
==== Front
Saudi J Gastroenterol
Saudi J Gastroenterol
SJG
Saudi J Gastroenterol
Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association
1319-3767
1998-4049
Wolters Kluwer - Medknow India

38988069
SJG-30-200
10.4103/sjg.sjg_86_24
Systematic Review/Meta-Analysis
The use of cap-mounted clips as a primary hemostatic modality in nonvariceal upper gastrointestinal bleeding: A systematic review and meta-analysis of randomized trials
Alali Ali A. 1
Almadi Majid A. 23
Martel Myriam 4
Barkun Alan N. 35
1 Department of Medicine, Faculty of Medicine, Kuwait University, Jabriyah, Kuwait, Saudi Arabia
2 Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
3 Division of Gastroenterology, The McGill University Health Center, Montreal General Hospital, McGill University, Montreal, Canada
4 Research Institute of the McGill University Health Center, Montreal, Canada
5 Division of Clinical Epidemiology, The McGill University Health Center, Montreal General Hospital, McGill University, Montreal, Canada
Address for correspondence: Dr. Alan N. Barkun, Division of Gastroenterology, The McGill University Health Center, Montreal General Hospital Site, 1650 Cedar Avenue, Room D16.125, Montréal, H3G 1A4, Canadá. E-mail: alan.barkun@muhc.mcgill.ca
Jul-Aug 2024
10 7 2024
30 4 200209
27 2 2024
30 4 2024
18 5 2024
Copyright: © 2024 Saudi Journal of Gastroenterology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Background:

Cap-mounted-clips, especially Over-The-Scope-Clip (OTSC™), are recommended for recurrent nonvariceal upper gastrointestinal bleeding (NVUGIB). There has been recent interest in their use as an initial hemostatic modality. We performed a systematic review of randomized controlled trials (RCTs) assessing cap-mounted clips’ efficacy as a primary hemostatic modality in NVUGIB.

Methods:

A literature search of MEDLINE, EMBASE, and ISI Web of Science databases up to April 2024 identified RCTs comparing cap-mounted clips to standard endoscopic therapy (SET) as a primary hemostatic modality in NVUGIB. The primary endpoint was the composite outcome of further bleeding (persistent or recurrent) at 30 days. Secondary outcomes included persistent bleeding at index endoscopy and 30-day rebleeding, individually. Other pertinent outcomes were also recorded. A meta-analysis was performed to determine pooled risk ratios (RRs), comparing cap-mounted clip to SET. Out of 516 citations, five RCTs (n = 555), all assessing OTSC™, were included.

Results:

The composite outcome of further bleeding was lower with cap-mounted clip versus SET (RR = 0.33 [95% confidence interval {CI}: 0.20–0.54]). There was no difference in persistent bleeding at initial endoscopy (RR = 0.30 [95%CI: 0.07–1.30]), but 30-day rebleeding was lower with cap-mounted clip (RR = 0.38 [95%CI: 0.21–0.70]). There were no differences in other outcomes. Grading of the evidence ranged from very low to moderate, mainly due to risk of bias and imprecision.

Conclusions:

Cap-mounted clips may be an efficacious primary hemostatic modality, associated with a lower further bleeding at 30 days compared to SET in NVUGIB. However, due to limitations in existing evidence, further research must better characterize an optimal subgroup of patients benefiting most from this approach before adopting its routine use.

Cap-mounted clip
clinical trial
esophagogastroduodenoscopy
hemostatics
meta-analysis
over-the-scope clips
==== Body
pmcINTRODUCTION

Nonvariceal upper gastrointestinal bleeding (NVUGIB) represents an important health-care burden, carrying significant morbidity and mortality.[12] The rates of NVUGIB have decreased globally over time,[34] but its associated mortality remains significant owing to affected patients’ increasing age and comorbidities.[56] Conventional endoscopic therapy can fail in achieving hemostasis in approximately 15% of patients, with rebleeding noted in up to 25% following initial successful therapy[7] and resulting in worsened patient outcomes including need for blood transfusions, intensive care unit (ICU) admission, or rescue therapy (radiologic embolization or surgical), as well as increased mortality.[5]

Cap-mounted clips, especially the Over-the-Scope Clip (OTSC™; Ovesco Endoscopy AG, Tübingen, Germany), originally designed for gastrointestinal defect closure, have increasingly been utilized for the management of NVUGIB.[89] Based principally on one landmark randomized clinical trial (RCT),[10] societal guidelines currently recommend cap-mounted clips or more specifically OTSC™ in NVUGIB when managing patients experiencing recurrent bleeding after initial successful endoscopic therapy.[911] Several meta-analyses have concluded that the cap-mounted clips are more effective than standard endoscopic approaches in limiting persistent or rebleeding, but these have included mainly observational, often noncomparative studies,[81213141516] and antedated full publication of many, let alone the largest, RCTs assessing cap-mounted clips as the first-line endoscopic approach.[17] Moreover, most of these meta-analyses amalgamated studies assessing cap-mounted clips as primary or rescue therapy and did not adequately identify important limitations in existing evidence.

Thus, the role of cap-mounted clips as primary hemostatic modality for NVUGIB remains insufficiently characterized, which is why we performed a timely systematic review and meta-analysis addressing this important clinical question.

