terlipressin vs. octreotide in bleeding esophageal varices as an adjuvant therapy with endoscopic...

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

nature publishing group ORIGINAL CONTRIBUTIONS 617

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Terlipressin vs. Octreotide in Bleeding Esophageal Varices as an Adjuvant Therapy With Endoscopic Band Ligation: A Randomized Double-Blind Placebo-Controlled Trial Shahab Abid, MD, FACG 1,2 , Wasim Jafri, MD, FACG 1 , Saeed Hamid, MD, FACG 1 , Mohammad Salih, MD 1 , Zahid Azam, MD 1 , Khalid Mumtaz, MD 1 , Hasnain Ali Shah, MD, FACG 1 and Zaigham Abbas, MD, FACG 1

OBJECTIVES: Data are scarce on the head-to-head effi cacy of terlipressin and octreotide as an adjuvant therapy to endoscopic management of variceal bleed. The aim of this study was to compare the effi cacy and safety of terlipressin with octreotide as an adjuvant therapy to endoscopic variceal band ligation in patients with esophageal variceal bleeding.

METHODS: Cirrhotic patients with esophageal variceal bleed were randomized on admission to receive terlipressin (group A) or octreotide (group B) along with the placebo in the other arm in a double-blind fashion. The two groups were compared for effi cacy, safety, overall survival, and length of hospital stay. “ Control of variceal bleed ” was the measure of effi cacy of terlipressin and octreotide. Factors predicting length of stay were also assessed.

RESULTS: A total of 324 patients were enrolled; 163 in the terlipressin group (group A) and 161 in the octreotide group (group B). The baseline characteristics of the two groups were comparable for age, gender, etiology of cirrhosis, hemoglobin at presentation, and Child – Pugh class, except that active bleed was seen during upper gastrointestinal endoscopy at the time of enrollment in 26 (16 % ) and 41 (25.5 % ) patients in groups A and B, respectively ( P = 0.034). Overall sixteen patients died (three failure to control bleed and thirteen from causes other than variceal bleed); nine in group A (5.5 % ) and seven (4.3 % ) in group B ( P = 0.626). In the intention to treat analysis, “ control of variceal bleed ” was noted in 305 patients (94.13 % ); 151 (92.63 % ) patients in group A and 154 (95.6 % ) patients in group B (confi dence interval: 0.219 – 1.492). Packed cell transfusions in group A were 3.7 ± 2.3 units, whereas in group B there were 3.9 ± 2.5 units ( P = 0.273). Length of hospital stay in groups A and B was 108.40 ± 34.81 and 126.39 ± 47.45 h, respectively ( P ≤ 0.001). No cardiovascular side effects were observed in either group. High pulse, low hemoglobin, prothrombin time, blood in nasogastric aspirate, and portosystemic encephalopathy (PSE) were predictors of prolonged hospital stay.

CONCLUSIONS: The effi cacy of terlipressin was not inferior to octreotide as an adjuvant therapy for the control of esophageal variceal bleed and in-hospital survival. The length of hospital stay in the terlipressin group was signifi cantly shorter but not of any clinical importance. The predictors of prolonged hospital stay were low hemoglobin, high pulse, prolonged prothrombin time, blood at nasogastric aspirate, and PSE.

Am J Gastroenterol 2009; 104:617–623; doi: 10.1038/ajg.2008.147 ; published online 17 February 2009

1 Section of Gastroenterology, Department of Medicine, Aga Khan University , Karachi , Pakistan ; 2 Department of Medicine, Karolinska Institute , Stockholm , Sweden . Correspondence: Shahab Abid , MD, FACG, Section of Gastroenterology, Department of Medicine, Aga Khan University, Stadium Road, PO Box 3500, Karachi 74800, Pakistan. E-mail: [email protected] Received 3 October 2007; accepted 30 September 2008

The American Journal of GASTROENTEROLOGY VOLUME 104 | MARCH 2009 www.amjgastro.com

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INTRODUCTION Gastroesophageal varices are identi3 ed in about 30 % of

patients with compensated cirrhosis and 60 % patients with

decompensated cirrhosis (1) . Esophageal variceal bleed (EVB)

occurs in 10 – 20 % of cirrhotic patients per year and more

frequently in those who have large varices (2) . Esophageal

variceal bleeding is a medical emergency that carries high

mortality despite appropriate management. Endoscopic

intervention along with pharmacologic treatment achieves

control of bleeding in nearly 70 – 80 % of episodes of variceal

bleeding (3) .

