This systematic review was performed according to the preferred reporting items for systematic reviews and meta-analysis statement[13]. A thorough search of the literature was conducted in the PubMed database to identify articles that described the use of OTSC for any GI indication from January 1, 2007 to January 15, 2020. The search was performed using the following terms: “over-the-scope-clip”, “OTSC”, “endoscopic fistula closure,” “over-the-scope clip bleeding”, “stent fixation”, and “endoscopic perforation closure.”

All English-language abstracts and/or full-text articles reporting original data of OTSC use (in humans, only) for the indication of fistulae, perforation, anastomotic leak closure, GI hemorrhage, endoscopic resection, and stent fixation were reviewed (authors: Bartell N and Bittner K) to assess eligibility for inclusion. Case reports and case series with fewer than five patients were excluded. Articles were also omitted if reported data did not include the rate of clinical success.

Data extraction included the following: Author(s), year of publication, study type/design, location(s), number of patients, indication(s) for OTSC use, clinical and technical success rates (TSR), duration of follow-up, and OTSC-related AEs. The primary outcome of interest was clinical success rate (CSR). Secondary outcomes included TSR, requirement for surgical intervention despite OTSC, and reported OTSC-related AEs. Pooled rates (per-indication and overall) were calculated as the number of patients with the event of interest divided by the total number of patients.

CSR was defined as complete and durable resolution of the respective defect, hemorrhage and/or stent fixation. TSR was defined as the successful deployment of the OTSC clip to the targeted lesion or defect. OTSC-related AEs were defined as unanticipated events probably or possibly directly related to the use of the OTSC clip.

A total of 512 record matches were located in the PubMed database, per the literature search strategy. Two authors (Bartell N and Bittner K) reviewed each title, abstract and/or full-text article prior to applying the full exclusion criteria. A total of 109 publications were retrieved for full review, with 24 excluded from the final analysis (Figure 3). Eighty-five articles[2-6,14-92] (Table 2) met inclusion criteria (n = 3025 patients). Indications for OTSC use included: Fistulae (n = 622), GI hemorrhage (n = 1303), perforation (n = 468), anastomotic leak closure (n = 391), endoscopic resection defect closure (n = 221), and stent fixation (n = 20). The overall CSR (inclusive of all indications) and TSR for OTSC placement was 78.4% (n = 2371/3025) and 94.4% (n = 2856/3025), respectively. Per-indication CSR, TSR, and post-OTSC surgery rates are described in Table 3.

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Figure 3 Article selection process, per preferred reporting items for systematic reviews and meta-analysis guideline.

Endoscopic management of GI hemorrhage is well-established, with a number of available modalities to effectively achieve mechanical or coagulative hemostasis. Conventional endoscopic techniques are successful in managing GI hemorrhage in most cases; however, the rate of re-bleeding has been reported at 10%-20%[93]. Patients presenting with a re-bleed often require repeat endoscopic intervention, angiography (interventional radiology), or definitive management with surgery[93]. Mechanical hemostasis is often attempted with TTS clips which can be effective for smaller lesions; however, large and/or complex lesions may require a clip with larger diameter (up to 14 mm) and more tensile strength to achieve effective hemostasis.

In current endoscopic practice, OTSC is mainly used in refractory bleeding cases (Figure 4) following a failure of conventional therapy; however, a head-to-head randomized control trial (RCT) is currently being conducted in Europe (ClinicalTrials.gov, NCT03551262) to evaluate its efficacy as a potential primary therapy for hemostasis. Manno et al[44] retrospectively reviewed 40 consecutive cases of high-risk non-variceal upper GI hemorrhage utilizing OTSC as a primary intervention. The authors reported a CSR of 100%, with no OTSC-related AEs (30-d follow up). In 2017, Wedi et al[74] highlighted the efficacy of OTSC in a retrospective review of 100 high-risk patients presenting with non-variceal upper GI bleeding. In this cohort, most (51%) of patients had severe cardiovascular comorbidities, with the majority (73%) on an antiplatelet regimen, thus potentially precluding a surgical approach in these patients. This article reported a CSR of 86% at 6 months of follow-up. In a subsequent study, Wedi et al[92] compared OTSC to standard of care treatment in non-variceal upper GI bleeding demonstrating superiority of OTSC, especially in high-risk patients. Specifically, patients with Rockall scores ≥ 8 showed significantly lower rates of re-bleeding when treated with OTSC as a first-line therapy as compared to patients treated with conventional modalities (10.9% vs 27.9%, respectively)[92]. Thus, OTSC can be used as the primary modality in high-risk patients such as those on anticoagulation, bleeding from large caliber vessels, or if they are not a good surgical candidate and/or as a rescue treatment for re-bleeding when conventional hemostasis options fail.

