Introduction
Gastric antral vascular ectasia (GAVE) is characterized by a collection of dilated
submucosal vessels as well as tortuous capillaries within the mucosal layer of the
stomach, typically found within the gastric antrum [1]
[2]. While the exact pathophysiology of GAVE remains less clear, several potential theories
have been proposed: mechanical stress, abnormal antral motility, hypergastrinemia-associated
hormonal imbalances, or vasoactive mediators [1]
[3]
[4]
[5]
[6]. Endoscopically, common findings of GAVE include erythematous or hemorrhagic lesions,
described as having a linear streaking or punctate appearance, leading to the classic
description as watermelon stomach or a honeycomb appearance, respectively [7]
[8]
[9]
[10]. Although GAVE remains a relatively infrequent cause of overt gastrointestinal bleeding,
persistent iron deficiency with transfusion-dependent anemia are not uncommon among
patients with this condition [11]
[12]
[13].
Currently, thermal therapy with argon plasma coagulation (APC) remains a first-line
endoscopic treatment strategy, though emerging data has suggested patients receiving
treatment with radiofrequency ablation (RFA) may have improved outcomes including
improved endoscopic success rates, fewer treatment sessions required, and lower rates
of adverse events [14]
[15]
[16]
[17]
[18]. Most studies have demonstrated APC and RFA to have an endoscopic success rate from
70 % to 90 % overall [18]. However, while these success rates up to 90 % are impressive with thermal therapy,
it is important to highlight that these treatment strategies act mostly upon the mucosal
layer, with limited ability to penetrate to the deeper submucosal layer [19].
Given our current understanding of GAVE, with involvement of both the mucosal and
submucosal layer, it stands to reason that treatment techniques designed to act upon
both gastrointestinal layers may be a more effective strategy [19]. One such treatment strategy, which is already the mainstay treatment for esophageal
varices, is endoscopic band ligation (EBL). This non-thermal endoscopic treatment
options affords the ability to treat dilated submucosal veins in addition to the tortuous
capillaries of the mucosal layer associated with GAVE. Yet, despite this strategy
already being familiar to endoscopists and perhaps mechanistically more plausible
as a treatment modality, there remains limited data and poor adoption of this technique
as both a first-line strategy or salvage therapy.
As such, the primary aim of this study was to perform a structured systematic review
and meta-analysis of all eligible studies to evaluate the effectiveness and safety
of EBL in the treatment of GAVE. Additional aims were to compare clinical outcomes
of EBL versus thermal endoscopic therapies.
Materials and methods
Study design
This study was prospectively submitted in PROSPERO, an international database of prospectively
registered systematic reviews in health and social care. The Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) statement outline and Meta-Analysis
of Observational Studies in Epidemiology (MOOSE) reporting guidelines for reporting
systematic reviews and meta-analyses was used to report findings (Appendix 1 and Appendix 2) [20]
[21].
Literature search
Two authors (TRM and KEH) independently conducted a comprehensive literature review
using a standardized protocol to identify articles that evaluated EBL for the treatment
of GAVE. Systematic searches of PubMed, EMBASE, Web of Science, and the Cochrane Library
databases were performed from inception through September 1, 2020. Literature search
terms included: “gastric antral vascular ectasia (GAVE)” and “endoscopic band ligation
(EBL)”. After preliminary search results were obtained and duplicate articles excluded,
the titles and abstracts of all potentially relevant studies were screened for eligibility.
The reference lists of studies of interest were then manually reviewed to identify
additional references through cross-checking bibliographies of retrieved full-text
papers.
Study selection criteria
Included studies were required to investigate the use of EBL for the treatment of
GAVE. Any retrospective, prospective, or randomized study involving EBL for treatment
of GAVE that reported at least one of the pre-defined outcomes was included. Studies
involving alternative endoscopic, medical, or surgical modalities were not included
in cases where EBL was specifically excluded. A particular study was excluded if deemed
to have insufficient data, as were review articles, editorials, and correspondence
letters that did not report independent data. Case series and reported studies with
< 8 patients were excluded. Only adult patients (age ≥ 18 years) were included with
studies including pediatric populations excluded from this analysis.
