- Email: [email protected]
Endoscopic hand-suturing is feasible, safe, and may reduce bleeding risk after gastric endoscopic submucosal dissection: a multicenter pilot study (with video)
Journal Pre-proof Endoscopic hand-suturing is feasible, safe, and might contribute in reducing bleeding risk after gastric endoscopic submucosal dissection: a multicenter pilot study (with video) Osamu Goto, Tsuneo Oyama, Hiroyuki Ono, Akiko Takahashi, Mitsuhiro Fujishiro, Yukata Saito, Seiichiro Abe, Mitsuru Kaise, Katsuhiko Iwakiri, Naohisa Yahagi PII:
S0016-5107(20)30007-9
DOI:
https://doi.org/10.1016/j.gie.2019.12.046
Reference:
YMGE 11910
To appear in:
Gastrointestinal Endoscopy
Received Date: 25 September 2019 Accepted Date: 22 December 2019
Please cite this article as: Goto O, Oyama T, Ono H, Takahashi A, Fujishiro M, Saito Y, Abe S, Kaise M, Iwakiri K, Yahagi N, Endoscopic hand-suturing is feasible, safe, and might contribute in reducing bleeding risk after gastric endoscopic submucosal dissection: a multicenter pilot study (with video), Gastrointestinal Endoscopy (2020), doi: https://doi.org/10.1016/j.gie.2019.12.046. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020 by the American Society for Gastrointestinal Endoscopy
Original article Endoscopic hand-suturing is feasible, safe, and might contribute in reducing bleeding risk after gastric endoscopic submucosal dissection: a multicenter pilot study (with video)
Osamu Goto,1 Tsuneo Oyama,2 Hiroyuki Ono,3 Akiko Takahashi,2 Mitsuhiro Fujishiro,4 Yukata Saito,5 Seiichiro Abe, 5 Mitsuru Kaise,1 Katsuhiko Iwakiri,1 Naohisa Yahagi6 1. Department of Gastroenterology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan 2. Division of Endoscopy, Saku Central Hospital Advanced Care Center, Saku, Japan 3. Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan 4. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan 5. Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan 6. Division of Research and Department for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan
Correspondence and request for reprints to: Osamu Goto, MD, PhD, Department of Gastroenterology, Nippon Medical School Graduate School of Medicine 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan Tel: +81-3-3822-2131; Fax: +81-3-5814-6289 Email: [email protected]
ABSTRACT Background and Aims: Endoscopic hand-suturing (EHS) provides secure intraluminal mucosal closure and should decrease the risk of adverse events after gastric endoscopic submucosal dissection (ESD). We prospectively investigated the feasibility and safety of EHS after gastric ESD, particularly for preventing post-ESD bleeding. Methods: Patients scheduled for gastric ESD at 3 institutions were prospectively recruited. Just after ESD, the mucosal defect was closed by EHS. The primary outcome was endoscopic assessment of adequately sustained closure of the defect on postoperative day (POD) 3. Endoscopy was performed to assess maintenance of the closure for the primary outcome. During postoperative week 3 to 4, the patients were interviewed as outpatients about any occurrence of delayed bleeding. Results: Data from 30 patients (15 each who did or did not take antithrombotic agents [ATAs]) were analyzed. Mucosal closure by EHS was completed in 29 of 30 cases (97%) and was well maintained on POD 3 in 25 cases (84%). Emergency endoscopy was required for major postoperative bleeding in 3 cases (10%), including the one in which suturing had been incomplete. Excluding one patient with a remnant stomach, the other 24 with sustained closure had no bleeding, regardless of whether they did or did not take ATAs (0/11 and 0/13, respectively). No serious adverse events occurred during EHS. Conclusions: The results show that EHS is feasible and safe with favorable outcomes. Provided that mucosal suturing is successfully completed and sustained, post-ESD bleeding can be decreased even in patients undergoing antithrombotic therapy.
