primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and...

Research Article

Primary prophylaxis of gastric variceal bleedingcomparing cyanoacrylate injection and beta-blockers: A

randomized controlled trial

Smruti Ranjan Mishra1, Barjesh Chander Sharma1, Ashish Kumar2, Shiv Kumar Sarin1,2,⇑

1Department of Gastroenterology, G B Pant Hospital, New Delhi, India; 2Department of Hepatology,Institute of Liver & Biliary Sciences (ILBS), New Delhi, India

Background & Aims: Gastric variceal bleeding is severe and is Introduction
associated with high mortality. We compared the efficacy of cya-noacrylate injection and beta-blockers in primary prophylaxis ofgastric variceal bleeding.Methods: Cirrhotics with large gastroesophageal varices type 2with eradicated esophageal varices or large isolated gastric varixtype 1, who had never bled from gastric varix, were randomisedto cyanoacrylate injection (Group I, n = 30), beta-blockers (GroupII, n = 29) or no treatment (Group III, n = 30). Primary end-pointswere bleeding from gastric varix or death.Results: The actuarial probability of bleeding from gastric vari-ces over a median follow-up of 26 months was 13% in Group I,28% in Group II (p = 0.039), and 45% in Group III (p = 0.003). Theactuarial probability of survival was higher in the cyanoacrylatecompared to the no-treatment group (90% vs. 72%, p = 0.048).The median hepatic venous pressure gradient (HVPG)was increased in Group I (14–15 mm Hg, p = 0.001) and III(14–16 mm Hg, p = 0.001) but decreased in Group II (14 to12 mm Hg, p = 0.001) during follow-up. Size of gastric varix>20 mm, a MELD score P17, and presence of portal hypertensivegastropathy predicted ‘high risk’ of first bleeding from gastricvarices.Conclusions: Primary prophylaxis is recommended in patientswith large and high risk gastric varices to reduce the risk of firstbleeding and mortality. Cyanoacrylate injection is more effectivethan beta-blocker therapy in preventing first gastric varicealbleeding.� 2010 European Association for the Study of the Liver. Publishedby Elsevier B.V. All rights reserved.
Journal of Hepatology 20

Keywords: Cirrhosis; Endoscopy.Received 7 June 2010; received in revised form 28 August 2010; accepted 7 September2010; available online 5 November 2010⇑ Corresponding author. Address: Department of Hepatology, Institute of Liver &Biliary Sciences (ILBS), New Delhi 110 070, India. Tel.: +91 11 23232013; fax: +9111 23219710.E-mail address: [email protected] (S.K. Sarin).Abbreviations: GV, gastric varix; EV, esophageal varix; PHG, portal hypertensivegastropathy; GOV2, gastroesophageal varix type 2; IGV1, isolated gastric varixtype 1; HVPG, hepatic venous pressure gradient; TIPS, transjugular intrahepaticportosystemic shunt; MELD, model for end-stage liver disease; BRTO, balloonoccluded retrograde transvenous obliteration.

Gastric varices (GV) are found in 20% of patients with portalhypertension [1]. The bleeding from GV is more severe, requiringmore blood transfusions, and has a higher mortality rate thanesophageal variceal bleeding [1–3]. The mortality from firstvariceal bleed remains as high as 20% within 6 weeks of theindex bleed [2,3]. GV could be associated with esophageal varices(along the lesser curve, gastroesophageal varices type 1 (GOV1);or along the fundus, type 2 (GOV2)) or could present as isolatedGV (IGV: in the fundus (IGV1), or at ectopic sites in the stomachor the first part of the duodenum (IGV2)) [1]. The 2-year inci-dence of variceal bleeding from IGV1 and GOV2 type of varicesis more frequent and profuse (78% and 54%, respectively) thanthe lesser curve (GOV1) varices (28%) [1]. In the presence offactors indicating a high risk of bleeding, the 2-year probabilityof GV bleeding is as high as 65% [4,5].

There is little data on primary prophylaxis of GV bleeding [6].Prophylactic treatment for preventing GV bleeding should bebased on the incidence of GV bleeding and mortality taking intoaccount size and location of GV, degree of liver dysfunction, andother factors. Generally, patients with GV, who also have esoph-ageal varices, are given non-selective beta-blockers to reduce theincidence of first bleeding from esophageal varices [7,8]. Whetherthis can prevent bleeding from GV is not well known as there areno randomized controlled trials of pharmacological therapy forprimary prevention of bleeding from GV.

Given the high rate of hemostasis and lower rate of rebleeding,endoscopic gastric variceal obturation with cyanoacrylate injec-tion is used as the first-line treatment for bleeding GV and in sec-ondary prophylaxis of GV bleed [9–15]. Its role in primaryprophylaxis of GV bleeding has, however, not been evaluated. Weperformed a randomized controlled open label study to comparethe efficacy of endoscopic cyanoacrylate injection versus beta-blockers, versus no treatment in the prevention of GV bleeding.

Patients and methods

Consecutive cirrhotic patients, admitted to our hospital from August 2006 to June2009 with GV (GOV2 or IGV1) of P10 mm size, were enrolled (Fig. 3). The studywas approved by the institutional review board, and written informed consentwas obtained from all patients and parents of the children. Cirrhotics withGOV2 (eradicated EV) or IGV1, who had never bled from GV, were included.

