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Original article Clinical endoscopy: Editorial| Volume 82, ISSUE 5, P910-911, November 2015

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Clipping after polyp resection: uncertainties of a randomized trial

      Abbreviation:

      ESD (endoscopic submucosal dissection)
      Endoscopic resection is considered the primary mode of removal of large colorectal polyps. A moderately high rate of delayed bleeding after endoscopic resection remains a concern, which occurs in 2% to 10% of patients after wide-field EMR of ≥20 mm polyps.
      • Burgess N.G.
      • Metz A.J.
      • Williams S.J.
      • et al.
      Risk factors for intraprocedural and clinically significant delayed bleeding after wide-field endoscopic mucosal resection of large colonic lesions.
      • Liaquat H.
      • Rohn E.
      • Rex D.K.
      Prophylactic clip closure reduced the risk of delayed postpolypectomy hemorrhage: experience in 277 clipped large sessile or flat colorectal lesions and 247 control lesions.
      Closing the mucosal defect after resection with clips has long been entertained as a way to reduce the risk of bleeding. Although clips are increasingly applied after EMR, the evidence to support this practice is largely based on 1 retrospective analysis by Liaquat et al
      • Liaquat H.
      • Rohn E.
      • Rex D.K.
      Prophylactic clip closure reduced the risk of delayed postpolypectomy hemorrhage: experience in 277 clipped large sessile or flat colorectal lesions and 247 control lesions.
      published 2 years ago. In that study, complete clip closure of the mucosal defect was associated with a 2% delayed bleeding rate compared with a 10% bleeding rate among historical control patients who did not undergo clip closure. A recent report from a large Spanish cohort presented at Digestive Disease Week also suggested a reduced risk of delayed bleeding after clip closure.
      • Albeniz E.
      • Fraile M.
      • MartíNez-Ares D.
      • et al.
      Delayed bleeding risk score for colorectal endoscopic mucosal resection.
      In contrast, a retrospective study and 1 randomized trial have not shown a benefit of clips to prevent bleeding.
      • Qumseya B.J.
      • Wolfsen C.
      • Wang Y.
      • et al.
      Factors associated with increased bleeding post-endoscopic mucosal resection.
      • Shioji K.
      • Suzuki Y.
      • Kobayashi M.
      • et al.
      Prophylactic clip application does not decrease delayed bleeding after colonoscopic polypectomy.
      However, the randomized trial enrolled low-risk patients with polyps of any size, and the study was underpowered to show a meaningful difference as significant.
      In this issue of the journal, Zhang et al
      • Zhang Q.-S.
      • Han B.
      • Xu H.-H.
      • et al.
      Clip closure of defect after endoscopic resection in patients with larger colorectal tumors decreased the adverse events.
      from Shanghai, China, present the first data from a randomized trial of using clips to close the mucosal defect after endoscopic resection of 10-mm to 40-mm nonpedunculated colorectal polyps. Patients underwent either an EMR for 10-mm to 19-mm polyps or an endoscopic submucosal dissection (ESD) or a circumferential ESD followed by snare resection (hybrid ESD) for ≥20 mm polyps. Patients receiving anticoagulant agents were excluded. The patients were randomized to undergo clip closure or no clip closure of the mucosal defect after resection. The study found significant improvements after clip application in all primary outcomes of interest: The clip group had a lower delayed bleeding rate (1.1% vs 6.9%), a lower rate of postpolypectomy syndrome (0.6% vs 4.6%), and a lower rate of abdominal pain (2.8% vs 16.7%). The authors also performed an economic analysis. On average, 7 clips were placed to close the defect, which led to a 7-minute longer procedure time. The hospital stay was shorter for patients who underwent clipping (3.1 days) compared with those who did not (4.7 days), resulting in an overall similar cost expense for both groups.
      The strength of the study lies in its randomized design. Although different resection methods were used, the baseline characteristics in both groups appear similar regarding factors that might affect bleeding or other adverse events, including resection methods, polyp size, and polyp location in the colon. However, before we adopt the results of the study as a game changer, and start clipping every lesion after an EMR, we should pause, examine the study details, and consider whether the results are valid and are applicable to our patients.
      Several issues about the study design and methods are worth noting. First, in contrast to previous studies on wide-field EMR of ≥20 mm polyps, this study included patients with smaller polyps ≥10 mm, in whom a lower risk for adverse events should be expected. The risk of delayed bleeding for these patients has been reported at approximately 2%.
      • Kaltenbach T.
      • Friedland S.
      • Maheshwari A.
      • et al.
      Short- and long-term outcomes of standardized EMR of nonpolypoid (flat and depressed) colorectal lesions > or = 1 cm (with video).
      • Watabe H.
      • Yamaji Y.
      • Okamoto M.
      • et al.
      Risk assessment for delayed hemorrhagic complication of colonic polypectomy: polyp-related factors and patient-related factors.
      • Gimeno-Garcia A.Z.
      • de Ganzo Z.A.
      • Sosa A.J.
      • et al.
      Incidence and predictors of postpolypectomy bleeding in colorectal polyps larger than 10 mm.
