A total of sixty (60) studies that seemed to be relevant to our study basing on screening titles and abstract, were sought for full texts. Five of these were eliminated after thorough full-text reading. Webb et al (1981)(8) did not report our outcome of interest; Datta et al. (2003)(13) and Smith et al. (2014)(14) utilized fibrin glue; Noh et al. (2004)(15) and Zhang et al. (2007)(16) used Korean and Chinese language, respectively. A total of 55 studies were included in the systematic review while 39 studies were pooled for statistical analysis.
Characteristics of included studies
Table 1 illustrates characteristics of all included studies in our pooled analysis. These were published between the year 1989 and 2019 from countries in Africa, Europe, Asia, and North America. Eleven studies were retrospective observational; sixteen were prospective observational; two were case series; and ten were randomized clinical trials. Thirteen studies were comparative, one arm of which was cyanoacrylate. Eleven studies were non-comparative involving only cyanoacrylate outcome assessment while of the two studies, one involved comparing different doses of cyanoacrylate (i.e. 0.5mls versus 1.0mls) while another compared diluted versus undiluted cyanoacrylate. Follow-up duration after treatment with cyanoacrylate ranged from six weeks to fifteen years in another study. One study did not report duration of follow-up.
A total of 39 studies reported 3630 who had either gastric or esophageal variceal and underwent hemostasis with cyanoacrylate alone or in combination with other treatments. A total of 497 had gastric or esophageal recurrent bleeding episodes during the follow-up period.
Table 1. Study characteristics
Author (Year)
|
Country of study
|
Study design
|
Comparison groups
|
Lesion location (Sample size)
|
Diagnoses
|
Participants rebleed
|
Type of tissue adhesive utilized
|
Follow-up duration
|
Ramond (1989)(17)
|
France
|
Case series
|
butyl cyanoacrylate versus Sclerosant
|
Gastric 27
|
Cirrhosis; Portal vein thrombosis
|
10 out of 27 followed up
|
butyl cyanoacrylate
|
1-38 Months (Mean: 14.7 ±11.0)
|
Oho 1995(18)
|
Japan
|
Randomized trial
|
ethanolamine oleate (n = 24) or butyl cyanoacrylate (n = 29
|
Gastric
|
Gastric varices
|
9 out of 29 in the cyanoacrylate group
|
cyanoacrylate
|
14 months
|
D’Imperio 1996(19)
|
Italy
|
Prospective
|
N-butyl-2- cyanoacrylate
|
Esophageal 24; Gastric 54; Duodenal 2
|
Upper gastrointestinal tract varices
|
2 from gastric varices; 0 from duodenal varices; Esophageal not reported
|
N-butyl-2- cyanoacrylate
|
6 Months
|
Omar 1998(20)
|
Egypt
|
Prospective trial
|
Polidocanol, Ethanolamine, Cyanoacrylate
|
Esophageal 60
|
Schistosoma hepatic fibrosis
|
0
|
Cyanoacrylate
|
Not accessed
|
Kind 2000(21)
|
Italy
|
Retrospective
|
One arm study: Bucrylate
|
Gastric 174
|
Gastric varices
|
27 (Occurred during the firt 30 days)
|
Bucrylate
|
12 years
|
Evrad 2003(22)
|
Belgium
|
Retrospective
|
N-butyl-2- cyanoacrylate versus Proprenolol
|
Esophageal 16; Gastric 5
|
Esophagogastric varices
|
Esophageal 4; Gastric 2
|
N-butyl-2- cyanoacrylate
|
6 weeks
|
Noophun 2005(23)
|
Thailand
|
Prospective
|
One arm study: cyanocrylate
|
Gastric 24
|
Gastric varices
|
10
|
N-butyl-2- cyanoacrylate
|
Minimum of 4 weeks
|
Tan 2006(24)
|
Taiwan
|
Prospective
|
Band ligation Vesus N-butyl-2- cyanoacrylate
|
49
|
Liver cirrhosis
|
11
|
N-butyl-2- cyanoacrylate
|
680.67 ±710.54 days
|
Cheng 2007(25)
|
China
|
Retrospective
|
One arm study: N-butyl-2- cyanoacrylate
|
Gastric 635
|
Gastric varices
|
44 out of 550 followed up
|
N-butyl-2- cyanoacrylate
|
Up to 10 years
|
Kuo 2007(26)
|
China
|
Randomized trial
|
Histoacryl versus Histoacryl + hypertonic glucose solution