1
Trial registration number: UMIN000033988.
Keywords Antithrombotic agents, Endoscopic hand-suturing, Endoscopic submucosal dissection.
INTRODUCTION Owing to the recent development and establishment of therapeutic endoscopy, endoscopic procedures for curative treatment have been expanded. In particular, endoscopic submucosal dissection (ESD), that is, circumferential mucosal incision followed by submucosal dissection, is widely accepted as a less-invasive, potentially curative procedure to treat node-negative, early stage gastrointestinal cancers.1-3 However, compared with other endoscopic treatments, ESD has a relatively high risk of adverse events.4 Effective countermeasures to prevent these events are therefore needed. Postoperative bleeding is a particularly urgent issue to address, especially as the number of patients taking antithrombotic agents (ATAs) for other disorders is increasing.5 The risk of bleeding after gastric ESD is estimated to be 5% in conventional low risk cases, but up to approximately 30% in a high-risk cohort of patients, including those on ATAs.6-9 A previous meta-analysis7 showed that influential factors for post-ESD bleeding included the male sex, cardiopathy, cirrhosis, chronic kidney disease, tumor/resected specimen size, location in the lesser curvature, flat or depressed type, carcinoma, ulceration, long procedure duration, histamine-2 receptor antagonists instead of proton pump inhibitors, and ATAs. Generally, the bleeding risk tends to increase with the increase in the number of ATAs, ie, patients undergoing dual antiplatelet therapy or combined use of antiplatelet agents and anticoagulants appear 2
to be at a higher risk of post-ESD bleeding compared with patients being administered a single agent. If postprocedure bleeding occurs, emergency endoscopy is necessary to identify the site of bleeding in the mucosal defect and to perform endoscopic hemostasis. Such patients often require blood transfusions or rehospitalization to stabilize their condition. In a patient taking ATAs, perioperative discontinuation of these agents would minimize the risk of post-ESD bleeding, but this must be weighed against the risk of potentially lethal thrombotic events for which the ATAs were prescribed in the first place.10-12 Therefore, a method that minimizes the risk of post-ESD bleeding while allowing patients to continue taking their ATAs is greatly needed. Although several measures such as the use of gastric antisecretory agents13-14 or precoagulation of exposed vessels just after resection15 have been attempted, these have not adequately reduced the incidence of postoperative bleeding. As long as the mucosal defect remains open, exposure to various stimuli such as gastric acid, reflux bile, food, and peristalsis still poses substantial risk. The most effective means of decreasing the chance of bleeding would seem to be closure of the mucosal defect. However, conventional endoscopic methods of tissue apposition with endoclips are often unsuccessful due to the thickness of the mucosal layer. Dehiscence easily occurs despite temporary closure of the defect.16 Therefore, a tight and long-lasting closure method is mandated to successfully prevent postoperative bleeding.17,18 Endoscopic hand-suturing (EHS) appears to be a suitable technique to address this problem. It involves continuous linear suturing endoscopically by using a commercially available absorbable barbed suture and a prototype of a through-the-scope flexible needle holder.19,20 We successfully demonstrated the
3
feasibility and safety of this technique ex vivo,19 in vivo, and in a small number of clinical cases.20 However, evidence is still lacking in terms of indications, technical ability to access the lesion, and whether it in fact reduces the incidence of post-ESD bleeding. Therefore, we prospectively investigated the feasibility, safety, and efficacy of this new suturing technique in a multicenter study to evaluate its value in routine clinical settings. METHODS
Participants This phase I pilot study was approved by the Institutional Review Board at all 3 participating institutions and registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000033988). Participants were prospectively recruited according to the following criteria: individuals were eligible if (1) aged ≥20 years with a single clinically or histologically diagnosed early gastric cancer of ≤3 cm, which fulfilled criteria for ESD in the Japanese gastric cancer treatment guidelines21; (2) they were scheduled to undergo gastric ESD at one of the participating institutions; and (3) they had an Eastern Cooperative Oncology Group performance status score of 0 or 1.22 All patients provided written informed consent, both to participate in the trial and to undergo ESD.
