Efficacy and safety of over-the-scope-clips in the therapy of acute nonvariceal upper gastrointestinal bleeding: Meta-analysis

Abstract

BACKGROUND

Acute nonvariceal upper gastrointestinal bleeding (ANVUGIB) is a frequent life-threatening acute condition in gastroenterology associated with high morbidity and mortality. Over-the-scope-clip (OTSC) is a new endoscopic hemostasis technique, which is being used in ANVUGIB and is more effective.

AIM

To summarize and analyze the effects of the OTSC in prevention of recurrent bleeding, clinical success rate, procedure time, hospital stay, and adverse events in the treatment of ANVUGIB, to evaluate whether OTSC can replace standard endoscopic therapy as a new generation of treatment for ANVUGIB.

METHODS

The literature related to OTSC and standard therapy for ANVUGIB published before January 2023 was searched in PubMed, Web of Science, EMBASE, Cochrane, Google, and CNKI databases. Changes in recurrent bleeding (7 or 30 days), clinical results (clinical success rate, conversion rate to surgery, mortality), therapy time (procedure time, hospital stay), and adverse events in the OTSC intervention group were summarized and analyzed, and the MD or OR of 95%CI is calculated by Review Manager 5.3.

RESULTS

This meta-analysis involved 11 studies with 1266 patients. Total risk of bias was moderate-to-high. For patients in the OTSC group, 7- and 30-days recurrent bleeding rates, as well as procedure time, hospital stay, and intensive care unit stay, were greatly inhibited. OTSC could significantly improve the clinical success rate of ANVUGIB. OTSC therapy did not cause serious adverse and was effective in reducing patient mortality.

CONCLUSION

OTSC may provide more rapid and sustained hemostasis, and thus, promote recovery and reduce mortality in patients with ANVUGIB. In addition, the safety of OTSC is assured.

Key Words: Acute nonvariceal upper gastrointestinal bleeding; Over-the-scope-clips; Recurrent bleeding; Adverse events; Meta-analysis

Core Tip: Upper gastrointestinal bleeding, especially Acute nonvariceal upper gastrointestinal bleeding (ANVUGIB) is a common life-threatening acute condition with high morbidity and mortality in gastroenterology. With the advancements in medical technology, a new endoscopic hemostatic technique, called the over-the-scope-clip (OTSC), is being used for ANVUGIB treatment. We performed a meta-analysis to study the role of OTSC in ANVUGIB treatment in terms of prevention of rebleeding, clinical success rate, procedure time, hospitalization time, and adverse events. We aim to determine whether OTSC could replace standard endoscopic treatment as a new generation of ANVUGIB treatment.

INTRODUCTION

Upper gastrointestinal bleeding, especially acute nonvariceal upper gastrointestinal bleeding (ANVUGIB), is a frequent life-threatening acute condition in gastroenterology associated with high morbidity and mortality[1]. In recent years, the number of people with gastrointestinal diseases, such as peptic ulcer, erosive esophagitis, and erosive gastritis, has increased yearly due to the influence of alcoholism, poor work habits, and high-intensity work[2]. According to statistics, the annual number of outpatient visits for gastrointestinal diseases in China was approximately 4 million in 2015[3]. Simultaneously, the incidence of the resulting ANVUGIB has increased. ANVUGIB is routinely treated endoscopically by thermal coagulation, hemostatic drug spray, and titanium clip hemostasis. However, approximately 26.3% suffer from recurrent bleeding in the early postoperative period due to excessive bleeding and decreased coagulation function[4], which has an essential role in increasing mortality in patients with ANVUGIB. Therefore, improving endoscopic hemostasis techniques to prevent rebleeding is the key to improving the cure rate of ANVUGIB.

With advances in medical technology, over-the-scope-clip (OTSC), a new endoscopic hemostasis technique, is being used in ANVUGIB therapy. OTSC was more effective than standard therapy for recurrent peptic ulcer bleeding, increasing hemostatic success rate by 42.4%[5]. Wei et al[6] found that OTSC had a 100% hemostasis rate when used as first-line treatment for patients with high-risk NVUGIB, with no cases of rebleeding during the 30-days follow-up. OTSC was effective in treating > 15-mm peptic ulcer perforations, thereby avoiding surgical intervention and restoring enteral nutrition in a short period[7]. The hemostatic clips used in OTSC are made of a new nickel-titanium alloy with excellent superelasticity and thermal shape memory, which facilitates better fit and effective clamping of bleeding tissue[8]. Compared to conventional hemostatic clips, OTSC has a wider range of clamping, allowing for better embedding and effective compression at the base of large or fibrotic ulcers, resulting in efficient hemostasis, which often requires multiple titanium clips to achieve[9]. For recurrent ulcer bleeding, OTSC can avoid the undesirable complications of standard titanium clips, such as detachment during therapy of scarred or fibrous tissue, thus avoiding more bleeding due to vascular tearing[10,11]. Thus, the significant compressive force of OTSC and the greater extent of tissue clamping has made the use of OTSC in ANVUGIB therapy more significant.