|
Gastric 67
|
Gastric varices
|
2 out of 34 who received Histoacryl alone
|
N-butyl-2- cyanoacrylate
|
37.9 ±18.5 months
|
Hong 2009(27)
|
Korea
|
Randomized trial
|
Endoscopic N-butyl-2-cyanoacrylate injection versus balloon-occluded retrograde transvenous obliteration
|
Gastric 27
|
gastric variceal hemorrhage
|
10 out of 14 in the N-butyl-2-cyanoacrylate group
|
N-butyl-2-cyanoacrylate
|
Up to 17 Months
|
Hou 2009 (28)
|
Taiwan
|
Randomized trial
|
0.5 mL Versus 1.0 mL of cyanoacrylate
|
Gastric 44
|
gastric variceal hemorrhage
|
14 out of 47 in the 0.5mls group; 17 out of 44 in the 1ml group
|
N-butyl-2-cyanoacrylate
|
Up to two years
|
Procaccini 2009(29)
|
USA
|
Retrospective
|
Cyanoacrylate versus TIPS
|
Gastric 105
|
gastric variceal hemorrhage
|
13 out of 61 in the Cyanoacryl group (4/58 at 72hrs; 5/47 at 3 months; 4/40 at 1year)
|
Cyanoacrylate
|
Up to one year
|
Rivet 2009(30)
|
France
|
Prospective
|
Cyanoacrylate versus Band ligation
|
Esophageal 8
|
Portal hypertension due to portal vein thrombosis, biliary atresia and antitrypsin deficiency
|
3 out of 8 in the cyanoacrylate group
|
Cyanoacrylate
|
12.5 10.6 weeks
|
Cheng 2010(31)
|
China
|
Retrospective
|
Butyl cyanoacrylate
|
Gastric varices 753
|
Gastric varices due to viral hepatitis and others
|
33
|
Butyl cyanoacrylate
|
Up to 6 months after initial endoscopy
|
Choudhuri 2010(32)
|
India
|
Prospective
|
N-butyl-2-cyanoacrylate
|
Gastric varices 170
|
Gastric variceal hemorrhage
|
23 out of 158 that were followed-up
|
N-butyl-2-cyanoacrylate
|
30.7 + 17.2 months
|
Mishra 2010(33)
|
India
|
Prospective
|
Cyanoacrylate versus beta blocker
|
Gastric 33; Esophageal 26
|
Gastric varices
|
3 out of 33
|
cyanoacrylate
|
26 Months
|
Soga 2010(34)
|
Japan
|
Case report
|
N-butyl-2-cyanoacrylate
cyanoacrylate
|
Gastric 1; Duodenal 1
|
Gastroduodenal varices
|
No rebleeding recorded
|
N-butyl-2-cyanoacrylate
cyanoacrylate
|
53 days
|
Binmoellar 2011(35)
|
USA
|
Retrospective
|
N-butyl-2-cyanoacrylate
cyanoacrylate
|
Gastric 30 (24 variceal; 6 non variceal)
|
Gastric varices; Non variceal lesion
|
No bleeding recorded from 24 variceal group
|
N-butyl-2-cyanoacrylate
cyanoacrylate
|
193 (24-589) days
|
Kang 2011(36)
|
Korea
|
Retrospective
|
N-butyl-2-cyanoacrylate
cyanoacrylate
|
Gastric varices 127
|
Gastric varices
|
29 out of 127
|
N-butyl-2-cyanoacrylate
cyanoacrylate
|
One year
|
Liao 2013(37)
|
Taiwan
|
Prospective
|
Cyanoacrylate
|
Gastric varices 69
|
Gastric varices
|
10 out of 69
|
Cyanoacrylate
|
More than 30 months
|
Tantau 2013(38)
|
Romania
|
Prospective
|
Cyanoacrylate versus Band ligation
|
Gastric 37
|
Gastric varices
|
6 out of 19 in the Cyanoacrylate group
|
Cyanoacrylate
|
27.26 ± 214.16 days
|
Al-Bawardy 2016(39)
|
USA
|
Retrospective
|
2-octyl cyanoacrylate
|
Gastric 95
|
Gastric Variceal
Hemorrhage
|
8 out of 95
|
2-octyl cyanoacrylate
|
Up to 15 years
|
Singh 2016(10)
|
India
|
Prospective
|
Diluted versus undiluted Cyanoacrylate
|
Gastric 30
|
Gastric Variceal
Hemorrhage
|
5 out of 30
|
Cyanoacrylate
|
Up to one year
|
Liu 2019(40)
|
China
|
Prospective
|
Cyanoacrylate with Versus without antibiotic
|
Gastric varices 107
|
Gastric varices
|
106 out of 107
|
Cyanoacrylate
|
4.59 ± 1.63; 4.30 ± 1.48 Days
|
Xiaoqing 2019(2)
|
China
|
Prospective
|
Cyanoacrylate versus Cyanoacrylate + Lauromacrogo
|
Gastric varices 130
|
Gastric varices
|
8 out of 62 in the Cyanoacrylate group
|
Cyanoacrylate
|
38.8 months for Cyanoacrylate group
|
Thakeb 1995 (41)
|
Egypt
|
Randomized trial
|
N-butyl-2-cyanoacrylate plus ethanolamine oleate 5% versus ethanolamine alone
|
Gastric varices 57; Esophageal varices 59
|
Gastroesophageal varices
|
3 out of 57 gastric varices; 1 out of 59 esophageal varices.