Endoscopic variceal band ligation (EVL) has been the

recommended preferred procedure for the control of acute

esophageal variceal bleeding, although endoscopic injection

sclerotherapy (EIS) can be used in this setting if EVL proves

technically di> cult (4) . Adjuvant pharmacological treatment

is the standard of care along with EVL for the control of

esophageal variceal bleeding.

Terlipressin and octreotide are two common agents used

as an adjuvant agent in the management of variceal bleed-

ing. Both agents have been claimed equivalent to endoscopic

therapy in randomized studies (5,6) . B e mechanism of

action of octreotide in portal hypertension is not fully under-

stood. Continuous intravenous (IV) octreotide therapy in

cirrhotic patients has been proposed as a measure to con-

trol hemorrhage from oesophageal varices because of an

assumed reduction in portal pressure and splanchnic blood

C ow (7) . Octreotide had no eE ect on hepatic venous pressure

gradient or wedged hepatic venous pressure or hepatic blood

C ow (8) . B e safety pro3 le of octreotide in EVB is good (9) .

Terlipressin is a vasopressin analogue and reduces portal

hypertension through its splanchnic vasoconstricting acti-

vity (10) . Unlike vasopressin, terlipressin is without plas-

minogen activating activity in patients with variceal bleed and

the chances of worsening coronary ischemia are minimal if

any (11) .

A randomized controlled trial has compared combination

of pharmacologic agent and EVL to EVL alone in patients

with acute EVB. In this trial, combination of adjuvant

pharmacologic therapy with EVL was superior to EVL alone

(12) . A meta-analysis has concluded that combination of

pharmacotherapy with endoscopic intervention was more

e> cacious in achieving initial control of EVB and 5 days

hemostasis (13) . However, comparison between terlipres-

sin and octreotide in combination with EVL has not been

studied extensively. Large head-to-head clinical trials are

not available in the literature in which terlipressin was

compared with octreotide as adjunct to EVL for the control

of variceal bleed. Hence, we planned an investigator

initiated double-blind placebo-controlled clinical trial to

compare the e> cacy and safety of terlipressin and octreo-

tide in combination with EVL in patients presenting

with EVB. Our hypothesis was that e> cacy of terlipressin

was noninferior to octreotide as an adjuvant therapy for the

EVB.

METHODS Study population Patients with cirrhosis who presented to the emergency room

(ER) of our hospital with upper gastrointestinal (GI) bleed

during November 2003 to July 2005 were screened for inclu-

sion aL er taking informed written consent from all potential

patients or next to kin if the patient was unable to sign the

consent.

Exclusion criteria . Patients were excluded from the study if

they had nonvariceal bleed on endoscopy or they had gastric

variceal / portal hypertensive gastropathy related bleed at en-

doscopy. Patients were also excluded if they underwent endos-

copy aL er 24 h because of any reason. Patient who underwent

sclerotherapy for EVB were excluded as EIS was used as rescue

treatment exclusively when EVL was not possible in this study.

Patients with established hepatorenal syndrome or patients

with a history of myocardial ischemia (myocardial infarction

or unstable angina) in past 6 months or electrocardiographic

changes at presentation suggestive of cardiac ischemia (ST

segment depression or elevation in contiguous leads) were

excluded from the study.