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Figure 4 Over the scope clip used in management of gastrointestinal bleeding. A: Massive gastrointestinal bleeding from duodenal bulb ulcer with an actively bleeding blood vessel; B: Successful hemostasis achieved using over-the-scope-clip.

In our systematic review, the overall CSR and TSR for the indication of GI hemorrhage was 86.0% and 96.8%, respectively. Surgical intervention for control of GI hemorrhage following OTSC placement was only required in 1.6% (21/1303) of patients.

Though infrequent, perforation is an established risk of any endoscopic procedure, with average rates from 1 in 2500 to 1 in 11000 esophagogastroduodenoscopy’s and 5.8 per 10000 for colonoscopy[94-96]. Advanced endoscopic interventions (including resection), have a higher risk of perforation than diagnostic procedures. Conventional management of acute iatrogenic perforation often necessitates surgical intervention; however, an effective and minimally invasive endoscopic approach to close these lesions during the index procedure is preferential to a higher-morbidity surgical intervention. Several endoscopic interventions have been utilized to manage perforations with varying degrees of success including: Self-expanding metal stents (SEMSs), TTS clips, endoscopic suturing, and OTSC[97]. SEMSs have been primarily used in the management of esophageal perforation; however, they carry the risk of migration and incomplete seal. TTS clips have limited ability to achieve complete closure of large defects and endoscopic suturing is limited by operator expertise, tedium and endoscope length in cases of perforation in the small bowel. Endoscopic suturing can also be challenging when managing defects in difficult locations such as gastric cardia, esophagus, duodenum, and proximal colon.

The European Society of GI Endoscopy currently recommends that endoscopic closure of iatrogenic perforations be considered during the index procedure[97]. OTSC is advantageous in this setting, as its ease of use, ability to close defects between 1-3 cm with a single clip application, and safety profile allow the endoscopist to effectively manage acute perforation immediately upon recognition (Figure 5)[97]. If the attempt to close perforation is delayed (> 72 h) or the defect is larger than 2 cm in diameter, endoscopic management is more likely to fail; however, the TG device can be utilized to approximate the edges of the defect for more effective closure with the OTSC, when dealing with larger defects (> 2 cm)[57,97]. Additionally, in cases of esophageal perforation, closure may be difficult with only suctioning the defect into the applicator cap (given the tangential orientation of the esophageal wall of to the endoscope). In this instance, the TG can help grasp the tissue to facilitate closure of the defect. Caution should be exercised while deploying the OTSC in difficult locations (e.g., gastro-esophageal junction, pylorus and the duodenal sweep) to avoid closing off the lumen entirely.

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Figure 5 Over the scope clip used in management of gastrointestinal perforation. A: Gastro-esophageal junction perforation caused during advancement of side viewing duodenoscope; B: Successful closure of perforation using over-the-scope-clip.

Honegger et al[43] reported on the efficacy of OTSC in a large cohort of patients (n = 72) with iatrogenic endoscopic perforations, with a stated CSR of 86.1%. Two patients experienced OTSC-related AEs, with one case of bleeding and one with a worsening of the index perforation. In a recent study, Wei et al[90] described the use of OTSC in patients with perforated peptic ulcer compared to a control group that was managed conventionally. The rate of clinical success in the OTSC group was 100% (n = 26/26) vs only 57.5% (n = 46/80) in controls. The requirement for surgical intervention in the OTSC cohort was significantly lower than controls (0% vs 30.0%, respectively, P < 0.001). No OTSC-related AEs were reported[90].

In our systematic review the overall CSR and TSR for the indication of perforation was 85.3% and 95.5%, respectively. Surgical intervention post-OTSC placement was required to achieve complete closure in 9.4% (n = 44/468) of patients.

Prior to the availability of OTSC, prophylactic closure of defects created by endoscopic resection of GI lesions would be managed with TTS clips. Prophylactic TTS clip closure following the resection of large (> 1 cm) proximal colonic lesions is an effective strategy that has reduced the incidence of post-procedure AEs (including post-polypectomy hemorrhage) and increased patient satisfaction[98-100]; however, TTS are limited by their diameter and often require a “suturing” technique involving the placement of multiple clips across the lesion. With the deployment of OTSC, a defect of 1-3 cm in diameter can be successfully closed utilizing a single clip[98].