Endoscopic submucosal dissection Patients were admitted and underwent ESD under intravenous sedation in a conventional manner described elsewhere.1-3 Briefly, after placing an overtube from the mouth to the upper esophagus, the 4
endoscope was introduced, the stomach was cleaned, and the location of the lesion was confirmed. The mucosa was marked circumferentially approximately 5 mm outside the margin of the neoplasm using the tip of the electrocautery device, followed by submucosal injection to elevate the lesion appropriately. Using an electrocautery knife specially designed for ESD, we made a circumferential mucosal incision outside the markings, followed by submucosal dissection to remove the lesion en-bloc with endoscopically negative surgical margins. Intraoperative bleeding was stopped with electrocautery knives or hemostatic forceps. After transoral retrieval of the lesion, the mucosal defect was closely observed and exposed visible vessels in the defect were ablated with electrocautery.
Endoscopic hand-suturing EHS to close the mucosal defect was then performed by a single endoscopist at each institution who had sufficient experience in gastric ESD (at least 500 cases; Figure 1, Video 1). For EHS, a V-loc 180 absorbable barbed suture (VLOCL0604; Covidien, Mansfield, Mass, USA) and a through-the-scope flexible needle holder (Olympus, Tokyo, Japan) were prepared.19,20 The suture was grasped with the needle holder close to the tail of the needle so that the needle dangled freely as it was carefully delivered into the stomach through the overtube. After freeing the suture and grasping the needle at the optimal site (one-third to one-fourth the distance from the tail of the needle), the first stitch was placed on either mucosal margin of the defect. The needle was extracted and passed through a loop on the tail of the suture. After tightening the first suture, continuous suturing was performed in a linear fashion at an interval of approximately 5 mm and a bite
5
of more than 8 mm. To facilitate suturing, grasping forceps (FG-21L-1; Olympus) were inserted through another working channel of an endoscope mounted with dual working channels (GIF-2TQ260M; Olympus) and used for assistance as needed. After obtaining complete closure, an endoclip (HX-610-090S; Olympus) was placed at the final stitch to bind the bottom of the suture and the mucosal surface. The needle was then removed by cutting the remaining suture with a prototype of scissors forceps (Olympus). The procedure was finished with retrieval of the needle transorally through the overtube by grasping the suture with the needle holder.
Postprocedural management Antisecretory agents (proton-pump inhibitors or a potassium-competitive acid blocker) were administered from the day of the procedure for at least 14 weeks. On postoperative day (POD) 1, after confirming the absence of symptoms or of abnormal findings on chest radiograph and laboratory tests, the patients not taking an ATA were allowed to have soft food, whereas those on ATAs were given a liquid diet. For the latter, the diet was gradually advanced to soft food while they were monitored for signs of bleeding. On POD 3, based on the presumed minimal tensile strength of a sutured site in an animal model,23 follow-up endoscopy was performed to judge whether the sutured mucosal defect remained closed without dehiscence. Patients were discharged on POD 4 or later depending on their condition, with an outpatient visit scheduled during postoperative week 3 to 4. They were asked about signs of postoperative bleeding after discharge. When major postoperative bleeding (as defined below) was suspected, emergency endoscopy was performed.
