Over-the-scope clips versus standard endoscopic therapy as first-line treatment for bleeding peptic ulcer disease: a systematic review and meta-analysis

Introduction

Peptic ulcer disease (PUD) is a common gastrointestinal condition with a lifetime prevalence of 5–10% and an incidence of 0.1–0.3% in the general population (1). Helicobacter pylori infection and non-steroidal anti-inflammatory drug (NSAID) use are the most common risk factors (2-4). Although PUD overall incidence and associated mortality have declined over the past three decades (3), complications such as bleeding, perforation, and fistula formation still occur in 10–20% of cases (5,6). Among these, bleeding is the most frequent and remains a major cause of non-variceal upper gastrointestinal bleeding (NVUGIB) (2,7). Endoscopic therapy is the cornerstone of NVUGIB management, with options including injection therapy (e.g., epinephrine), thermal coagulation, and mechanical methods like through-the-scope (TTS) clips (8,9). Over-the-scope clips (OTSCs) have emerged as an effective alternative, particularly for patients with high-risk or recurrent bleeding, or those on antithrombotic therapy. While OTSCs have shown promise as rescue therapy, their role as first-line treatment remains unclear. This study aims to evaluate the efficacy of OTSC as a first-line treatment for bleeding PUD compared to standard endoscopic therapy (SET), focusing on outcomes such as primary hemostasis, rebleeding, hospital stay duration, and mortality. We present this article in accordance with the PRISMA reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0011/rc).

Methods

Search strategy and data extraction

A comprehensive literature search was conducted across Embase, Scopus, Web of Science, and MEDLINE databases from inception to March 13, 2026. Boolean operators were used to combine terms related to the intervention and target population. The following search strategy was used (“over the scope clip” OR “over-the-scope clip” OR OTSC OR “OTSC clip”) AND (“peptic ulcer” OR “gastroduodenal ulcer” OR “duodenal ulcer” OR “gastric ulcer”) AND (“bleeding” OR “hemorrhage” OR “haemorrhage” OR “gastrointestinal bleeding” OR “upper gastrointestinal bleeding” OR “NVUGIB” OR “hemostasis”).

The search strategy aimed to identify studies evaluating the use of OTSC in patients with PUD.

This systematic review and meta-analysis was not prospectively registered (e.g., in PROSPERO), as the study protocol was developed internally prior to formal registration. Two independent reviewers performed the literature screening and data extraction using a standardized form. Disagreements were resolved by consensus or through consultation with a third reviewer. Extracted data included study characteristics, patient demographics, intervention details and comparators, and reported outcomes (10,11).

Inclusion criteria and study outcomes

Studies were eligible if they included patients with primary bleeding PUD treated with OTSC versus standard therapy, studies focusing only on recurrent, rebleeding or perforated PUD were excluded. Eligible study designs included randomized controlled trials (RCTs) and observational studies. Exclusion criteria were non-English language publications without adequate translation, conference abstracts without full text, case reports, systematic reviews, editorials, letters, animal studies, or studies not involving human subjects.

The primary outcome was clinical success, which is the absence of bleeding throughout the follow-up period up to 30 days. Secondary outcomes included immediate hemostasis, need for surgery, length of hospital stay, and in-hospital mortality.

Risk of bias assessment

Two reviewers independently assessed the risk of bias. The Cochrane Risk of Bias 2 (ROB 2) tool was used for RCTs, while the Newcastle-Ottawa Scale was applied for observational studies. Any disagreements were resolved through discussion or with a third reviewer. Given the procedural nature of the interventions, blinding of participants and investigators was not feasible, which was considered during risk of bias assessment (12,13).

Statistical analysis

Meta-analysis was conducted using Review Manager (RevMan) version 5.4. Due to expected heterogeneity across study populations and designs, a random-effects model was applied. For dichotomous outcomes, pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated. Continuous variables were summarized using mean differences with corresponding 95% CIs. Statistical significance was set at P<0.05. Heterogeneity was assessed using the I² statistic, with values above 50% indicating substantial heterogeneity per the Cochrane Handbook (14).