MATERIALS AND METHODS

Search strategy

A comprehensive literature search was performed, from inception to April 2024 using Ovid MEDLINE, EMBASE, and ISI Web of Science databases, with a sensitive search strategy for identifying controlled trials and a combination of Medical Subject Heading terms and controlled vocabulary to identify studies related to 1) randomized controlled trials and 2) cap-mounted clips [Supplementary Table 1]. Abstracts presented at major gastroenterology conferences (American College of Gastroenterology, Canadian Digestive Disease Week, Digestive Disease Week, United European Gastroenterology Week, Asian Pacific Digestive Week, and European Society of Gastrointestinal Endoscopy Days) in the past 5 years were also hand-searched. Additional relevant studies were identified from cross-referencing and hand-searches of references of retrieved articles. EndNote™ version 20.6 was used as the referencing software.

Validity assessment, data abstraction, and rating of evidence

Two reviewers (AA, MM) evaluated the eligibility of all identified citations independently, with a third reviewer (AB) resolving disagreements. Study quality was assessed using revised risk of bias (ROB 2) as recommended by the Cochrane Handbook[18] with the Risk-Of-Bias VISualization tool to create risk-of-bias plots.[19]

Inclusion and exclusion criteria

RCTs assessing the use of cap-mounted clips including OTSC™ as the primary hemostatic modality in the setting of NVUGIB were considered for inclusion. Only studies with adult populations published in English were included. We excluded cohort studies, case–control studies, case reports, review articles, and nonhuman studies.

Study definitions

“Further bleeding” was defined as the composite outcome made up of persistent bleeding at the conclusion of the index endoscopy and 30-day recurrent bleeding.[1720] “Persistent bleeding” was defined, in turn, as failure to control bleeding at the index endoscopy, while “30-day recurrent bleeding” was defined as evidence of recurrent bleeding in the form of overt gastrointestinal bleeding or a drop in hemoglobin ≥2 g/dL after having initially achieved immediate hemostasis at 30 days.[20]

“Technical success” was defined as the successful application of the assigned intervention during endoscopy without any technical problems (e.g., in the absence of deciding not to apply the cap-mounted clip in a patient having fulfilled the selection criteria, misfiring or dislodgement of the device). Standard endoscopic therapy (SET) includes through-the-scope (TTS) clips, thermal therapy, and injection therapy (e.g., epinephrine) used as monotherapy or in combination.

Outcomes

The primary outcome was the composite endpoint of further bleeding at 30 days as defined above. Secondary outcomes included persistent bleeding and 30-day rebleeding. Other outcomes of interest included 30-day all-cause mortality, 30-day bleeding-related mortality, technical success, adverse events related to application of the assigned treatment, the need for blood transfusions, ICU admission, as well as the need for additional treatments including repeat endoscopic treatment, embolization by interventional radiology, or surgery.

Sensitivity and subgroup analyses

Preplanned sensitivity analyses for the primary and both secondary outcomes included assessments according to the type of lesion (peptic ulcer disease [PUD], other lesions including, and not limited to, anastomotic ulcers, Dieulafoy’s lesions, and gastrointestinal stromal tumors), Forrest classification (Ia, Ib, IIa), size of the lesion, anatomic location of the lesion, and performing a fixed effects model rather than a random effects model (when appropriate).

Statistical analysis

The primary analysis was performed according to an intention-to-treat (ITT) principle, but we also completed a per-protocol (PP) analysis. For each outcome and in every comparison, effect size was calculated as the risk ratio (RR) for categorical variables. The Mantel–Haenszel method for fixed effects model was used to determine corresponding overall effect sizes with confidence intervals (CIs), except when statistical heterogeneity was noted, in which case a random effects model was used according to the DerSimonian and Laird method.[21] Statistical heterogeneity across studies was defined using a Chi-squared test of homogeneity with a 0.10 significance level.[22] Higgins I2 statistic was calculated to quantify the proportion of variation in treatment effects attributable to between-study heterogeneity values of 0%–40%, 30%–60%, 50%–90%, and 75%–100%. These represent low, moderate, substantial, and considerable heterogeneity, respectively. To ensure that zero event trials did not significantly affect calculations of heterogeneity or corresponding P values, a continuity correction was added to each trial with zero events using the reciprocal of the opposite treatment arm size for primary and secondary outcomes.[23] Weighted mean differences were handled as continuous variables using the inverse variance approach for all comparisons. Publication bias was evaluated using funnel plots as well as the Begg-adjusted rank correlation test[24] and the Egger regression asymmetry test.[25] All statistical analyses were done using Revman 5.4 and Meta package in R version 2.13.0 (R Foundation for Statistical Computing, Vienna, Austria, 2008).

Evidence rating

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was adopted to rate the overall quality of evidence.[26] Accordingly, the certainty of evidence for each selected outcome of interest was rated as high, moderate, low, or very low using the GRADEpro GDT software (Evidence Prime Inc., Hamilton, Canada).