All relevant English language articles (both full-text and published abstracts) were
included regardless of year of publication were included. The titles and abstracts
of all potentially relevant studies were screened for eligibility. Two reviewers (TRM
and KEH) independently screened the titles and abstracts of all the articles according
to predefined inclusion and exclusion criteria. Any differences were resolved by mutual
agreement and in consultation with the third reviewer (WWC). In the case of studies
with incomplete information, contact was attempted with the principal authors to obtain
additional data.
Measured outcomes
Multiple outcome measurements were reported in this systematic review and meta-analysis,
including endoscopic success of EBL for the treatment of GAVE, defined as complete
eradication or evidence of endoscopic improvement of GAVE on follow-up endoscopy.
Additional outcomes included clinical success, as measured by average pre- and post-procedure
hemoglobin levels, transfusion and hospitalization requirements before and after procedure,
as well rates of rebleeding. Further measured outcomes of interest included adverse
events and rebleeding-associated mortality rates. Other measured variables abstracted
from the literature included baseline patient characteristics, year of publication,
type of publication (i. e., full manuscript, abstract, comparative, or non-comparative
study), and duration of follow-up.
Statistical analyses
This systematic review and meta-analysis was performed by calculating pooled proportions.
After appropriate studies were identified through systematic review, the individual
study proportion was transformed into a quantity using the Freeman–Tukey variant of
the arcsine square root transformed proportion. Then the pooled proportion was calculated
as the back transform of the weighted mean of the transformed proportions, DerSimonian–Laird
weights for the random effects model [22]
[23]. The pooled rates were estimated using random effects models and presented as point
estimates (rates) with 95 % confidence intervals (CIs) [24]
[25]
[26]. For pre- and post-procedure measurements, pooled or weighted mean difference as
calculated with corresponding 95 % CIs with corresponding Pvalues.
Additional sensitivity analyses were performed for only randomized controlled trial
data (excluding prospective and retrospective studies). Further subgroup analyses
were performed for direct comparator studies to compare outcomes between EBL therapy
versus APC thermal-based treatment. Again, treatment with alternative thermal therapy,
including RFA, was excluded from this study. Mean differences between pre- and post-hemoglobin,
transfusion, and hospitalizations were compared along with odds ratios (ORs) calculated
to compare additional outcomes between treatment modalities. Univariate meta-regression
was also performed to assess measured outcomes for patients with treatment naïve versus
APC-refractory GAVE. All calculated P values were 2-sided, and P < 0.05 was considered statistically significant. Tabular and graphical analyses were
performing using Comprehensive Meta-Analysis software, version 3 (BioStat, Englewood,
New Jersey, United States). Combined weighted proportions were determined by use of
the Stata 15.0 software package (Stata Corp LP, College Station, Texas, United States).
Risk of bias and quality assessment
Risk of bias and quality of observational studies was evaluated using the Newcastle-Ottawa
Quality Assessment Scale and JADAD score for quality of randomized trials [27]
[28]. In this study, high quality was defined as a Newcastle-Ottawa Quality Assessment
Scale score ≥ 4 or a JADAD score ≥ 3. Two authors (TRM and KEH) independently extracted
data and assessed the risk of bias and study quality for each of the articles. Any
disagreements were resolved by discussion and consensus between the two authors or
in consultation with a third author (WCC).
Investigations of heterogeneity and prediction interval
Heterogeneity was assessed for the individual meta-analyses using the chi squared
test and the I
2 statistic [29]. Significant heterogeneity was defined as P < 0.05, with I
2 > 50 % indicating substantial heterogeneity. Further quantification of heterogeneity
was categorized based upon I
2 with values of 25 %, 50 %, and 75 % indicating low, moderate, and high amounts of
heterogeneity, respectively. Given the use of random effects model to estimate average
effect, a 95 % prediction interval was calculated to determine the dispersion of effects
and clearly illustrate heterogeneity in the calculated effect size [30]
[31]
[32].
Publication bias
To assess for publication bias, a funnel plot was created and visually inspected for
asymmetry and quantitatively using Egger regression testing [33]
[34]. The trim and fill method was used to correct for funnel plot asymmetry and provide
an adjusted effect [35]. The classic fail-safe test was also applied to assess risk of bias across studies.