Outcome definitions

The following outcomes were defined prior to data extraction:

• Clinical success: resolution of bleeding without the need for additional therapeutic intervention during follow-up.
• Primary success: achievement of immediate and sustained hemostasis following the index endoscopic intervention without early failure.
• Technical success: successful deployment of the OTSC device at the target lesion.
• 7-day rebleeding: clinically significant rebleeding occurring within 7 days post-procedure.
• 30-day rebleeding: recurrence of upper gastrointestinal bleeding after initial hemostasis, defined by clinical signs (e.g., hematemesis, melena, or haemoglobin drop ≥2 g/dL) with endoscopic confirmation from the treated ulcer within 30 days.
• Overall bleeding: any bleeding event occurring during the study follow-up period, irrespective of the specific follow-up duration across included studies.
• Need for re-therapy: requirement for additional endoscopic, radiologic, or surgical intervention following initial treatment.
• Repeat endoscopy: performance of a subsequent endoscopic procedure after the initial intervention.
• Repeat transarterial embolization (TAE): need for arterial embolization for ongoing or recurrent bleeding.
• In-hospital mortality: all-cause mortality occurring during the hospitalization period.
• Total mortality: all-cause mortality during the follow-up period, regardless of hospitalization status.
• Adverse events: any complication or undesired outcome related to endoscopic intervention, e.g., fever or pneumonia or leak.
• Length of hospital stay: number of days from hospital admission to discharge.

Results

Study selection and characteristics

Search results

A total of 521 records were identified (520 from databases, 1 from citation searching). After removing 221 records, 300 studies were screened, with 284 excluded. Sixteen full-text articles were assessed, of which 10 were excluded (9 abstracts, 1 wrong design). Ultimately, 6 studies were included, including 3 RCTs and 3 observational studies (Figure 1).

Figure 1 PRISMA 2020 flow diagram. Of 521 records identified, 6 studies met eligibility criteria and were included in the final analysis (3 randomized controlled trials and 3 observational studies).

Characteristics of included population

The total number of patients was 454, 220 in the OTSC group and 234 in the control group. The mean age in the OTSC group was 67.7 [standard deviation (SD) 15.7] years while the mean age in the control group was 67.9 (SD 13.3) years. The duodenal bulb was the most common site of ulcers in the OTSC group, involving 55.7% of patients, while in the control group, it accounted for 50.7% of ulcers. Active bleeding (Forrest Ia/Ib) was present in 23.1% of patients in the OTSC group and in 19.7% of patients in the control group (Table 1).

Quality of included studies

Among the six studies included, all six had a low risk of bias (Figure 2). All the 3 RCTs had low risk of bias, although some concerns were present due to the absence of blinding the operator or the participants but there was no evidence of an impact on the study’s results (Table S1). Out of the 3 retrospective studies, three had a low risk of bias (Table S2).

Figure 2 Risk of bias assessment of included studies. (A) Domain-level risk of bias evaluation of RCTs using the Cochrane RoB 2. (B) Overall risk of bias summary of observational studies using NOS. NOS, Newcastle-Ottawa Scale; RCT, randomized controlled trial; RoB 2, Risk of Bias 2.

Meta-analysis and included outcomes

Clinical success

Six studies assessed clinical success comparing OTSC with SET. OTSC was associated with significantly higher clinical success (pooled RR =1.16, 95% CI: 1.06–1.27, P=0.002). A total of 205 of 220 patients in the OTSC group achieved clinical success compared with 191 of 242 patients in the standard therapy group. Heterogeneity was low to moderate (I²=33%, P=0.19; Figure S1A, Table 2).

Subgroup analysis of included RCTs showed higher clinical success with OTSC compared with SET (RR =1.22, 95% CI: 1.08–1.39, P=0.002), with low heterogeneity (I²=29%, Figure S1B).

Primary success

Five studies evaluated primary hemostasis. The pooled analysis did not demonstrate a statistically significant difference between OTSC and SET (pooled RR =1.04, 95% CI: 0.97–1.11, P=0.28). Statistical heterogeneity was moderate to substantial (I²=67%, Figure S1C).

Subgroup analysis of RCTs showed no significant difference between OTSC and SET (RR =1.05, 95% CI: 0.92–1.19, P=0.47), with substantial heterogeneity among studies (I²=79%, Figure S1D).

Technical success

Five studies assessed technical success. The pooled analysis showed no statistically significant difference between OTSC and SET (RR =1.02, 95% CI: 0.97–1.07, P=0.42). Heterogeneity was moderate (I²=54%, P=0.07, Figure S1E).