RESULTS

Included studies, quality assessment, and publication bias

We initially identified 516 citations. After review, a total of five RCTs were included [Table 1, Figure 1]. No significant heterogeneity was noted for any of the primary and secondary outcomes. The funnel plots, as well as Begg-adjusted rank correlation and Egger regression asymmetry tests did not suggest publication bias for any of the outcomes assessed [Supplementary Figure 1a–c; additional data available upon request]. The Cochrane risk bias tool [Figure 2] revealed high deviations from intended interventions bias for all studies since blinding of endoscopists was not possible and no definition for ascertaining persistent bleeding was set a priori (thus also providing risk of bias across groups when deciding on crossovers). Other sources of high-risk of bias at randomization process included overlap between lack of efficacy and limited generalizability, as evidenced by exclusion of a number of patients who had already fulfilled the formal selection criteria (without considering them treatment failures), thus potentially favoring cap-mounted clips.[1727] Possible cointervention because of varying practices as to injection of epinephrine was allowed across all trials and was more specifically noted in three.[282930] There also existed possible risk of bias in measurement of the outcome in one study that adopted systematic routine second-look endoscopy performance,[30] since this approach is not recommended for all cases by guidelines.[211] The grading of the evidence was found to be “low” for the composite primary outcome of further rebleeding, “very low” for persistent bleeding at initial endoscopy, and “moderate” for 30-day rebleeding due to varying risks of bias and imprecision. Additional grading of the evidence is detailed in Supplementary Table 2.

Table 1 Detailed description of the studies included in the meta-analysis

Study	Intervention Control	Patient population	Lesion type	Stigmata of bleeding	Lesion size	
Jensen et al.,[29] 2021
USA
NCT03065465	OTSC™ (n=25) - 11/3a clip
Standard therapy (n=28)
-TTS hemoclips
- MPEC Crossover not allowed	Severe NVUGIB
No routine second-look endoscopy.
All lesions pre-injected with epinephrine
Enrolled from January 2016 to December 2019	OTSC™
Duodenal ulcer=52%
Gastric ulcer=36%
Anastomotic ulcer=4%
Dieulafoy’s lesion=8%
Standard therapy Duodenal ulcer=39.3%
Gastric ulcer=35.7%
Anastomotic ulcer=14.3%
Dieulafoy’s lesion=10.7%	OTSC™
Forrest Ia=8%
Forrest Ib=8%
Forrest IIa=48%
Forrest IIb=12%
Forrest IIc=24%
Standard therapy Forrest Ia=25%
Forrest Ib=7.1%
Forrest IIa=42.9%
Forrest IIb=14.3%
Forrest IIc=10.7%	OTSC™ <15 mm=52.0%
≥15 mm=48.0%
Standard therapy <15 mm=56.0%
≥15 mm=44.0%	
Meier et al.,[30] 2022
Germany
NCT03331224	OTSC™ (n=48)
- OTSC™ type not prespecified
Crossover: 0.0%
Standard therapy (n=52)
- TTS hemoclips
- Thermal modality
Crossover: 11.5%	Severe NVUGIB
Routine second-look endoscopy (day 3)
Pre-injection with epinephrine optional
Enrolled from September 2017 to February 2021	OTSC™ Peptic ulcer=87.5%
Anastomotic ulcer=6.2%
Dieulafoy’s lesion=4.2%
Reflux esophagitis=2.1%
Mallory–Weiss tear=0%
Standard therapy Peptic ulcer=80.7%
Anastomotic ulcer=5.8%
Dieulafoy’s lesion=5.8%
Reflux esophagitis=5.8%
Mallory–Weiss tear=1.9%	OTSC™
Forrest Ia=12.5%
Forrest Ib=50.0%
Forrest IIa=35.4%
Standard therapy Forrest Ia=17.3%
Forrest Ib=44.2%
Forrest IIa=30.8%	OTSC™
≤20 mm=93.8%
>20 mm=6.2%
Standard therapy ≤20 mm=84.6%
>20 mm=15.4%	
Chan et al.,[28] 2022
Hong Kong
NCT03160911	OTSC™ (n=50) - -OTSC™ type not prespecified
Crossover: 0.0%
Standard therapy (n=50)
- TTS hemoclips
- Thermal modality
Crossover: 11.5%	Severe peptic ulcer
UGIB-included ulcer ≥1.5 cm only
No routine second-look endoscopy
Pre-injection with epinephrine optional
Enrolled from September 2017 to February 2021	OTSC™
Duodenal ulcer=62%
Gastric ulcer=38%
Standard therapy Duodenal ulcer=52%
Gastric ulcer=48%	OTSC™
Forrest Ia=6.0%
Forrest Ib=16.0%
Forrest IIa=78.0%
Standard therapy Forrest Ia=4.0%
Forrest Ib=16.0%
Forrest IIa=80.0%	OTSC™
<15 mm=0%
≥15 mm=100%
Standard therapy <15 mm=0%
≥15 mm=100%	
Lau et al.,[17] 2023
Hong Kong
NCT03216395	OTSC™(n=93) - 11T clip
Crossover: 4.3%
Standard therapy (n=97)
- TTS hemoclips
- Thermal modality
Crossover: 4.1%	Acute NVUGIB
No routine second-look endoscopy
Pre-injection with epinephrine optional in standard therapy group
Enrolled from January 2018 to December 2022	OTSC™
Peptic ulcer=92.5%
Dieulafoy’s lesion=4.3%
Angiodysplasia=0%
Duodenal diverticulum=0%
Gastrointestinal stromal cancer=2.2%
Mallory–Weiss tear=1.1%
Standard therapy Peptic ulcer=89.7%
Dieulafoy’s lesion=4.1%
Angiodysplasia=2.1%
Duodenal diverticulum=1.0%
Gastrointestinal stromal cancer=1.0%
Mallory–Weiss tear=2.1%	OTSC™
Forrest Ia=10.8%
Forrest Ib=23.7%
Forrest IIa=62.4%
Standard therapy Forrest Ia=5.1%
Forrest Ib=30.9%
Forrest IIa=57.7%	OTSC™
(n=86) <10 mm=44.2%
10–20 mm=44.2%
≥20 mm=11.6%
Standard therapy (n=87) <10 mm=47.1%
10–20 mm=42.5%
≥20 mm=10.3%	
Soriani et al.,[31] 2024
Italy
NCT03551262	OTSC™ (n=61)
- OTSC™ type not prespecified
Crossover: 1.6%
Standard therapy (n=51)
- TTS hemoclips
Crossover: 21.6%	Forrest Ia–IIb gastroduodenal peptic ulcer bleeding
No routine second-look endoscopy
Pre-injection with epinephrine optional in standard therapy group
Enrollment from October 2018 to October 2022	OTSC™
Duodenal ulcer=72.1%
Gastric ulcer=27.9%
Standard therapy Duodenal ulcer=78.4%
Gastric ulcer=21.6%	OTSC™
Forrest Ia=4.9%
Forrest Ib=21.3%
Forrest IIa=60.7%
Forrest IIb=13.1%
Standard therapy Forrest Ia=0%
Forrest Ib=23.5%
Forrest IIa=62.8%
Forrest IIa=13.7%	OTSC™
<20 mm=78.7%
≥20 mm=21.3%
Standard therapy <20 mm=72.6%
≥20 mm=27.4%	
MPEC=Multipolar probe thermal coagulation, NVUGIB=Nonvariceal upper gastrointestinal bleeding, OTSC=Over-the-scope-clip, TTS=Through the scope