Results
Characteristics of included studies
This systematic review and meta-analysis included a total of 11 studies (n = 393)
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]. A PRISMA flow chart of search results is shown in [Fig. 1]. Of the 393 patients with GAVE, 219 patients underwent treatment with EBL, with
the remaining patients receiving thermal therapy with APC. Eight of the 11 included
studies were comparative in nature (EBL: n = 143 versus APC: n = 174). [Table 1] demonstrates the baseline patient characteristics of included studies. All but two
studies were full-text published manuscripts with the remaining being published abstracts
from annual gastroenterology scientific meetings. Four prospective, randomized controlled
trials, one prospective observational study, and 6 retrospective cohort studies were
included with publication years ranging from 2008 to 2020.
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart
of literature search results.
Table 1
Baseline characteristics of included studies to assess endoscopic band ligation and
argon plasma coagulation for the treatment of gastric antral vascular ectasia.
|
Author
|
Year
|
Country of Study
|
Type of Study
|
Study design
|
No. patients
|
No. males
|
Mean age (years)
|
Follow-up (months)
|
No. treatment sessions
|
Endoscopic success
|
Adverse events
|
Rebleeding
|
Bleeding-associated mortality
|
Risk of bias[1]
|
|
EBL therapy
|
|
Wells et al
|
2008
|
United States
|
Full-Text
|
Retrospective, single-center comparative study vs APC thermal therapy
|
9
|
5
|
68 ± 3
|
10.1 ± 7.5
|
1.89 ± 0.6
|
9/9
|
0/9
|
0/9
|
0/9
|
4.5
|
|
Sato et al
|
2012
|
Japan
|
Full-Text
|
Retrospective, single-center comparative study vs APC Thermal Therapy
|
12
|
6
|
|
14.6
|
3 (2–4)
|
12/12
|
1/12
|
1/12
|
0/12
|
4
|
|
Koehane et al
|
2013
|
Ireland
|
Full-Text
|
Retrospective, single-center comparative study vs APC thermal therapy
|
8
|
2
|
70.4
|
26
|
2.5 (1–5)
|
8/8
|
1/8
|
0/8
|
0/8
|
4
|
|
Abdelhalim et al
|
2014
|
Egypt
|
Full-Text
|
Single-center, randomized controlled trial
|
20
|
9
|
55.65
|
6
|
2.25
|
19/20
|
0/20
|
1/20
|
|
3
|
|
Zepeda-Gomez et al
|
2014
|
Canada
|
Full-Text
|
Prospective, single-center non-comparative study
|
21
|
6
|
65 ± 13
|
10 (2–17)
|
2.28 (1–6)
|
19/21
|
0/21
|
|
|
5
|
|
Elhendawy et al
|
2016
|
Egypt
|
Full-Text
|
Single-center, randomized controlled trial
|
44
|
19
|
51.41 ± 7.54
|
6
|
2.93 ± 0.85
|
|
6/44
|
1/44
|
|
3
|
|
Fabian et al
|
2016
|
Hungary
|
Abstract
|
Retrospective, multicenter comparative study vs APC thermal therapy
|
12
|
|
|
|
1.5
|
|
|
|
|
4
|
|
Abd Al-Waab et al
|
2019
|
Egypt
|
Full-Text
|
Single-center, randomized controlled trial
|
18
|
11
|
65 ± 9
|
6
|
2 (2–3)
|
13/18
|
6/18
|
3/18
|
|
3
|
|
Abdel Ghaffar et al
|
2019
|
Egypt
|
Full-Text
|
Single-center, randomized controlled trial
|
20
|
|
42.5 ± 17.6
|
6
|
1.85 ± 0.81
|
19/20
|
0/20
|
1/20
|
0/20
|
3
|
|
Eccles et al
|
2019
|
Canada
|
Full-Text
|
Retrospective, non-comparative study
|
33
|
9
|
67 (55–77)
|
35.9 (4.0–76.5)
|
3 (2–4)
|
27/33
|
|
|
0/33
|
4.5
|
|
Hasan et al
|
2020
|
Bangladesh
|
Abstract
|
Retrospective, non-comparative study
|
22
|
|
|
22
|
2.8
|
19/20
|
|
3/20
|
0/20
|
4.5
|
|
Thermal therapy
|
|
Wells et al
|
2008
|
United States
|
