Prophylactic clip closure after endoscopic mucosal resection in the proximal colon: are we missing the mark or just the right technique?

Conventional endoscopic mucosal resection (EMR) is the existing standard of care for treating large (≥20 mm) nonpedunculated colorectal polyps (LNPCPs). Within the proximal colon, delayed bleeding remains the most common adverse event (9%–12%), and may require unplanned healthcare utilization, including the need for hospital admission, transfusion, endoscopic re-evaluation, and/or radiological intervention [1]. Recently, three large independent randomized controlled trials (RCTs), by Pohl et al., Albéniz et al., and Gupta et al., each demonstrated a relatively homogeneous effect with reduction in delayed bleeding from 9.6%–10.6% to 3.3%–4.6% following clip closure of the post-EMR defect in the proximal colon [2] [3] [4]. An individual-patient data meta-analysis (IPDMA) of these RCTs (n = 1150 patients) confirmed a reduction from 9% to 3.5% (odds ratio 0.31, 95 %CI 0.17–0.54), and yielded a number needed to treat of only 18 [5]. This benefit persisted in the presence of traditional risk factors for delayed bleeding, including LNPCP size >40 mm, cecal location, and antiplatelet therapy. Importantly, this Level 1 evidence has since been incorporated into major European and American guidelines [6] [7].

“… the theoretical benefit of a prophylactic technique such as clipping may not readily translate into real-world effectiveness if the technique is not applied with meticulous skill, with appropriate tools, and with a clear understanding of what constitutes effective closure.”

As these RCTs were predominantly conducted in expert tertiary centers, we must then ask, can the same results be obtained in a community setting? In this issue of Endoscopy, Kemper et al. answer this important question through the CLIPPER trial [8]. Recruiting between May 2018 and December 2021, this multicenter RCT enrolled 356 patients in 19 Dutch centers. Individuals were randomized to either clip closure (n = 177) or no closure (n = 179). Of the 19 centers, 13 were nonacademic, where the majority of EMRs (n = 259, 72.8%) were performed. A total of 59 endoscopists participated, including trainees. The primary end point of delayed bleeding within 30-days occurred in 9.0% of patients in the clip group and 6.1% in the no-clip group (P = 0.30). This disparity between groups and to the prior RCTs is incredible but highlights crucial deficiencies in the application of prophylactic clipping in a less controlled, more heterogeneous practice environment. One can only speculate, but these differences may be explained by: 1) a large number of endoscopists with varying EMR experience; 2) concerns pertaining to the efficacy of clips used and insufficient detail on the quality of clipping; and 3) inherently low-risk defects due to LNPCP location, size, and timing of randomization.

The real-world nature of the CLIPPER trial, while a strength in terms of generalizability, may also be its Achilles’ heel. The 59 participating endoscopists had a wide spectrum of both EMR experience and, critically, familiarity with clipping techniques. Furthermore, by crude estimates, each endoscopist performed an average of 6 cases during the 3.5-year study period (range 1–53). This is not a criticism but rather, highlights the variation in practice outside of expert centers. Importantly, in the Netherlands, expert endoscopists are not limited to academic centers but also work in nonacademic centers, and vice versa. Although a paradoxical finding, this may partly explain why delayed bleeding was consistently higher after clipping in both academic (10.4% vs. 8.2%) and nonacademic (8.5% vs. 5.4%) centers. Perhaps a better stratification would have been expert vs. nonexpert endoscopist. However, this was not defined, nor recorded in the study. Although the authors state clipping was “standardized in tutorial meetings,” this may fall short of the rigorous, consistent technique likely employed by highly experienced endoscopists in tertiary referral centers that dominate previous RCTs.

This leads to the second crucial point: effective clipping, especially of large, complex defects in the proximal colon, is technically demanding. The CLIPPER trial exclusively used the QuickClip Pro (Olympus, Tokyo, Japan). A prior ex vivo study demonstrated this clip to have poor rotatability in cases of strained scope configuration, including retroflexed positions within the proximal colon. Furthermore, it exhibited poor closure strength when compared with other commercially available clips, including those used in prior RCTs [9]. The performance characteristics of the chosen clip, particularly in less experienced hands or on challenging defects, may have significantly impacted closure efficacy. Nonetheless, the importance of proper technique cannot be overstated. Effective alignment and deployment require excellent communication with the assistant. The first clip should generally be placed at the gravity-dependent side to prevent the stem from falling across the defect, which only makes further clipping challenging. The clip should be closed slowly, once luminal gas has been sufficiently suctioned to facilitate eversion of the defect edges into the clip. Sequential closure should then be performed, aiming for a <5 mm gap between clips. In the CLIPPER trial, authors noted that “several participating endoscopists reported unsuccessful attachment of the clips,” a concerning observation that was unfortunately not systematically documented.

Perhaps most illuminating are the data on closure completeness. In line with prior RCTs, a complete closure rate of 71.8% was reported. In this subset, delayed bleeding occurred in 4.8%, which is not dissimilar to the 2.6% reported in the IPDMA [5]. However, the most striking difference occurs with partial closure. In the CLIPPER trial, this was associated with an alarming delayed bleeding rate of 19.6%, compared with 1.7% in the IPDMA. This is surprising, as partial closure should partly reduce the shear forces exerted on exposed submucosa and associated vessels. The authors rightly concede that there might have been an overestimation in partial closure at the expense of underestimated failed closure. Furthermore, the inability to independently assess the quality of clip closure from images due to absence or insufficient quality is a significant limitation.

Compared with prior RCTs, post-EMR defects may have been at an inherently lower risk of delayed bleeding. For example, Gupta et al. included a higher proportion of LNPCPs >40 mm and those within the cecum, a location that confers a >9-fold increase in delayed bleeding when compared with the proximal-to-mid transverse colon [4] [5]. Furthermore, in the CLIPPER trial, the proximal colon was defined as being proximal to and including the splenic flexure, a location at lower risk of delayed bleeding. Finally, the timing of randomization after EMR completion introduced a selection bias that allowed defects deemed too difficult to close to be excluded from the study. If enrolled and allocated to the clip group, they perhaps would have been classified as failed closure, a rate reported as only 1.7% (3/177) in this study compared with 8.3% (8/97) by Gupta et al. [4]. Thus, it is conceivable that the overall delayed bleeding risk profile in the CLIPPER cohort was lower, potentially diluting the true benefit of clip closure.

RCTs are important as they provide some of the highest levels of evidence. We commend the authors on conducting this multicenter RCT, including both academic and nonacademic centers. Despite its unexpected findings, the CLIPPER trial provides valuable insights. It underscores that the theoretical benefit of a prophylactic technique such as clipping may not readily translate into real-world effectiveness if the technique is not applied with meticulous skill, with appropriate tools, and with a clear understanding of what constitutes effective closure. Until these are optimized and consistently applied, the promise of prophylactic clipping may remain, for many, an unfulfilled one. It further highlights the idea that high-risk LNPCPs should be resected in expert centers where the risk of delayed bleeding may be better mitigated.

Publikationsverlauf

Artikel online veröffentlicht:
01. August 2025

• References

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