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 ]. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD),
including hybrid EMRs, and hybrid ESDs, are the commonly used ER techniques [1 ]. Despite the high technical success rates, delayed post-procedural bleeding remains
a complication, with rates of 2 % to 15 %, especially in high-risk situations despite
standard prophylactic techniques [2 ].
Delayed bleeding (DB) can manifest as overt bleeding with hematemesis, hematochezia,
melena, hemodynamic instability, or a 2-g drop in hemoglobin after the first 24 hours
[1 ]. Major risk factors for DB include the resection site, resected lesion size, and
antiplatelet, anticoagulant, or nonsteroidal anti-inflammatory 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 example, Nishizawa
et al. did not find a significant reduction in DB with prophylactic clipping [5 ], while Pohl et al. [6 ] noted a decrease 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 prophylactically with hemostatic clips [7 ]. Moreover, achieving adequate hemostasis with clips can be challenging even in experienced
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 resection 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 exists as a viscous
solution in an acidic environment. When exposed 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 (3 D) hydrogel [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-thinning and
thixotropic properties allow the product to be delivered 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 unique tool for controlling
intraprocedure and post-procedure bleeding associated with advanced ER. Recently a
commercial formulation of RADA 16 (PuraStat; 3 D 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 venous
bleeding or prophylactic treatment to prevent post-procedure bleeding. In one of the
first studies evaluating the use of SAP in post-ER bleeding, Yoshida et al. reported
that it was “remarkably effective” in 92 % of patients who underwent gastric ESDs
[9 ]. More extensive and well-devised studies have subsequently evaluated the efficacy,
safety, and feasibility of SAP in this setting [10 ]
[11 ]
[12 ]
[13 ]
[14 ]. 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 potential complications [9 ]. We conducted this systematic review of literature and performed a meta-analysis
to evaluate the efficacy 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 database engines MEDLINE through
PubMed, Ovid, Cochrane Library (Cochrane Central Register of Controlled Trials and
Cochrane 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 novel SAP, otherwise known as RADA
16 and commercially available as PuraStat in the prevention of DB after advanced ER.
Keywords used were EMR, ESD, ER, PuraStat, PuraMatrix, RADA 16, SAP, and gastrointestinal
bleeding. The retrieved studies were carefully examined to exclude potential duplicates
or overlapping data. An additional literature search was also performed to screen
for relevant studies found in the reference list of reviewed 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 following advanced ER. Articles were excluded
if they were not in the English language. Studies in animal models, editorials, abstracts
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
management 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 authors (HG, SP) into a standardized
form: Study characteristics (primary author, period of study, year of publication,
and country of the population studied), study design, baseline characteristics of
the study population (number of patients enrolled, participant demographics), and
intervention details. The quality 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 discussion.
Outcomes evaluated
The primary outcome evaluated was the efficacy of this novel SAP in preventing post-procedure
DB after advanced ER of gastrointestinal 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 product. An AE was defined as any allergic reaction
or hypersensitivity, 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 proportions. 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 I2
statistic. I2
values of 0 % to 39 % were considered non-significant heterogeneity, 40 % to 75 %
moderate heterogeneity, and 76 % to 100 % considerable heterogeneity. P > 0.10 rejects the null hypothesis that the studies are heterogeneous. The findings
of this meta-analysis are reported using the fixed-effects model, as there was no
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-Mazumdar 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-analysis.
Results
Study characteristics and quality
The initial search identified 277 articles, of which 63 relevant studies were reviewed.
Six studies [9 ]
[10 ]
[11 ]
[12 ]
[13 ]
[14 ] that met the inclusion 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 36.20 mm (95 % CI = 33.37–39.02). ESD or hybrid ESD was used in 72.69 % (95 %
CI = 67.62–77.48) of procedures, while EMR or hybrid EMR was used in the other 26.42 %
(95 % CI = 21.69–31.44). Characteristics 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. All the pooled estimates given are estimates calculated by the fixed-effects
model. The estimates calculated using fixed and random-effects models were similar.
Table 1
Study details and demographics of patients included in this meta-analysis.
Study, year, location
Study Design
Patients (lesions)
Females, n (%)
Age (yr)
Mean lesion size, mm (SD)
No. EMR
No. ESD
No. DB
No. lesions based on location (DB, n)
Esophagus
Stomach
Duodenum
Ampulla
Colon Rectum
Yoshida et al. 2014, Japan [9 ]
Single-center case series
12 (12)
NR
NR
NR
NR
12
0
0
12 (0)
0
0
0
Pioche et al. 2016,
France [10 ]
Retrospective multicenter
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 Kingdom [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 Kingdom [13 ]
Prospective single-center RCT
46 (46)
13 (28)
Mean 68.60 (SD 10.60)
33.70 (12.10)
0
46
2
28 (1)
0
0
0
18 (1)
Soons et al. 2021, Netherlands [14 ]
Prospective single-center
48 (48)
19 (40)
Median 68.50 (55.3–73.0)
NR
48
0
7
16 (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.
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,
Hoffmann TC, 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-statement.org/
Table 2
Modified Newcastle-Ottawa scale assessing quality of included non-randomized studies.