6
If active bleeding or any signs of recent bleeding from exposed vessels was seen, endoscopic hemostasis was performed mechanically with endoclips or using electrocautery with hemostatic forceps. Perioperative management of ATAs was determined by the endoscopist based on guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment.24
Outcome measures The primary outcome of the study was closure of the sutured site on POD 3. Closure was defined as sustained if the mucosal defect remained closed without dehiscence, partially sustained if there was partial opening with dehiscence, or unsustained if the defect was completely open. Technical aspects of EHS assessed included completeness of suturing, time required for suturing (minutes), and number of stitches. Completeness was defined as suturing with no discontinuities. The time required was measured from the first insertion of the needle in the mucosa to cutting the remaining suture to freeing the needle. To assess safety, adverse events associated with EHS were recorded. To evaluate the efficacy of EHS, postoperative bleeding, major or minor, was analyzed. Major bleeding was defined as endoscopically diagnosed bleeding or stigma of bleeding at the post-ESD mucosal defect on emergency endoscopy, which was performed in cases of hematemesis or melena or for a decrease in the serum hemoglobin level of >2 g/dL. Minor bleeding was defined as clinically irrelevant bleeding, such as transient melena with spontaneous bleeding or incidental bleeding seen on the follow-up endoscopy on POD 3.
7
Bleeding was compared between patients who were or were not taking ATAs. The technical aspects were compared among the participating institutions.
Sample size Because this was a phase I pilot study, we did not calculate a required sample size. Based on projected enrollment at each institution, we aimed to recruit a total of 30 participants (10 per institution), equally divided between those who were or were not taking ATAs.
Statistical analysis For the 2 groups with or without ATAs, categorical data were compared using the Fisher exact test and continuous data using the t-test or Mann–Whitney U test for data with a normal or non-normal distribution, respectively. For comparisons among the 3 institutions, categorical data were analyzed using the Pearson chi-squared test and continuous data using one-way analysis of variance or the Kruskal–Wallis test, depending on the data distribution. All analyses were performed by with IBM SPSS statistics version 25 (IBM Corp., Armonk, NY, USA), and a P-value <0.05 was considered significant. RESULTS Enrollment and procedures Between December 2018 and June 2019, 32 patients were enrolled in the study. One was excluded when ESD had to be discontinued due to severe bradycardia requiring resuscitation. This left 31 patients who
8
underwent ESD with EHS. However, one erroneously underwent follow-up endoscopy on POD 1. Therefore, 30 patients (10 from each institution), underwent the complete study protocol and were analyzed (Figure 2, Table 1). One patient had previously undergone distal gastrectomy for gastric cancer and therefore had only a remnant stomach. ATAs that were administered to 15 patients (5 from each institution) were aspirin (n = 3), apixaban (n = 2), ethyl icosapentate (n = 2), clopidogrel sulfate (n = 2), omega-3-acid ethyl esters (n = 1), prasugrel hydrochloride (n = 1), ticlopidine hydrochloride (n = 1), aspirin and clopidogrel sulfate (n = 1), aspirin and prasugrel hydrochloride (n = 1), and clopidogrel sulfate, rivaroxaban, and ethyl icosapentate (n = 1). Antiplatelet agents were the predominant ATA (13 patients, 87%). In all 15 cases, the ATAs were continued periprocedurally. In all 30 cases, ESD was successfully performed without adverse events (Table 1). The lesions were completely resected, as evaluated both endoscopically and histologically. Overall outcomes Feasibility and safety The mean defect size created by ESD was 37.3 ± 7.0 mm (Table 2). EHS was successfully completed in 29 of the 30 cases (97%). The mean time needed for suturing was 46.2 ± 17.0 minutes, and a mean of 8.7 ± 1.4 stitches were placed, indicating an average of 5.3 minutes/stitch. One patient had a 20-mm mucosal defect in the lesser curvature at the upper third of the stomach, and EHS was discontinued due to technical difficulty. In this case, the defect was partially closed with 3 stitches, requiring 75 minutes. Follow-up endoscopy on POD 3 showed sustained closure in 25 patients (83%) and partially sustained closure in 5 (17%, including the 1 patient with incomplete EHS). In all of the latter cases, the defect
9
was in the lesser curvature. None of the closures were unsustained. Discounting the case in which EHS was discontinued after 3 stitches, complete closure was sustained in 25 of 29 cases (86%). In one case, minor arterial bleeding occurred from the puncture site when the tip of the needle was inserted into the mucosa but then removed to correct the direction of insertion. This bleeding was easily stopped endoscopically by electrocoagulation with hemostatic forceps and EHS was continued thereafter. No other adverse events occurred during EHS.
