283
Prevention of recurrent variceal bleeding in alcoholic cirrhotic patients: prospective controlled trial of propranolol and sclerotherapy
We conducted a prospective randomized
controlled
compared to a control group, in the prevention included,
the distribution
study to evaluate the effectwness
of patienls according to Child-Pugh
lol was given twice daily with a mean final dose of 54 t 26 + 7%.
Sclerotherapy
was performed
mean follow up of 19 f rebleeding 45-82);
81%
(95%
Cl: 60-93);
f’nd paints were rebleeding or death. During
confidence
imerval
92% (95% Cl: 76-98);
the% differences were not statistically sigmficant.
patients, war an independent
and C, 38%. Proprano-
(Ct):
63-92);
sclerotherapy, Alcohol
the
percentages of patients free of sclerotherapy,
these differences did not reach statistical significance.
ages of patients alive at 1 year were: propranolol, 81% (95%
classification was: A. 22%; 8.40%;
weekly using 1% polidocanol.
54% (95% CI: 36-71);
and sclerotherapy.
16 mglday, this resulted in a mean reduction in resting heart rate of
16 months, 43 patients bled and 22 patients died. The cumulative
at 1 year were: propranolol,
control,
of propranolol
of variceal rebleeding in alcoholic cirrhotic patients. Among the 19 patients
64%
(95%
withdrawal,
Cl:
The cumulative percent-
79% (95% Cl: 58-91):
control,
which occurred in 66% of
predictive factor associated with a decreased risk of rehleeding or death. In conclusion, a life
table analysis of patients free of rebleeding.
as well as of patients surviving. revealed a tendency in favoor of propr;molol.
The lack of a statistical support for these two favorable
effects could he due to poor statistical power. Tbis latter might be
ascribed to a low level of bleeding and death rates due to study monitoring
since improvement
in drinking habits was an in-
dependent significant predictive factor for bleeding and death
Upper
gastrointestinal
bleeding from esophageal vari-
ces is the main life threatening The prevention
Patientsand Methods
consequence of cirrhosis.
of variceal rebleeding can be euiar
cal and include various procedures
surge-
of decompression
the portal vein, or medical usingfi-blockers
Patients All adult alcoholic patients with arrhosis
of
or endoscopic
ou
unit for upper gastrointestinal
admitled
hemorrhap
to
due to rup-
variceal sclerothempy.
At the beginning of I98ds, the ef-
tured esophageal varices were considered for inclusian in
ficacy
and sclerotherapy
the study. Hemorrhage
of propranolol
bleeding or lowering the risk resub,
of death
we began a prospective
study in 1983 to evaluate sclerotherapy
was debated.
randomized
and death
As a
controlled
the effects of propranolol
on the rebleeding
pared to a control group.
in preventing
and
rates com-
ws defined as an hematemesia or
meiena which required
at least two units of blood.
tients were inc!uded if cirrhosis was confirmed tally or suggested by biochemical tients were younger
Pa-
bisroiogi-
and clinical data, if pa-
than 75 years, if bleeding
was ar-
crihed to esophageal vatices when varices bled actively.
2x3
and when there were recent signs of bleeding such 8s ad-
months in the first year and every 6 months thereafter.
hercnt clot or platelet aggregate or when esophageal vati-
each visit the patient‘s clinical condition was assessed and
ccs were the only lesion in the upper gastrointestinal with concomitant
presence of blood.
cludcd if they pre,rntcd or concomit.mt
wtb
hepatic rsrcinoma
1?enr (t.c.,Child-Pugh
expectancy under
scvcrc diwaw).
o: a life
Score >I3
congestive gastropathy. bleeding
(1)
They were also excluded
if there ws nnother cause of upper gastrointestinal ing, gastric or duodenal
tract
Patients were CX-
ulcer. gartrk
wices
hleed-
or severe
It hns been suggested that the
risk of these two lesion: might have been in-
creased by aclerotbcmpy.