Figure 1 Preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram. RCT = randomized controlled trial

Figure 2 Cochrane risk of bias

Supplementary Table 2 Grading of the evidence

Certainty assessment	Summary of findings	
		
Participants (studies) follow-up	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Overall certainty of evidence	Study event rates (%)	Relative effect (95% CI)	Anticipated absolute effects	
		
With comparator	With OTSC	Risk with comparator	Risk difference with OTSC	
Further rebleeding	
	
555 (five RCTs)	Very seriousa	Not serious	Not serious	Not serious	None	⨁⨁◯◯Low	58/278 (20.9%)	19/277 (6.9%)	RR 0.33 (0.20–0.54)	209 per 1000	140 fewer per 1000 (from 167 fewer to 75 fewer)	
	
Persistent bleeding	
	
555 (five RCTs)	Very seriousa	Not seriousb	Not serious	Seriousc	None	⨁◯◯◯ Very low	25/278 (9.0%)	6/277 (2.2%)	RR 0.30 (0.07–1.30)	90 per 1000	63 fewer per 1000 (from 84 fewer to 27 more)	
	
Rebleeding (follow-up: 30 days)	
	
543 (five RCTs)	Seriousd	Not serious	Not serious	Not serious	None	⨁⨁⨁◯ Moderate	35/267 (13.1%)	13/276 (4.7%)	RR 0.38 (0.21–0.70)	131 per 1000	81 fewer per 1000 (from 104 fewer to 39 fewer)	
	
Bleeding-related mortality (follow-up: 30 days)	
	
443 (four RCTs)	Seriouse	Not serious	Not serious	Seriousc	None	⨁⨁◯◯ Low	2/227 (0.9%)	0/216 (0.0%)	RR 0.34 (0.04–3.23)	9 per 1000	6 fewer per 1000 (from 8 fewer to 20 more)	
	
Mortality – all cause (follow-up: 30 days)	
	
443 (four RCTs)	Not serious	Not serious	Not serious	Seriousc	None	⨁⨁⨁◯ Moderate	12/227 (5.3%)	7/216 (3.2%)	RR 0.61 (0.25–1.51)	53 per 1000	21 fewer per 1000 (from 40 fewer to 27 more)	
	
Technical success	
	
443 (four RCTs)	Seriousf	Seriousb	Not serious	Not serious	None	⨁⨁◯◯ Low	227/227 (100.0%)	207/216 (95.8%)	RR 0.97 (0.93–1.02)	1000 per 1000	30 fewer per 1000 (from 70 fewer to 20 more)	
aNo definition of immediate hemostasis and lack of efficacy versus limited generalizability. bModerate heterogeneity was noted. cWide CI. dSecond-look endoscopy in Meier et al. eLinkage of patient death reason was not ascertained by independent blinded reviewer. fLack of efficacy versus limited generalizability and no definition in immediate hemostasis. CI=confidence interval, OTSC=Over-the-scope-clip, RCT=Randomized controlled trial, RR=Risk ratio