11 vol. 54 j 1161–1167

mailto:[email protected]

Research Article
The exclusion criteria were presence of EV, non-cirrhotic portal hypertension,acute bleed or past history of bleed from GV, contraindications to beta-blockersand cyanoacrylate injection, prior treatment for prevention of bleeding fromGV, patients on beta-blockers, hepatic encephalopathy grade III/IV, hepatorenalsyndrome, hepatocellular carcinoma, presence of deep jaundice (serum bilirubin>10 mg/dl), cardiorespiratory failure, age >75 years, pregnancy, and patients notgiving informed consent.
Patients were randomized in 1:1:1 ratio using sealed envelope technique toreceive endoscopic cyanoacrylate injection (Group I) or beta-blocker (Group II)or no treatment (Group III). The random allocation sequence remained concealedfrom the investigators until the intervention was assigned. Endoscopic and b-blocker treatments were started immediately after randomization. The follow-up was started at the time of randomization and was done for at least 3 monthsafter enrollment of the last patient.

The size of GV was calculated by zebra guide wire with markings made at5 mm interval and the fundal varix was classified as small (<10 mm) and large(>10 mm). The color of GV was observed as red or blue. The presence or absenceof EV and the portal hypertensive gastropathy were also evaluated. An upper gas-trointestinal endoscopy was done to determine the variceal status at baseline andwas repeated at 6 month intervals or during bleeding. Size of GV, appearance ofEV, and portal hypertensive gastropathy were recorded. Conscious sedation usingmidazolam was used prior to the endoscopic procedure. Variceal bleeding wasdefined as occurrence of hematemesis and/or melena requiring P2 U of bloodor a decrease of 3 gm/dl of hemoglobin if no blood transfusion is given [6]. Theevidence of gastric variceal bleeding included (1) active spurting or oozing ofblood from gastric varices during endoscopy and (2) stigmata of recent hemor-rhage such as blood clots coating on the gastric varices or ulcer on gastric varices.

Primary end-points of the study were bleeding from GV or death. The actuarialprobabilities of bleeding from GV and mortality were calculated. Secondary end-points were increase or decrease in the size of GV, appearance of new EV, andappearance or worsening of portal hypertensive gastropathy and complications.

The diagnosis of cirrhosis was based on clinical, biochemical, radiological, andhistological findings. Ultrasonography of the abdomen with Doppler of spleno-portal axis was done to diagnose cirrhosis and to exclude extrahepatic portal ve-nous obstruction. MR portovenography and Doppler ultrasound were done tolook for the presence of spontaneous shunt. Models for end-stage liver disease(MELD) and Child-Turcotte-Pugh scores were calculated at baseline and serialintervals. Patients were advised to refrain from consuming alcohol and takingnon-steroidal anti-inflammatory drugs.

Technique of cyanoacrylate injection

Endoscopic injection was performed intravariceally using a therapeutic endo-scope and a transparent Teflon injector, with a 6–8 mm long, 21-gauge needle,with N-butyl-2-cyanoacrylate. The cyanoacrylate was injected without dilutionwith lipiodol. Maximum amount of cyanoacrylate injected per site was 2 ml,and the total amount of cyanoacrylate required to completely obliterate the GVwas recorded. An attempt was made to completely obturate the GV in one ses-sion, by injecting cyanoacrylate at multiple sites. If a second session was consid-ered necessary, it was done within one week of the initial session. The injected GVwas palpated using the hub of the injector with the needle retracted to determinesolidification and obliteration of the GV. If the GV was not completely obturated,cyanoacrylate was reinjected until all the GV became solidified. Caution was ta-ken to prevent damage to endoscope by applying silicon oil over the endoscopetip and flushing the endoscope channel with acetone. All patients in the cyanoac-rylate group received proton pump inhibitors for 4 weeks.

Beta-blockers therapy

Propranolol was started at a dose of 20 mg, twice daily. The dose was increasedby 20 mg every alternate day to achieve a target heart rate of 55/min, or to themaximal dose of 360 mg/day if the medication was well tolerated and the systolicblood pressure was >90 mm Hg. Compliance was assessed by pill count (>80%)and interview with patients or relatives. Patients were monitored every day untiladequate b-blockade was achieved and then every month for the first 3 months,and subsequently, every 3 months.

HVPG measurement

After an overnight fast, HVPG measurement was performed using the standardprocedure, as previously described [16]. Baseline HVPG was measured and re-peated after 1 year in all groups. In patients who bled from GV, HVPG was mea-sured within 24 h of bleeding. Responder was defined as P20% reduction in HVPGor HVPG <12 mm Hg.