Full-Text
|
Full – retrospective, comparative study vs thermal therapy
|
13
|
5
|
66 ± 11
|
15.3 ± 13.5
|
4.69 ± 4.69
|
|
1/13
|
7/13
|
0/13
|
4.5
|
|
Sato et al
|
2012
|
Japan
|
Full-Text
|
Full – retrospective, comparative study vs APC thermal therapy
|
22
|
9
|
|
16.6
|
2.3 (1–3)
|
22/22
|
0/22
|
15/22
|
2/22
|
4
|
|
Koehane et al
|
2013
|
Ireland
|
Full-Text
|
Full – retrospective, comparative study vs APC thermal therapy
|
15
|
4
|
75.9
|
26
|
4.1 (1–11)
|
7/15
|
0/15
|
0/15
|
0/15
|
4
|
|
Abdelhalim et al
|
2014
|
Egypt
|
Full-Text
|
Single-center, randomized controlled trial
|
20
|
10
|
57.17
|
6
|
5.5
|
12/20
|
0/20
|
13/20
|
|
3
|
|
Elhendawy et al
|
2016
|
Egypt
|
Full-Text
|
Full – randomized controlled trial
|
44
|
15
|
53.09 ± 7.16
|
6
|
3.48 ± 0.90
|
|
9/44
|
0/44
|
|
3
|
|
Fabian et al
|
2016
|
Hungary
|
Abstract
|
Retrospective, multicenter comparative study vs APC thermal therapy
|
22
|
|
|
|
5.23
|
|
|
|
|
4
|
|
Abd Al-Waab et al
|
2019
|
Egypt
|
Full-Text
|
Single-center, randomized controlled trial
|
18
|
15
|
60 ± 11
|
6
|
2 (2–4)
|
10/18
|
0/18
|
8/18
|
|
3
|
|
Abdel Ghaffar et al
|
2019
|
Egypt
|
Full-Text
|
Single-center, randomized controlled trial
|
20
|
|
42 ± 25.4
|
6
|
4.15 ± 1.22
|
12/20
|
0/20
|
7/20
|
0/20
|
3
|
APC, argon plasma coagulation.
1 Risk of bias and quality of observational studies was evaluated using the Newcastle-Ottawa
Quality Assessment Scale and JADAD score for randomized controlled trials.
Included patient characteristics
Mean age of included patients who underwent EBL was 58.65 ± 8.85 years. Fifty-nine
percent of patients were female. In terms of baseline patient characteristics and
presenting symptoms, 71.97 % of patients carried a diagnosis of cirrhosis. More than
half (57.14 %) of patients presented with evidence of overt bleeding at time of EBL.
Of studies reporting prior therapies, 37.80 % of patients included in this meta-analysis
had refractory GAVE despite prior treatment with APC. The mean follow-up period was
14.32 ± 11.10 months.
Endoscopic success
The outcome of endoscopic success, defined as complete eradication or improvement
in GAVE on follow-up endoscopy, was noted to occur in 87.84 % [(95 % CI, 80.25 to
92.78); I2 = 11.96 %; prediction interval 72.60 to 95.17] ([Fig. 2a]). This was accomplished with a mean number of 2.50 ± 0.49 treatment sessions with
an average of 12.40 ± 3.82 bands applied per treatment session. On sensitivity analysis
limited to randomized trials, endoscopic success was achieved in 88.73 % [(95 % CI,
63.83 to 97.23); I2 = 59.39 %] of patients. Excluding published abstracts, 86.95 % [(95 % CI, 78.58 to
92.37); I2 = 11.99 %] demonstrated treatment success endoscopically. Summary data for endoscopic
and clinical success of EBL for the treatment of GAVE is highlighted in [Table 2].
Fig. 2 a Endoscopic success rate of endoscopic band ligation for the treatment of gastric
antral vascular ectasia. b Change in hemoglobin with of endoscopic band ligation for the treatment of gastric
antral vascular ectasia. c Change in red cell transfusions with endoscopic band ligation for the treatment of
gastric antral vascular ectasia. d Rebleeding-associated hospitalization with endoscopic band ligation for the treatment
of gastric antral vascular ectasia.
