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Efficacy of self-assembling peptide in mitigating delayed bleeding after advanced endoscopic resection of gastrointestinal lesions. A meta-analysis

Georg Thieme Verlag KG
Endoscopy International Open
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Abstract and Figures

Background and study aims Advanced endoscopic resection techniques carry a risk of delayed bleeding (DB). A novel fully synthetic self-assembling peptide (SAP) has shown promising results in mitigating this risk. In this meta-analysis, we evaluated all available data and analyzed the effectiveness of SAP in reducing DB after advanced endoscopic resection of gastrointestinal luminal lesions. Patients and methods Electronic databases (PubMed, Embase, and Cochrane Library) from January 2010 through October 2022 were searched for publications addressing the use of SAP solution in patients undergoing advanced endoscopic resection of gastrointestinal lesions. Pooled proportions were calculated using fixed (inverse variance) and random-effects (DerSimonian-Laird) models. Results The initial search identified 277 studies, of which 63 relevant articles were reviewed. The final analysis included data from six studies comprising 307 patients that met inclusion criteria. The pooled rate of DB was 5.73 % (95 % confidence interval [CI] = 3.42–8.59). Mean patient age was 69.40 years ± 1.82. The weighted mean size of resected lesions was 36.20 mm (95 % CI = 33.37–39.02). Endoscopic submucosal dissection was used in 72.69 % (95 % CI = 67.62–77.48), while endoscopic mucosal resection was used in 26.42 % (95 % CI = 21.69–31.44) of the procedures. Among the 307 patients, 36 % were on antithrombotic medications. No adverse events (AEs) were attributable to using SAP, with a pooled rate of 0.00 % (95 % CI = 0.00–1.49). Conclusions SAP solution appears promising in reducing post-procedural DB after advanced endoscopic resection of high-risk gastrointestinal lesions with no reported AEs.
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Introduction
Advanced endoscopic resection (ER) is the preferred initial
management for large and often pre-malignant lesions. ER is
also the procedure of choice for curative resection of early-
stage malignant gastrointestinal luminal lesions [1]. Endo-
scopic mucosal resection (EMR) and endoscopic submucosal
dissection (ESD), including hybrid EMRs, and hybrid ESDs, are
the commonly used ER techniques [1]. Despite the high techni-
cal success rates, delayed post-procedural bleeding remains a
complication, with rates of 2 % to 15%, especially in high-risk si-
tuations despite standard prophylactic techniques [2].
Efficacy of self-assembling peptide in mitigating delayed bleeding
after advanced endoscopic resection of gastrointestinal lesions:
A meta-analysis
Authors
Harishankar Gopakumar1,IshaanVohra
1,NeilR.Sharma
2,SrinivasR.Puli
1
Institutions
1 Department of Gastroenterology and Hepatology,
University of Illinois College of Medicine at Peoria,
Peoria, Illinois, United States
2 Parkview Cancer Institute, Interventional Oncology &
Surgical Endoscopy (IOSE) division, GI Oncology Tumor
Site Team, Fort Wayne, Indiana, United States
submitted 27.10.2022
accepted after revision 22.2.2023
accepted manuscript online 17.03.2023
Bibliography
Endosc Int Open 2023; 11: E553E560
DOI 10.1055/a-2057-4505
ISSN 2364-3722
© 2023. The Author(s).
This is an open acce ss article published by Thie me under the terms of the C reative
Commons Attribut ion-NonDerivative-NonCommercial License, permitti ng copying
and reproducti on so long as the origin al work is given appropriate credit . Contents
may not be used for comme rcial purposes, or adapted, remixed , transformed or
built upon. (http s://creativecommons.org/licens es/by-nc-nd/4. 0/)
Georg Thieme Verlag KG, Rüdigerstraße 14,
70469 Stuttgart, Germany
Corresponding author
Harishankar Gopakumar, MD, FACP, Department of
Gastroenterology and Hepatology, 530 NE Glen Oak Ave,
Peoria, IL USA 61637, United States
Fax: +1-312-872-8570
harishankar.gopakumar@oshealthcare.org
hgopakumarmd@gmail.com
ABSTRACT
Background and study aims Advanced endoscopic re-
section techniques carry a risk of delayed bleeding (DB). A
novel fully synthetic self-assembling peptide (SAP) has
shown promising results in mitigating this risk. In this
meta-analysis, we evaluated all available data and analyzed
the effectiveness of SAP in reducing DB after advanced
endoscopic resection of gastrointestinal luminal lesions.
Patients and methods Electronic databases (PubMed,
Embase, and Cochrane Library) from January 2010 through
October 2022 were searched for publications addressing
the use of SAP solution in patients undergoing advanced
endoscopic resection of gastrointestinal lesions. Pooled
proportions were calculated using fixed (inverse variance)
and random-effects (DerSimonian-Laird) models.
Results The initial search identified 277 studies, of which
63 relevant articles were reviewed. The final analysis includ-
ed data from six studies comprising 307 patients that met
inclusion criteria. The pooled rate of DB was 5.73% (95 %
confidence inter val [CI]= 3.428.59). Mean patient age
was 69.40 years ± 1.82. The weighted mean size of resected
lesions was 36.20 mm (95% CI= 33.3739.02). Endoscopic
submucosal dissection was used in 72.69 % (95 % CI =
67.6277.48), while endoscopic mucosal resection was
used in 26.42 % (95 % CI= 21.6931.44) of the procedures.