Efficacy Major postoperative bleeding occurred in 3 patients (10%), 2 on POD 1 and 1 on POD 6. Of those 3, 2 had a partially sustained closure and one was the patient with a remnant stomach. Consequently, of the 24 patients with a surgery-naïve stomach who had sustained closure, no major bleeding occurred. One patient who was not on an ATA had hematemesis on POD 1. A 30-mm mucosal defect on the lesser curvature in the mid stomach had been closed with 9 stitches in 72 minutes. Emergency endoscopy revealed bleeding from a partially dehisced closure site. The other patient with bleeding on POD 1 was the one in whom EHS was discontinued as mentioned above. This patient was taking aspirin for ischemic heart disease. The patient who bled on POD 6 reported melena and dizziness and was readmitted the next day. This was the patient with the remnant stomach who was also being treated with clopidogrel sulfate for valvular heart disease. The 35-mm mucosal defect on the lesser curvature below the cardia was successfully sutured, a closure which was sustained on the POD 3 follow-up endoscopy. On rehospitalization on POD 7, the patient’s
10
hemoglobin level had dropped, requiring transfusion. On emergency endoscopy, however, there was no apparent active bleeding or blood in the stomach. The sutured site remained closed with only slight black stigmata seen. Although no definite evidence of bleeding could be detected at the sutured site, we still counted the patient as having delayed postoperative bleeding. One case of minor bleeding occurred in a patient taking apixaban, which was incidentally found at a scheduled endoscopy on 3POD. Bleeding was easily stopped endoscopically.
Comparison of groups with or without antithrombotic agents In terms of the technical aspects of EHS, there were no apparent differences between patients taking or not taking ATAs (Table 3). The sustainability of closure was equivalent. Major postoperative bleeding occurred in 2 patients taking and one not taking ATAs. The one case of minor bleeding occurred in a patient taking ATAs. None of these differences were statistically significant.
Comparison of institutions The technical outcomes of EHS did not differ significantly among the 3 participating institutions (Table 4). However, all 5 cases of partially sustained closure on POD 3 were at C (a significant difference), as were 2 of the 3 cases of major bleeding. DISCUSSION This prospective multicenter pilot study demonstrated that EHS for closure of mucosal defects after
11
gastric ESD was safe regardless of administration of ATAs. There was a high rate of sustained closure on POD 3. The postoperative bleeding rate was considered acceptable, and the data suggest that successful EHS with sustained closure might decrease the risk of bleeding, particularly in patients being administered ATAs. In closing mucosal defects created by gastric ESD, the following 2 issues must be addressed: technical feasibility and sustainability of the closure. The technical challenge arises because the gastric mucosa is thick and quite firm compared with other parts of the tract such as the esophagus or colon. Therefore, conventional endoclips easily slip on the mucosal surface when attaching the edges of the defect to each other. Even if closure is initially obtained, sustainability is a problem. Outward traction on the defect facilitates dehiscence. Indeed, sustained closure using endoclips has been reported in only about 60% of humans.16 That may be because the remnant seromuscular layer continuously gives the outward traction to the suturing site. Therefore, even though mucosal closure can be completed, the sustainability of the closure is in jeopardy. In EHS, these 2 problems can be overcome with secure and tight suturing. By using a surgically proven suture with a curved needle and a needle holder to firmly grasp the needle, endoscopists can suture the mucosal rims as necessary. The edges can be tightly opposed by pulling on the slack part of the suture. This hand suturing method is similar to that in routine surgical practice and should provide secure and long-lasting closure of a gastric mucosal defect. In this study, we successfully demonstrated good results with EHS, completely closing the mucosal defect in 97% of cases, a complete closure that was sustained in 86%. EHS thus may be an ideal technique for endoscopic tissue apposition, although more evidence must be accumulated in humans on the frequency of dehiscence according to the location of the defect.