Table 2
Cumulative data for endoscopic band ligation and comparison to argon plasma coagulation
for the treatment of gastric antral vascular ectasia.
|
Cumulative data:EBL
|
Comparative data: EBL versus APC
|
P value
|
|
Mean age in years
|
58.65 ± 8.85
(8 studies, n = 173)
|
56.27 ± 8.86 versus 55.88 ± 9.54
(6 studies, n = 132 vs n = 117)
|
0.735
|
|
No. females
|
89 (59.39 %)
(8 studies, n = 165)
|
54.03 % versus 55.46 %
(6 studies, n = 131 vs n = 132)
|
0.824
|
|
No. with cirrhosis
|
113 (71.97 %)
(7 studies, n = 133)
|
86.21 % versus 90.38 %
(5 studies, n = 103 vs n = 117)
|
0.340
|
|
Overt gastrointestinal bleeding
|
76 (59.39 %)
(7 studies, n = 157)
|
75.00 % versus 63.75 %
(5 studies, n = 79 vs n = 03)
|
0.110
|
|
Follow-up in months
|
14.32 ± 11.10
(10 studies, n = 207)
|
8.92 ± 5.38 versus 9.84 ± 6.82
(6 studies, n = 132 vs n = 117)
|
0.212
|
|
No. treatment sessions
|
2.50 ± 0.49
(11 studies, n = 219)
|
2.56 ± 0.81 versus 3.78 ± 1.17
(8 studies, n = 143 vs n = 174)
|
< 0.001
|
|
No. bands applied
|
12.40 ± 3.82
(6 studies, n = 141)
|
–
|
–
|
|
Endoscopic success
|
87.84 %
(95 % CI, 80.25 to 92.78) I2 = 11.96 %
(9 studies, n = 163)
|
OR 6.04 (95 % CI 1.97 to 18.56)
(5 studies, n = 78 vs n = 95)
|
0.002
|
|
Change in hemoglobin
|
2.23 gm/dL
(95 % CI, 1.39 to 3.07) I2 = 91.00 %
(8 studies, n = 173)
|
Mean diff 0.59 (95 % CI 0.17 to 1.00)
(6 studies, n = 119 vs n = 130)
|
0.006
|
|
Change in transfusion requirements
|
–1.63 units
(95 % CI, –2.39 to –0.86) I2 = 89.39 %
(6 studies, n = 108)
|
Mean diff –1.46 (95 % CI –2.80 to –0.12)
(5 studies, n = 75 vs n = 86)
|
0.033
|
|
Change in number of hospitalizations
|
–1.01
(95 % CI, –1.35 to –0.67) I2 = 0.00 %
(3 studies, n = 49)
|
–
|
–
|
|
Adverse events
|
10.90 %
(95 % CI, 5.14 to 21.65) I2 = 38.23 %
(8 studies, n = 152)
|
OR 2.07 (95 % CI, 0.45 to 9.48)
(7 studies, n = 131 vs n = 152)
|
0.347
|
|
Rebleeding events
|
9.00 %
(95 % CI, 5.02 to 15.62)
I2 = 0.00 %
(8 studies, n = 153)
|
OR 0.11 (95 % CI, 0.04 to 0.36)
(7 studies, n = 131 vs n = 152)
|
< 0.001
|
|
Bleeding-associated mortality
|
3.09 %
(95 % CI, 1.00 to 9.16)
I2 = 0.00 %
(6 studies, n = 104)
|
OR 0.33 (95 % CI, 0.02 to 7.40)
(4 studies, n = 49 vs n = 70)
|
0.483
|
EBL, endoscopic band ligation; APC, argon plasma coagulation.
Clinical success
On average, patients required 2.76 ± 2.74 units of red-cell transfusions and were
hospitalized 2.06 ± 0.31 times prior to EBL. Mean pre-procedure hemoglobin values
were 7.66 ± 0.96 gm/dL with an increase in hemoglobin post-EBL of 2.23 gm/dL [(95 %
CI, 1.39 to 3.07); I2 = 91.00 %; P < 0.001] ([Fig. 2b]). The number of transfusions decreased significantly post-EBL [weighted mean difference
–1.63 gm/dL (95 % CI, –2.39 to –0.86); I2 = 89.39 %; P < 0.001] as did bleeding-associated hospitalizations [weighted mean difference –1.01
times (95 % CI, –1.35 to –0.67); I2 = 0.00 %; P < 0.001] ([Fig. 2c] and [Fig. 2 d]). Among randomized controlled trial studies, pooled mean hemoglobin increased 1.48
gm/dL [(95 % CI, 0.40 to 2.56); I2 = 93.00 %; P = 0.007] after treatment with EBL. Further analyses limited to randomized trials,
amplified this decrease in transfusions post-EBL [weighted mean difference –4.28 gm/dL
(95 % CI, –7.22 to –1.34); I2 = 94.57 %; P = 0.004]. Only 2 studies reported hospitalization data pre- and post-EBL, therefore
pooled proportions could not be calculated.