Among the 307 patients, 36 % were on antithrombotic
medications. No adverse events (AEs) were attributable to
using SAP, with a pooled rate of 0.00% (95% CI = 0.00
1.49).
Conclusions SAP solution appears promising in reducing
post-procedural DB after advanced endoscopic resection
of high-risk gastrointestinal lesions with no reported AEs.
Original article
Gopakumar Harishankar et al. Efficacy of self-assemblingEndosc Int Open 2023; 11: E553E560 | © 2023. The Author(s). E553
Accepted Manuscript online: 2023-03-17 Article published online: 2023-05-26
Delayed bleeding (DB) can manifest as overt bleeding with
hematemesis, hematochezia, melena, hemodynamic instabil-
ity, or a 2-g drop in hemoglobin after the first 24 hours [1]. Ma-
jor risk factors for DB include the resection site, resected lesion
size, and antiplatelet, anticoagulant, or nonsteroidal anti-in-
flammatory drug use [3, 4]. Success with techniques employed
to reduce DB, such as prophylactic clipping and coagulation,
have been suboptimal and have shown varied results. For exam-
ple, Nishizawa et al. did not find a significant reduction in DB
with prophylactic clipping [5], while Pohl et al. [6] noted a de-
crease from 7.10 % to 3.50 %. A large randomized controlled
trial (RCT) by Feagins et al. found no difference in the rate of
post-procedural DB after ER of large colon polyps treated pro-
phylactically with hemostatic clips [7]. Moreover, achieving
adequate hemostasis with clips can be challenging even in ex-
perienced hands, depending on the site of ER [7]. On the other
hand, electrocoagulation has the potential for thermal injury
and can also distort the resection base. Topical hemostatic
spray powders, due to their opaque nature, will obscure the re-
section field and are not ideal in the setting of ER. Their effects
are also relatively short-lived and less likely to reduce DB. Post-
ER DB can often be significant, requiring hospital admission,
blood transfusions, and repeat procedures.
The use of a self-assembling peptide (SAP), RADA 16, has
been reported in recent years as a hemostatic tool with good
results across various indications. It is a synthetic 16-amino
acid, non-biogenic, biocompatible resorbable peptide that ex-
ists as a viscous solution in an acidic environment. When ex-
posed to the physiological pH of blood, interstitial fluid, or
lymph, the RADA 16 nanofibers spontaneously crosslink within
seconds to form a transparent, stable 3-dimensional (3D) hy-
drogel [8]. This property has enabled its use as a hemostatic
agent. The nanofiber hydrogel structure also closely resembles
the 3 D structure of extracellular matrices, and this property has
been hypothesized to augment wound healing. Its shear-thin-
ning and thixotropic properties allow the product to be deliv-
ered to the bleeding site through narrow endoscopic catheters.
Its viscous form will enable it to flow and conform to the tissue
surface's peaks and troughs. Being transparent, it also does not
obscure the view of the resection field [8]. Moreover, it does
not alter the surgical site anatomy, as can happen with clips
and coagulation. These properties position RADA 16 as a un-
ique tool for controlling intraprocedure and post-procedure
bleeding associated with advanced ER. Recently a commercial
formulation of RADA 16 (PuraStat; 3D Matrix Ltd, France) has
been approved by the US Food and Drug Administration for
mild and moderate bleeding post-ESD or EMR, as an adjunct,
bridge, prophylactic, or rescue therapy for intraprocedure ve-
nous bleeding or prophylactic treatment to prevent post-pro-
cedure bleeding. In one of the first studies evaluating the use
of SAP in post-ER bleeding, Yoshida et al. reported that it was
remarkably effectivein 92% of patients who underwent gas-
tric ESDs [9]. More extensive and well-devised studies have sub-
sequently evaluated the efficacy, safety, and feasibility of SAP in
this setting [1014]. SAP as a hemostatic agent during ER is
considered safe with no adverse events (AEs) related to its use.
However, hypersensitivity, pain related to the application of
SAP, and thromboembolic events have been proposed as po-
tential complications [9]. We conducted this systematic review
of literature and performed a meta-analysis to evaluate the ef-
ficacy and feasibility of this novel agent in the prophylaxis of
post-procedural DB following advanced ER of gastrointestinal
luminal lesions.
Patients and methods
Search methodology
A literature search was conducted using the electronic data-
base engines MEDLINE through PubMed, Ovid, Cochrane Li-
brary (Cochrane Central Register of Controlled Trials and Co-
chrane Database of Meta-Analysis), EMBASE, ACP journal club,
Database of Abstracts of Reviews of Effects (DARE) according
to the Preferred Reporting Items for Systematic Reviews and
Meta-Analysis (PRISMA) guidelines from January 2010 through
October 2022 to identify studies addressing the use of this no-
vel SAP, otherwise known as RADA 16 and commercially avail-
able as PuraStat in the prevention of DB after advanced ER. Key-
words used were EMR, ESD, ER, PuraStat, PuraMatrix, RADA 16,
SAP, and gastrointestinal bleeding. The retrieved studies were
carefully examined to exclude potential duplicates or overlap-
ping data. An additional literature search was also performed
to screen for relevant studies found in the reference list of re-
viewed studies.