|
N-butyl-2-cyanoacrylate
|
Up to 32 months
|
Maruyama 2010(42)
|
Japan
|
Retrospective
|
Cyanoacrylate plus ethanolamine
|
Gastric varices 20
|
Gastric varices
|
10 out of 20 gastric varices
|
Cyanoacrylate
|
28.1 months
|
Bhat 2016(43)
|
United States of America
|
Retrospective
|
cyanoacrylate and coils guided by endoscopic ultrasound
|
Gastric varices 125
|
Gastric varices
|
10 out of 125 gastric varices
|
cyanoacrylate
|
Median: 436 days;
|
Robles-Medranda 2019(44)
|
Eqcuador
|
Prospective
|
cyanoacrylate and coils guided by endoscopic ultrasound
|
Gastric varices 30
|
Gastric varices
|
1 out of 27 gastric varices patients followed up
|
cyanoacrylate
|
Up to 12 months
|
Zhang 2007(16)
|
China
|
Randomized trial
|
Cyanoacrylate with percutaneous transhepatic variceal embolization
|
Esophageal varices 92
|
Esophageal varices
|
14 out of 86 esophageal varices patients followed up
|
cyanoacrylate
|
Mean: 31.5 months
|
Zhang 2008 (45)
|
China
|
Randomized trial
|
Cyanoacrylate with percutaneous transhepatic variceal embolization
|
Esophageal varices 52
|
Esophageal varices
|
8 out 0f 52 esophageal varices patients followed up
|
cyanoacrylate
|
Median: 25 months
|
Tian 2011(46)
|
China
|
Prospective
|
Cyanoacrylate with percutaneous transhepatic variceal embolization
|
Gastric varices 71
|
Gastric varices
|
7 out of 71 gastric varices patients followed
|
cyanoacrylate
|
Mean; 24.2 ± 12.4 months
|
Feritis 1995(47)
|
Greece
|
Randomized trial
|
cyanoacrylate with sclerotherapy
|
Esophageal varices 126
|
Esophageal varices
|
8 out of 67 esophageal varices patients followed up
|
N-butyl-2-cyanoacrylate
|
30 days
|
Dhiman 2002(48)
|
India
|
Prospective
|
cyanoacrylate with sclerotherapy
|
Gastric varices 29
|
Gastric varices
|
3 out of 29 esophageal varices patients followed up
|
N-butyl-2-cyanoacrylate
|
Up to 6 months
|
Shi 2014(49)
|
China
|
Retrospective
|
transjugular intrahepatic portosystemic shunt alone versus combined with Cyanoacrylate
|
Esophageal Variceal 53
|
Esophageal Variceal Bleeding
|
3 out of 53 esophageal varices patients followed up
|
Cyanoacrylate
|
35.8 months
|
Ma 2018(50)
|
China
|
Prospective
|
combined cyanoacrylate with balloon-occluded retrograde transvenous obliteration
|
gastroesophageal varices 28
|
gastroesophageal varices and reported a rebleeding risk of 0.31
|
8 out of 26
|
cyanoacrylate
|
90 days
|
Dai 2017(51)
|
China
|
Randomized trial
|
band ligation alone versus in combination with cyanoacrylate
|
Gastroesophageal varices 97
|
gastroesophageal varices
|
7 out of 49 esophageal varices patients followed up
|
Cyanoacrylate
|
20 months
|
Zeng 2017(52)
|
China
|
Randomized trial
|
cyanoacrylate plus Polidocanol versus cyanoacrylate plus lipiodol in
|
gastric varices 96
|
gastric varices
|
11 out of 94 gastric varices patients followed up
|
cyanoacrylate
|
6 months
|
Pooled risk of rebleeding in gastric varices treated with cyanoacrylate alone
Figure 2 illustrates a forest plot of pooled risk of rebleeding for gastric varices after cyanoacrylate treatment. A total of twenty-five studies reported 2590 gastric variceal patients, of whom 402 had had rebleeding after initial treatment with cyanoacrylate hemostasis. The risk ranged from the minimum of 0.04 (4%) to a maximum of 0.99 (99%) in another study. Two studies were excluded for not having rebleeding incidences during the follow up period. The pooled overall risk of rebleeding was 0.30 (confidence interval: 0.30-0.31).
