Screening colonoscopy can identify cancers at treatable stages and allow for the removal of adenomas before they become cancerous.1 A study of the natural history of unresected colonic polyps larger than one centimeter in size among patients who opted out of resection revealed a 24% chance of invasive adenocarcinoma development at the original polyp site and a 35% likelihood of carcinoma emergence at any colonic location over a 20-year period.2 Recent studies show that colorectal cancer screening and removal of precancerous colonic adenomas can reduce cancer incidence and related deaths by approximately 50%.3,4

Diminutive (measuring less than 5 mm) and small (ranging from 5 to 9 mm) colorectal polyps account for most colonic polyps. Strong evidence supports using en-bloc or oligo-piecemeal cold snare polypectomy (CSP) to remove these polyps.5 For medium-sized colorectal polyps (10 to 19 mm), cold snare endoscopic mucosal resection (CS-EMR) is increasingly preferred due to its safety.6 Current consensus published in the United States (US) recommended either EMR or CS-EMR as the appropriate techniques for removing lesions measuring 10 to 19 mm in size.5 Research suggests that CSP is a safe and effective method of managing colorectal polyps that are 6–20 mm in size. For non-pedunculated polyps between 6 and 15 mm, CS-EMR provides a high histological complete resection rate, similar to that of EMR, with fewer delayed complications. CS-EMR may become a valuable new cold-cutting technique following CSP.7 For large non-pedunculated colorectal polyps greater than 20 mm in size, conventional EMR is preferred for endoscopic resection due to its superior safety, efficacy, and cost-effectiveness to those of surgery or endoscopic submucosal dissection (ESD).8,9 Large polyps involving the ileo-cecal valve are difficult to resect but have better survival outcomes.10

After undergoing an EMR, patients may experience adverse events (AEs) such as bleeding during or after the procedure, bowel perforation, or post-polypectomy syndrome. The incidence of post-polypectomy bleeding or post-EMR bleeding ranges between 1% and 7%, mostly manifesting between several days and two weeks after the procedure. Post-polypectomy bleeding can be divided into two groups: immediate bleeding, which lasts for up to two days, and delayed bleeding (DB), which stands out as the most prevalent major AE and lasts for up to 30 days. It manifests in approximately 4% to 7% of patients after colorectal EMR, according to some studies. Most cases of the bleeding are treated endoscopically, and pre-procedure and peri-procedure planning can effectively prevent major bleeding.11-13 Recent advancements, such as using CO₂-insufflation, submucosal layer injection with chromo-injectables, employing a systematic inject-and-snare technique, and removing a margin of 2 to 3 mm of normal mucosa, have significantly enhanced the safety and efficacy of EMR, preventing major bleeding.14

Risk factors for post-EMR bleeding risk include polyps that are 10 mm or larger in size, right-sided colonic lesions, laterally spreading lesions, flat lesions, and sessile lesions. Anticoagulant use, thick-stalked pedunculated lesions, and comorbidities like cardiovascular or chronic renal disease also increase bleeding risk. The use of electrosurgical current also affects the risk of bleeding.15 These factors collectively contribute to the complexity and risk profile of post-EMR bleeding.16 Although various risk factors have been identified, the best method to prevent bleeding after colorectal EMR is still unclear, and no consensus exists on prophylactic therapy criteria, such as criteria on patient selection or lesion characteristics. Several risk scoring systems and risk prediction models have been validated to individualize management, but clear guidelines for prophylactic treatment are still lacking.17-19 Table 1 compares the European Society of Gastrointestinal Endoscopy (ESGE) guidelines to the American consensus guidelines on polypectomy in relation to the risk factors for bleeding after polypectomy.5,20