Finally.
if there was a contraindication
a blood sample was taken to perform a laboratory and alcohol level. Current In the propronolol
Compliance
monitoring
resting heart rate.
there had
to the treatmenl
endoscopy and recurrem writes
the trial took place and did not known
or if +L
been given. Recruitment
had required
a transfusion
of more then 6 units of blood
within the first 24 h to restore the haematocrit than 25% defining a severe bleeding).
level (more
Patients were also
either death,
the censoring
If
identify
(~.e., patients lo:1 to follow up) oc-
In patiens who rehled,
endoscopy was performed,
the location
propranolol
date ot !mtil
was defined in the s.une way as bleed-
ing prior to inclusion. gastrointestinal
consem.
one
Patients were
until
bleeding or withdrawal
gave oral informed
31, 1988, i.e.,
year after the last patient started treatment.
curred. Rebleeding
Ail patients
had
1983. The cen-
followed
excluded if they were expected to have a poor level of
The study protocol was approved by the local ethics
hicb treatment
began in Janwy
soring date for the study was March
compliance or refused to participate.
committee.
were im-
assessing the outcome did not hclong 10 the center where
known
patient
who upper
injectlwtr.
or any trratment
haemodynamics,
patients
underwent
End points were either death or bk:eding. The person
been a previous course of sclsrotherapy to alter portal
was adrate by at
was assessed by
In addition,
with nclerotherap!
mediately treated by additional
patients were excluded to @blockers,
grouP, the dose of propranolol
least 20%.
gastrointestinal
profile
drinking habtts were recoraed
justed, if necessary. in order to decrcnso hart
had been treated
At
of the hemorrhage:.
an upper
if pasaihle, to Patier.&
group had their trial medictltion
in the
stopped.
All
necessary. index vnriceal hleedittg was treated by conser-
patients received identical standard emergency treatment
vative treatment
including intravenous
for
loon tamponade.
It should be noted that, in 1982, our pol-
Glypressin or hal-
icy was not in favour of emergency endoscopic sclerother-
rehleeding.
bleeding.
For
variceal
intravenous
oon tamponade
Clypressin
persisted,
namic conditions
pending open the patient’s
eligible
randomly
assigned to treatment
numbered
series of sealed individual
patients
were
using a consecutively opaque envelopes.
Patiects u’ere not blioded since the two treatment
proce-
dures were dlfferent,
group
and therefore,
was not given placebo. also not blinded.
ihe cornto,
Consequently,
physicians
Twice a day a conventional
dose of propranolol
was given and was titrated
a mesenteric
inactive
was administered.
Ball-
If hleeding
caval shunt wa!: considered condition.
de-
All bleeders were
followed
up for 2 weeks following
the episode of rebleed-
ing (i.e..
the date of introduction
of the treatment
aimed
to prevent further rehleeding).
were
formulated until a 20
Calculation
of sample size was based on a 1 year sponta-
neons rehleeding
to 25% reduction in resting heart rate occurred 6 h follow-
risk by 50%
ing drug administration
0.05 for n error,
or until the maximal
and
was used for active bleeding.
apy. As soon as bleeding stopped and systemic haemodybecame stable.
hemorrhage
permitted
rate of 80% (2) and a reduction
with treatment.
Having
of that
selected a level of
and a level of 0.1 for @ error in a one-
dose had been dispessed. The daily starting dose of pro-
tailed test. 24 subjects would need to he included in each
pranololw86
group.
40 mg and this was increased. as required,
16J mg. Sclerotherapy or GIF-IT
was performed
with either GlF-G
Olympus endoscopes. Patents
dared wth 5 to 10 ma diazepam. was paformed
were mildly se-
Intravascular
sclerosine
at the last 5 cm of the esophagus,
above the gastro-esophageal
to
just
We further
10% drop-out
estimated
that,
rate, we would
group and a total of 75 patients. choosen for sample we armed trial (3).
in each
the formula
calculat~~~~ pertained
Five ml of 1% poli-
the results should he cautiously
docanol were used for each injection,
and a total of 30 to
variables were compared
was repeat-
However,
to a two-
Since a and ,r9 risks are underestimated,
junction.
45 ml was inlectcd per sessmn. Sclerotherapy
due to an estimated
need 26 patients
interpreted.
Qualitative
using 2 test, while Student’s
test or variance analysis were used for quantitative
t
vari-
ed at 5 to 7 day intervals unnl varices were no longer visi-
ables which were expressed as mean f
ble. Injection
viation.
The method of life table analysis as described by
Kaplan
and Meier
into the varix was usually avoided
in the
presence of large ulcerations AI1 patients were submitted to follow up visits of every 3
time
was applied
and to the time unttl
one standard de-
to the patient’s
patients
mhled.
w&al Resulting
285 cuwes were compared using the log rank test. Data were analysed according to the intentionm-treat principle, that is. all randomized Pabents were analyrad. All p values are two tailed. In addition, a prognostic analysis was performed to account for Possslbleeffects of other variables on both rebleeding and death rae. In n first step, the predictive value of variables was evaluated in univariate analysis using log rank test for qualitative vatiables and likelihood raGa rest for quantitative variables. Then, variables with a p value