Patient and study characteristics

Overall, five RCTs (n = 555 patients), all using OTSC™, were included.[1728293031] Two studies limited inclusion to PUD-related bleeding,[2831] while others included a variety of bleeding etiologies. All studies included only ulcers with Ia, Ib, IIa, and IIb lesions, except for Jensen et al.,[29] which also included IIc lesions as the treatment selection was based on endoscopic Doppler probe signal results. Various endoscopic hemostatic tools were utilized in the SET group, including TTS clips, thermal electrocoagulation, and/or injection therapy, either as monotherapy or in combination based on the endoscopist’s preference [Table 1]. Pre-injection with epinephrine was optional before applying a cap-mounted clip, except for one RCT in which all lesions were injected before cap-mounted clip application.[29] Crossovers to the other arm were permitted in all studies but one.[28] The study by Meier et al.[30] allowed for a routine second-look endoscopy on day 3. One trial only included large ulcers above 15 mm in size.[28] Studies used different cutoff sizes for ulcers when reporting their results according to subgroups [Table 1]. The definition of technical success varied, and in many studies, patients were removed from the trial before attempting cap-mounted clip placement because of anatomic considerations that were not part of the explicitly listed population selection criteria, and thus were not considered as failures of technical success.

Primary outcome

The composite primary outcome of further bleeding at 30 days was significantly lower in the cap mounted clip group compared to the SET group (RR = 0.33 [95% CI: 0.20–0.54, I2 = 47%]) in ITT analysis (five RCTs (n = 555)) [Figure 3]. The PP analysis included only three RCTs (n = 343) as two studies did not report detailed follow-up information on patients having failed standard treatment.[3031] Here too, according to the PP approach, the risk of the primary composite endpoint of further bleeding at 30 days remained significantly lower in the cap-mounted clip compared to SET group (RR = 0.24 [95% CI: 0.12–0.51, I2 = 0%]) [Table 2].

Figure 3 (a) Forest plot – further bleeding at 30 days (composite outcome). CI = confidence interval, RR = risk ratio. (b) Forest plot – persistent bleeding. CI = confidence interval, RR = risk ratio. (c) Forest plot – 30-day rebleeding. CI = confidence interval, RR = risk ratio

Table 2 Primary and secondary outcomes

	No. of studies	No. of patients	Risk ratio (95% CI)	P for heterogeneity	I 2	
Primary outcome						
 Further bleeding at 30 days (ITT)	5	555	0.33 (0.20–0.54)	0.11	45%	
 Further bleeding at 30 days (PP)	3	343	0.24 [0.12–0.51]	0.62	0%	
Secondary outcomes						
 Persistent bleeding (ITT)a	5	555	0.30 (0.07–1.30)	0.15	43%	
 Persistent bleeding (PP)a	4	443	0.99 (0.14–7.00)	1.00	0%	
 30-day rebleeding (ITT)	5	555	0.38 [0.21–0.70]	0.73	0%	
Other outcomes:						
 Mortality- all cause (30 days)	5	555	0.52 [0.23–1.15]	0.89	0%	
 Bleeding-related mortality (30 days)	5	555	0.58 [0.12–2.85]	0.98	0%	
 ICU admission	1	100	1.00 [0.21–4.72]	-	-	
 Adverse events related to device	3	355	2.38 (0.36–15.80)	0.73	0%	
 Technical success	4	443	0.97 [0.93–1.02]	0.08	56%	
 Blood transfusion	2	302	0.78 (0.55–1.11)	0.59	0%	
 Additional treatment	4	443	0.57 [0.28–1.18]	0.42	0%	
 IR embolization treatment	4	443	1.57 [0.44–5.60]	0.41	0%	
 Surgical treatment	4	443	1.03 [0.24–4.47]	0.80	0%	
Sensitivity analyses						
 According to the etiology of NVUGIB – PUD						
 Persistent bleeding	4	428	1.06 [1.01–1.11]	<0.01	74%	
 30-day rebleeding	4	428	0.32 [0.15–0.66]	0.54	0%	
 Further bleeding at 30 days	4	428	0.28 [0.10–0.81]	0.05	62%	
According to the etiology of NVUGIB – Forrest Ia						
 Persistent bleeding	1	9	0.99 (0.01–85.62)	-	-	
 30-day rebleeding	1	9	0.38 [0.03–5.39]	-	-	
 Further bleeding at 30 days	2	24	0.30 [0.06–1.63]	0.81	0%	
According to the etiology of NVUGIB – Forrest Ib						
 Persistent bleeding	-	-	-	-	-	
 30-day rebleeding	-	-	-	-	-	
 Further bleeding at 30 days	1	52	0.27 [0.01–5.35]	-	-	
According to the etiology of NVUGIB – Forrest IIa						
 Persistent bleeding	1	24	1.00 (0.02–46.4)	-	-	
 30-day rebleeding	1	24	0.33 [0.04–2.77]	-	-	
 Further bleeding at 30 days	2	138	0.21 [0.06–0.69]	0.62	0%	
According to the etiology of NVUGIB – Forrest IIb						
 Persistent bleeding	1	7	1.01 (0.03–39.28)	-	-	
 30-day rebleeding	1	7	0.25 [0.02–3.86]	-	-	
 Further bleeding at 30 days	1	7	0.25 [0.02–3.86]]	-	-	
According to lesions >10–15 mm						
 Persistent bleeding	-	-	-	-	-	
 30-day rebleeding	-	-	-	-	-	
 Further bleeding at 30 days	2	194	0.39 [0.06–2.66]	0.07	69%	
According to lesions <10–15 mm						
 Persistent bleeding	-	-	-	-	-	
 30-day rebleeding	-	-	-	-	-	
 Further bleeding at 30 days	1	79	0.54 [0.10–2.78]	-	-	
aAll studies with double-zero event. CI=Confidence interval, ICU=Intensive care unit, ITT=Intention to treat, NVUGIB=Nonvariceal upper gastrointestinal bleeding, PP=Per protocol