However, OTSC has limitations in ANVUGIB therapy, such as delayed closure of OTSC in lesions with large caliber arterial injury and deep basal fibrosis, as well as misplacement or shallow placement of OTSC due to poor visualization or unstable endoscopic position[12,13]. Because OTSC has a large size and clamping area, it is not easily dislodged like conventional hemostatic clips, which can cause intestinal stenosis[14]. A literature analysis revealed many studies comparing the efficacy of OTSC with standard therapy in ANVUGIB; however, at a relatively small scale. In addition, the safety and related complications of OTSC during therapy were not reported, which to can limit the use of OTSC in the first-line therapy of ANVUGIB. Therefore, this meta-analysis aims to examine the efficacy and safety of OTSC in ANVUGIB therapy, to provide clinical guidance for the improvement of its first-line treatment regimens.

MATERIALS AND METHODS

Data retrieval & collection

We searched PubMed, Web of Science, EMBASE, Cochrane, Wanfang, Weipu, and CNKI databases to obtain literature that met the requirements. The following keywords were used in the search: “upper gastrointestinal bleeding” or “upper gastrointestinal tumor” or “stress ulcer” or “peptic ulcer” or “gastric ulcer” or “bleeding” or “hemorrhage” and “acute” or “high-risk” or “refractory” and “over-the-scope clips” and “standard therapy” or “hemoclips” or “thermocoagulation” or “epinephrine” or “recurrent bleeding” or “recurrent hemorrhage” or “clinical success rate” or “procedure time” or “hospital stay” or “mortality” or “adverse events” or “surgery” or “safety”. The search was from January 2000 to January 2023 and was conducted by two researchers with three years of experience.

Inclusion criteria

The literature included in this meta-analysis had to compound the following criteria: (1) Patients diagnosed with ANVUGIB; (2) studies containing the OTSC group, in which patients were treated with OTSC, and the standard therapy group, in which patients were treated with hemoclips, thermocoagulation, or epinephrine under endoscope; (3) contain relevant study indicators, such as recurrent bleeding, clinical success rate, procedure time, hospital stay, or safety (mortality, adverse events, or surgery); and (4) randomized controlled trial study.

Exclusion criteria

(1) Case reports and reviews; (2) without detailed data; (3) < 10 people included in the study; (4) experiments were conducted on animals; and (5) relevant research indicators were not included.

Extraction of data

We extracted key data from the included literature in detail, namely the author, year of publication, patient number, therapeutic method, recurrent bleeding, clinical success rate, procedure time, hospital stay, and safety. When necessary, we corresponded with the authors by e-mail to request detailed data.

Quality evaluation of included literature

Two reviewers independently assessed the quality of the literature using the Cochrane risk of bias assessment tool, which contains seven domains: randomized sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. The methodological quality of prospective cohort studies and retrospective cohort studies was assessed using the Newcastle-Ottawa Scale. The risk of bias for each study was rated as low, medium, or high. The quality of evidence was assessed using the GRADEpro software and was categorized as high, moderate, low, and very low. A third reviewer arbitrated any disagreements.

Statistical analysis

Revman 5.3 was used for meta-analysis. The continuous variables in-hospital stay and procedure time were expressed by MD and 95%CI. The dichotomous variables in recurrent bleeding, clinical success rate, and adverse events were expressed by OR and 95%CI. A forest plot was generated using a random-effects or fixed-effects model. For each meta-analysis, Cochran Q and I² were used to evaluate study heterogeneity. If combined SMD or OR of 95%CI or in the meta-analysis did not overlap with 0, the effect of the outcome index was considered statistically significant. Funnel plots, Egger’s test, and Begg’s tests were used to examine publication bias data analysis was completed using STATA (version 15.0).