Study eligibility
Published studies were eligible if they reported using novel SAP,
RADA 16 or PuraStat, to prevent or reduce the risk of DB follow-
ing advanced ER. Articles were excluded if they were not in the
English language. Studies in animal models, editorials, ab-
stracts with incomplete data, case reports, case series with
less than ten patients, and comments were excluded. Studies
evaluating the use of SAP for other indications, including man-
agement of acute bleeding, were also excluded. Six studies
matched the study criteria and two authors reviewed full-text
articles independently (HG, IV). Differences were resolved by
mutual agreement or review by a third author (SP).
Data extraction and quality assessment
The following data were independently abstracted by two au-
thors (HG, SP) into a standardized form: Study characteristics
(primary author, period of study, year of publication, and coun-
try of the population studied), study design, baseline charac-
teristics of the study population (number of patients enrolled,
participant demographics), and intervention details. The quali-
ty of included studies was assessed using a modified version of
the Newcastle-Ottawa Scale based on three broad components
for the included non-randomized studies and the Jadad scale
for the one RCT. Quality was graded as high if the total score
was 6 from a maximum possible score of 8. Discrepancies
were resolved by consensus. Differences were resolved by dis-
cussion.
E554 Gopakumar Harishankar et al. Efficacy of self-assemblingEndosc Int Open 2023; 11: E553E 560 | © 2023. The Author(s).
Original article
Outcomes evaluated
The primary outcome evaluated was the efficacy of this novel
SAP in preventing post-procedure DB after advanced ER of gas-
trointestinal luminal lesions. Secondary outcomes assessed
were the rate of DB based on the location of ER, AE rates, and
the endoscopist reported ease of use of this hemostatic prod-
uct. An AE was defined as any allergic reaction or hypersensitiv-
ity, pain, thromboembolic events, or any other unintended
events with an untoward outcome ascribed to the use of SAP
by the authors of the included studies.
Statistical analysis
Meta-analysis was performed by calculating pooled propor-
tions. Individual study proportions were transformed into a
quantity using the Freeman-Turkey variant of the arcsine
square-root transformed proportion. The pooled proportion is
calculated as the back-transform of the weighted mean of the
transformed proportions, using inverse arcsine variance
weights for the fixed-effects model and DerSimonian-Laird
method for the random-effects model. The heterogeneity of
the studies was evaluated by calculating the I2statistic. I2values
of 0 % to 39 % were considered non-significant heterogeneit y,
40 % to 75 % moderate heterogeneity, and 76% to 100% consid-
erable heterogeneity. P>0.10 rejects the null hypothesis that
the studies are heterogeneous. The findings of this meta-analy-
sisarereportedusingthefixed-effectsmodel,astherewasno
statistically significant heterogeneity. Forest plots were drawn
to show the point estimates in each study in relation to the
summary of pooled estimate. The width of point estimates in
the Forest plots indicates the assigned weight to that study.
The effects of publication and selection bias on the summary
estimates were tested by the Egger bias indicator and Begg-Ma-
zumdar bias indicator. Funnel plots were constructed to assess
potential publication bias. Microsoft Excel 19 was the software
used to perform the statistical calculations for this meta-analy-
sis.
Results
Study characteristics and quality
The initial search identified 277 articles, of which 63 relevant
studies were reviewed. Six studies [914] that met the inclu-
sion criterion, comprising 307 patients, were included in the
final analysis. These 307 patients underwent a total of 322
advanced ER procedures. Mean patient age was 69.40 ± 1.82
years. The pooled mean size of resected lesions was 36.20mm
(95 % CI = 33.3739.02). ESD or hybrid ESD was used in 72.69%
(95 % CI = 67.6277.48) of procedures, while EMR or hybrid EMR
was used in the other 26.42 % (95 % CI = 21.6931.44). Charac-
teristics of included studies and patient demographics are
shown in Table 1. PRISMA describing the details of the review
process are shown in Fig. 1. The quality of included studies
was good as evaluated using Newcastle-Ottawa and Jadad
scales shown in Table 2 and Table 3,respectively.Allthe
pooled estimates given are estimates calculated by the fixed-
effects model. The estimates calculated using fixed and ran-
dom-effects models were similar.
Primary and secondary outcomes
The overall pooled DB rate post-ER was 5.73 % (95 % CI = 3.42
8.59). There was no significant heterogeneity, with an I2score
of 36.20 % (95% CI = 0.00 73.70). Forest plot showing individ-
ual study estimates and the pooled estimate for DB rate is
shown in Fig. 2. The Begg-Mazumdar bias indicator gave a
Kendall's tau b value of 0.6 (P=0.13), suggesting no publication
bias. Funnel plot on publication bias is shown in Fig.3. None
of the reported AEs were attributable to the use of SAP. Hence,
the pooled AE rate attributable to using a SAP for managing DB
after ER was 0.00% (95 % CI =0.001.40). A forest plot showing
individual study estimates and the pooled estimate for AE rate
is shown in Fig. 4. The rate of DB based on the location of ER
was analyzed and showed a pooled rate of 5.64% (95 % CI =
2.0210.92) for esophageal ER, 4.15% (95 % CI = 0.3711.69)
for gastric ER, 10.62 % (95 %f CI = 2.5423.31) for duodenal ER
and 5.07 % (95 % CI = 1.0011.99) for colorectal ERs. Forest
plots of individual study estimates and the pooled estimates
for DB based on location are shown in Fig. 5, Fig. 6, Fig.
7,andFig. 8. All studies reported that SAP was easy to apply
with complete coverage of the resection base and did not add
significantly to total procedure time.