Representativeness of the exposed cohort
Selection of non-exposed cohort
Ascertainment of exposure
Outcome of interest not present at start of study
Comparability
Assessment of outcome
Follow-up long enough for outcome to occur
Adequacy of follow-up
Quality score
Quality
Yoshida et al. 2014 [9 ]
[1 ]
NA
[1 ]
[1 ]
NA
[1 ]
[1 ]
[1 ]
6
High
Pioche et al. 2016 [10 ]
[1 ]
NA
[1 ]
[1 ]
NA
[1 ]
[1 ]
[1 ]
6
High
Uraoka et al. 2016 [11 ]
[1 ]
NA
[1 ]
[1 ]
NA
[1 ]
[1 ]
[1 ]
6
High
Subramaniam et al. 2019 [12 ]
[1 ]
NA
[1 ]
[1 ]
NA
[1 ]
[1 ]
[1 ]
6
High
Soons et al. 2021 [14 ]
[1 ]
NA
[1 ]
[1 ]
NA
[1 ]
[1 ]
[1 ]
6
High
NA, not applicable.
1 Indicates that the study meets criterion in the respective column. A score of 6 was
considered high quality.
Table 3
Jadad Quality assessment tool for randomized control trial included in this meta-analysis.
Subramaniam et al. 2020 [13 ]
Described as randomized[1 ]
1
Described as double-blinded[1 ]
0
Description of withdrawals[1 ]
1
Randomization method described and appropriate[2 ]
1
Double blinding method described and appropriate[2 ]
0
Total score
3
A total score of 3 or more indicates good quality trials
1 A study receives a score of 1 for Yes and 0 for No.
2 A 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 inappropriate.
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 I2 score of 36.20 % (95 % CI = 0.00 – 73.70). Forest plot showing individual 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 = 0.00–1.40).
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 = 2.02–10.92) for esophageal ER, 4.15 % (95 % CI = 0.37–11.69)
for gastric ER, 10.62 % (95 %f CI = 2.54–23.31) for duodenal ER and 5.07 % (95 % CI = 1.00–11.99)
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 ], and [Fig. 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.
Fig. 2 Forest plot showing individual study rates and the pooled estimate for DB rate.
Fig. 3 Funnel plot of publication bias for DB rate.
Fig. 4 Forest plot showing individual study rates and the pooled estimate for adverse event
rate.
Fig. 5 Forest plot showing the individual study rates and the pooled estimate of DB in the
esophagus.
Fig. 6 Forest plot showing the individual study rates and the pooled estimate of DB in the
stomach.
Fig. 7 Forest plot showing the individual study rates and the pooled estimate of DB in the
duodenum.
Fig. 8 Forest plot showing the individual study rates and the pooled estimate of DB in the
colorectum.
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 hybrid ESDs. Choosing the ideal method depends on lesion size, location,
pathology, and available expertise [1 ]. Intraprocedural and DB are complications associated with advanced ER procedures.
These can often be severe, requiring hospital admissions, 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 attributable to the use of this product in the control of DB. These
results are comparable and better than other modalities used previously to prevent
DB after advanced ER [5 ]
[6 ]
[7 ]
[15 ].
The risk for DB is affected by multiple factors such as the choice of ER technique,
periprocedure exposure to antithrombotic 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
findings from this study can be applied to various standard advanced ER procedures.
However, data were not available to calculate 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 [16 ]
[17 ]
[18 ]
[19 ]. We analyzed the rate of DB after prophylactic SAP based on the location of ER and
showed a pooled rate of 5.60 % for esophagus, 4.15 % for gastric, 10.60 % for duodenal,
and 5.07 % for colorectal ERs. DB in the esophagus is considered 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 antithrombotic
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 individuals
on direct oral anticoagulants, the DB rates were much higher at 13 % [20 ]. Hence the rate of DB in esophageal ER can vary widely (0.3 %–13 %) depending on
periprocedure antithrombotic 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 %, irrespective 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 %
[22 ]
[23 ]
[24 ]. There is wide variability in the reported rates of DB following colonic EMRs and
colonic ESDs that depend on various factors. Cold snare polypectomy is the recommended
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 increases to about 6 % to 7 % with larger polyps and approximately
10 % for polyps > 2 cm in the proximal colon [26 ]
[27 ]
[28 ]. Delayed post-procedure bleeding following colorectal ESDs has been reported to
be between 1 % to 5 % in previously reported studies [29 ]
[30 ]
[31 ]
[32 ]. 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 anticoagulants 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 % despite 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 actively on antithrombotic medications at the time of ER, which
is not the standard practice. Other observations were the increased proportion of
duodenal EMRs in this study and its inherent increased risk for DB [18 ]
[19 ]. This study also had patients 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 mitigating the risk of
DB. These include the use of prophylactic clipping, coagulation, fibrin glue, and
the use of topical polysaccharide hemostats. However, results with these have been
suboptimal and varied. No significant reduction in the risk of DB was observed in
a meta-analysis evaluating prophylactic clipping 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-recognized predictor of DB [2 ]. The pooled mean size of resected lesions in this meta-analysis was about 36 mm
and, hence, is representative of lesions at increased risk for DB due to size. Based
on these observations, this study is a pragmatic, real-world representation 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-analysis
was the transparent nature of the SAP agent, which allows visibility for ongoing resections,
and the lack of alteration of the resection base. These properties of SAP offer a
distinct advantage for “real-time use” during complex resections such as ESD compared
to closure devices or coagulation. SAP as a hemostatic 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 surgeries [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 efficacy of SAP in reducing the risk of DB after advanced ER of gastrointestinal
luminal lesions.
There are a few limitations to this study. All the studies available 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
reported 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 exercised in interpreting their
results when considering a different 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 reducing the incidence
of post-procedural DB after advanced ER of high-risk gastrointestinal lesions with
no reported AEs.