Randomization and blinding . Study subjects were randomized

into two groups. Patients, attending physicians, and care pro-

viders were blinded to the study medications. Upon receiv-

ing information from the investigators through live physician

order entry system, the allocation of drug assignment was

carried out by pharmacist using computer generated simple

random sequence at the central pharmacy of the hospital. B e

trial medication and placebo were dispensed in look alike prep-

aration so that no one could diE erentiate between the placebo

and active drug in either arm. B e patients were randomized as

potential study subjects at initial presentation in the ER, where

either study drug had to be started. B e 3 nal enrolment in the

study was determined at emergency endoscopy ( Figure 1 ).

Group A received terlipressin 2 mg (10 ml) by IV bolus fol-

lowed by 1 mg (5 ml) IV every 6 h along with a placebo bolus of

100 ml and then infusion by infusion pump at the rate of 50 ml / h

for 72 h (0.45 % dextrose saline as placebo for octreotide).

Group B received 100 ml bolus of 100- � g IV octreotide pre-

pared as 1 � g octreotide in 1 ml of 0.45 % dextrose saline and a

placebo 10 ml IV bolus (0.45 % dextrose saline as placebo for ter-

lipressin). B e group B then was continued on 50 � g / h octreo-

tide as continuous infusion by infusion pump at the rate of

50 ml / h (prepared as 1 � g octreotide in 1 ml of 0.45 % dextrose

saline) for 72 h and a six hourly IV injection of 5 ml of placebo

of terlipressin (0.45 % dextrose saline) equivalent in amount

of 1 mg terlipressin for 72 h. B e duration of study medicines

for 72 h was based upon our earlier observations of using these

pharmacologic agents (14) .

Ethical approval . B is double-blind randomized clinical

trial was approved by the ethical committee of our university

hospital. An informed consent was obtained from all potential


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Terlipressin vs. Octreotide in Bleeding Esophageal Varices

patients or their next of kin in case the patients were unable

to give consent in ER.

Patient management All patients were managed in the GI bleeding control unit, with

continuous noninvasive cardiac and hemodynamic monitoring

including cardiac rhythm, pulse rate, blood pressure, and oxy-

gen saturation and documented in the patient ’ s chart hourly by

nurse as per protocol of the bleeding control unit of our hospital.

Hemoglobin (Hb) was checked every 6 h for 48 h and then every

12 h till discharge. Likewise, serum creatinine and liver func-

tions were checked every 12 hourly. Packed red blood cells were

transfused to maintain Hb up to 10 g / dl. Fresh frozen plasma and

platelets were transfused at the discretion of the attending physi-

cian. All patients received prophylactic IV antibiotics (ceL riax-

one 2 g IV daily for 3 days; antibiotics were stopped if there was

no other indication to continue). All patients received routine

standard supportive management with IV C uids, blood sugar

monitoring and oral metronidazole or lactulose if indicated.

Endoscopic variceal band ligation was performed in all

patients within 24 h of admission, using the Six Shooter Saeed

MultiBand Ligator , Wilson-Cook Medical GI Endoscopy . B e

attending gastroenterologists performed all endoscopies.

Primary end points . Primary end point was e> cacy of the

agent to control the EVB as de3 ned in Baveno III consensus

statement (14) .

Secondary end points . Length of hospital stay, in-hospital

survival, and safety pro3 le were secondary end points.

Upper GI bleed(n=513)

Portal hypertension-related bleed

(n= 371)

Nonvariceal/ ulcerbleed

(n=142)

Potential randomization of EVB

(n=359)

Excluded: n=5 (EKG changes)Refused to participate (n=7)

Excluded after EGD (n=35) (combined EIS and EVBL in 2; EGD >24 h

in 3; Gastric varix bleed in 27, portalhypertensive gastropathy bleed in 3)

Final randomization (EGD confirmed EVB)

(n=324)

Terlipressin (group A) (n=163)

Octreotide (group B) (n=161)

Control of EVB (ITT analysis)

(n=151)

Failed to control EVB (ITT analysis)

(n=12)

Control of EVB (ITT analysis)

(n=154)

Failed to control EVB (ITT analysis)

(n=7)

Figure 1 . Flow chart of all patients with upper GI bleeds and randomization of patients. EGD, esophagogastroduodenoscopy; EIS, endoscopic injection sclerotherapy; EKG, electrocardiogram; EVB, esophageal variceal bleed; EVBL, esophageal variceal bleed ligation; GI, gastrointestinal; ITI, intention to treat.