1162 Journal of Hepatology 2011

Statistical analyses

The incidence of bleeding from GOV2 and IGV1 is 55–78% [1]. We hypothesizedbeta-blockers would not be effective in preventing first bleeding from GV andequivalent to those patients who received no treatment (expected GV bleedingrate of 55% in beta-blockers and no-treatment groups). We expect the rate ofGV bleeding in cyanoacrylate injection group to be 15% (extrapolated from stud-ies of prevention of GV rebleeding by cyanoacrylate) [7,9–15]. First, we calculatedthe sample size between cyanoacrylate injection and beta-blocker group, andfound that 24 patients will be required in each group. We also calculated the sam-ple size between cyanoacrylate injection and no-treatment group, and found that24 patients will be required in each group. Thus, we made 3 groups, and, toachieve a statistical power of 80% with an error of 5% and drop-out rate of 10%,a sample size of 24 patients in each group was calculated.

Fisher’s exact test was used to compare categorical groups. Student’s t-testand Mann–Whitney U-test were used for the parametric and non-parametricdata, respectively. One-way ANOVA test was used to compare baseline param-eters and treatment end-points. For comparison of pre- and post-therapyparameters between groups, the paired Student’s t-test was used. CumulativeGV bleeding and survival were expressed using the Kaplan–Meier method,and differences were assessed using the log-rank test. Cox proportional regres-sion analysis was used to assess variables predicting the end-points. Eachpatient was analyzed in an intention to treat manner. p Value of <0.05 wasconsidered significant. Statistical analysis was done using SPSS (version 15,Chicago, IL).

Results

Between August 2006 and June 2009, of 1050 consecutive cir-rhotic patients with portal hypertension presented to our hospi-tal, 961 did not meet inclusion criteria and were excluded.Eighty-nine cirrhotics with GV (GOV2/IGV1) without EV, whohad no history of GV bleeding, were randomized to receive cya-noacrylate injection (Group I, n = 30), beta-blockers (Group II,n = 29) or no treatment (Group III, n = 30).

The baseline characteristics of the three groups were compa-rable (Table 1). The most common etiology of cirrhosis was alco-hol or cryptogenic. Four patients each in Group I and II and fivepatients in Group III had IGV1, the rest of the patients hadGOV2. Size of GV, color of GV, and portal hypertensive gastropa-thy in the 3 groups were similar (Table 1). MR portovenographyand Doppler ultrasound demonstrated spontaneous lieno-renalshunts in 13 patients in Group I, 10 patients in Group II, and 11patients in Group III. Four children between 10–12 years of agewere included in the trial. Etiology of cirrhosis in children wascryptogenic (n = 2), autoimmune hepatitis (n = 1), and hepatitisB virus related (n = 1). Only one child received beta-blockersand was a non-responder.

Gastric variceal obturation

Endoscopic intervention could be performed with 100% technicalsuccess. Complete obturation of GV was achieved in all patients.The mean number of sessions required to achieve obliterationwas 1.6 ± 0.4 (range 1–3). The mean volume of cyanoacrylate re-quired was 5.0 ± 1.7 (range 3–8) ml. The mean time period toachieve obturation was 1.4 ± 0.6 (1–3) days.

Beta-blockers therapy

All patients were compliant to beta-blocker therapy. The meandaily dose was 140 (80–240) mg. The desired heart rate couldbe achieved in all patients, unless they were intolerant or hadside-effects. The median time interval to achieve the desired

vol. 54 j 1161–1167

Table 1. Baseline characteristics of patients.

Age (Median,range) yrsSex (Male:Female)Etiology of Cirrhosis (Alcohol/cryptogenic/others)AscitesHE (Grade I/II)Serum Bilirubin (Median,range) mg/dlSerum Albumin (Median,range) g/dlINR (Median,range)Platelet (Median,range)105/mlSerum Creatinine (Median,range) mg/dlChild Score (Median,range)Child A/B/CMELD Score (Median,range)HVPG (Median,range) mmHgFollow Up (Median,range) moGastroesophageal varix type 2Isolated gastric varix type 1Size of GV (Median,range) mmPortal Hypertensive GastropathyColor of GV (Red/Blue)Spontaneous shunt

40 (10-71)20:1016/9/512/3001.8 (0.6-9.5)3.2 (1.8-3.8)1.3 (1.1-2.1)1.2 (0.7-3.2)0.6 (0.3-1.5)8 (5-12)10/12/813 (7-26)14 (8-26)26 (3-34)26/304/3020 (10-35)7/3015/1513/30

40 (10-65)21:814/8/711/3002.0 (0.8-6.3)3.1 (2.2-3.6)1.3 (1.1-2.3)1.0 (0.7-2.3)0.6 (0.4-1.4)8 (5-12)9/11/913 (7-30)14 (11-26)26 (3-34)25/294/3020 (10-30)9/3016/1310/29

38 (11-60)23:715/9/613/3011.8 (0.5-6.6)3.2 (2.2-3.7)1.3 (1.2-2.1)1.1 (0.4-2.1)0.7 (0.3-1.5)8 (6-12)10/12/813 (8-25)14 (8-24)26 (3-34)25/305/3020 (10-30)9/3015/1511/30

0.8500.3560.43780.87010.9520.9760.5550.3720.7060.7820.5610.8830.8150.9890.9270.9270.1620.2110.8540.885

Parameters CyanoacrylateGroup I(n = 30)

Beta-blockerGroup II(n = 29)

No treatmentGroup III (n = 30)

p value

HE, hepatic encephalopathy; INR, international normalized ratio; MELD, model for end-stage liver disease; HVPG, hepatic venous pressure gradient.