There was a significant heterogeneity observed with I2 of 99.7%, p-Value<0.05. This led us to conduct sensitivity analysis, eliminating peculiar studies from the analysis. Figure 3 illustrates a sensitivity analysis forest plot of pooled risk of rebleeding for gastric varices after elimination of peculiar studies. Ramond et al (1989)(17) and Soga et al (2010)(34) were case series and case report respectively; D’Imperio et al. (1996)(19), Omar et al. (1998)(20), Noophun et al. (2005)(23), Rivet et al (2009)(30), Cheng et al (2010)(31), Binmoellar et al (2011)(35) and Tantau et al. (2013)(38) had less than one-year of follow-up; while Kind et al. (2000)(21), Tan et al. (2006)(24), Procaccini et al. (2009)(29), Choudhuri et al. (2010)(32), Mishra et al. (2010)(33), Liao et al. (2013)(37), Singh et al. (2016)(10), Cheng et al. (2007)(25), Kuo et al (2007)(26), Huo et al. (2009)(28), Kang et al. (2011)(36), Al-Baward et al. (2016)(39) and Xiaoqing et al. (2019)(2) were excluded by meta-regression. Evrad et al. (2003)(22), Hong et al. (2009)(27), Soga et al. (2010)(34) and Liu et al. (2019)(40) were excluded because their findings did not fulfill normality test criteria for calculation of confidence interval (i.e.N(1-Pe) ≥10). The resulting overall pooled risk was 0.16 (Confidence interval: 1.13-0.18) with no significant heterogeneity (i.e. I2=0.0%, p-Value=0.619).
Pooled risk of rebleeding in esophageal varices treated with cyanoacrylate alone
Figure 4 illustrates a forest plot of pooled risk of rebleeding for esophageal varices after cyanoacrylate treatment. A total of five studies reported 134 esophageal variceal patients, 7of whom had had rebleeding after initial treatment with cyanoacrylate hemostasis. The risk of rebleeding ranged from the minimum of 0.25 (25%) to a maximum of 0.38 (99%) in another study. Three studies were excluded for not having rebleeding incidences during the follow up period. The pooled overall risk of rebleeding was 0.29 (confidence interval: 0.11-0.47). There was no significant heterogeneity observed; I2 of 0.0%, p-Value=0.53.7).
Pooled risk of rebleeding in gastric varices treated with cyanoacrylate with ethanolamine
Two studies illustrated treatment with a combination of cyanoacrylate and ethanolamine; Thakeeb et al. (1995)(41) and Maruyama et al. (2010)(42). Thakeeb reported 3 (i.e. risk= 0.052) rebleeding events among gastric variceal patients; and one (risk=0.017) rebleeding events among esophageal varices patients. Maruayama reported 10 (i.e. risk =0.5) rebleeding events among gastric varices patients. Figure 5 illustrates a forest plot of pooled risk, 0.08(0.02-0.14) of rebleeding in gastric varices treated with a combination of cyanoacrylate with ethanolamine.
Pooled risk of rebleeding in gastric varices treated with cyanoacrylate with endoscopic ultrasound guided coils
Two studies illustrated treatment with a combination of cyanoacrylate and coils guided by endoscopic ultrasound; Bhat et al. (2016)(43) and Robles-medranda et al. (2019)(44). Bhat et al. (2016) reported 10 rebleeding events out of 125 gastric varices patients who were followed-up. This corresponds to the risk of 0.08 (Confidence interval: 0.03-0.13). Robles-medranda et al. (2019) reported 1 rebleeding event out of 27 gastric varices patients, which corresponds to the risk of 0.04(Confidence interval: -0.03-0.11). Figure 6 illustrates a forest plot of pooled risk of rebleeding in gastric varices treated with cyanoacrylate with endoscopic ultrasound guided coils.