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Operative defi nitions Control of variceal bleed . Control of variceal bleed was

achieved when any of the following features of Baveno III

criteria (of failure to control bleed) were not met.

B e failure to control bleed was de3 ned on the basis of

Baveno III criteria as (14) :

(a) Within 6 h : Either of the following: (i) transfusion of four

units blood or more, (ii) inability to achieve an increase in

the systolic blood pressure of 20 or to 70 mm Hg or more,

and / or (iii) or inability of a pulse reduction to less than

100 per min or a reduction of 20 per min from baseline

pulse rate.

(b) A" er 6 h : Any of the following factors: (i) the occurrence

of hematemesis, (ii) reduction of blood pressure of more

than 20 mm Hg from 6 h point, and / or (iii) increase of

pulse rate of more than 20 per min from the 6 h point

on two consecutive readings 1 h apart, (iv) transfusion

of 2 units of blood or more (over and above the previous

transfusions) required to increase the Hb to above 9 g / dl.

(c) Deaths were taken as failure to control bleed in intention

to treat analysis.

Hospital stay . Hospital stay was noted in hours and compared.

B e patients were considered for discharge if bleeding control

has been achieved and they had 72 h of adjuvant pharmaco-

logic treatment along with at least 48 h of stay outside bleeding

control unit (high dependency unit).

Sample size and statistical analysis Sample size was based on noninferiority assumptions for the

e> cacy of two trial drugs. Sample sizes of 157 from the experi-

mental group (terlipressin) and 157 from the standard group

(octreotide) would achieve 80 % power at a 5 % signi3 cance level

using a one-sided equivalence test of proportions; so we took

the proportion in the standard group (octreotide) as 0.53 and

the proportion in the experimental group (terlipressin) being

tested for equivalence as 0.50 (resulting from the fact that there

is no head-to-head clinical trial of terlipressin and octreotide

as an adjuvant therapy) and the maximum allowable diE erence

between these proportions that still results in equivalence (the

range of equivalence) is 0.11. InC ating the sample size to 4 %

for consent withdrawal or drop outs we needed 163 patients

in each arm.

No interim analysis was planned or performed.

Patients were analyzed as per protocol and intention to

treat analysis. Frequency distribution was assessed in terms of

mean ± 1 s.d. for quantitative variables and number (percent-

ages) for categorical variables. In univariate analysis, the cat-

egorical variables were compared in the two groups by using

� 2 -test or Fisher ’ s exact test where appropriate. For continuous

variables, the independent sample t -test was used to compare

the means in the two treatment arms. Cox regression analysis

was carried out for the identi3 cation of factors likely to be asso-

ciated with prolonged hospital stay in hours.

All analyses were carried out by using the Statistical Package

for Social Sciences (release 13, standard version, SPSS; Chicago,

IL, 2004).

RESULTS Patients ’ characteristics A total of 513 patients presented to ER with upper GI bleed dur-

ing study period; 371 patients with portal hypertension related

bleed were considered for the study. Out of 371 patients, 324

patients ful3 lled the inclusion criteria and were randomized

to two groups; 163 in group A (terlipressin) and 161 in group

B (octreotide; Table 1 ). B e study population was male domi-

nant with 230 men (71 % ) and women 94 (29 % ). Mean age was

53.2 ± 10.9 years, range 18 – 83 years. Both groups were compa-

rable in age, Hb level at presentation in ER, maximum drop in

Hb during hospital stay, creatinine, and hemodynamic param-

eters. When two groups were compared for the base line char-

acteristics, active bleed was seen during upper GI endoscopy at

the time of enrolment in 26 (16 % ) and 41 (25.5 % ) patients in

groups A and B, respectively ( P = 0.034; Table 1 ).