Subgroup analysis of RCTs showed no significant difference between OTSC and SET (RR =1.11, 95% CI: 0.89–1.38, P=0.36), with considerable heterogeneity among studies (I²=86%, Figure S1F).

7-day rebleeding

Three studies reported rebleeding within seven days of treatment. The pooled analysis showed no statistically significant reduction in 7-day rebleeding with OTSC compared with SET (RR =0.53, 95% CI: 0.24–1.15, P=0.09). Heterogeneity was absent (I²=0%, P=0.11, Figure S2A).

30-day rebleeding

Six studies reported rebleeding within 30 days of treatment. The pooled analysis showed no statistically significant reduction in 30-day rebleeding with OTSC compared with SET (RR =0.55, 95% CI: 0.29–1.07, P=0.08). Heterogeneity was absent (I²=0%, P>0.99, Figure S2B).

Subgroup analysis of 3 RCTs showed no significant difference between OTSC and SET (RR =0.51, 95% CI: 0.22–1.19, P=0.12), with no heterogeneity among studies (I²=0%, Figure S2C).

Overall bleeding

Six studies reported bleeding rates after treatment. OTSC was associated with a significant reduction in bleeding incidence compared with SET (RR =0.46, 95% CI: 0.25–0.82, P=0.009). Heterogeneity was absent (I²=0%, P=0.88, Figure S2D).

Subgroup analysis of 3 RCTs showed a significant reduction with OTSC compared with SET (RR =0.42, 95% CI: 0.18–0.98, P=0.04), with no heterogeneity among studies (I²=0%, Figure S2E).

Need for re-therapy

Four studies evaluated the need for further intervention after initial treatment. The pooled analysis showed no statistically significant reduction in the need for re-therapy with OTSC compared with SET (RR =0.51, 95% CI: 0.25–1.03, P=0.06). Heterogeneity was absent (I²=0%, P=0.99, Figure S3A,S3B).

Repeat endoscopy

Four studies assessed the need for repeat endoscopy. The pooled analysis showed no statistically significant difference between OTSC and SET (RR =1.13, 95% CI: 0.60–2.11, P=0.71). Heterogeneity was absent (I²=0%, P=0.75, Figure S3C,S3D).

Repeat TAE

Three studies examined the need for TAE following endoscopic treatment. The pooled analysis showed no statistically significant difference between OTSC and SET (RR =1.27, 95% CI: 0.25–6.31, P=0.77). Heterogeneity was moderate (I²=35%, P=0.21, Figure S3E,S3F).

In-hospital mortality

Four studies assessed in-hospital mortality. The pooled analysis showed no statistically significant difference between OTSC and SET (RR =0.37, 95% CI: 0.11–1.24, P=0.11). Heterogeneity was absent (I²=0%, P=0.82, Figure S4A,S4B).

Total mortality

Four studies evaluated total mortality. Although results favored OTSC (RR =0.36, 95% CI: 0.10–1.35), statistical significance was not reached (P=0.12). Heterogeneity was low (I²=20%, Figure S4C,S4D).

Adverse events

Two studies assessed overall adverse events or complications. The pooled analysis showed no statistically significant difference between OTSC and SET (RR =0.12, 95% CI: 0.01–2.19, P=0.15). Heterogeneity was not applicable.

Length of hospital stay

Five studies reported on hospital stay duration. No statistically significant difference was observed between OTSC and SET (mean difference =−0.21 days, 95% CI: −0.80 to 0.38, P=0.49). Heterogeneity was absent (I²=0%, P=0.86, Figure S4E,S4F).

Discussion

Bleeding PUD remains one of the most common gastrointestinal emergencies, affecting 5–10% of the global population (1,2). It is a leading cause of NVUGIB, contributing substantially to patient morbidity, mortality, and healthcare burden (2). The etiology of PUD is multifactorial, with H. pylori infection and chronic NSAID use being the most common contributors (3,4). Among PUD complications, bleeding is the most frequent, occurring in 10–20% of cases, with an annual prevalence of approximately 150 per 100,000 individuals (5). Clinical presentations range from melena to life-threatening hematemesis and hypovolemic shock (21). Standard management includes proton pump inhibitors (PPIs) (22), often combined with endoscopic interventions such as mechanical hemoclips, thermal coagulation, or epinephrine injection (8,9). However, in high-risk patients or those with large or fibrotic ulcer bases, SET fails in 15–20% of cases (23).