The full-thickness resection device (FTRD; Ovesco Endoscopy AG, Tübingen, Germany) is now commercially available. This accessory combines the ability to complete resection and clipping with a single device. Aepli et al[46] reported the first clinical data in 2016 on the use of FTRD, demonstrating a CSR (n = 24 patients) of 87.5% and a post-OTSC AE rate of 12.5% (n = 4/24) with 3 post-procedure bleeding events and one post procedure perforation.

In our systematic review the overall CSR and TSR for the indication of defect closure following endoscopic resection was 92.8% and 95.9%, respectively. The necessity for post-OTSC surgical intervention was rare (n = 2/221; 0.9%).

GI fistulae are difficult to manage with either endoscopic or surgical interventions, likely due to the chronicity of the problem, fibrotic non healing tracts and prior treatment attempts making subsequent closure increasingly difficult. In addition, the underlying pathogenesis combined with a presentation of impaired nutritional status contribute to slow or non-healing of the fistula. Conventional management of GI fistulae focuses on control/prevention of infection, optimization of nutrition/ hydration, and limiting of fistula output. Surgical management can be attempted as a definitive therapy in lower-risk patients; however, patients with complex fistulae may be too medically frail for surgical intervention and/or those presenting with a small bowel fistula may not have enough remnant bowel to allow for further resection.

In recent years, endoscopy been considered as a possible primary therapy for the closure of GI fistulae[101]. Prior to the advent of OTSC, endoscopic treatment of GI fistulae had been attempted with TTS, absorbable loop snares or glues to varying degrees of success[102]. OTSC has potential in the management of GI fistulae (Figure 6), as the suction utilized in the clip application can create a more robust closure than TTS; however, definitive closure of a fistula relies on the complete grasping of involved tissue within the clipping device, which may be difficult when fibrotic tissue is present, as in most fistulae. High rates of clinical success for fistula closure have not yet been reported with OTSC. Haito-Chavez et al[50] reported the largest study of OTSC use in patients with fistulae (n = 91 patients) secondary to percutaneous endoscopic gastrostomy or jejunostomy tubes, post-bariatric surgery, malignancy-related, trauma, inflammatory bowel disease or diverticulitis. Deployment of the OTSC was successful in 89.4% of patients; however, clinical success at a median of 121 d was only 42.9%[50]. Other studies have reported similar CSR for fistula closure with OTSC[48]. Haito-Chavez et al[50] discuss the likelihood that fistulae with fibrotic and retracted rims were most associated with clinical failure, possibly related to the difficulty in properly targeting and suctioning the tissue during OTSC application. Fistulae smaller than 1 cm could be considered for closure with OTSC; however, in cases with a large fistula (> 1 cm) more than one clip could be applied and/or utilized in combination with endoscopic suturing with reinforced OTSC or glue to successfully achieve closure.

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Figure 6 Over the scope clip used in management of gastrointestinal fistula. A: Gastro-gastric fistula in a patient with Roux-en-Y gastric bypass; B: Argon plasma coagulation ablation of the fistula margin; C: Successful closure of fistula using over-the-scope-clip.

In our systematic review the overall CSR and TSR for the indication of fistulae was 55.8% and 92.8%, respectively. Surgical intervention post-OTSC placement was required in 7.6% (n = 47/622) of patients.

Conventional management for anastomotic leaks often follows a conservative approach of broad-spectrum antibiotics for lower-risk lesions and/or repeated surgical intervention for higher-risk lesions. The probability of a post-surgical anastomotic leak is higher in patients with a low serum albumin, longer operative time, higher intraoperative blood loss, positive resection margins or the presence of inflammatory bowel disease[103]. An effective minimally invasive endoscopic approach is preferable, as many of these patients may be too high-risk for additional surgical intervention.

Manta et al[42] presented the largest case series of patients (n = 76) with anastomotic leaks included in this review. Post-surgical leaks appeared in both the upper (n = 47) and lower (n = 29) GI tract. Overall clinical success was achieved in 80.3% of patients (83% and 75.9% for upper and lower GI leaks, respectively)[42].

In our systematic review the overall CSR and TSR for the indication of anastomotic leak closure was 72.6% and 86.7%, respectively. Surgical intervention post-OTSC placement was required in 7.4% (29/391) of patients.