Table 2. Results of treatment.

GV BleedBleed from GOV2Bleed from IGV1Increase in GV size Decrease in GV sizeAppearance of esophageal varixAggravation/appearance of PHGBleed related mortality GOV2 IGV1Overall mortality GOV2 IGV1Complications

3/30 (10%)2/26 (4%)1/4 (33%)025/25 (100%)7/30 (23%)7/30 (23%)0/30 0/260/4 2/30 (7%)2/26 (8%)0/4 1 (3%)

11/29 (38%)11/25 (47%)0/4 11/29 (33%)03/29 (10%)2/29 (7%)3/29 (10%)3/25 (12%)0/4 5/29 (17%)5/25 (20%)0/4 1 (3%)

16/30 (53%)13/25 (52%)3/5 (60%)13/30 (43%)03/30 (10%)3/30 (10%)5/30 (24%)5/25 (20%)1/5 (20%)8/30 (26%)6/25 (24%)2/5 (40%)2 (7%)

0.0030.0010.1970.0030.0020.2160.1540.0340.02510.1130.1220.4641

Characteristics CyanoacrylateGroup I(n = 30) (n, %)

Beta-blockerGroup II(n = 29) (n, %)

No treatmentGroup III (n = 30) (n, %)

p value

GV, gastric varix; SD, standard deviation; GOV2, gastroesophageal varix type 2; IGV1, isolated gastric varix type 1; PHG, portal hypertensive gastropathy.

JOURNAL OF HEPATOLOGY

heart rate was 12 (5–20) days and during this period no patientbled from GV. In total, 6 patients experienced side effects. Mostof these were minor, and permitted continued use. Three patientsrequired dose reduction and, after 1–2 weeks, a dose close to theprevious dose could be achieved.

Gastric variceal bleeding

Over a median follow-up period of 26 (3–34) months, 11 out of29 (38%) patients in Group II and 16 out of 30 (53%) patients in


Group III bled, compared to 3 out of 30 (10%) patients in GroupI (Table 2). The actuarial probability of bleeding from GV was13% in the cyanoacrylate group compared to 28% in the beta-blocker group (p = 0.039) and 45% in the no-treatment group(p= 0.003) (Fig. 1A). However, between Group II and III, no signif-icant difference in GV bleeding was observed (p = 0.374). The dif-ference in bleeding from GOV2 was also significant betweenGroup I and III (p = 0.001) and Group I and II (p = 0.003), however,no significant difference was observed between Group II and III(p = 0.575) (Table 2).

vol. 54 j 1161–1167 1163

0.0

0.2

0.4

0.6

0.8

1.0C

umul

ativ

e Bl

eedi

ng F

ree

Rat

e

Follow up (months)0 6 12 18 24 30 36

302930

Patients at riskCyanoacrylate

Beta-blockerNo treatment

No treatmentCyanoacrylateBeta-blocker

302626

302425

301721

151415

877

Group I vs III: Log-rank = 8.888, p = 0.003

Gr I, 87%

Gr II, 72%

Gr III, 55%

Gr I, 90%Gr II, 85%

Gr III, 72%

Group I vs II: Log-rank = 4.261, p = 0.039Group II vs III: Log-rank = 0.791, p = 0.374

0.0

0.2

0.4

0.6

0.8

1.0

Cum

ulat

ive

Surv

ival

Rat

e

Follow up (months)0 6 12 18 24 30 36

302930

Patients at riskCyanoacrylate

Beta-blockerNo treatment

No treatmentCyanoacrylateBeta-blocker

302626

302425

301721

151415

877

Group I vs III: Log-rank = 3.852, p = 0.048Group I vs II: Log-rank = 1.295, p = 0255Group II vs III: Log-rank = 0.468, p = 0.494

Fig. 1. Actuarial probability of freedom from bleeding from the gastric varices (A) and survival (B) in the endoscopic cyanoacrylate injection, beta-blockers, and no-treatment group.

Research Article

Size and color of gastric varices

Over a median follow-up period of 26 months, all (100%) patientsin Group I had a decrease in GV size. On the other hand, 11 out of29 (38%) patients in Group II and 13 out of 30 (43%) patients inGroup III had an increase in GV size (Table 2). The median sizeof GV increased from 20 (10–30) to 25 (15–35) mm (p <0.01) inGroup II and 20 (10–30) to 30 (15–40) mm (p <0.01) in GroupIII. In Group I, the median size of GV decreased from 20 (10–35) to 5 (0–10) mm (p <0.01). All patients, bleeding from GV inGroup II and III, had an increase in size of at least 5 mm. Thenumber of patients having blue color GV was higher amongbleeders [23 out of 30 (76%)], in comparison to non-bleeders[20 out of 59 (34%), (p <0.01)].

Appearance of esophageal varices and PHG

Seven out of 30 patients (23%) in Group I, and 3 (10%) patientseach in Group II and III, developed esophageal varices on fol-low-up. All patients developed small varices which did not bleed.No significant difference was observed among groups [Group I, 7out of 30 (23%); Group II, 2 out of 29 (7%); and Group III, 3 out of30 (10%)] for the appearance or worsening of portal hypertensivegastropathy (Table 2).