Discussion
Advanced ER techniques are the first-line minimally invasive
method for treating large and early neoplastic gastrointestinal
luminal lesions. These include EMR, ESD, hybrid EMRs, and hy-
brid ESDs. Choosing the ideal method depends on lesion size,
location, pathology, and available expertise [1]. Intraprocedur-
al and DB are complications associated with advanced ER pro-
cedures. These can often be severe, requiring hospital admis-
sions, blood transfusions, and the need for repeat endoscopy
or other interventions to treat the bleeding. Our study shows
that RADA 16 effectively mitigates the risk of post-ER delayed
bleeding across a spectrum of techniques and locations with a
pooled DB rate of 5.70%. There were no reported AEs attributa-
ble to the use of this product in the control of DB. These results
are comparable and better than other modalities used pre-
viously to prevent DB after advanced ER [57, 15].
The risk for DB is affected by multiple factors such as the
choice of ER technique, periprocedure exposure to antithrom-
botic medications, lesion size, and location [3,4]. This pooled
analysis included patients who underwent different advanced
ER procedures, including EMRs, ESDs, hybrid EMRs, and hybrid
ESDs. ESD or hybrid ESD was used in about 73%, while EMR or
hybrid EMR was used in 26 % of the procedures. Hence the find-
ings from this study can be applied to various standard ad-
vanced ER procedures. However, data were not available to cal-
culate the pooled effect of SAP in reducing the risk of DB based
on ER technique used. DB rates after ER can significantly vary
based on the location of the lesion, with studies reporting rates
ranging from 0 % following esophageal ERs to 20 % following
duodenal EMRs [1619]. We analyzed the rate of DB after pro-
Gopakumar Harishankar et al. Efficacy of self-assemblingEndosc Int Open 2023; 11: E553E560 | © 2023. The Author(s). E555
Table 1 Study details and demographics of patients incl uded in this meta-analysis.
Study, year,
location
Study Design Patients
(lesions)
Females,
n(%)
Age (yr) Mean le-
sion size,
mm (SD)
No.
EMR
No.
ESD
No.
DB
No.lesions based on location (DB, n)
Esopha-
gus
Stom-
ach
Duo-
de-
num
Am-
pulla
Colon
Rec-
tum
Yoshida et al. 2014,
Japan [9]
Single-center case
series
12 (12) NR NR NR NR 12 0 012(0)00 0
Pioche et al. 2016,
France [10]
Retrospective mul-
ticenter
56 (65) 22 (39) Mean 66.90
(SD 11.40)
37.90
(2.20)
22 40 4 8 (2) 22 (0) 10 3 (1) 22 (1)
Uraoka et al. 2016,
Japan [11]
Prospective single-
center
45 (51) 12 (27) Mean 71.90
(SD 8.80)
36.50
(11.30)
0 51 1 NR NR NR NR NR
Subramaniam et al.
2019, United King-
dom [12]
Prospective single-
center
100
(100)
32 (32) Mean 69.30
(SD NR)
36.70
(21.20)
21 79 3 48(1) 11 (2) 10 (0) 0 31 (0)
Subramaniam et al.
2020, United King-
dom [13]
Prospective single-
center RCT
46 (46) 13 (28) Mean 68.60
(SD 10.60)
33.70
(12.10)
046228(1)000 18(1)
Soons et al. 2021,
Netherlands [14]
Prospective single-
center
48 (48) 19 (40) Median
68.50
(55.373.0)
NR 48 0716(1)0 11 (4) 0 17 (2)
EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; DB, delayed bleeding; NR, not reported; SD, standard deviation; RCT, randomized controlled trial.
Table 2 Modified Newcastle-Ottawa scale assessing quality of included non-randomized studies.
Representa-
tiveness of
the exposed
cohort
Selection
of non-
exposed
cohort
Ascertainment
of exposure
Outcome of
interest not
present at
start of study
Comparability Assess-
ment of
outcome
Follow-up
long
enough for
outcome to
occur
Ade-
quacy of
follow-
up
Quality
score
Quality
Yoshida et al. 2014 [9] 1NA 11
NA 111
6High
Pioche et al. 2016 [10] 1NA 11
NA 111
6High
Uraoka et al. 2016 [11] 1NA 11
NA 111
6High
Subramaniam et al. 2019 [12] 1NA 11
NA 111
6High
Soons et al. 2021 [14] 1NA 11
NA 111
6High
NA, not applicable.
1Indicates that the study meets criterion in the respective column. A score of 6 was considered high quality.
E556 Gopakumar Harishankar et al. Efficacy of self-assemblingEndosc Int Open 2023; 11: E553E 560 | © 2023. The Author(s).