Secondary outcomes

Thirty-day rebleeding was lower in the cap-mounted clip compared to the SET group in both ITT (RR = 0.38 [95% CI: 0.21–0.70, I2 = 0%]) and PP (RR = 0.16 [95% CI: 0.05–0.53, I2 = 0%]) analyses. However, there was no difference in the risk of persistent bleeding at initial endoscopy when cap-mounted clip was compared to SET in ITT (RR = 0.30 [95% CI: 0.07–1.30, I2 = 51%]) or PP analysis (RR = 0.99 [95% CI: 0.14–7.00, I2 = 0%]) [Table 2].

Other outcomes

No differences were noted in all-cause or bleeding-related mortality at 30 days (RR = 0.52 [95% CI: 0.23–1.15] and RR = 0.58 [95% CI: 0.12–2.85]), respectively. Similarly, none of the other studied outcomes differed significantly between both groups. Detailed results for all are listed in Table 2.

Sensitivity and subgroup analyses

When limiting the analysis of the composite outcome to PUD lesions (four RCTs, n = 428), the risk of the composite primary outcome of further bleeding at 30 days was lower in the cap-mounted clip group, although significant heterogeneity was noted (RR = 0.28 [95% CI: 0.10–0.81, I2 = 62%]). The 30-day rebleeding was also significantly lower among PUD patients in the cap-mounted clip group (RR = 0.32 [95% CI: 0.15–0.66, I2 = 0%]). Persistent bleeding at initial endoscopy was significantly higher in the control group (RR = 1.06 [95% CI: 1.01–1.11), I2 = 74%]) [Table 2]. The only significant difference in any of the remaining sensitivity analyses according to Forrest class or lesion size was that of the primary composite outcome of further bleeding at 30 days among patients with Forrest IIa lesions (RR = 0.21 [95% CI: 0.06–0.69, I2 = 0%]) [Table 2].

DISCUSSION

Five RCTs have been published – all recently – pertaining to the use of cap-mounted clip as the primary hemostatic modality in NVUGIB patients at high risk of adverse events.[1728293031] Results of these trials have been variable with most of the patients,[172930] but not all,[28] identifying superiority of cap-mounted clip compared to SET. Many meta-analyses have already been published on the topic,[81213141516] but up till now, none has assessed sole RCT-derived information as these were lacking at the time. In addition, many assessed cap-mounted clip while amalgamating both rescue and initial therapy indications, while some included non-bleeding indications as well. The most recent of these meta-analyses concluded that cap-mounted clip reduces 30-day rebleeding but has no effect on other important outcomes.[32] However, this study combined the data from RCTs that utilized cap-mounted clip as a primary therapy with a study that used cap-mounted clip as a rescue therapy for recurrent bleeding and did not report the composite outcome “further bleeding” that is suggested by the international consensus conference as an important outcome for gastrointestinal bleeding trials.[20] Another recent meta-analysis by Faggen et al.[33] assessed cap-mounted clip as a primary therapy using RCT data in subgroup analysis, but had a serious methodological flaw by including a commentary of a RCT (Lambin et al.) as a separate study in the analysis, which limits the validity and conclusions of this meta-analysis.[33] In addition, these systematic reviews did not address, or did not identify, the important gaps in the certainty of evidence resulting from important methodological issues present in the existing data. Indeed, these shortcomings impact internal validity, generalizability, and heterogeneity across adopted protocols. All are critical factors in deciding whether and how to adopt this new technology.[1326] Our systematic review and meta-analysis attempts to address such issues in a timely fashion through appropriate and rigorous methodological steps of all published RCTs to date, with the aim of informing practitioners and subsequent societal guidelines as to the efficacy and safety of using cap-mounted clip as a primary hemostatic modality in patients with NVUGIB.

The European Society of Gastrointestinal Endoscopy practice guidelines made a weak recommendation to use the cap-mounted clip as a first-line therapy in select patients with large ulcers (>2 cm),[9] despite the lack of high-quality data to support this recommendation. Among the five RCTs identified, only one focused exclusively on patients with bleeding ulcers over 15 mm and it did not demonstrate a benefit attributable to cap-mounted clip compared to SET, raising uncertainty about any superiority of cap-mounted clip when treating patients with large lesions.[28] The remaining studies included small number of patients with large ulcers, limiting any meaningful analysis of this subgroup. Nevertheless, cap-mounted clips may be more effective in such a high-risk group, but further data is required to support this conclusion in this subgroup. Our summary results support the safety and efficacy of OTSC®, the only cap-mounted-technology used in these trials, as a primary hemostatic modality in NVUGIB, but with a very low to moderate level of certainty, depending on the outcome. As such, important methodological issues need to be discussed, affecting the robustness, including the generalizability of the conclusions that can be drawn from the existing data.