Hepatic venous pressure gradient

Baseline HVPG was measured in 28 out of 30 patients in Group I(1 patient refused and, in another patient, the hepatic vein couldnot be cannulated), and in all patients of Group II and III. The fol-low-up HVPG was measured in 25 patients in Group I (2 patients


refused and, in 1 patient, the hepatic vein could not be cannulat-ed), 29 in Group II, and 27 in Group III (3 patients refused forHVPG measurement). On follow-up, the HVPG value increasedin Group I [(p = 0.001), (Fig. 2A)] and Group III [(p = 0.001),(Fig. 2C)], and decreased in Group II [(p = 0.001), (Fig. 2B)]. Inpatients with GOV2, the baseline median HVPG was 16 (12–26) mm Hg and in IGV1 patients the baseline median HVPGwas 14 (5–24) mm Hg. There was no difference in baseline HVPGbetween cases who bled, 14 (8–24) mm Hg and those who didnot bleed, 14 (10–26) mmHg (p = 0.265). In those patients whobled (n = 27), the median HVPG at baseline was 14 (8–24) mm Hgand the follow-up HVPG was unchanged at 14 (10–27) mm Hg(p = 0.302).

In Group I, 19 out of 23 (82%) patients had HVPG >12 mm Hgat baseline and 18 out of 20 (90%) patients had HVPG >12 mm Hgon follow up. In Group II, 22 out of 24 (92%) patients hadHVPG >12 mm Hg at baseline and 12 out of 24 (50%) patientshad HVPG >12 mm Hg on follow-up. In Group III, 21 out of 25(84%) patients had HVPG >12 mm Hg at baseline and 21 out of22 (95%) patients had HVPG >12 mm Hg on follow-up.

Response to therapy and bleeding

In Group I and III, none of the patients showed a reduction inHVPG. In Group II, 10 out of 29 (34%) patients were responders[median baseline HVPG 14 (13–16) and follow-up HVPG 11(8–12) mm Hg, (p = 0.001)] and 4 of these responders (40% ofresponders) bled and all had GOV2. Importantly, the meandecrease in HVPG from baseline was 25% in comparison to 21%in those patients who bled. Among non-responders [median base-line HVPG 17 (11–26) and follow-up HVPG 16 (12–22) mm Hg,

vol. 54 j 1161–1167

0

5

10

15

20

25

30

Baseline HVPG Follow-up HVPG

Cyanoacrylate Group (N = 25)

p = 0.001A B C

14 (8-26) 15 (11-25)

Med

ian

HVP

G in

mm

Hg

0

5

10

15

20

25

30


Beta-blocker Group (N = 29)

p = 0.001

14 (11-26) 12 (8-22)

Med

ian

HVP

G in

mm

Hg

0

5

10

15

20

25

30


No Treatment Group (N = 27)

p = 0.001

14 (8-24) 16 (12-27)

Med

ian

HVP

G in

mm

Hg

Fig. 2. Baseline and follow-up HVPG in cyanoacrylate group (A), beta-blockers group (B), and no-treatment group (C).


p = 0.179], 7 out of 19 (37%) patients in Group II bled. Patients,with spontaneous shunt (n = 34), had a low HVPG than those with-out a shunt (n = 55) [13 (8–15) vs. 18 (13–26) mm Hg (p = 0.001)].A significant decrease of 2 mm Hg in median HVPG was observedon follow-up. In the beta-blocker group, 40% of responders bled onfollow-up (p = 0.9) compared to 37% of non-responders.

Complications

No significant difference in the frequency of complications wasobserved between the three groups. One (3%) patient each in

Assessed for eligib

Not bled from Gastric Varix [GORandomization

Lost to follow up, n = 0Discontinued intervention, n = 0

Allocated to cyanoacrylate injection, n = 30 Received allocated intervention, n = 30Refused allocated intervention, n = 0

Analyzed, n = 30Excluded from analysis, n = 0

Lost to followDiscontinued inte

Allocated to beta-bReceived allocated in

Refused allocated in

Analyzed, Excluded from an

Fig. 3. Trial profile.


Group I and II, and 2 (7%) patients in Group III developed sponta-neous bacterial peritonitis and improved on treatment (Table 2).

Mortality

Over a median follow-up period of 26 months, overall mortalitywas significantly lower in Group I (n = 2, 7%) than in Group III(n = 8, 26%); and there was no significant difference in mortalityobserved between Group I vs. Group II, and Group II vs. Group III(Table 2, Fig. 2B). The actuarial survival rate at 26 months was90% in the cyanoacrylate group, 85% in the beta-blocker group,

Excluded, n = 961Inclusion criteria not met, n = 957Refusal to participate, n = 3Other reasons, n = 1

ility, n = 1050

V2(Eradicated EV)/IGV1] , n = 89

up, n = 0rvention, n = 0

locker, n = 29 tervention, n = 29tervention, n = 0

n = 29alysis, n = 0

Lost to follow up, n = 0Discontinued intervention, n = 0

Allocated to no treatment, n = 30 Received allocated intervention, n = 30Refused allocated intervention, n = 0