Adverse events and bleeding-associated mortality
Adverse events occurred in 10.90 % [(95 % CI, 5.14 to 21.65); I2 = 38.23 %; prediction interval 1.71 to 46.18] of patients who underwent EBL. All
studies reporting adverse events were full-text manuscripts. Rebleeding post-EBL occurred
in 9.00 % [(95 % CI, 5.02 to 15.62); I2 = 0.00 %; prediction interval 4.33 to 17.78] of patients. Among only randomized controlled
trials, adverse events were reported among 12.59 % [(95 % CI, 4.08 to 32.82); I2 = 62.29 %] of cases. Excluding abstracts, the rebleeding rate was 7.47 % % [(95 %
CI, 3.75 to 14.32); I2 = 0.00 %]. Data limited to randomized studies demonstrated a rebleeding rate of 7.06 %
% [(95 % CI, 2.73 to 17.05); I2 = 23.24 %]. No patients died as a result of rebleeding after treatment with EBL.
EBL versus APC therapy
Comparison between patients who received non-thermal or thermal therapies revealed
no difference in mean age (EBL: 56.27 ± 8.86 versus 55.88 ± 9.54; P = 0.735). There was also no difference in gender between EBL and APC groups (54.03 %
versus 55.46 % female; P = 0.824). Additionally, there was no difference in percentage of patients with underlying
cirrhosis (EBL: 86.21 % versus APC: 90.38 %; P = 0.340) or patients presenting with overt hemorrhage (EBL: 75.00 % versus APC: 63.75 %;
P = 0.110) between the two groups. Mean follow-up was not different for patients who
underwent EBL versus thermal therapy (8.92 ± 5.38 versus 9.84 ± 6.82 months; P = 0.212).
When comparing endoscopic success between EBL versus APC, patients who underwent EBL
had a significantly higher endoscopic success rate [OR 6.04 (95 % CI 1.97 to 18.56;
P = 0.002] ([Fig. 3a]). This was also accomplished with fewer number of endoscopic treatment sessions
(EBL 2.56 ± 0.81 versus APC 3.78 ± 1.17 sessions; P < 0.001). Endoscopic success in randomized studies alone was also higher for EBL
compared to APC [OR 5.35 (95 % CI 1.46 to 19.58; P = 0.011]. Comparison data between EBL versus APC is shown in [Table 2].
Fig. 3 a Endoscopic success: endoscopic band ligation and comparison to argon plasma coagulation
for the treatment of gastric antral vascular ectasia. b Change in hemoglobin: endoscopic band ligation and comparison to argon plasma coagulation
for the treatment of gastric antral vascular ectasia. c Change in red cell transfusions: endoscopic band ligation and comparison to argon
plasma coagulation for the treatment of gastric antral vascular ectasia. d Change in recurrent bleeding: endoscopic band ligation and comparison to argon plasma
coagulation for the treatment of gastric antral vascular ectasia.
Pretreatment hemoglobin was not different between groups (EBL: 7.65 ± 0.88 versus
APC: 7.55 ± 0.77 gm/dL; P = 0.3501); however, EBL was associated with a greater increase in post-procedure
hemoglobin [difference in means 0.59 (95 % CI 0.17 to 1.00; P = 0.006] ([Fig. 3b]). Examination of data from randomized trials, revealed EBL again was associated
with a greater increase in hemoglobin when compared to APC [difference in means 0.35
(95 % CI 0.07 to 0.62; P = 0.0140]. Endoscopic band ligation was also associated with a greater reduction
in transfusions required [difference in means –1.46 (95 % CI – 2.80 to –0.12; P = 0.0330] ([Fig. 3c]). The number of tranfusions required post-EBL was also greater based upon randomized
trial data along [difference in means –2.30 (95 % CI –4.11 to –2.48; P = 0.0130].
There was no significant difference in adverse events between EBL versus APC [OR 2.07
(95 % CI, 0.45 to 9.48); P = 0.347]. Randomized controlled trial adverse events were also not different [OR
2.59 (95 % CI, 0.09 to 72.27); P = 0.576]. With regard to rebleeding, EBL was associated with decreased recurrent
bleeding [OR 0.11 (95 % CI, 0.04 to 0.36); P < 0.001 ([Fig. 3d]). Again, this finding was similar for randomized studies [OR 0.17 (95 % CI, 0.04
to 0.82); P = 0.027]. There was no statistically significant difference found for bleeding-associated
mortality between groups [OR 0.33 (95 % CI, 0.02 to 7.4); P = 0.483].