RESULTS

Literature retrieval

In this meta-analysis, we searched 1255 papers related to OTSC, of which 277 were duplicates. Subsequently, we read the titles and abstracts of the literature to exclude 821 papers with different scope of salvage and correction outcomes from this meta-analysis and retrieved the full-text of 157 papers. After reading the entire text, we excluded 146 papers: Case reports (31), reviews (130), no detailed data provided (59), < 10 people included in the study (29), and the study was conducted on animals (25); 11 studies with 1266 patients were finally included[4-7,11-17] (Figure 1). In the OTSC group, patients with ANVUGIB were treated with OTSC. In the standard therapy group, patients with ANVUGIB were treated with thermal coagulation, anticoagulant spraying, or hemostatic clips. Basic information about the patients included in the literature, the mode of treatment received, and relevant outcome indicators are summarized in Table 1.

Figure 1 Flow chart for data search and gathering.

Table 1 Basic information and relevant observables of included studies.

Ref.	Country	Number of patients		Therapeutic method		Recurrent bleeding				Clinical success rate		Procedure time (minute)		Therapy time				Safety
						7 days		30 days						Hospital stay (day)		ICU stay (day)		Rate of surgery		In-hospital mortality		Adverse events
		OTSC	SET	OTSC	SET	OTSC	SET	OTSC	SET	OTSC	SET	OTSC	SET	OTSC	SET	OTSC	SET	OTSC	SET	OTSC	SET	OTSC	SET
Buddam et al[15], 2021	United States of America	21	47	OTSC	Hemoclips, thermocoagulation, epinephrine	2/21	10/47			20/21	39/47	17.08 ± 5.57	23 ± 13.77	5.72 ± 3.18	6.77 ± 5.35					0/21	2/47
Chan et al[7], 2023	China, Thailand	50	50	OTSC	Hemoclips, thermocoagulation, epinephrine	2/50	3/50	5/50	9/50	46/50	48/50			13.72 ± 24.33	13.27 ± 16.13			3/50	1/50	2/50	4/50
Jensen et al[11], 2021	the United States	25	28	OTSC	Hemoclips, thermocoagulation, epinephrine	0/25	7/28	1/25	8/28					7.56 ± 8.17	10 ± 16.19	2.4 ± 3.48	11.11 ± 37.06	0/25	0/28	0/25	0/28	0/25	4/28
Kuellmer et al[13], 2023	Germany	66	37	OTSC	Hemoclips			10/66	5/37	49/66	31/37			15.2 ± 12.4	23.1 ± 18.4	4.7 ± 6.6	16.2 ± 18			6/66	13/37	3/66	26/37
Mangiafico et al[14], 2020	Italy	112	215	OTSC	Hemoclips, epinephrine			13/112	32/215					15 ± 12	13 ± 19					8/112	20/215	0/112	1/215
Meier et al[17], 2022	Germany	48	52	OTSC	Hemoclips	4/48	8/52	6/48	8/52	44/48	38/52	27 ± 15	28 ± 20
Qiu et al[16], 2022	China	21	115	OTSC	Hemoclips, thermocoagulation, epinephrine			3/21	34/115	18/21	80/115
Robles-Medranda et al[12], 2021	Ecuador	46	49	OTSC	Hemoclips, epinephrine	0/46	3/49	2/46	1/49			12.06 ± 3.83	25.31 ± 19.09	11.15 ± 20.66	11.43 ± 20.62
Schmidt et al[8], 2020	Germany	33	33	OTSC	Hemoclips, thermocoagulation, epinephrine	3/33	5/33	5/33	19/33	31/33	19/33	29.27 ± 35.65	33.2 ± 44.17					1/33	1/33	4/33	2/33	5/33	1/33
Toka et al[4], 2019	Turkey	56	56	OTSC	Hemoclips			2/56	8/56	55/56	45/56	5 ± 1.46	9.47 ± 2.34	3.5 ± 1.04	4.37 ± 1.86
Wei et al[6], 2019	China	26	80	OTSC	Hemoclips, thermocoagulation, epinephrine					26/26	46/80			8.86 ± 3.53	9.97 ± 3.59			0/26	24/80	0/26	11/80

SET: Standard endoscopic therapy; OTSC: Over-the-scope-clip; ICU: Intensive care unit.

Literature quality

After evaluation, the quality of included studies was moderate-to-high. All included literature was randomized and triple-blinded to the investigators, participants, and outcome analysis during the study, and the study data were complete. Two studies had “selective reporting” and one study did not mention “allocation consideration” (Figure 2).