Analyzed, n = 30Excluded from analysis, n = 0

vol. 54 j 1161–1167 1165

Research Article
and 72% in the no-treatment group. Bleed-related mortality wasfound in 8 patients (n = 3, Group II and n = 5, Group III). Therewas a significant difference in bleed-related mortality betweenGroup I and III (p = 0.026). In Group I and II, one patient each diedof hepatic encephalopathy. One patient each in Group I, II, and IIIdied of spontaneous bacterial peritonitis, hepatorenal syndrome,and sepsis. In the beta-blocker group, all 5 patients who diedwere non-responders.
In univariate analysis, the variables which influenced GVbleeding were size of GV >20 mm, blue color of GV, presence ofPHG, INR P1.4, Child score P9, MELD score P17, and treatmentmodality. In multivariate analysis, size of GV >20 mm (95% CI0.018–0.888, p = 0.038), MELD score P17 (95% CI 0.011–0.460,p = 0.006), and presence of portal hypertensive gastropathy(95% CI 0.008–0.486, p = 0.008) independently correlated withGV bleed. In univariate analysis, the variables which influencedsurvival included GV bleeding, presence of PHG, Child scoreP9, MELD score P17, and treatment modality (Group I versusIII). In multivariate analysis, MELD score P17 (95% CI 0.010–0.499, p = 0.008) and GV bleeding (95% CI 0.006–0.783,p = 0.031) independently correlated with mortality.

Discussion

Gastric variceal bleeding has the characteristics of more severeblood loss and higher mortality and is a more difficult manage-ment problem than esophageal variceal hemorrhage. Therefore,it is important to identify patients with ‘high risk’ GV and to de-fine successful approaches to prevent the first bleeding fromlarge GV.

The results of this first large prospective randomized con-trolled clinical trial, comparing the efficacy of beta-blockers ther-apy with endoscopic cyanoacrylate injection or no treatment inlarge GV, clearly show that endoscopic injection of cyanoacrylate,is significantly more effective than beta-blockers or no treatmentin the prevention of first bleeding from high risk GV. The cyano-acrylate glue injection also reduced the overall mortality in thesepatients in comparison to no treatment.

The beta-blocker therapy has been found to be effective inpreventing the first bleeding from esophageal varices [17–19].Its efficacy in preventing GV bleeding has not been well studied.The overall GV bleeding and mortality rates in patients whoreceived beta-blockers were 38% and 17%, respectively. In thepresent study, the propranolol dose, the tolerance (>90%), thereduction of HVPG, and response rates (34%) are quite similarto what has been previously reported with beta-blocker therapyin primary prevention of esophageal variceal bleeding [20]. A sig-nificant decrease of 2 mm Hg in median HVPG was observed onfollow-up, and 34% patients were responders. In the beta-blockergroup, 40% of responders and 37% of non-responders bled onfollow-up. The risk of first variceal bleeding in patients withesophageal varices is significantly reduced by beta-blockers(30% in controls vs. 14% in beta-blocker treated patients) thoughthe mortality rate has not been significantly reduced [20]. In con-trast, our results show that in patients with GV, the beta-blockertherapy could not reduce the incidence of first bleeding from GVor the mortality, despite reduction in HVPG. This could be due tofactors other than HVPG, responsible for bleeding from gastricvarices like size of GV, high rate of blood flow in the large varices,and severity of underlying liver disease.


In the cyanoacrylate group, following endoscopic obturationof GV, none of the patients bled or died up to 1 year of follow-up. The overall GV bleeding rate and the mortality rate was10% and 7%, respectively. Complete obturation of GV wasachieved in all patients without serious adverse effects. A smallopen label pilot study of 25 patients with GV, which included afew patients with high-risk varices that presumably had not bled,showed some promise for the use of cyanoacrylate injection toprevent and control bleeding [21].

Patients who received cyanoacrylate injection, in comparisonto beta-blocker therapy or no treatment, had a lower rate of GVbleeding. The patient’s survival was significantly better in thecyanoacrylate group compared to the no-treatment group (7%vs. 26%, p = 0.048). These results show that patients withuntreated large GV have a high incidence of bleeding andbleed-related mortality. This supports the justification for theuse of prophylactic therapy in the prevention of the first varicealbleeding in patients with large GV. Furthermore, our data alsosuggest that the first-line treatment for such patients should becyanoacrylate glue injection.

In the cyanoacrylate group, 23% of patients had appearance ofnew esophageal varices compared to 10% each in the othergroups, however, none of the patients bled from esophageal var-ices. Although the frequency of appearance or worsening of PHGin cyanoacrylate group was higher (23%) in comparison to beta-blocker group (7%), no significant difference was observed. Whilecyanoacrylate injection significantly reduced the GV bleedingrate as compared to the beta-blocker therapy, there was no sig-nificant survival benefit (mortality: 7% vs. 17%, p = 0.393). Thesurvival benefit in the cyanoacrylate group compared to thebeta-blocker group could have been observed if more patientshad been included in the study.