Treatment-naïve versus APC-refractory GAVE
A total of six studies (n = 127 patients) included patients with prior APC therapy,
of which 48 patients (37.80 %) reported APC-refractory GAVE. Individual reporting
of data from these patients was not possible; however, data from these six studies
were compared to the remaining 5 studies that included only treatment naïve patients.
Based upon univariate meta-regression, there was no difference in endoscopic success
[OR 0.94 (95 % CI 0.26 to 3.46; P = 0.927] between groups (Supplemental Fig. 1). Mean improvement in hemoglobin was not different between treatment naïve and APC-refractory
patients though there was a trend towards more improvement among patients with no
prior treatment [OR 0.29 (95 % CI 0.08 to 1.05; P = 0.060] (Supplemental Fig. 2). Treatment naïve patients did, however, experience a greater reduction in transfusions
compared to patients with APC-refractory GAVE [OR 0.20 (95 % CI 0.04 to 0.96; P = 0.045] (Supplemental Fig. 3). Adverse events were not statistically different between studies that included patients
with and without prior APC therapy [OR 1.60 (95 % CI 0.28 to 9.21)] (Supplemental Fig. 4).
Risk of bias assessment
Quality assessment for each study shown in [Table 1]. Visual inspection of the funnel plot demonstrated that smaller and statistically
insignificant studies appeared to be missing likely due to publication bias ([Fig. 4a]). With the Duval and Tweedie’s trim and fill method, overall endoscopic success
of EBL for the treatment of GAVE was slightly decreased from 87.84 % (95 % CI, 80.25
to 92.78) to 84.55 % (95 % CI 75.80 to 90.53) though this was not statistically significant
due to the presence of overlapping confidence intervals ([Fig. 4b]).
Fig. 4 a Funnel plot of publication bias and egger’s regression test for included studies.
b Duval and Tweedie’s trim and fill method to assess publication bias.
Discussion
While GAVE encompasses approximately 4 % of all upper gastrointestinal, non-variceal
bleeding etiologies, it remains a condition that is difficult to treat and often associated
with profound iron deficiency anemia. Despite thermal therapy with APC being a first-line
treatment strategy, this systematic review and meta-analysis demonstrated EBL is associated
with a higher rate of ectasia eradication, greater increase in post-procedure hemoglobin,
and lower rate of rebleeding. This greater endoscopic success rate was accomplished
with fewer treatment sessions as well, with no difference in adverse events compared
to APC. Based upon these results, EBL appears to be a safe and effective primary and
refractory therapy for the treatment of GAVE.
First described by Rider and colleagues in 1953, GAVE remains a challenging condition
to successful treat, with many patient remaining transfusion dependent despite iron
supplementation [7]. As the precise etiology of GAVE remains uncertain, multiple treatment modalities
have been attempted. While pharmacotherapy has been shown to be ineffective for GAVE,
endoscopic management, most commonly with thermal-based therapies such as APC and,
less commonly, RFA have traditionally been the preferred treatment modality [47]
[48]
[49]
[50]
[51]. Yet, based upon this recent systematic review and meta-analysis, EBL appears to
be an effective therapy for GAVE.
Available evidence has shown endoscopic treatment of GAVE with RFA may have a better
efficacy and tolerability as compared to APC, perhaps due to the difference in thermal
technique [17]
[18]. Application of RFA involves high frequency alternating electrical current delivered
locally to tissue which may provide a more controlled depth of thermal coagulative
necrosis, as compared to APC which is a non-contact technique with more variable depth
of coagulation [50]
[52]. However, given the submucosal involvement of GAVE, it would therefore make sense
that EBL may provide better or equivalent outcomes and improved endoscopic success,
along with fewer treatment sessions required.
These findings, including higher operator-reported endoscopic success, fewer endoscopic
treatment sessions required, lower adverse event rates, and familiarity with the band
ligation device, suggest EBL may be a more cost-effective therapy for patients with
GAVE. However, at this time, there is no cost-effectiveness data to support this claim.