Original article
phylactic SAP based on the location of ER and showed a pooled
rate of 5.60 % for esophagus, 4.15 % for gastric, 10.60% for duo-
denal, and 5.07 % for colorectal ERs. DB in the esophagus is con-
sidered rare, with reported rates between 0 % and 0.7 % [16,
17]. However, this can change considerably with periprocedure
antithrombotic use or coexistent conditions such as severe liver
disease. Horie et al. evaluated the role of antithrombotic drug
use on DB after ER of esophageal lesions [20]. They found that
the post-ER bleeding rate was 0.3% in the group without antith-
rombotic drug use, consistent with prior reported rates. DB
rates were 4.5% in the aspirin-continued group and 2.9% in
the aspirin-discontinued group.However, in the group of indi-
viduals on direct oral anticoagulants, the DB rates were much
higher at 13 % [20]. Hence the rate of DB in esophageal ER can
Records identified
through database
searching
(n = 277)
Records screened
(n = 63)
Records identified
through other
sources
(n = 4)
Records excluded
after titel/abstract
review
(n = 45)
Full text articles
assessed for eligibility
(n = 18)
Studies included in qualitative synthesis
(n = 6)
Studies included in quantitative synthesis
(n = 6)
Full text articles
excluded after
Inclusion/Exclusi-
on review
(n = 12)
IdentificationScreeningEligibilityIncluded
Fig. 1 Preferred Reporting Items for Systematic reviews and
Meta-Analysis describing the details of the review process. From:
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, HoffmannTC, Mulrow
CD, et al. The PRISMA 2020 statement: an updated guideline for
reporting systematic reviews. BMJ 2021;372: n71. doi: 10.1136/
bmj.n71 For more information, visit: http://www.prisma-state-
ment.org/
Table3 Jadad Quality assessment tool for randomized control trial
included in this meta-analysis.
Subramaniam
et al. 2020 [13]
Described as randomized11
Described as double-blinded10
Description of withdrawals11
Randomization method described and appro-
priate2
1
Double blinding method described and appro-
priate2
0
Tot al sc ore 3
A total score of 3 or more indicates good qualit y trials
1A study receives a score of 1 for Yes and 0 for No.
2A study receives a score of 0 if no description is given, 1 if the method is
described and appropriate, and 1 if the method is described but inap -
propriate.
Yoshida et al, 0 (0, 0.26)
2014 [9]
Pioche et al, 0.07 (0, 0.17)
2016 [10]
Uraoka et al, 0.02 (0, 0.12)
2016 [11]
Subramaniam et al, 0.3 (0, 0.09)
2019 [12]
Subramaniam et al, 0.04 (0, 0.15)
2020 [13]
Soons et al, 0.15 (0, 0.28)
2021 [14]
Combined 0.06 (0, 0.09)
Proportion meta-analysis plot [fi xed eff ects]
0.00 0.05 0.10 0.15 0.20
Proportion (95 % confi dence intervall)
0.25 0.30
Fig. 2 Forest plot showing individual study rates and the pooled
estimate for DB rate.
–0.10 –0.05 0.05
Proportion
0.00 0.10 0.15 0.20
Standard error
0.02
0.03
0.04
0.05
0.06
007
Fig. 3 Funnel plot of publication bias for DB rate.
Gopakumar Harishankar et al. Efficacy of self-assemblingEndosc Int Open 2023; 11: E553E560 | © 2023. The Author(s). E557
vary widely (0.3 %13 %) depending on periprocedure antith-
rombotic use. Similarly, in a large nationwide multicenter study
evaluating perioperative management of antiplatelet agents
and the risk of post-ESD bleeding in early gastric cancer, Miura
et al. reported that among aspirin users, the continuation
group experienced significant post-ESD bleeding [21]. The
rate of post-ESD bleeding was approximately 10 % to 20 %, irre-
spective of the status of antiplatelet agent administration
among dual antiplatelet therapy users in this study [21]. Other
studies have reported DB rates after gastric ESDs to be between
4% and 9% [2224]. There is wide variability in the reported
Yoshida et al, 0 (0, 0.26)
2014 [9]
Pioche et al, 0 (0, 0.26)
2016 [10]
Uraoka et al, 0 (0, 0.08)
2016 [11]
Subramaniam et al, 0 (0, 0.04)
2019 [12]
Subramaniam et al, 0 (0, 0.08)
2020 [13]
Soons et al, 0 (0, 0.07)
2021 [14]
Combined 0 (0, 0.01)
Proportion meta-analysis plot [fi xed eff ects]
0.00 0.05 0.10 0.15 0.20
Proportion (95 % confi dence interval)
0.25
Fig. 4 Forest plot showing individual study rates and the pooled
estimate for adverse event rate.
Pioche et al, 0.25 (0, 0.65)
2016 [10]
Subramaniam et al, 0.02 (0, 0.11)
2019 [12]
Subramaniam et al, 0.04 (0, 0.18)
2020 [13]
Soons et al, 0.06 (0, 0.30)
2021 [14]
Combined 0.06 (0, 0.11)
Proportion meta-analysis plot [fi xed eff ects]
0.0 0.1 0.2 0.3 0.4
Proportion (95 % confi dence interval)
0.60.5
Fig. 5 Forest plot showing the individual study rates and the
pooled estimate of DB in the esophagus.
Yoshida et al, 0 (0.00, 0.26)
2014 [9]
Pioche et al, 0 (0.00, 0.15)
2016 [10]
Subramaniam 0.18 (0.02, 0.52)
et al, 2019 [12]
Combined 0.06 (0, 0.11)
Proportion meta-analysis plot [fi xed eff ects]
0.0 0.1 0.2 0.3 0.4
Proportion (95 % confi dence interval)
0.5
Fig. 6 Forest plot showing the individual study rates and the
pooled estimate of DB in the stomach.
Pioche et al, 0 (0, 0.31)
2016 [10]
Subramaniam 0 (0, 0.31)
et al, 2019 [12]
Soons et al, 0.36 (0.11, 0.69)
2021 [14]
Combined 0.11 (0, 0.23)
Proportion meta-analysis plot [fi xed eff ects]
0.0 0.1 0.2 0.3 0.4
Proportion (95 % confi dence interval)
0.5 0.6 0.7
Fig. 7 Forest plot showing the individual study rates and the
pooled estimate of DB in the duodenum.