Chronic hepatitis C was the predominant cause of cirrhosis

followed by non-B, non-C, and chronic hepatitis B ( Table 1 ).

Majority of patients belonged to Child – Pugh classes B and C.

Patients with advanced Child – Pugh scores that is classes B and

C were present uniformly in both groups ( Table 1 ).

Management and outcome of variceal bleeding B e control of variceal bleed was achieved in 318 out of 324

subjects; 158 of 163 (96.9 % ) patients in group A and 160 patient

out of 161 patient (99.4 % ) in group B ( P = 0.107, Fisher ’ s exact

test). Out of these six patients in whom we failed to control the

variceal bleed, three died. Overall sixteen patients died in the

trial; nine in group A and seven in group B ( P = 0.313).

In the intension to treat analysis, “ control of variceal bleed ”

was noted in 305 patients (94.13 % ); 151 patients (92.63 % ) in

group A and 154 (95.6 % ) patients in group B (con3 dence inter-

val (CI): 0.219 – 1.492). B is CI was falling into our a priory range

of equivalence of 11 % (noninferiority region). Table 2 shows

the features in the two groups in whom control of variceal bleed

was achieved on the basis of intension to treat analysis. Require-

ment of packed cell transfusions to maintain Hb up to 10 g / dl

were 3.7 ± 2.3 units in the terlipressin group and 3.9 ± 2.5 units in

octreotide group ( P = 0.273). Requirement of platelets and fresh

frozen plasma transfusions were found similar in both groups.

Factors associated with prolonged hospital stay Length of hospital stay in groups A and B was 108.40 ± 34.81

and 126.39 ± 47.45 h, respectively ( P ≤ 0.001). On Cox regres-

sion analysis, high pulse, low Hb, prothrombin time, blood in

nasogastric aspirate and portosystemic encephalopathy (PSE)

were predictors of prolonged hospital stay ( Table 3 ).

We did not encounter cardiovascular side eE ects in either

arm of the study. None of the patients developed chest pain or

ST segment changes during hospital stay.


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B e results of our study have shown that terlipressin was

noninferior to octreotide in its e> cacy to control variceal bleed

when used as adjuvant agent in combination with endoscopic

band ligation in patients with EVB. B e overall e> cacy of com-

bination of either terlipressin or octreotide with endoscopic

band ligation in EVB was 94.13 % . A relatively small rand-

omized trial of 30 patients from Italy showed that terlipressin

was superior to octreotide when pharmacotherapy was used

alone in acute EVB (17) . Although another study had shown

that both octreotide and terlipressin agents were equally e> ca-

cious in the control of EVB (18) . A Cochrane systemic review

had recommended the use of terlipressin as the 3 rst line of

treatment in control of EVB as terlipressin was found to reduce

the relative mortality risk by 34 % (19) . We found no diE erence

in mortality among the groups. Unfortunately 1 month mortal-

ity aL er the index bleed was not assessed because many patients

came from remote areas and it was impossible to follow them.

B is study has also demonstrated another important feature

that the use terlipressin was associated with shorter hospital

stay. B is could be resulting from the fact that higher number

DISCUSSION B is is the largest randomized comparison of e> cacy and

safety of terlipressin and octreotide in the management of EVB

as adjuvant to endoscopic intervention in EVB. B is cohort of

patients with EVB was dominated by male gender, and major-

ity of the patients had advanced liver disease; Child ’ s – Pugh

classes B and C being present in 40 % and 54 % , respectively.

Predominance of advanced chronic liver disease was concord-

ant with other therapeutic trials of EVB, in which patients with

Child ’ s – Pugh classes B and C were 43 % and 39 % , respectively

(13) . Hepatitis C related cirrhosis was the most common etiol-

ogy of liver disease in this series that reC ects the higher preva-

lence of hepatitis C virus in the region (15) .