We found, with a low level of certainty, that the risk of the composite outcome of further bleeding at 30 days was significantly less in the cap-mounted clip compared to the SET group (RR = 0.33 [95% CI: 0.20–0.64 in ITT]); an even greater benefit was seen in the PP approach (that could only be calculated using data from three of the five RCTs; RR = 0.24 [95% CI: 0.12–0.51]). The chosen composite outcome measure of further bleeding, defined as persistent bleeding at the conclusion of the index endoscopy, and 30-day recurrent bleeding,[20] which was the primary endpoint of our meta-analysis, has now been recommended for over one decade by expert consensus because it provides a standardized, clinically relevant summary of the hemostatic impact of an endoscopic modality.[20] Sensitivity analysis confirmed significant improvements in the composite outcome of further bleeding at 30 days among patients with Forrest IIa lesions. Furthermore, the use of cap-mounted clip in PUD was also associated with reduced risks of the composite outcome (odds ratio [OR] = 0.28 [95% CI: 0.10–0.81]) and 30-day rebleeding (OR = 0.32 [95% CI: 0.15–0.66]), while the use of conventional endoscopic tools was associated with increased risk of persistent bleeding at the conclusion of index endoscopy (OR = 1.06 [95% CI: 1.01–1.11]). Admittedly, caution must be exercised in interpreting the subgroup analyses results because of the small number of patients included in this subgroup. We could not conclude confidently on the impact of location for PUD (gastric vs. duodenal) because of a paucity of subgroup data present in the published RCTs.

Importantly, when teasing out the two endpoints that make up the composite primary outcome, important differences were found: 30-day rebleeding was significantly lower in the cap-mounted clip group in both ITT and PP analyses; however, no benefits were observed in persistent bleeding (the inability to achieve immediate hemostasis at the initial endoscopy), with a surprising RR of 0.99 (95% CI: 0.14–7.00) in PP analysis. The point estimate of RR is striking even if the CI is wide. These results suggest there remain poorly characterized variables when attempting to apply the cap-mounted clip in an urgent setting; but once positioned successfully, this modality is indeed superior to SET in preventing subsequent rebleeding, as has been suggested.[2728] Further reinforcing this interpretation is the biological plausibility of improved hemostasis when considering the transmural nature of the ligation provided by the cap-mounted clip, and its higher compression force, both potentially resulting in obliteration of the offending submucosal vessel.[34] With regards to persistent bleeding, the observed results may also represent an overestimate. Indeed, the true technical success rate in cap-mounted clip application, unfortunately, could not be reliably assessed, owing to disparate or absent definitions across studies. In the largest trial, patients were removed from the analysis citing anatomic reasons that precluded cap-mounted clip placement, but these had not been prespecified in protocol selection criteria.[1727] To better understand the impact of this issue, a post hoc analysis with a composite endpoint of “failure to successfully apply assigned treatment and further bleeds” was performed by the investigators.[17] This analysis yielded a risk difference of 9.1% that favored cap-mounted clip, but achieved only borderline statistical significance with a 95% CI ranging between 0.004% and 18.3%. An additional unresolved technical question is the prior injection of epinephrine that was performed variably across trials, from routinely to not at all. All these technical considerations are especially important as bleeding after clip misfire is high. Moreover, in situations of persistent bleeding despite cap-mounted clip application, endoscopic salvage may prove challenging due to the presence of the cap-mounted clip, resulting in a high rate of rebleeding often requiring rescue transarterial embolization[28] (especially as removal of the cap-mounted clip could be difficult[17]). In summary, operator expertise is critical in the successful manipulation of the scope with a cap-mounted clip and its proper positioning, especially at the junction of the first and second parts of the duodenum, in the posterior wall of the duodenal bulb, near the fundus or pylorus, and in cases of ulcers with a fibrotic base.[2830] It is worth emphasizing that the RCTs were performed in centers with expertise in managing gastrointestinal bleeding, with some protocols specifying the endoscopists had to be experienced in applying cap-mounted clip.[30] Some even required prior experience with cap-mounted clip in 20 endoscopic hemostatic procedures.[28] Despite this, although two trials reported no technical failures,[2930] two others noted failure rates of 5.4% and 8%[1728] (the latter in patients with large ulcers). Moreover, the risk of perforation or pseudopolyp formation[1729] was noted in 1.7% of patients across two RCTS. The latter applies only to cap-mounted clip and may relate in part to proper patient selection. In summary, important external validity issues surfaced relating to both patient and operator selection that limit the generalizability of the conclusions, especially if considering a routine first-line approach. This important take-home message is critical when aiming to optimize implementation of cap-mounted clip as first line in NVUGIB. Yet it only clearly emerges as a result of our informative meta-analysis that required amalgamation of all available trials, further justifying our work and its timing.

Schmidt et al.[10] reported significantly lower persistent bleeding with cap-mounted clip compared to SET among patients with recurrent peptic ulcer bleeding. Despite these important observations, this study was not included in our analysis since the indication for using cap-mounted clip is different, namely utilizing cap-mounted clip as a primary rather than rescue therapy for upper gastrointestinal bleeding.