Pioche et al, 0 (0, 0.41)
2016 [10]
Subramaniam et al, 0 (0, 0.21)
2019 [12]
Subramaniam et al, 0. (0, 0.27)
2020 [13]
Soons et al, 0 (0, 0.29)
2021 [14]
Combined 0.05 (0.01, 0.12)
Proportion meta-analysis plot [fi xed eff ects]
0.0 0.05 0.10 0.15 0.25 0.300.20
Proportion (95 % confi dence interval)
0.35 0.40
Fig. 8 Forest plot showing the individual study rates and the
pooled estimate of DB in the colorectum.
E558 Gopakumar Harishankar et al. Efficacy of self-assemblingEndosc Int Open 2023; 11: E553E 560 | © 2023. The Author(s).
Original article
rates of DB following colonic EMRs and colonic ESDs that de-
pend on various factors. Cold snare polypectomy is the recom-
mended ER technique for small colon polyps (<10 mm). Studies
that evaluated the role of EMR for these small colon polyps have
reported very low rates of clinically significant delayed post-
procedure bleeding rates of around 0.5% [25]. However, this in-
creases to about 6% to 7 % with larger polyps and approximately
10 % for polyps > 2 cm in the proximal colon [2628]. Delayed
post-procedure bleeding following colorectal ESDs has been re-
ported to be between 1 % to 5 % in previously reported studies
[2932]. However, most of these studies included only a few
patients on antithrombotic medications, while others included
patients who were treated prophylactically with hemostatic
clips. In a multicenter study evaluating the effect of anticoagu-
lants on DB after colorectal ESDs, Ogiyama et al. described a DB
rate of 17.2% [33]. Duodenal ERs are considered the highest
risk for DB, with reported rates of up to 20 % [18, 19]. In their
single-center prospective cohort study of 48 patients who all
underwent EMR, Soons et al. observed a DB rate of 15.70 % de-
spite prophylactic SAP, which was higher than those reported in
other studies [14]. As the authors of this study pointed out, this
could have been due to the higher proportion of patients ac-
tively on antithrombotic medications at the time of ER, which
is not the standard practice. Other observations were the in-
creased proportion of duodenal EMRs in this study and its in-
herent increased risk for DB [18,19]. This study also had pa-
tients with larger mean lesion size, a known risk factor for DB.
The results of previous studies on SAP and the findings of
this meta-analysis support the use of this novel agent in the
prophylaxis of DB after advanced ER. With the advancement of
ER techniques, various modalities have been evaluated in miti-
gating the risk of DB. These include the use of prophylactic clip-
ping, coagulation, fibrin glue, and the use of topical polysac-
charide hemostats. However, results with these have been sub-
optimal and varied. No significant reduction in the risk of DB
was observed in a meta-analysis evaluating prophylactic clip-
ping for colorectal ESDs [5]. Similarly, no significant difference
in DB was observed with prophylactic endoscopic coagulation
after wide-field EMR of large sessile colon polyps [34]. A recent
RCT of fibrin glue failed to show a preventive effect on overall
post-ESD bleeding in high-risk patients undergoing gastric
ESDs [15].
This meta-analysis had studies that included a significant
proportion of patients on antithrombotic medications (36 %)
and patients with other predictors of DB, such as advanced liver
disease. For example, in the study by Pioche et al., post-ESD
bleeding was observed in a patient with known cirrhosis and
esophageal varices. A lesion size > 30 mm is another well-recog-
nized predictor of DB [2]. The pooled mean size of resected le-
sions in this meta-analysis was about 36mm and, hence, is rep-
resentative of lesions at increased risk for DB due to size. Based
on these observations, this study is a pragmatic, real-world re-
presentation of patients at increased risk for DB after advanced
ER of gastrointestinal lesions. Another common observation
made by the authors of all the studies included in this meta-a-
nalysis was the transparent nature of the SAP agent, which al-
lows visibility for ongoing resections, and the lack of alteration
of the resection base. These properties of SAP offer a distinct
advantage for real-time useduring complex resections such
as ESD compared to closure devices or coagulation. SAP as a he-
mostatic is not limited to ER of gastrointestinal luminal lesions.
There have also been studies evaluating the utility of SAP as a
hemostatic across other indications like cardiac and aortic sur-
geries [35], liver surgeries [36] and functional endoscopic sinus
surgery [37]. These further emphasize the evolving role of this
novel agent in the area of hemostasis. To our knowledge, this is
the first systematic review and meta-analysis evaluating the ef-
ficacy of SAP in reducing the risk of DB after advanced ER of gas-
trointestinal luminal lesions.
There are a few limitations to this study. All the studies avail-
able had relatively small sample sizes, with the largest study
having 100 patients. The definition of DB varied slightly across
the studies, which could impart some heterogeneity in the re-
ported results. However, this was thoroughly reviewed by the
authors to ensure the consistency of the data analyzed. All of
the studies included in this meta-analysis were conducted in
Europe and Asia with different demographic profiles, in high-
volume centers, and were done by experts. Caution must be ex-
ercised in interpreting their results when considering a differ-
ent demographic profile and proceduralist experience. Given
the results of this study and some of the proposed benefits
such as ease of application, augmented wound healing, and
the advantages of being transparent, this novel SAP solution
could have a promising role in the management of post-ER
bleeding. More extensive well-designed prospective RCTs are
needed to establish its true efficacy and potential indications.