Esophageal variceal band ligation (EVL) had replaced injec-

tion sclerotherapy (EIS) for EVB as EVL was superior to EIS

(16) . We included patients who underwent EVL for EVB only;

as EVL was 3 rst line intervention practiced at our center and

would do sclerotherapy as a rescue whenever EVL was techni-

cally di> cult. Hence patients were excluded if they had sclero-

therapy alone or in combination with EVL to have uniformity.

Table 1 . Baseline patient characteristics in the terlipressin and octreotide groups

Parameters/characteristics Terlipressin ( n =163)

Octreotide ( n =161)

Age (years) 48.9 ± 10.4 51.7 ± 11.4

Hb at presentation (g/dl) 9.0 ± 1.7 9.2 ± 2.4

Maximum drop in Hb during hospital stay (mm Hg)

0.7 ± 0.3 0.8 ± 0.3

Pulse in ER (beats/min) 99.2 ± 20.1 96.0 ± 20.6

Systolic BP in ER (mm Hg) 112.7 ± 20.0 115.0 ± 19.5

Diastolic BP in ER (mm Hg) 67.6 ± 13.2 68.3 ± 13.2

Serum creatinine (mg/dl) 1.2 ± 0.8 1.16 ± 0.5

Active bleed during endoscopy 26 (16%)* 41 (25.5%)*

Child – Pugh class

A 12 (7.4%) 8 (5%)

B 76 (46.6%) a 53 (33%) a

C 75 (46.0%) a 100 (62%) a

Etiology of cirrhosis

HCV 114 (70%) 106 (66%)

Cryptogenic 22 (14%) 23 (14%)

HBV 17 (10%) 16 (10%)

Other b 10 (6%) 16 (10%)

BP, blood pressure; ER, emergency room; Hb, hemoglobin; HBV, hepatitis B virus; HCV, hepatitis C virus. a Child’s – Pugh classes B and C were analyzed together. b Includes patients with alcohol liver disease and coinfection with HBV/HDV and HBV/HCV. * P value = 0.034.

Table 2 . Comparison of terlipressin and octreotide patients in whom control of variceal bleed was achieved (intention to treat analysis)

Parameters/characteristics

Terlipressin ( n =151)

Octreotide ( n =154)

P value

Age (years) 48.07 ± 9.94 51.73 ± 11.49 0.001

Hb at presentation (g/dl)

8.95 ± 1.80 9.25 ± 2.44 0.115

Pulse in ER (beats/min)

98.95 ± 20.28 95.76 ± 20.60 0.087

Systolic BP in ER (mm Hg)

112.23 ± 20.52 115.0 ± 19.5 0.079

Serum creatinine (mg/dl)

1.1 ± 0.6 1.1 ± 0.4 0.432

Prothrombin time (s) 20.2 ± 5.8 21.1 ± 5.9 0.089

Total bilirubin 3.0 ± 3.3 2.8 ± 3.1 0.233

Serum albumin 2.4 ± 0.5 2.3 ± 0.5 0.465

No. of packed cells transfusion

3.7 ± 2.3 3.9 ± 2.5 0.272

Length of hospital stay (h)

108.40 ± 34.81 126.39 ± 47.45 < 0.001

C – P classes B and C 141 (93.4%) a 146 (94.8%) a 0.298

PSE at presentation 19 (12.6%) 47 (30.5%) < 0.001

Blood in NGT 123 (81.5%) 111 (72.1%) 0.026

Active EV bleed at EGD 25 (16.6%) 38 (24.7%) 0.040

BP, blood pressure; C – P, Child – Pugh; EGD, esophagogastroduodenoscopy; ER, emergency room; EV, esophageal variceal; Hb, hemoglobin; NGT, nasogastric tube; PSE, portosystemic encephalopathy. a Child – Pugh classes B and C were analyzed together.