12
No severe adverse events occurred in this study. To avoid injury to the esophagus with the tip of the needle, we placed the overtube in the throat and held the suture rather than the needle itself, allowing the needle to dangle freely during delivery. Bleeding during EHS suturing was not serious. Even the one case of arterial bleeding we encountered was easily managed. This is not surprising as arterial bleeding frequently occurs during ESD and experienced endoscopists are equipped to manage it with endoscopic hemostasis. Complete and sustained closure of mucosal defects after gastric ESD would be expected to prevent postoperative bleeding. We found no bleeding in 24 cases of a completely sutured, sustained closure of a mucosal defect in a normal stomach. In contrast, among 5 cases with a partially sustained closure (including one incomplete closure), bleeding occurred in 2. It suggests that exposure of the mucosal defect inside the stomach will cause delayed bleeding. In the patient with a remnant stomach, bleeding occurred on POD 6 despite complete and sustained closure. The reason for this delayed bleeding is unclear, although the nature of the remnant stomach may be a possible cause. Vascularity in the remnant stomach is generally poor compared with the normal stomach due to systematic lymphadenectomy accompanied with removal of several major feeding arteries in gastrectomy. Relatively diminished blood flow may worsen healing of the mucosal defect. Therefore, a post-ESD bleeding in the remnant stomach may be more likely than in a surgically naïve stomach. Prevention of post-ESD bleeding by adequate defect closure is particularly important in patients with a high risk of bleeding. A meta-analysis reported a risk of delayed bleeding after gastric ESD of 5.0% in patients not on ATAs compared with 23.4% in those who continued taking ATAs perioperatively.8 Effective
13
means to prevent delayed bleeding in such individuals are desired. EHS appears to be a promising technique for this purpose, and we found it to have essentially the same efficacy regardless of whether patients were or were not taking ATAs. EHS may also reduce the length of hospital stay for patients at low risk of bleeding. In this study, the patients not taking ATAs tolerated an essentially normal diet the day after ESD. It is conceivable that same-day surgery may eventually be possible. A major drawback of EHS is that it is time-consuming. In the present study, EHS for mucosal defects approximately 4 cm in size required three-quarters of an hour for placement of n9 stitches. Even for endoscopists skilled in ESD, EHS is technically demanding. Furthermore, the time required and sustainability of the closure varied among endoscopists. This may be due to differences in the length of the bites as well as the degree of tightening, which would be difficult to standardize. However, over time, accumulating clinical experience may help overcome these technical drawbacks as is the case with other advanced endoscopic techniques such as ESD.25 Overstitch is a leading device among currently available endoscopic suturing methods.18 It can provide reliable mechanical suturing in a short time but is more complex and expensive. In contrast, EHS is manual and simple but time consuming. It enables endoscopists to suture the mucosa as desired by using a regular curved needle, although gentle maneuvering is required, which takes time. Every suturing technique has advantages and disadvantages, and combined use of different techniques might be a good alternative for complete and secure suturing. For example, Overstitch is difficult to use in some locations and angles. In these cases, additional use of EHS can complement Overstitch.