Conclusions
The use of a novel SAP solution appears to be promising in re-
ducing the incidence of post-procedural DB after advanced ER
of high-risk gastrointestinal lesions with no reported AEs.
Competing interests
Dr. Sharma is a consultant for Boston Scientific, Medtronic, Steris, and
Olympus.
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Original article
... 6 Especially regarding anticoagulant, a Japanese large-scale randomized control trial (RCT) showed that DBR in CSP with continuous anticoagulant was high at 4.7% (95% CI: 0.2-9.2). 8 PureStat is an absorbent local hemostatic agent for oozing from various organs, and it has been covered by Japanese insurance since 2021 as hemostatic agent for oozing from various gastrointestinal tracts. 9,10 Amino acid peptides aggregate to form peptide nanofibers and hydrogel when in contact with body fluids and hydrogel coats bleeding point for hemostasis. 11 Various reports have demonstrated the efficacy of PuraStat for perioperative bleeding (POB) in esophageal/gastric/duodenal endoscopic mucosal resection (EMR) and CSP, esophageal/gastric/colorectal endoscopic submucosal dissection (ESD), endoscopic papillectomy, and acute upper/lower gastrointestinal bleeding. ...
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Background and Aim A hemostatic gel, PuraStat (3‐D Matrix, Tokyo, Japan), is used for various gastrointestinal hemostasis. In this study, we analyzed the efficacy of PuraStat for perioperative bleeding (POB) and prevention of delayed bleeding (DB) to colorectal cold snare polypectomy (CSP) with continuous anticoagulant. Methods This was a single‐center, retrospective study. Subjects were lesions of 2–9 mm under continuous anticoagulant from 2021 to 2023 and treated with PuraStat for POB. The definition of POB was bleeding which did not stop spontaneously by 1.0–1.5 min after resection and needed hemostasis. Successful hemostasis was defined as cessation of bleeding within 1.0–1.5 min after spraying PuraStat and the rate of it and risk factors of POB were analyzed. For comparison, cases receiving previous CSP without PuraStat were extracted from all cases with CSP (2018‐2021), and POB and DB rate (DBR) were analyzed after propensity score matching. Results One hundred twenty‐two lesions (91: direct oral anticoagulant (DOAC), 31: warfarin) with anticoagulant were analyzed and the rate of successful hemostasis with PuraStat was 92.6% (DOAC/warfarin: 93.4%/80.6%, P = 0.01). The rate of DB was 0.0%. Multivariate analysis showed that significant risk factors about unsuccessful hemostasis for POB with PuraStat were lesion size 8–9 mm ( P < 0.01), warfarin ( P = 0.01), and combination of antiplatelet ( P = 0.01). Regarding the comparison about CSP with/without PuraStat, the clipping rate and DBR were 8.5%/94.9% ( P < 0.01) and 0%/1.7% ( P = 1.0). Conclusion The effects of PuraStat for POB and DB in colorectal CSP with continuous anticoagulant were acceptable.
... ESD resulted in maximal technical and clinical success with 100% en bloc resection with negative margins and the lowest recurrence rate; however, this was associated with a higher rate of adverse events, including bleeding and perforation [46]. Risk of delayed bleeding after endoscopic resection can be reduced by prophylactic clip closure, including over-the-scope-clip or newer methods like applying hemostatic agents like gels and powders [47][48][49]. Tran et al. found no difference in survival between EMR and SR among 104 patients with d-NENs 1-2 cm. Endoscopic full-thickness resection (EFTR) with laparoscopic assistance is another technique that has been described for managing d-NENs with excellent results, although data are limited at this time [50]. ...
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Background and aims: Data about the detail of post-endoscopic submucosal dissection (ESD) bleeding in patients with early gastric cancer (EGC) who take antiplatelet agents (APAs), particularly in those taking thienopyridine and cilostazol, are lacking. We aimed to clarify the association between the status of APA medication and post-ESD bleeding risk. Methods: This study is a secondary analysis using data from a recently conducted nationwide multicenter study in Japan. We retrospectively reviewed patients treated with APAs or on no antithrombotic therapy recruited from 33 institutions who underwent ESD for EGC between November 2013 and October 2016. The primary outcome of this study was the relationship between the rate of post-ESD bleeding and the status of each APA medication. Results: A total of 9736 patients were included in the analysis. Among aspirin users (n=665), the continuation group was significantly associated with post-ESD bleeding (odds ratio [OR], 2.79; 95% confidence interval (CI), 1.77-4.37). Among thienopyridine users (n=227), the aspirin or cilostazol replacement group was not significantly associated with post-ESD bleeding (OR, 1.85; 95% CI, 0.72-4.78). Among cilostazol users (n=158), there was no significant association with post-ESD bleeding, irrespective of medication status. The rate of post-ESD bleeding was approximately 10-20% irrespective of the status of APA administration among dual antiplatelet therapy users. No patients experienced thromboembolic events in this study. Conclusions: Replacement of thienopyridine with aspirin/cilostazol may be acceptable for minimizing both the risk of post-ESD bleeding and thromboembolism in patients with EGC. In patients on cilostazol monotherapy undergoing ESD, continuation of therapy may be acceptable.