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of patients in terlipressin had signi3 cantly low rate of active

bleeding compared to patients in octreotide group at base

line when seen at initial endoscopic intervention and also

PSE was seen in lower proportion of patients in the terlipres-

sin group. In the Cox regression analysis, high pulse, low Hb,

prothrombin time, blood in nasogastric aspirate, and PSE were

predictors of prolonged hospital stay. However, to the best of

our knowledge no previous study had demonstrated the eE ect

of terlipressin and octreotide on the duration of hospital stay

and hence further studies are required to clarify this issue.

Although the cost analysis was not the objective of the current

study, however, the calculated cost of 3 days of terlipressin was

US $180 whereas that of octreotide was US$ 280 at our institu-

tion. Considering the cost diE erence between octreotide and

terlipressin and the diE erence in the duration of hospital stay it

would be appropriate to study the relative cost eE ectiveness of

terlipressin and octreotide as adjuvant to EVL in the manage-

ment of EVB.

B e safety of terlipressin had been questioned time and again

as this may lead to or worsen the ongoing coronary ischemia.

B e Cochrane review conducted few years ago evaluated the

safety of terlipressin in terms of adverse eE ects, drug with-

drawal, and deaths, found no diE erence in terms of control

of bleeding or rebleeding rate in terlipressin or octreotide

(19) . B ough we did not encountered adverse cardiovascular

events in any group, however, the safety of terlipressin cannot

be generalized by this study as patients with active ischemia or

recent myocardial infarction were excluded because of ethical

reasons.

In our study, we took a priori range of equivalence (non-

inferiority region) as 11 % . B e CI of our primary outcome

measure was well with in this range and hence terlipressin was

noninferior to octreotide. In the sample size calculation, the

proportion in the octreotide was taken as 53 % and for terli-

pressin we took 50 % as there was no trial available as an adju-

vant therapy. B is was carried out to capture the maximum

sample size. In this trial, the control of variceal bleeding was

much higher than expected as 94.13 % . B is may be because of

the fact that the patients who were not 3 t for the endoscopy

in the initial 24 h were excluded. Patients were also excluded

who underwent sclerotherapy for EVB as EIS was used as

rescue treatment.

In our study, the patients were randomized as potential

study subjects at initial presentation to the ER, as either

study drug had to be started from the presentation. B e

3 nal eligibility to be enrolled in the study was decided once

esophagogastroduodenoscopy was performed within initial

24 h and con3 rmed EBV as their source of bleeding. Ideally,

randomization should be carried out once 3 nal inclusion and

exclusion criteria are met. In our study, we opted to start the

trial medication before 3 nal inclusion to utilize the vasoactive

eE ect of terlipressin and octreotide to control variceal bleed

and hence give the better endoscopic view to perform thera-

peutic intervention, B is was the limitation in the design of

our study.

B e e> cacy of terlipressin was noninferior to octreotide

as an adjuvant therapy for the control of EVB and in-hospi-

tal survival. B e length of hospital stay in terlipressin group

was signi3 cantly shorter without any clinical importance. B e

predictors of prolonged hospital stay were low Hb, high pulse,

prolonged prothrombin time, blood at nasogastric aspirate,

and PSE.

No noticeable side eE ects were observed in either group

speci3 cally the cardiovascular side eE ects. Studies are required

for further evaluation of diE erence in the duration of hospi-

tal stay and cost eE ective comparison between terlipressin and

octreotide in patients with EVB.

CONFLICT OF INTEREST

Guarantor of the article: Ethics Review Committee and

Chair Department of Medicine Aga Khan University.

Speci� c author contributions: Shahab Abid contributed

in terms of original idea, study design, writing protocol,

organizing logistics, and editing the article. Wasim Jafri and

Saeed Hamid contributed to study design, logistics, caring

for patients under study and editing the article. Mohammed

Salih, coordination between various departments, literature

search, writing of the article with 3 rst author. Zahid Azam

contributed in statistical analysis and review the revisions of

the submitted article. Khalid Mumtaz, Hasnain Ali Shah, and

Zaigham Abbas contributed in study design, care of study

patients, and editing of the article.

