Further new evidence regarding clipping following colorectal endoscopic mucosal resection

Delayed bleeding is the most common major complication of endoscopic mucosal resection (EMR). The mean rate of delayed bleeding after EMR of large (≥ 2 cm) nonpedunculated colorectal lesions (LNPCLs) is between 2.6 % and 9.7 % and the bleeding usually occurs 1–7 days following patient discharge from the endoscopic unit [1].

Clip closure after EMR is a frequent practice, but the clips are expensive and several studies have shown no preventive effect, especially when the polyp size is less than 20 mm [2]. However, two recent randomized controlled trials (RCT) and a meta-analysis provide strong evidence that, in polyps presenting a substantial risk of bleeding or located in the right colon, clipping of the mucosal defect after resection reduces the risk of post-resection bleeding [3] [4] [5]. Until very recently this prophylactic measure was not recommended in clinical guidelines, but in 2020 the US Multi-Society Task Force reviewed this recent evidence and now recommends clip closure for all such lesions [6].

The preventive effect in terms of reducing the risk of delayed bleeding is obtained when the mucosal defect is completely closed, that is, apposition of the mucosal edges is achieved without revealing areas of submucosa. Another important criterion to consider is that the maximum distance between clips should not exceed 10 mm; an interval of around 5 or 6 mm between clips is ideal. Closure of the mucosal defects is not infallible nor is it achieved in 100 % of cases; at least one-third of large scars cannot be closed with clips.

In this issue of Endoscopy, the study by Ortiz et al. provides information on factors associated with complete closure after EMR of LNPCPs [7]. This is a post hoc analysis of the well-conducted RCT by Pohl et al. in 18 renowned medical centers. The study included 458 patients with 494 polyps with complete clip closure. Such closure was achieved on 68.4 % of occasions and was associated with smaller size lesions, serrated histology, good endoscopic access, complete submucosal lifting, and en bloc resection.

“Factors that hinder or prevent complete closure of the resection defect include several, such as size, histology, or submucosal lifting, that are not modifiable, but others, such as ease of access to the polyp and en bloc resection, that could be improved, at least in part. New studies are needed to corroborate the role of both these and additional factors.”

The article aims to identify potentially modifiable risk factors in order to further reduce delayed bleeding following colorectal EMR. A very interesting and complete analysis of the variable size of polyp is performed, examining the traditional longitudinal diameter, the transverse diameter, and the area. The authors observed a 6 % improved odds of achieving clip closure for each 1 mm decrease in polyp size, and a correlation between the three variables. The authors explain the association between serrated histology and a lower frequency of submucosal fibrosis compared with adenomas, although the association disappears for lesions greater than 30 mm and thus will require corroboration in new studies. Serrated histology and submucosal lifting are usually not modifiable, but accessibility may be partially modifiable by adequate technique and training in endoscopy or the use of auxiliary equipment such as caps or overtubes, and could therefore be regarded as a mixed factor. A surprising finding is the independent association of en bloc resection with complete clip closure, although the authors offer no explanation for it. Although the data originate from a rigorous clinical trial, the authors’ post hoc analysis is under some limitations as certain aspects were not considered: for example, specific anatomical locations such as the anal canal or the valve orifice, where mucosal defects cannot be completely closed, were not taken into account.

This study opens up new investigative paths for optimizing preventive treatment against post-resection delayed bleeding, although additional studies are needed to corroborate the effect of these or other variables associated with the success of clip closure. These studies should take into account the experience of the endoscopist in closing large mucosal defects, and it is clear that educational programs on advanced resection of early neoplasms should teach and include techniques for preventive management of complications.

The studies carried out to date have the limitation that, for obvious reasons of maintaining homogeneity, the effectiveness of only the standard 11-mm clips was studied, but we have other options for closure: larger clips, combinations of clip sizes, and the use of other auxiliary techniques (endoloops, surgical threads, rubber bands, use of small incisions in the healthy mucosa to anchor the clips, among others). There are initial reports of complete covering of the mucosal defect with platelet-rich plasma or a novel self-assembling peptide [8] or other gels currently under study with promising results, although the preventive role of these treatment options is yet to be determined and quantified.

The available evidence surrounding clipping can be summed up in the following statements:

1. It is essential to identify patients at high risk of post-resection bleeding. There is consensus about the role of large polyps located in the right colon. It also seems logical that the use of antiaggregants or anticoagulants increases the risk of bleeding. Other variables such as major comorbidity may play a role, although they are less important.

2. Clipping reduces the risk of delayed bleeding in large polyps located in the right colon, and when risk factors for delayed bleeding are combined.

3. Despite the fact that up to one-third of mucosal defects cannot be closed, clip closure remains effective globally in the subgroups that have been discussed.

4. Clip closure is not only effective but also cost-effective or even cost-saving in high-risk contexts.

5. It is essential to recognize the factors that hinder or prevent the complete closure of the scar. Several, such as size, histology, or submucosal lifting, are not modifiable, but others, such as ease of access to the polyp and en bloc resection, could be improved, at least in part. New studies are needed to corroborate the role of both these and additional factors.

6. New strategies for closing mucosal defects or covering them with hemostats are needed for patients where closure is considered indicated but is not possible.

7. Studies are needed to elucidate the role of clip closure in settings where there is a lower risk of delayed bleeding, such as large polyps of the left colon.

8. Despite knowledge gaps in this area, clear progress has been made in recent years.

Please take care in this pandemic so that we can continue moving forward.

Publication History

Article published online:
22 July 2021

• References

• 1 Hassan C, Repici A, Sharma P. et al. Efficacy and safety of endoscopic resection of large colorectal polyps: a systematic review and meta-analysis. Gut 2016; 65: 806-820
• 2 Nishizawa T, Ogata H, Suzuki H. et al. Effect of prophylactic clipping in colorectal endoscopic resection: a meta-analysis of randomized controlled studies. United Eur Gastroenterol J 2017; 5: 859-867
• 3 Pohl H, Grimm IS, Moyer MT. et al. Clip closure prevents bleeding after endoscopic resection of large colon polyps in a randomized trial. Gastroenterology 2019; 157: 977-984
• 4 Albéniz E, Álvarez MA, Espinós JC. et al. Clip closure after resection of large colorectal lesions with substantial risk of bleeding. Gastroenterology 2019; 157: 1213-1221
• 5 Spadaccini M, Albéniz E, Pohl H. et al. Prophylactic clipping after colorectal endoscopic resection prevents bleeding of large, proximal polyps: meta-analysis of randomized trials. Gastroenterology 2020; 159: 148-158
• 6 Shaukat A, Kaltenbach T, Dominitz JA. et al. Endoscopic recognition and management strategies for malignant colorectal polyps: recommendations of the US Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc 2020; 92: 997-1015
• 7 Ortiz O, Rex DK, Ian G. et al. Factors associated with complete clip closure after endoscopic mucosal resection of large colorectal polyps. Endoscopy 2021; 1150-1159
• 8 Soons E, Turan A, van Geenen E. et al. Application of a novel self-assembling peptide to prevent hemorrhage after EMR, a feasibility and safety study. Surg Endosc 2020; DOI: 10.1007/s00464-020-07819-7.