Conventionally, EBL has been considered a salvage therapy, for individuals that may
not response to prior treatment with APC. While 37.80 % of patients included in this
meta-analysis had GAVE that was refractory to APC, a majority of patients received
EBL therapy without prior thermal treatment, perhaps suggesting EBL may be considered
an early treatment option for GAVE. One randomized study of 30 participants is underway
comparing EBL versus APC for treatment of GAVE (NCT01601639) [53]. However, future, higher-powered randomized studies are needed to directly compare
EBL versus APC, as well as RFA among patients with both treatment-naive and refractory
GAVE.
A previous meta-analysis, including a total of five studies (n = 207 patients – EBL:
93 patients vs APC: 114 patients) has recently been published on this topic [54]. While this study included fewer studies and shorter duration of follow-up, these
authors found similar results regarding the effectiveness of EBL vs APC, including
significantly lower transfusion requirements and treatment sessions required to achieve
eradication with no differences in adverse events. However, among EBL and APC patients
with comparable pre-treatment hemoglobin levels, we found EBL to be associated with
a significantly greater increase in post-procedure hemoglobin, different from the
previous meta-analysis and likely a result of greater power associated with our study.
In this current manuscript, we also compared baseline characteristics of EBL and APC
patients and found no differences in age, gender, percentage of patients with cirrhosis,
number with overt gastrointestinal hemorrhage, and duration of follow-up, thereby
improving the interpretability and generalizability of our findings.
In this systematic review and meta-analysis, we performed additional regression analyses
to determine if EBL outcomes differed based upon prior APC therapy. Importantly, based
upon our regression analyses, we found no statistically significant differences in
endoscopic success, change in hemoglobin, or adverse events among studies that included
patients with and without APC-refractory GAVE. It should be noted that there was a
trend toward greater improvement in post-EBL hemoglobin among treatment naïve patients
(P = 0.060) and treatment naïve patients showed a significantly greater reduction in
transfusion requirements compared to APC-refractory patients. Despite this, these
results should be interpreted with some caution given the lack of individualized data
reported and need for dedicated studies to examine this critically important clinical
question.
This systematic review and meta-analysis is not without limitations. Firstly, given
the cumulative nature of this systematic review and meta-analysis, as well as the
variability in type of GAVE and comorbid conditions of patients, it is not surprising
heterogeneity was significant for multiple study outcomes. Unfortunately, regression
analyses could not be performed to identify if factors such as presence or absence
of cirrhosis, acute hemorrhage, type or severity of GAVE (watermelon stomach versus
honeycomb appearance), as well as a nodular or flat appearance may impact treatment
strategies. Furthermore, observational studies were included alongside randomized
trials – introducing the possibility of selection bias and confounding – however,
sensitivity analyses were performed for only randomized controlled studies. Additionally,
significant variability was noted between study authors’ definitions of eradication
and subjective visual evidence of endoscopic improvement (i. e., endoscopic success).
This variability and lack of standardization in outcome underscores the need for a
well-defined clinical or endoscopic grading system; however, objective measures regarding
clinical outcomes such as hemoglobin level, transfusion requirements, and adverse
events were also reported. While a histologic grading system has been established
for GAVE, this is not routinely used in clinical practice and was not reported in
the included studies [55]
[56]. Lastly, it should be emphasized these results are reported as ORs and not as relative
risk, which may overestimate our findings [57].
Despite these limitations, our study has several strengths. Chiefly, this systematic
review and meta-analysis is the first to analyze EBL for the treatment of GAVE, and
directly compares outcomes to APC among a population of patients that are similar.
Additionally, given the familiarity of endoscopists with band ligation for esophageal
variceal treatment, there is a minimal learning curve to expand this treatment to
GAVE. Furthermore, the inclusion of patients with previous APC may actually under-estimate
the true effectiveness of EBL. Lastly, inclusion of endoscopic and clinical outcomes
including hemoglobin, transfusion dependency, as well as number of sessions for treatment
are highly relevant for clinicians and readily translate to real-world clinical practice.
Conclusions
Based upon the results of this systematic review and meta-analysis, EBL is a safe
and effective modality for the treatment of GAVE. Comparing this strategy to traditional
thermal therapy, EBL was associated with a higher endoscopic success rate and improved
clinical success including a greater increase in hemoglobin, reduction in transfusion
dependency, and decreased rate of rebleeding. Ultimately, the endoscopic and clinical
success of EBL suggest an emerging role for the use of this modality in patients with
GAVE.