Prophylactic clipping during or after polypectomy, suturing, and use of coagulation methods have been used to reduce the AEs associated with EMR. The static clipping device was first introduced by Hachisu et al.21 to control bleeding in endoscopic procedures.22 Currently, several preloaded clip systems are commonly used, including the resolution clip manufactured by Boston Scientific in the US, the Quick-Clip manufactured by Cook Medical, and the Instinct clip produced by Cook Medical in the US. All existing clips were developed as preloaded clips and are rotatable after the introduction of the Resolution 360 clip by Boston Scientific. Additionally, EZ-clip (Olympus), which is a reloadable clip system, and some Chinese clips developed to reduce cost currently lack scientific evidence that supports their use.23,24 The selection of clips primarily depends on their mechanical properties, such as rotatability, overshoot, open/close precision, tensile strength, and deployment success rate, as well as pricing, availability, and endoscopist preference. The over-the-scope-clip system is a new device for endoscopically closing large mucosal defects and is mainly used for treating perforations during EMR. Its role in EMR has so far been mainly confined to the treatment of perforations.25 Resolution clips are known for their strong adherence to tissue and lasting for at least four weeks, which covers the period when most DB occurs. This makes them a popular choice among endoscopists for preventing DB.26 All types of clips demonstrated similar efficacy and safety, achieving successful deployment and mucosal healing. However, the overall retention rate of clips on fibrotic tissue is low; however, resolution clips have a better retention rate than the others.27

Two strategies for achieving hemostasis using through the scope clips include directly clipping the bleeding vessel or covering the entire wound area with clips. Clipping the bleeding vessel is generally preferred because it is faster and requires fewer clips. However, placing a clip within the resection ulcer can potentially cause perforation or new bleeding at the clip’s attachment site within the ulcer, which is a significant drawback. Dealing with DB caused by induration around the clip can be particularly challenging due to difficulty in clipping scarred granulation tissue. Clipping the entire resection area is accomplished through the zipper method or by using a modified version of the zipper closure technique, especially for those with larger or circular surface areas.27 Approximating the periphery of a wound before closure with the zipper technique involves strategically positioning clips. In cases of larger or circular lesions with widely spaced edges, the application of clips at two opposing peripheries of the wound can effectively reshape it into an almond-like-shaped wound. Subsequently, the process of clipping is continued between the initial clips in a manner resembling the closure of a zipper.23

A spacing of several millimeters to up to one centimeter between clips has been shown to be effective in achieving complete closure of the resection margins (Fig. 1).23 This technique is associated with a significant reduction in DB rates from 9.7% to 1.8%, indicating that patients in the control group are six times more likely to experience DB. Additionally, another study demonstrated that complete closure resulted in less DB than partial closure, with rates of 1.4% versus 5.9%, respectively (p=0.041). These findings suggest that optimal clip spacing and complete closure can substantially decrease the risk of DB after endoscopic procedures.18 Another study found no significant difference in efficacy between complete and partial closure (5.8% vs. 9.7%; p=0.17).28 A limitation of complete closure with prophylactic clipping is the abnormal appearance of the EMR scar, which is caused by tissue traction from the clips and is known as the clip artifact. This has been observed in about one-third of patients, especially after prophylactic clipping.29 An important aspect of the management of large proximal polyps is whether to perform full clip closure versus partial clip closure. Therefore, the authors would like to recommend full clip closure rather than partial clip closure (Fig. 2). Although the extent of effective partial clip closure for preventing post-EMR bleeding is not clearly defined, it remains a better alternative to no closure. For extensive circular resection surfaces, a variety of supplementary techniques, such as the combination of clips with an endoloop, have been recorded but are not very popular.30 Despite evidence supporting the efficacy of prophylactic clipping, it is imperative that stringent criteria govern its safe and appropriate application. Specifically, prophylactic clipping should be limited to radical resections to prevent the entrapment of residual adenomatous tissue. Authors usually space clips 0.5 to 1.0 cm apart (Fig. 2). None of the studies or guidelines has clear directions on these.

Prophylactic clipping is considered crucial for the routine management of EMR-related DB. This is particularly important for resections of large flat or sessile lesions in the proximal colon of greater than 2 cm in size, especially in patients receiving anticoagulant therapy. Studies on the benefit, efficacy, and effectiveness of prophylactic clipping have shown mixed results. A meta-analysis including randomized controlled trials found that the routine use of prophylactic clipping does not generally reduce the risk of post-polypectomy bleeding. However, it showed that clipping may reduce bleeding following the removal of large proximal lesions (greater than 20 mm).31-33 Some studies suggest that prophylactic clipping must be selective, and endoscopists should be more specific when selecting patients to undergo this procedure. Regarding the efficacy of clipping to prevent significant post-polypectomy bleeding, no difference was observed among subgroups, including subgroups by age, sex, antiplatelet/anticoagulant use, American Society of Anesthesiologists score, or size of the polyp. Clipping was not more effective in any specific subgroup.13 Clips were used effectively to manage deep mural injuries.34