There also exist additional methodological limitations that may have affected internal validity of the trials. These include the lack of blinding of endoscopists coupled to the absence of strict criteria to determine immediate hemostasis at the time of the index endoscopy, even if subsequent rebleeding assessment is not expected to be affected by such an operator bias. These, coupled to the adoption of a routine second-look approach in one RCT,[30] may have influenced both the randomization process (with exclusion of possible cap-mounted clip failures as suggested by some[1730]) and any ascertainment of failure of immediate hemostasis with a downstream decision to crossover patients.[172830] Other limitations of the data included high control rates of recurrent bleeding, imbalances in between-group covariates, and failure to meet enrollment targets.[35] Disparities also exist across trials in the measured time intervals when defining rebleeding and in lesional size cutoff categorization.

Limitations of our meta-analysis relate principally to the limited number of patients studied, the available certainty of evidence, as well as an inability to perform a per-patient analysis that could have allowed for partial adjustment of heterogeneity related to differences in patient populations, lesion characteristics, etc., that varied across trial protocols. We also did not aim to review costs of the cap-mounted clip technology, although a cost-effectiveness analysis modeling for cases of medium and high-risk peptic ulcers with Rockall scores ≥4 found that the use of cap-mounted clips as a first-line strategy may be more cost-effective, based on observational data published before any RCT results.[36] In addition, it remains unclear which type of OTSC™ (traumatic vs. atraumatic) is the ideal to manage bleeding, given the different types of clips used in the studies, and whether other types of cap-mounted clips are equally effective (e.g., Padlock Clip®).

In conclusion, cap-mounted clip appears to be an efficacious primary hemostatic modality in patients with NVUGIB, which results in significantly lower risks of the composite measure of further bleeding at 30 days. However, results should be interpreted with caution due to possible observer bias. As this technology becomes more widely adopted, additional concerns that need to be addressed include better characterization of optimal patient selection and ensuring sufficient operator training and expertise. Future trials should confirm anatomic and morphologic lesion characteristics that can most confidently predict successful cap-mounted clip application, even more so in patients likely to fail SET, while carefully assessing not only hemorrhagic, but also safety and cost outcomes.

Financial support and sponsorship

The authors extend their appreciation to the International Scientific Partnership Program ISPP at King Saud University for funding this research work through ISPP-21-156 (1).

Conflicts of interest

There are no conflicts of interest.

Supplementary Figure 1 (a) Funnel plot further bleeding. (b) Funnel plot persistent bleeding. (c) Funnel plot 30-day rebleeding

SUPPLEMENTARY TABLE 1 - SEARCH STRING

EMBASE (Cochrane Highly Sensitive Search Strategy for identifying controlled trials in Embase)1

(Randomized controlled trial/or Controlled clinical study/or random*.ti, ab. or randomization/or intermethod comparison/or placebo.ti, ab. or (compare or compared or comparison).ti. or ((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab. or (open adj label).ti, ab. or ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti, ab. or double blind procedure/or parallel group*1.ti, ab. or (crossover or cross over).ti, ab. or ((assign* or match or matched or allocation) adj5 (alternate or group*1 or intervention*1 or patient*1 or subject*1 or participant*1)).ti, ab. or (assigned or allocated).ti, ab. or (controlled adj7 (study or design or trial)).ti, ab. or (volunteer or volunteers).ti, ab. or human experiment/or trial.ti.) not (((random* adj sampl* adj7 (“cross section*” or questionnaire*1 or survey* or database*1)).ti, ab. not (comparative study/or controlled study/or randomi?ed controlled.ti, ab. or randomly assigned.ti, ab.)) or (Cross-sectional study/not (randomized controlled trial/or controlled clinical study/or controlled study/or randomi?ed controlled.ti, ab. or control group*1.ti, ab.)) or (((case adj control*) and random*) not randomi?ed controlled).ti, ab. or (Systematic review not (trial or study)).ti. or (nonrandom* not random*).ti, ab. or “Random field*”.ti, ab. or (random cluster adj3 sampl*).ti, ab. or ((review.ab. and review.pt.) not trial.ti.) or (“we searched”.ab. and (review.ti. or review.pt.)) or “update review”.ab. or (databases adj4 searched).ab. or ((rat or rats or mouse or mice or swine or porcine or murine or sheep or lambs or pigs or piglets or rabbit or rabbits or cat or cats or dog or dogs or cattle or bovine or monkey or monkeys or trout or marmoset*1).ti. and animal experiment/) or (Animal experiment/not (human experiment/or human/))).

AND over-the-scope-clip.mp. OR OTSC.mp. OR (endoscopic adj2 closure).mp.

Medline (Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE:)1

(randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or randomised.ab. or placebo.ab. or drug therapy.fs. or randomly.ab. or trial.ab. or groups.ab.) not (exp animals/not humans.sh.).

AND (over-the-scope-clip.tw. OR OTSC.tw. OR (endoscopic adj2 closure).tw.).

ISI Web of Science:

(randomized AND controlled trial AND controlled clinical trial).pt. or randomized.ab. or randomised.ab. or placebo.ab. or drug therapy.fs. or randomly.ab. or trial.ab. or groups.ab.) not (exp animals/not humans.sh.).

AND (over-the-scope-clip.tw. OR OTSC.tw. OR (endoscopic adj2 closure).tw.).
==== Refs
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