Figure 2 Risk of bias graph and bias summary of included studies. A: Bias graph; B: Bias summary.

OTSC prevented recurrent bleeding

In the assessment of recurrent bleeding, we performed subgroup analyses according to recurrent bleeding at 7 and 30 days. Data from 15 groups of the 10 studies suggested that the incidence of 7-days recurrent bleeding in the OTSC group was significantly lower, as was the incidence of recurrent bleeding at 30 d, and combined OR values were 2.08 (95%CI: 1.18-3.67; P = 0.01) and 2.20 (95%CI: 1.47-3.31; P = 0.0001; Figure 3A). Therefore, OTSC could prevent the occurrence of rebleeding after ANVUGIB therapy and improve patient prognosis.

Figure 3 Meta-analysis results. A: Recurrent bleeding; B: Success rate of hemostasis; C: Hemostasis time. OTSC: Over-the-scope-clip.

OTSC improved the success rate of hemostasis

To assess the hemostatic efficacy of ANVUGIB, we analyzed data from 7 groups of 7 studies regarding hemostatic success rate. OTSC had a higher rate of hemostatic success, with a combined OR of 0.2 (95%CI: 0.11-0.36; P < 0.00001; Figure 3B). Therefore, the use of OTSC in ANVUGIB therapy can improve hemostasis, and thus, enhance the clinical success rate.

OTSC shortened hemostasis time

By analyzing 5 sets of data on hemostasis time from 5 studies, we found that OTSC took less time in ANVUGIB rescue, with a combined MD of -6.02 (95%CI: -9.67 to -2.38; P = 0.001; Figure 3C). This indicates that OTSC can achieve definitive hemostasis in a shorter time and improve clinical efficiency.

OTSC reduced hospital stay

To better assess patient recovery, a comprehensive analysis of mean length of hospital stay and intensive care unit (ICU) stay was performed. In total, 8 sets of data from 8 studies showed that the OTSC system was effective in reducing mean length of stay in patients with ANVUGIB, with a combined MD of -0.88 (95%CI: -1.38 to -0.38; P = 0.0005; Figure 4A). The OTSC system could markedly reduce ICU length of stay, with a combined MD of -11.05 (95%CI: -16.57 to -5.54; P < 0.0001; Figure 4B). Therefore, patients with ANVUGIB have better recovery outcomes and shorter hospital stays after OTSC therapy.

Figure 4 Meta-analysis of hospital stay and intensive care unit stay. A: Hospital stay; B: Intensive care unit stay. OTSC: Over-the-scope-clip.

OTSC is safe

We evaluated the safety of the OTSC system in terms of operative rate, mortality, and complications. In total, 4 groups of data from 4 studies showed no obvious difference in patient number referred to surgical hemostasis after OTSC compared with standard therapy, with a combined OR of 1.80 (95%CI: 0.12 to 27.06; P = 0.67; Figure 5A). Analysis of data from 7 groups of 7 studies on in-hospital mortality revealed that OTSC was effective in reducing mortality, with a combined OR of 2.11 (95%CI: 1.23 to 3.65; P = 0.007; Figure 5B). Regarding occurrence of adverse events, such as luminal stenosis, gastroesophageal junction obstruction, and procedural deviations due to tissue fibrosis, data from 3 groups in 3 studies showed that OTSC was useful in minimizing the associated complications, with a combined OR of 13.5 (95%CI: 1.71 to 106.57; P = 0.01; Figure 5C). Therefore, the safety of the OTSC system for ANVUGIB is guaranteed.

Figure 5 Meta-analysis of safety after over-the-scope-clip therapy. A: Conversion rate to surgery; B: In-hospital mortality; C: Adverse events. OTSC: Over-the-scope-clip.

Analysis of publication bias

We selected the 5 main indicators for publication bias analysis: recurrent bleeding, hemostatic success, procedure time, length of stay, and mortality. The funnel plots for these indicators were generally symmetrical (Figure 6), indicating no significant publication bias.

Figure 6 Funnel diagram of recurrent bleeding, hemostatic success rate, procedure time, hospital stay, and mortality. A: Recurrent bleeding; B: Hemostatic success rate; C: Procedure time; D: Hospital stay; E: Mortality.