A meta-analysis that analyzed four homogeneous randomized trials with a total of 1,248 patients found that the baseline risk of clinically significant post-endoscopy bleeding (CSPEB) after EMR of transverse colonic lesions was one percent. It was 6.1% in the ascending colon and 9.1% in the cecum, irrespective of the size of the lesion (the size ranged from 32.2–32.9 mm). The study concluded that prophylactically clipping lesions in the transverse colon was less efficacious in preventing CSPEB than prophylactically clipping lesions in the ascending colon or cecum. This finding differs from those of previous studies, which indicate that proximal colonic lesions (including those of the transverse colon) would benefit from prophylactic clipping. Because the distinction between the transverse colon and the ascending colon is not always obvious, it may be argued that it is reasonable to consider universal clipping of all proximal lesions. This differs from previous studies that have suggested that all proximal colonic lesions, including those of the transverse colon, benefit from clipping, leading some to advocate for the universal clipping of all proximal lesions.35 The perforation rate after colonic EMR for lesions greater than 2 cm in size was only 1.5%. A few other meta-analyses on prophylactic clipping are compared in Table 2.36-38

Nevertheless, prophylactic clipping has been shown to be cost-effective only when selectively applied to high-risk patients. Because of uncertainty about its overall effectiveness, recommendations for prophylactic clipping to prevent bleeding are nonspecific and based on moderate-quality evidence.39,40 The ESGE guidelines do not mention clipping for patients being administered antiplatelets or anticoagulants, but the American guidelines recommend it conditionally (Table 3). Therefore, the guidelines for managing colonic polyps vary between the organizations, reflecting their different approaches to balancing risks and benefits.5,20

This warrants consideration of various other dimensions, such as the cost-effectiveness and consideration of other modalities. The cost-effectiveness of prophylactic clip closure after EMR of large polyps was evaluated in a prospective multicenter study across both Spanish and US economic contexts. It was found that selective clipping in the high-risk DB GSEED-RE2 subgroup was more cost-effective and cost-saving than universal clipping, further emphasizing the value of selective clipping for high-risk patients.41

The inquiry into the cost-effectiveness of prophylactic clipping runs parallel to the investigation of its efficacy. A preliminary assessment of cost-effectiveness can be conducted by using the average number of clips used and the estimated costs per clip. An economic model for prophylactic clipping was employed by Bahin et al.,42 and they determined that an average cost of €15.57 per clip was required to offset the expenses incurred from therapies for DB (with an average cost per incident of €2,445) when prophylactic clipping was judiciously applied to proximal lesions. Nonetheless, this cost may escalate in instances where a reduced number of clips are required to achieve adequate prophylaxis. A 2013 cost-effectiveness study conducted in Australia found that using multiple prophylactic clips in low-risk cases, or more than one clip in patients on antiplatelets and anticoagulants, at a cost of 150 Australian dollars per clip was not cost-effective.43

Moreover, it is essential to consider whether clipping consistently represents the most effective method for achieving hemostasis and preventing delayed hemorrhage after EMR. Numerous alternative hemostatic agents and devices are in development, which may potentially rival clips in managing and preventing bleeding. Several topical agents, including Hemospray (Cook Medical), EndoClot (Plus LTD), and PuraStat gel (3D Matrix), are available, but no direct comparative studies with clips have been performed. Clips are currently considered superior to these agents in treating and preventing bleeding in high-risk, large lesions. However, it is conceivable that these agents may have a future role in managing smaller lesions or in situations where clipping is technically challenging.

The most established powder agents used for controlling gastrointestinal bleeding are TC-325 (Hemospray), EndoClot, and Ankaferd Blood Stopper (ABS; Hüseyin Cahit Fırat). These agents have been successfully applied to the management of upper and lower gastrointestinal bleeding of variety etiologies in the form of primary, combination, salvage, and bridging therapy. Few AEs have been reported with these agents, including visceral perforation, venous embolism, and self-limited abdominal pain.