In the present study, the risk of first bleeding in the group ofpatients with no treatment (Group III) was 53%, which is compa-rable to previous reports of bleeding rates in GV patients [1]. Thishigh incidence of first bleeding is due to the inclusion of a major-ity of patients with large and high risk gastric varices. In fact, themedian size of GV in our patient population was 20 mm. Suchpatients, indeed, need to be treated on priority to prevent theGV bleeding and the related risk of mortality. Our data is alsosupported by previous studies reporting that nearly 2/3rd ofthe patients with large GV and red color signs bleed within2 years [4,5].

Our data has also identified risk factors, other than size of gas-tric varix, which could predict first bleeding from GV. In multivar-iate analysis, the independent factors found to predict a ‘highrisk’ of GV bleeding were size of GV >20 mm, presence of portalhypertensive gastropathy, and MELD score P17. In a previousstudy, we had reported that presence of portal hypertensive gas-tropathy indicates a more severe course of GV [1]. Presence ofportal hypertensive gastropathy indicates a more severe vasodi-latory state of portal hypertension [22]. A high MELD score isknown to reflect a more advanced liver disease and a highmortality.

Spontaneous splenorenal or gastrorenal shunts commonly de-velop between the splenic vein (splenorenal shunt) and gastricvarices, respectively, and connect via the inferior phrenic orsuprarenal vein to the left renal vein [23]. These shunts are seenin up to 60% of patients with GV [23,24]. We found spontaneousshunts in 38% of our patients. Median HVPG in patients withspontaneous shunt was lower as compared to those without

vol. 54 j 1161–1167

spontaneous shunt (13 vs. 18 mm Hg), and even in presence ofspontaneous shunt, the HVPG was P10 mm Hg in 92% of pa-tients. Unlike a previous study [25], we observed relatively higherHVPG in patients with GV (both GOV2 and IGV1). Treatment withbeta-blockers decreased HVPG in our patients, even in the pres-ence of spontaneous shunt.
Balloon retrograde transvenous obliteration of GV or sclero-therapy has been found to be effective for prophylaxis of high riskfundal variceal bleeding [5,24,26,27]. However, expertise for theseprocedures is not readily available in many centers, and certainprocedure-related complications are often seen [5,24,26,27]. TIPSis effective in the prevention of GV rebleeding, but for primaryprophylaxis of GV bleed its role is not proven. Moreover, this pro-cedure is quite expensive, needs expertise, and is associated withshunt occlusion and hepatic encephalopathy over time [25,28].Cyanoacrylate injection on the other hand, is easily available, costeffective, requires less expertise, and proved to be safe and effec-tive in preventing GV rebleeding [9–15].

The strengths of our trial are a randomized controlled design,large sample size, longer follow-up period and minimal drop-outrate, and specific inclusion of patients with large ‘high risk’ gas-tric varices of IGV1 and GOV2 types. Gastric varices of GOV2and IGV1 types are quite common and are associated with morefrequent and more severe bleeding with higher mortality rates ascompared to other types of gastric varices [1]. The lower mortal-ity and relative favorable course in our patient population couldbe due to prevention of bleeding from gastric varices by cyanoac-rylate injection. Moreover, patients were advised high proteinand calorie diet, abstinence from alcohol, frequent follow-upvisits, and close monitoring for associated complications.

In conclusion, our data strongly indicates that patients withhigh risk gastric varices need prophylactic therapy to preventfirst variceal bleeding and consequent mortality. Cyanoacrylateinjection should be the first line of treatment for primary prophy-laxis of ‘high risk’ fundal GV. Endoscopic injection of cyanoacry-late into fundal GV is safe and effective and also improves thesurvival in patients with ‘high risk’ GV as gastric variceal bleedingis an independent predictor of mortality.

Beta-blockers are not effective in preventing first GV bleeding.Reduction by 20% of HVPG by beta-blockers does not always helpin prevention of GV bleeding. It remains to be seen whether acombination of treatment with cyanoacrylate injection andbeta-blockers would offer greater benefit than either of treat-ments given alone.

Conflict of interest

The authors who have taken part in this study declared that theydo not have anything to disclose regarding funding or conflict ofinterest with respect to this manuscript.

Trial registered with ClinicalTrials.gov: NCT00905996.

References

[1] Sarin SK, Lahoti D, Saxena SP, et al. Prevalence, classification and naturalhistory of gastric varices: a long-term follow-up study in 568 portalhypertension patients. Hepatology 1992;16:1343–1349.

[2] Trudeau W, Prindiville T. Endoscopic injection sclerosis in bleeding gastricvarices. Gastrointest Endosc 1986;32:264–268.

[3] Thakeb F, Salem SA, Abdallah M, et al. Endoscopic diagnosis of gastricvarices. Endoscopy 1994;26:287–291.


[4] Kim T, Shijo H, Kokawa H, et al. Risk factors for haemorrhage from gastricfundal varices. Hepatology 1997;25:307–312.

[5] Shiba M, Higuchi K, Nakamura K, et al. Efficacy and safety of balloon-occluded endoscopic injection sclerotherapy as a prophylactic treatment forhigh-risk gastric fundal varices: a prospective, randomized, comparativeclinical trial. Gastrointest Endosc. 2002;56:522–528.