      The authors’ assumption of a 7% bleeding rate in designing the trial was likely overestimated in this group, leading to a possibly underpowered study. This estimate was abstracted from studies on ESD of much larger lesions than those included in the study, and it should not have been applied to their patient population. Therefore, one wonders more about the high bleeding rate observed in the control group rather than the low rate in the intervention group. A 5% rate of postpolypectomy syndrome in the control arm is also higher than the 1% to 2% rate after EMR of even larger lesions.
      • Moss A.
      • Bourke M.J.
      • Williams S.J.
      • et al.
      Endoscopic mucosal resection outcomes and prediction of submucosal cancer from advanced colonic mucosal neoplasia.
      Abdominal pain occurred in 17% of patients in the control group, again higher than previously reported. In a large cohort study, abdominal pain requiring admission occurred in fewer than 6% of patients after wide-field EMR when air insufflation was used, but decreased to only 1% after introduction of CO2.
      • Bassan M.S.
      • Holt B.
      • Moss A.
      • et al.
      Carbon dioxide insufflation reduces number of postprocedure admissions after endoscopic resection of large colonic lesions: a prospective cohort study.
      It is also difficult to explain how clip closure would lead to an improvement in abdominal pain.
      One may speculate about the reasons for the unexpected high rate of adverse events. Despite similar presented baseline characteristics, patients in the intervention group may still have been different from the control group (varying bleeding risk, multiple polyps, use of antiplatelet agents), or they may have undergone a different intervention (more ESD than EMR), or were treated differently at participating centers. It would have added strength to the study if it had provided additional details on patients who had adverse events in reference to those who did not.
      Second, the intervention included variable endoscopic resection techniques including ESD and hybrid ESD for ≥20-mm polyps. In contrast to the common practice in Asian countries, this would not reflect typical practice in the West, where EMR is more common.
      Third, the main outcomes of interest are not well defined. To understand, interpret, and generalize the main findings of a study, one needs to know what exactly was measured. Delayed bleeding was defined as overt hematochezia. It is possible that less than severe bleeding events were considered as delayed bleeding, making interpretation more subjective. Similarly, the definition of postpolypectomy syndrome leaves room for interpretation. Signs or symptoms of peritoneal irritation were sufficient to make the diagnosis. Furthermore, no definition of abdominal pain was provided. Clearly, a vague definition of outcomes that matter leaves room for subjective interpretation, introduces bias, and makes the main results less interpretable.
      Fourth, patients were admitted to the hospital after polyp resection for 3 to 5 days, a practice that is very different from that in many other countries, where the majority of patients are discharged the same day. The cost analysis is therefore applicable only to local practice.
      Given some of the methodologic problems, the study does not provide definitive guidance on the topic. What are important design features for a definitive clip trial? First, patient selection should reflect those patients we care for most frequently. Second, the resection technique should reflect general clinical practice. Third, the outcome measures should be clearly defined and, more importantly, less subjective in nature. For example, delayed bleeding should be defined as an event with clear clinical implications (eg, admission to the hospital or minimum drop in hemoglobin). More subjective outcomes may be better assessed by standardized validated instruments completed by patients unaware of the assignment. Finally, an economic analysis is important enough for a separate exercise. Trialists should focus on performing the main study well and gather appropriate information for a formal cost-effectiveness analysis; a “back of the envelope” calculation that does not consider all relevant costs (direct and indirect) and benefits (short-term and long-term benefits) is not generalizable and should be avoided.
      In conclusion, the study does not provide a final answer to whether the mucosal defect after polyp resection should be closed with clips, despite its randomized design. Clearly, this study strongly points to closing the defect. However, based on variable resection techniques that were used in this study, not well-defined outcome measures, and limited information on patient outcome, the results need to be considered with caution. Although clip closure has become standard in many practices, we should continue to examine its value, not just because of the high cost of clips, but also because we should strive for high-quality endoscopy and critically examine whether our practice improves care.

      Disclosure

      Dr Pohl is a consultant for Interscope.

      References

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        Prophylactic clip closure reduced the risk of delayed postpolypectomy hemorrhage: experience in 277 clipped large sessile or flat colorectal lesions and 247 control lesions.
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        Delayed bleeding risk score for colorectal endoscopic mucosal resection.
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        Prophylactic clip application does not decrease delayed bleeding after colonoscopic polypectomy.
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