Hemospray (constituted of bentonite) is a non-reactive powder made up of minerals that swiftly assimilates water when it interacts with blood, thereby forming an adhesive barrier that aids in mechanical tamponade and concentrates clotting factors.44 Hemospray (TC-325) is the most widely researched static powder in the medical field, and it is also the most often used. Numerous studies support its efficacy in various gastrointestinal bleeding contexts. Its effectiveness is well documented in post-procedural bleeding, such as after EMR and polypectomy, even when used by less experienced practitioners. AEs are rare, with rebleeding rates of 11% at 7 days and 14% at 30 days, according to a comprehensive meta-analysis.45 Thromboembolic disease and abdominal pain are some AEs associated with its use, and one case of endoscope adhesion to the mucosa for 48 hours was also reported.46,47 Spray catheter occlusion is well documented. To prevent this, prolonged insufflation is performed by some practitioners after blood aspiration to dry the channel before applying the powder.

EndoClot is a polysaccharide static system used in controlling upper gastrointestinal bleeding, and it has immediate hemostasis rates that range from 83% to 100% and bleeding recurrence rates that range from 11% to 23%.48 One observational study involving 82 patients with 181 lesions showed that Endoclot is effective in controlling and preventing EMR-related bleeding.49 Preventive use after high-risk EMR and ESD for gastric polyps resulted in a 7.3% rebleeding rate within 3 days.50

Some studies have compared the rates of hemostasis and rebleeding between TC-325 and EndoClot, with the results being similar. However, the sample sizes were small, and the studies were not randomized controlled trials.51 Like TC-325, EndoClot has a shorter residence time in the intestinal lumen, which may restrict its use for high-risk lesions due to frequent rebleeding within 24 to 72 hours.

ABS is made up of herbal extracts from five different plants, including Glycyrrhiza glabra, Urtica dioica, Vitis vinifera, Thymus vulgaris, and Alpinia officinarum. No quality evidence for its use for post-EMR bleeding exists other than case reports.52

The previously mentioned powders exhibit high rates of immediate hemostasis, particularly in situations unsuitable for traditional endoscopic techniques; however, their use is constrained by a considerable incidence of rebleeding.53

PuraStat, a biocompatible synthetic peptide gel from 3D Matrix Europe SAS, is another hemostatic agent used in endoscopic therapy. Effective in managing perioperative bleeding and preventing DB in high-risk CSP cases, it is proposed as an alternative to clipping.54 A few studies also found that it is clinically effective in reducing the use of heat therapy during ESD and EMR, and it also improves wound healing.55,56 The transparent gel, made from a specific amino acid sequence, self-assembles into beta-protein sheets upon contact with neutralizing fluid, forming a hydrogel scaffold resembling the human extracellular matrix. Its transparency ensures clear visibility of the bleeding area and a clear endoscopic view, while its formulation avoids catheter channel clogging, which is a common problem with other powder formulations.

PuraStat with an additional hemostatic method achieved successful hemostasis in 91% of cases, with a rebleeding rate of 10% in patients that underwent EMR. It was also used to stop intraprocedural bleeding during the EMR.57 PuraStat might not be adhesive enough to hold its position over time in moderately or severely inflamed tissues, such as those in inflammatory bowel disease, highlighting the need for further studies.58

Endoscopists reported a high degree of satisfaction with the application of hemostatic powders in studies assessing the ease of their use. No endoscope blockages or camera obscuration were reported in the reviewed studies, compared with other methods. Currently, no recommendations can be made about the optimal gel quantity. Problems include difficulty applying the gel to dependent surfaces and premature rinsing due to peristalsis and mucus.59

However, when considering the cost, cost-saving models have shown that prophylactic clipping can save US dollar (USD) 287 for all large colon polyps, USD 434 for right colon polyps, USD 131 for all extra-large colon polyps, and USD 69 for all large colonic polyps in patients on anticoagulants.60 PuraStat costs USD 250 and USD 430 for 3 mL and 5 mL, respectively, with USD 18 for the designated catheter.61 The cost-effectiveness of PuraStat for preventing CSPEB has not been evaluated.

Prophylactic clipping, except in cases of large left-sided colonic polyps, seems ineffective in preventing bleeding or perforation. However, it is still performed by many endoscopists worldwide due to a “fear” of bleeding and perforation. This practice is not cost-effective. Prophylactic clipping coupled with PuraStat or PuraStat alone may be a better option, but this requires further studies.