[6] de Franchis R. Evolving Consensus in Portal Hypertension Report of theBaveno IV Consensus Workshop on methodology of diagnosis and therapy inportal hypertension. J Hepatol 2005;43:167–176.

[7] Ryan BM, Stockbrugger RW, Ryan JM. A pathophysiologic, gastroenterologic,and radiologic approach to the management of gastric varices. Gastroenter-ology 2004;126:1175–1189.

[8] D’Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a metaanalytical review. Hepatology 1995;22:332–354.

[9] Sarin SK. Long-term follow-up of gastric variceal sclerotherapy: an eleven-year experience. Gastrointest Endosc 1997;46:8–14.

[10] Lo GH, Lai KH, Cheng JS, et al. A prospective, randomized trial of butylcyanoacrylate injection versus band ligation in the management of bleedinggastric varices. Hepatology 2001;33:1060–1064.

[11] Ramond MJ, Valla D, Mosnier JF, et al. Successful endoscopic obliteration ofgastric varices with butyl cyanoacrylate. Hepatology 1989;10:488–493.

[12] Huang YH, Yeh HZ, Chen GH, et al. Endoscopic treatment of bleeding gastricvarices by N-butyl-2-cyanoacrylate (Histoacryl) injection: long-term effi-cacy and safety. Gastrointest Endosc 2000;52:160–167.

[13] Sarin SK, Jain AK, Jain M, Gupta R. A randomized controlled trial ofcyanoacrylate versus alcohol injection in patients with isolated fundicvarices. Am J Gastroenterol 2002;97:1010–1015.

[14] Akahoshi T, Hashizume M, Shimabukuro R, et al. Long-term results ofendoscopic histoacryl injection sclerotherapy for gastric variceal bleeding: a10-year experience. Surgery 2002;131:S176–S181.

[15] Petruska M. Fauze Maluf-Filho, Atul Kumar, et al. Long-term outcomes ofacute gastric variceal bleeding in 48 patients following treatment withcyanoacrylate. Dig Dis Sci 2008;53:544–550.

[16] Wadhawan M, Dubey S, Sharma BC, Sarin SK. Hepatic venous pressuregradient in cirrhosis: correlation with the size of varices, bleeding, ascites,and child’s status. Dig Dis Sci 2006;51:2264–2269.

[17] Lebrec D. Pharmacological treatment of portal hypertension: hemodynamiceffects and prevention of bleeding. Pharmacol Ther 1994;61:65–107.

[18] Hayes PC, Davis JM, Lewis JA, et al. Meta-analysis of value of propranolol inprevention of variceal haemorrhage. Lancet 1990;336:153–156.

[19] Sarin SK, Groszmann RJ, Mosca PG, et al. Propranolol ameliorates thedevelopment of portal-systemic shunting in a chronic murine schistosomi-asis model of portal hypertension. J Clin Invest 1991;87:1032–1036.

[20] Bosch J, Berzigotti A, Garcia-Pagan JC, et al. The management of portalhypertension: rational basis, available treatments and future options. JHepatol 2008;48:S68–S92.

[21] Rengstorff DS, Binmoeller KF. A pilot study of 2-octyl cyanoacrylate injectionfor treatment of gastric fundal varices in humans. Gastrointest Endosc2004;59:553–558.

[22] Kumar A, Mishra SR, Sarin SK. Portal, systemic, and pulmonary hemody-namics in portal hypertensive gastropathy (PHG) – evidence of additionalvasodilation: a study of 254 cirrhotics. J Clin Gastroenrerol 2009, [Epubahead of print].

[23] Watanabe K, Kimura K, Matsutani S, et al. Portal hemodynamics in patientswith gastric varices. A study in 230 patients with esophageal and/or gastricvarices using portal vein catheterization. Gastroenterology 1988;95:434–440.

[24] Matsumoto A, Hamamoto N, Nomura T, et al. Balloon-occluded retrogradetransvenous obliteration of high-risk gastric fundal varices. Am J Gastroen-terol 1999;94:643–649.

[25] Tripathi D, Therapondos G, Jackson E, et al. The role of the transjugularintrahepatic portosystemic stent shunt (TIPSS) in the management ofbleeding gastric varices: clinical and haemodynamic correlations. Gut2002;51:270–274.

[26] Yoshitaka T, Kazuhiro N, Yasuhiro Makino, et al. Prophylactic balloon-occluded retrograde transvenous obliteration for gastric varices in compen-sated cirrhosis. Clin Gastroenterol Hepatol 2005;3:1245–1252.

[27] Akahoshi T, Hashizume M, Tomikawa M, et al. Long-term results of balloon-occluded retrograde transvenous obliteration for gastric variceal bleedingand risky gastric varices: a 10-year experience. J Gastroenterol Hepatol2008;23:1702–1709.

[28] Lo GH, Liang HL, Chen WC, et al. A prospective, randomized controlled trial oftransjugular intrahepatic portosystemic shunt vs. cyanoacrylate injection inthe prevention of gastric variceal rebleeding. Endoscopy 2007;39:679–685.

vol. 54 j 1161–1167 1167

primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and...

Documents