Pooled risk of rebleeding in esophageal varices treated with cyanoacrylate with percutaneous transhepatic variceal embolization
Three studies illustrated treatment with a combination of cyanoacrylate and percutaneous transhepatic variceal embolization in gastroesophageal varices; Zhang et al. (2007)(16) and Zhang et al. (2008)(45) involved esophageal varices patients, and reported rebleeding risks of 0.16(confidence interval: 0.08-0.24) and 0.15 (confidence interval: 0.06-0.25), respectively. Tian et al. (2011)(46) involved gastric varices patients and reported rebleeding risk of 0.10(confidence interval: 0.03-0.17). Figure 7 illustrates a forest plot of pooled risk of rebleeding in esophageal varices treated with cyanoacrylate with percutaneous transhepatic variceal embolization.
Risk of rebleeding in gastroesophageal varices treated with cyanoacrylate with sclerotherapy
Two studies assessed the efficacy of combination of cyanoacrylate and sclerotherapy in the treatment of gastroesophageal varices. In one study, Feretis et al. (1995)(47) compared the combination versus sclerotherapy alone in the treatment of esophageal varices and reported the risk for rebleeding in the combination group to be 0.12 (Confidence interval: 0.04-0.20). In another one arm study, Dhiman et al.(48)(2002) assessed the outcome of the combination therapy in the treatment of gastric varices and reported a risk of 0.10 (Confidence interval: 0.05-0.18). Forest plot was not constructed as the two studies involved different participants (i.e. gastric and esophageal varices).
Other combination treatments with cyanoacrylate
In their study Shi et al. (2014)(49) compared between transjugular intrahepatic portosystemic shunt alone versus combined with Cyanoacrylate for Esophageal Variceal Bleeding. The combination therapy reduced the rebleeding risk to a third of one observed in transjugular intrahepatic portosystemic shunt alone. That is from 0.19 to 0.06, p-Value of 0.04. In another study, Ma et al. (2018)(50) combined cyanoacrylate with balloon-occluded retrograde transvenous obliteration in 28 patients with gastroesophageal varices and reported a rebleeding risk of 0.31 (confidence interval: 0.13-0.49).
Dai et al. (2017)(51) compared band ligation alone versus in combination with cyanoacrylate in the treatment of gastroesophageal varices. The risk of rebleeding in the combination therapy was reduced to a quarter that recorded in band ligation alone. That is from 0.56 to 0.14, p-Value<0.01. Zeng et al. (2017)(52) compared two combinations; cyanoacrylate plus Polidocanol versus cyanoacrylate plus lipiodol in the treatment of gastric varices. The later showed the risk of rebleeding of 0.13 (Confidence Interval: 0.03-0.22) as compared to 0.10 (Confidence interval: 0.02-0.19) in the polidocanol combination.
Table 2 summarizes risks of rebleeding in gastric and esophageal varices when treated with cyanoacrylate alone or in combination with other treatments as discussed earlier.
Table 2 risks of rebleeding in gastric and esophageal varices when treated with cyanoacrylate alone or in combination with other treatments
Hemostasis treatment type
|
Pooled risk of gastric varices rebleeding (Confidence interval)
|
Pooled risk of esophageal varices rebleeding (confidence interval)
|
Cyanoacrylate alone
|
0.16 (0.13-0.18)
|
0.29 (0.11-0.47)
|
Cyanoacrylate combined with ethanolamine
|
0.08(0.02-0.14)
|
0.02 (-0.02-0.05).
|
Cyanoacrylate combined with endoscopic ultrasound guided coils
|
0.07(0.03-0.11)
|
-
|
Cyanoacrylate combined with percutaneous transhepatic variceal embolization
|
0.10(0.03-0.17) *
|
0.16(0.10-0.22)
|
Cyanoacrylate combined with transjugular intrahepatic portosystemic shunt
|
-
|
0.06(-0.01-0.12) *
|
Cyanoacrylate combined with sclerotherapy
|
0.10 (0.05-0.18) *
|
0.12 (0.04-0.20) *.
|
Cyanoacrylate combined with band ligation
|
-
|
0.10(0.04-0.24) *
|
cyanoacrylate combined with polidocanol
|
0.10 (0.02-0.19) *
|
-
|
cyanoacrylate combined with lipiodol
|
0.13 (0.03-0.22) *
|
-
|
Cyanoacrylate combined with balloon-occluded retrograde transvenous obliteration
|
0.31 (0.13-0.49) **
|
Key: * Calculated from a single study (Not pooled); ** Gastric or esophageal varices not specified (Gastroesophageal)
Note: The values in the table are independently calculated and the table does not mean statistical comparison between them.