaluated for
liver transplantation.
The area of management of variceal hemorrhage has advanced
over the past year with current first line management recommen-
dations summarized in Figure 6. However, there are areas such
as the management of gastric varices and the role of HVPG
measurements that require further study, preferably in the setting
of prospective randomized trials. Deficiencies such as underpow-
ering and premature discontinuation of trials should be avoided.
As more therapies arise and as outcomes become more infre-
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Address requests for reprints to: Debra Raden, Assistant Managing Editor, at
draden@gastro.org or mail request to 4930 Del Ray Avenue, Bethesda, Maryland 20814.