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Introduction: This study evaluated the efficacy of fibrin glue for preventing post-endoscopic submucosal dissection (ESD) bleeding in high-risk patients for bleeding (expected iatrogenic ulcer size ≥ 40 mm or receiving antithrombotic therapy). Methods: A multicenter, open-label, randomized controlled trial was performed at four tertiary-medical centers in Korea between July 1, 2020, and June 22, 2022. Patients with gastric neoplasm and a high risk of post-ESD bleeding were enrolled and allocated at 1:1 to a control group (standard ESD) or a fibrin glue group (fibrin glue applied to iatrogenic ulcers after standard ESD). The primary outcome was overall bleeding events within 4 weeks. The secondary outcomes were acute bleeding (within 48 hours post-ESD) and delayed bleeding (48 hours to 4 weeks post-ESD). Results: In total, 254 patients were randomized and 247 patients were included in the modified intention-to-treat population (125 patients in the fibrin glue group, 122 patients in the control group). Overall bleeding events occurred in 12.0% (15/125) of the fibrin glue group and 13.1% (16/122) of the control group (p=0.791). Acute bleeding events were significantly less common in the fibrin glue group than in the control group (1/125 vs. 7/122, p=0.034). Delayed bleeding events occurred in 11.2% (14/125) of the fibrin glue group and 7.3% (9/122) in the control group (p=0.301). Discussion: This trial failed to show a preventive effect of fibrin glue on overall post-ESD bleeding in high-risk patients. However, the secondary outcomes suggest a potential sealing effect of fibrin glue during the acute period.
Article
Background and aim: Whether antithrombotic drugs increase the risk of post-esophageal endoscopic resection bleeding is unknown. This study examined the effect of antithrombotic drugs, aspirin, thienopyridine, direct oral anticoagulants (DOAC), and warfarin, on post-esophageal endoscopic resection bleeding. Methods: We enrolled 957 patients (1,202 esophageal tumors) treated with endoscopic resection and classified them based on antithrombotic drug use as no use, aspirin, thienopyridine, DOAC, and warfarin. Patients using antiplatelet drugs (i.e., aspirin and thienopyridine) were further sub-classified based on their continued or discontinued use before endoscopic resection. The bleeding rates were compared between these groups to assess the effects of antithrombotic drug use and interruption of antiplatelet therapy on post-esophageal endoscopic resection bleeding. Results: The post-endoscopic resection bleeding rate was 0.3% (95% CI, 0.1-1) in the group without antithrombotic drug use, 4.5% (95% CI, 0.1-23) in the aspirin-continued group, 2.9% (95% CI, 0.1-15) in the aspirin-discontinued group, 0% (95% CI, 0-78) in the replaced thienopyridine with aspirin group, 0% (95% CI, 0-26) in the thienopyridine-discontinued group, 13% (95% CI, 1.6-38) in the DOAC group, and 0% (95% CI, 0-45) in the warfarin group. The post-endoscopic resection bleeding rate in the DOAC group was significantly higher than that in the group without antithrombotic drugs (p = 0.003). The post-endoscopic resection bleeding rates did not differ between the other groups. Conclusions: Our results suggest that discontinuing aspirin is not necessary for esophageal endoscopic resection while we must be careful regarding DOAC.
Article
Introduction: Functional endoscopic sinus surgery (FESS) is a treatment option for patients with chronic rhinosinusitis. Bleeding and adhesions are common complications postoperatively. Objective: To assess the effectiveness of PuraStat™ (3-D Matrix Medical Technology Pty Ltd, Melbourne, Australia) for use in FESS to achieve haemostasis and reduce adhesion formation. Materials and methods: A retrospective chart review over four years was performed on 94 patients undergoing FESS by a single surgeon, using PuraStat™ in absence of nasal packing. Results: Twenty-eight patients underwent complete FESS and 66 cases limited FESS most often combined with nasal surgery. Six patients had bleeding postoperatively, of which only four required additional treatment (4.25%). Twenty-three patients (24.47%) required debridement during the follow up, simply performed by suction for 13 or by scissors for 10. No patient required revision surgery for adhesion. Conclusion: PuraStat™ used for the first time in context of FESS seems to be effective in achieving haemostasis, reducing adhesion formation, and avoiding nasal packing in most patients.
Article
Background PuraStat® is a non-bioactive haemostatic agent that has demonstrated efficacy in a number of different surgical procedures. We performed a prospective multi-centre post-market study to evaluate the efficacy and safety of PuraStat® in liver resections performed for metastatic tumors. Methods This was a prospective cohort study. Patients undergoing liver resection for metastatic tumor were screened for eligibility, and included if they were ≥ 18 years old, undergoing open elective liver resection, had normal liver function, and required application of PuraStat® for haemostasis where standard haemostatic techniques were either insufficient or impractical. The primary endpoint was “time to haemostasis” (TTH). Secondary endpoints included blood loss, total postoperative drainage volume, transfusion of blood products, and ease of use. Results Eighty patients were included for analysis in the intention to treat population. 207 bleeding sites were treated with PuraStat. Of these, 190 (91.7%) bleeding sites reached haemostasis after PuraStat® application. Mean TTH (mm:ss) was 1:01 (SD 1:06, range 0:09-6:55). Ease of use of the product was described as either “excellent” or “good” in 78 (98.8%) patients. No serious adverse events were identified. Conclusion This study confirms the safety, efficacy and ease of use of PuraStat® in the management of bleeding in liver surgery.