Financial support: Institutional support and research fund

from Department of Medicine.

Potential competing interests: None.

Table 3 . Factors associated with increased length of stay

Adjusted odds ratio

95% CI for adjusted odds ratio

P value

Pulse 1.007 1.001 – 1.014 0.013

Hemoglobin at presentation

0.923 0.859 – 0.992 0.014

Packed cell transfusion 0.831 0.772 – 0.894 < 0.001

Prothrombin time (PT) 0.977 0.955 – 1.000 0.025

Nasogastric tube (NGT) aspirate

Clear aspirate 1

Blood tinged aspirate 1.642 1.188 – 2.271 0.001

Portosystemic encephalopathy

Absent 1

Present 0.470 0.332 – 0.663 < 0.001

Cox regression analysis: Adjusted for agents used (terlipressin or octreotide) and systolic blood pressure at presentation. CI, confi dence interval. Empty cells denote that clear aspirate was taken as reference value.


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5 . Escorsell A , Arbol LRD , Planas R et al. Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: the TEST study . Hepatology 2000 ; 32 : 471 – 6 .

6 . Bildozola M , Kravetz D , Argonz J et al. E> cacy of octreotide and sclero-therapy in the treatment of acute variceal bleeding in cirrhotic patients. A prospective, multicentric, and randomized clinical trial . Scand J Gastroenterol 2000 ; 35 : 419 – 25 .

7 . Besson I , Ingrand P , Person B et al. Sclerotherapy with or without octre-otide for acute variceal bleeding . N Engl J Med 1995 ; 333 : 555 – 60 .

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9 . de Franchis R . Somatostatin, somatostatin analogues and other vasoactive drugs in the treatment of bleeding esophageal varices . Dig Liver Dis 2004 ; 36 (Suppl 1) : S93 – 100 .

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11 . Douglas JG , Forrest JA , Prowse CV et al. EE ects of lysine vasopressin and glypressin on the 3 brinolytic system in cirrhosis . Gut 1979 ; 20 : 565 – 7 .

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Study Highlights

WHAT IS CURRENT KNOWLEDGE 3 Octreotide and terlipressin are the two most commonly

used vasoactive agents for the management of esopha-geal variceal bleeding.

3 There are strong arguments in favor of the combination of vasoactive drugs started at the time of presentation and later endoscopic intervention to control variceal bleed. This is the best therapeutic option in patients with ongoing variceal bleeding.

3 Octreotide and terlipressin signifi cantly reduce variceal pressure and azygos fl ow. Both were found to be superior to placebo in the control of variceal bleeding. Terlipressin also has some effect in the improvement of renal perfusion in cirrhotic patients with hepatorenal syndrome.

WHAT IS NEW HERE 3 Terlipressin was not inferior to octreotide in its effi cacy

for controlling variceal bleed.

3 In this study, no signifi cant adverse events were noted with either terlipressin or octreotide particularly cardiac adverse event.

REFERENCES 1 . D ’ Amico G , Pagliaro L , Bosch J . B e treatment of portal hypertension: a

meta-analytic review . Hepatology 1995 ; 22 : 332 – 54 . 2 . de Franchis R , B e North Italian Endoscopic Club for the Study and Treat-

ment of Esophageal Varices . Prediction of the 3 rst variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices . N Engl J Med 1988 ; 319 : 983 – 9 .

3 . D ’ Amico G , Pietrosi G , Tarantino I et al. Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: a Cochrane meta-analy-sis . Gastroenterology 2003 ; 124 : 1277 – 91 .

4 . de Franchis R . Evolving consensus in portal hypertension report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension . J Hepatol 2005 ; 43 : 167 – 76 .

terlipressin vs. octreotide in bleeding esophageal varices as an adjuvant therapy with endoscopic...

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