DISCUSSION

To investigate whether OTSC can be the first-line therapy for ANVUGIB, we compared it with standard endoscopic hemostasis protocols through a meta-analysis, including topical spray coagulants, thermal coagulation, and titanium clip hemostasis, thus confirming the effectiveness and safety of OTSC in therapy. We compared two therapy regimens in terms of recurrent bleeding, hemostatic success rate, hospital stay, and safety. We found that OTSC prevented recurrent bleeding better and improved the hemostatic success rate, thus decreasing hospital stay and mortality in patients. In terms of safety, OTSC was useful in minimizing adverse events during treatment.

Recurrent bleeding during ANVUGIB therapy is an important indicator of patient prognosis and can be life-threatening in severe cases. Our analysis of data from 15 groups in 10 studies showed that the incidence of recurrent bleeding at 7 and 30 d was significantly lower in the OTSC group. This was because the hemostatic protocols in standard therapy are aimed at minor or small-vessel bleeding and will not be effective if the ulcer is large or has fibrous tissue proliferation at the base[15,18]. OTSC has a greater ability to clamp more tissue during treatment, thus providing effective compression of the tissue surrounding the ulcer. To achieve the same hemostatic effect often requires the use of multiple titanium clips, which tends to increase the risk of dislodging the hemostatic clip, and thus, cause bleeding from a torn vessel[16]. Furthermore, the OTSC is made of a new nickel-titanium alloy, which has good elasticity and thermal shape memory, facilitating better fit to soft tissue during clamping, and thus, achieving effective clamping. However, one study showed that the recurrent bleeding rate at 7 days after OTSC therapy was higher (15.15% vs 13.51%)[13], which may be related to the shallow placement of the OTSC due to its premature deployment and its misplacement due to poor visualization. Therefore, treatment with OTSC requires a learning curve and clinicians must familiarize with the OTSC system accessory to master hemostasis techniques, especially in emergency situations. Thanks to the better hemostatic effect of OTSC and its preventive effect on recurrent bleeding, the clinical therapy success rate is effectively improved. In total, 6/7 studies showed higher clinical efficiency in the OTSC group.

The time spent on hemostasis can laterally reflect the therapy effect of ANVUGIB and the complexity of the operation. We found that the hemostasis time used for OTSC was significantly lower. It is possible that OTSC can better fit soft tissue and has stronger clamping ability, thus treating bleeding caused by large ulcers with a single clamping, which can effectively avoid the therapy time consumed by placing multiple hemostatic clips and multiple sprays of epinephrine[17]. Through practice, clinicians can master the OTSC system and choose the appropriate diameter of OTSC, to shorten hemostasis time.

Because OTSC is mainly used for the therapy of perforation, fistula closure, and gastrointestinal anastomotic leakage in the early stage and is gradually applied to ANVUGIB therapy, its safety in therapy is a key concern. We evaluated the safety of OTSC mainly in terms of conversion rate to surgery, in-hospital mortality, and complications. The included literature showed that in-hospital mortality and adverse event rates were significantly reduced in the OTSC group, and conversion rate to surgery was not increased, which suggests that the therapeutic effect of OTSC is definite with guaranteed safety. It takes 7-14 days for patients with ANVUGIB to recover and be discharged from the hospital, and their rapid recovery helps to accelerate the hospitalization turnover rate[19]. Our results showed that average hospitalization time was significantly decreased for patients in the OTSC group, especially ICU admission time, indicating that its hemostasis effect is more stable and definite, and that patients are less likely to experience recurrent bleeding and have better recovery outcomes.

This meta-analysis has some limitations. First, our more stringent inclusion criteria allowed only 11 publications to be included in the study, which may have resulted in insufficient data on outcome indicators. In addition, we did not evaluate the etiology of NVUGIB and performed subgroup analysis, which can lead to heterogeneity and bias in the results. Moreover, we did not perform subgroup analyses for the doses of PPI drugs used in each paper to exclude the impact of high-dose PPI on recurrent bleeding outcome indicators, which may have biased results. In the future, we will collect literature related to OTSC and present a summary to better guide first-line therapy of ANVUGIB in clinical practice.

CONCLUSION

In summary, OTSC significantly reduced the rebleeding rate of ANVUGIB with a higher clinical success rate and relatively shorter therapy time. OTSC reduced hospital stay and lowered clinical mortality. Furthermore, the safety of OTSC is guaranteed. Therefore, OTSC shows great potential in the first-line therapy of ANVUGIB.