To address these limitations, OTSC has been developed as a novel mechanical device capable of providing strong tissue approximation and vessel compression, even in challenging lesions (19).

Our study findings indicate that OTSC is associated with significantly higher clinical success (RR =1.16, 95% CI: 1.06–1.27, P=0.002) and a significantly lower overall bleeding rate (RR =0.46, 95% CI: 0.25–0.82, P=0.009) when compared to conventional endoscopic therapy. These results suggest that OTSC may offer more durable hemostasis and better overall outcomes when used as an initial treatment rather than as a rescue tool. The enhanced performance may be due to OTSC’s superior mechanical grip and ability to securely close bleeding ulcers, particularly in anatomically difficult or fibrotic locations (19).

In addition, OTSC was associated with a numerically lower risk of 7-day rebleeding (RR =0.53, 95% CI: 0.24–1.15), though this did not reach statistical significance (P=0.09), possibly reflecting limited power from the small number of contributing studies. Similarly, the need for re-therapy and surgical intervention trended in favour of OTSC but without reaching significance, consistent with findings from Manno et al., who reported no surgical interventions required in 40 consecutive cases where OTSC was used as a first-line treatment (24), suggesting a potentially important role in improving safety and reducing the need for escalated care.

Although OTSC use showed a numerically lower in-hospital mortality (RR =0.37, 95% CI: 0.11–1.24), this did not reach statistical significance (P=0.11), likely reflecting limited statistical power due to the low absolute number of mortality events across studies. These findings are consistent with prior meta-analyses that have not consistently demonstrated a mortality benefit with OTSC (25,26).

However, OTSC did not significantly reduce hospital stay duration or total mortality. These findings may reflect variability in patient comorbidities, institutional discharge protocols, or timing of intervention. Similarly, the lack of a significant difference in primary success may be attributed to variability in procedural technique, ulcer characteristics, or how this outcome was defined across studies.

Most secondary outcomes, including re-intervention, surgical intervention, in-hospital mortality, and adverse events, did not reach statistical significance, though all trended in favour of OTSC. The wide confidence intervals across these outcomes suggest possible underpowering rather than a true lack of effect, and inconsistencies in outcome reporting across studies may also have contributed. Similar variability was noted in the study by Mega et al. (25).

Despite its promising efficacy, the widespread adoption of OTSC faces important practical challenges. The device carries a higher acquisition cost compared to standard endoscopic clips, which may limit its availability in resource-constrained settings or healthcare systems (26). Furthermore, successful OTSC deployment requires dedicated endoscopic training, as the technique demands familiarity with clip loading, tissue capture, and correct positioning, particularly in anatomically challenging locations such as the posterior duodenal bulb (27). A learning curve has been described, and suboptimal deployment may result in incomplete tissue apposition or clip misfiring, potentially compromising hemostatic outcomes (28).

A further consideration is the substantial heterogeneity in the composition of the control (SET) group across included studies. Comparator interventions ranged from epinephrine injection alone to various combinations of injection, thermal coagulation, and through-the-scope clips. This variability in the nature and intensity of standard therapy may have meaningfully influenced the pooled effect estimates. The interpretability of the results is therefore limited in this respect, and findings should be understood in the context of a heterogeneous comparator rather than a single standardised intervention.

Our review has several strengths. A comprehensive search strategy across multiple databases ensured wide literature coverage and minimized selection bias. The inclusion of a separate analysis of RCTs limits bias associated with retrospective studies. The inclusion of studies from different geographic regions enhances the generalizability of our findings. Furthermore, rigorous quality assessment allowed for a critical evaluation of methodological integrity across studies.

Nonetheless, this review has limitations. The small number of included studies and the mix of randomized and retrospective designs may introduce heterogeneity and bias. Variability in outcome definitions, operator expertise, and institutional practices may also affect the comparability of results. In addition, publication bias cannot be excluded, and moderate-to-high heterogeneity was observed in some outcomes. Importantly, no formal assessment of publication bias was performed in this case, given the limited number of included studies, which renders these methods unreliable

Conclusions

OTSC represents a promising and effective first-line option for bleeding PUD with higher clinical success and lower overall bleeding rates compared to SET for bleeding PUD. However, the evidence base remains limited by small sample sizes, heterogeneous comparators, and mixed study designs, necessitating larger, well-designed RCTs to confirm these findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0011/rc

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0011/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0011/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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