GI stenting (most often for tumor palliation) though effective in immediate symptomatic relief, is often plagued by stent migration, especially in the case of fully covered stents[104]. The availability of SEMSs has reduced the risk of migration; however, the potential still exists[105]. OTSC can be used to anchor SEMS to mitigate the risk of stent migration. Limited data exist on the application of OTSC in this setting. The largest paper in the literature was presented by Mudumbi et al[16], demonstrating a high CSR (83%) in 12 patients who underwent OTSC fixation of SEMS, with no reported OTSC-related AEs. If it is necessary to remove a stent anchored by OTSC, the clip itself will need to be detached to do so, which is neither easy nor predictable. Traditionally, the only feasible method to remove the OTSC was with argon plasma coagulation; however, a novel device (remOVE system; Ovesco Endoscopy AG, Tubingen, Germany) has since been developed to effectively detach the OTSC[106,107].

In our systematic review the overall CSR and TSR for the indication of stent fixation was 80.0% and 100%, respectively; however, only 20 patients were included due to the paucity of data regarding OTSC for stent fixation in the literature. No patients required surgical intervention following OTSC placement or as a result of removal.

Sixty-four studies (n = 1942 patients) reported OTSC-related AE data (Table 4), with an overall rate of 2.1% (n = 40/1,942). These events included: “incorrect placement site” (n = 11/40; 27.5%), perforation (n = 9/40; 22.5%), bleeding (n = 10/40; 25%), and infection (n = 10/40; 25%). No deaths occurred as a result of OTSC use.

A perforation was defined as an AE if the OTSC: (1) Caused a de novo perforation, or (2) Worsened an already existing perforation that the OTSC was intended to close. “Incorrect placement site” was defined as the placement of the OTSC in a location other than the targeted defect and/or the disruption of nearby tissue/structures by the OTSC. For instance, Honegger et al[43] reported three cases of inadvertent OTSC deployment on the tongue during withdrawal of the endoscope and one case of OTSC deployment in the rectum causing a pseudopolyp formation resulting in a clinically significant obstruction. Raithel et al[14] reported a case of colonic perforation managed with OTSC resulting in fixation of the small bowel to the colon and subsequent rupture of the small bowel requiring surgical intervention. Khater et al[86] further described the potential of the OTSC to disrupt nearby tissue/structures reporting a case of rectosigmoid perforation that was effectively closed with OTSC; however, follow-up imaging studies demonstrated dilation of the urinary tract and ureter obstruction as a result of the ureter being suctioned into the application cap during clip deployment. Ultimately this patient required surgical intervention[86]. Such cases highlight the potential hazards and drawbacks related to the application of the OTSC clip, therefore careful consideration of surrounding anatomy should be entertained prior to OTSC deployment. Though the incorrect placement of OTSC can be a significant AE (due to difficulty in OTSC removal), the remOVE device is now available to detach the OTSC if placement of the clip is not satisfactory. Preliminary data suggest successful fragmentation of the OTSC with remOVE in 97.3% of cases, with minimal AEs (bleeding in 2.7% of patients, and superficial mucosal tearing in 1.4% of patients)[107].

The over-the-scope-clip (OTSC) device has become widely utilized in endoscopic practice. Limited data exist evaluating the overall clinical success and adverse event (AE) rates of OTSC across gastrointestinal (GI) indications.

The key significance of this systematic review is to provide endoscopists with a real-world estimate of the efficacy and safety of OTSC in clinical practice.

The aim of this study was to determine the rates of clinical success (CSR), technical success (TSR), AE and post-OTSC (salvage) surgery rates.

A PubMed search was conducted for eligible articles describing the use of OTSC for any GI indication. Any article or case series reporting data for less than 5 total patients was excluded. Articles were included from January 1, 2007 to January 15, 2020. The following terms were used to perform the literature search: “over-the-scope-clip”, “OTSC”, “endoscopic fistula closure,” “over-the-scope clip bleeding”, “stent fixation”, and “endoscopic perforation closure.”

Eighty-five articles met inclusion criteria (n = 3025 patients). The overall CSR (inclusive of all indications) and TSR for OTSC placement was 78.4% (n = 2371/3025) and 94.4% (n = 2856/3025), respectively.

OTSCs are a novel advancement in endoscopic practice. They are safe and effective for use in GI hemorrhage, anastomotic leak, perforation, defects created by endoscopic resection and stent fixation; however, there is room for improvement in use for fistula closure.

Future large randomized control trials comparing OTSC with conventional and/or surgical interventions are needed to develop clinical guidelines for the most appropriate endoscopic application(s).