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There are several limitations in this study. First, this is a single-arm study with a relatively small number of participants and therefore a possible selection bias because we designed it as a multicenter phase I study. On the basis of our results, to demonstrate the clinical utility of EHS in patients being administered ATAs, in the near future, we will conduct a prospective, multicenter, single-arm phase II study that sets the post-ESD bleeding rate as a primary outcome measure. Second, the sustainability of defect closure was only evaluated on POD 3. Therefore, we still have no data regarding the condition of the sutured site later than that, although we expected sustained closure on POD 3 based on an animal study investigating the tensile strength of the closure of a site surgically sutured in a layer-to-layer manner.23 Third, the endoscopists involved in this study were experienced and skilled in therapeutic endoscopy. Therefore, we are not sure whether our results are generally reproducible. Understanding the learning curve for EHS will be important. In conclusion, the findings in our multicenter study suggest that EHS is feasible, safe, and potentially effective in decreasing the risk of postoperative bleeding after gastric ESD. Complete and sustained closure of a post-ESD mucosal defect by EHS might reduce the risk of delayed bleeding, even in patients at high risk of bleeding because of antithrombotic treatment. Further prospective investigation is required to confirm the efficacy of EHS for this purpose.
Acknowledgments This study was supported by a grant-in-aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology in Japan in 2018–2020 (Grant No. 18K07919).
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Conflicts of interest The flexible needle holder and the scissors forceps which were used in this study were complimentarily provided by Olympus Co Ltd. REFERENCES
1.
Ono H, Kondo H, Gotoda T, Shirao K, Yamaguchi H, Saito D, et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001;48:225–229.
2.
Oyama T, Tomori A, Hotta K, Morita S, Kominato K, Tanaka M, et al. Endoscopic submucosal dissection of early esophageal cancer. Clin Gastroenterol Hepatol 2005;3:S67–70.
3.
Yahagi N, Uraoka T, Ida Y, Hosoe N, Nakamura R, Kitagawa Y, et al. Endoscopic submucosal dissection using the Flex and the Dual knives. Tech Gastrointest Endosc 2011;13:74–78.
4.
Park YM, Cho E, Kang HY, Kim JM. The effectiveness and safety of endoscopic submucosal dissection compared with endoscopic mucosal resection for early gastric cancer: a systematic review and metaanalysis. Surg Endosc 2011;25:2666–2677.
5.
Hallas J, Dall M, Andries A, Andersen BS, Aalykke C, Hansen JM, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ 2006;333:726.
6.
Ono S, Fujishiro M, Yoshida N, Doyama H, Kamoshida T, Hirai S, et al. Thienopyridine derivatives as
16
risk factors for bleeding following high risk endoscopic treatments: Safe Treatment on Antiplatelets (STRAP) study. Endoscopy 2015;47:632–637. 7.
Libânio D, Costa MN, Pimentel-Nunes P, Dinis-Ribeiro M. Risk factors for bleeding after gastric endoscopic submucosal dissection: A systematic review and meta-analysis. Gastrointest Endosc 2016;84:572–586.
8.
Dong J, Wei K, Deng J, Zhou X, Huang X, Deng M, et al. Effects of antithrombotic therapy on bleeding after endoscopic submucosal dissection. Gastrointest Endosc 2017;86:807–816.
9.
Koh R, Hirasawa K, Yahara S, Oka H, Sugimori K, Morimoto M, et al. Antithrombotic drugs are risk factors for delayed postoperative bleeding after endoscopic submucosal dissection for gastric neoplasms. Gastrointest Endosc 2013;78:476–483.
10. Fujishiro M, Oda I, Yamamoto Y, Akiyama J, Ishii N, Kakushima N, et al. Multi-center survey regarding the management of anticoagulation and antiplatelet therapy for endoscopic procedures in Japan. J Gastroenterol Hepatol 2009;24:214–218. 11. Sibon I, Orgogozo JM. Antiplatelet drug discontinuation is a risk factor for ischemic stroke. Neurology 2004;62:1187–1189. 12. Blacker DJ, Wijdicks EF, McClelland RL. Stroke risk in anticoagulated patients with atrial fibrillation undergoing endoscopy. Neurology 2003;61:964–968. 13. Uedo N, Takeuchi Y, Yamada T, Ishihara R, Ogiyama H, Yamamoto S, et al. Effect of a proton pump inhibitor or an H2-receptor antagonist on prevention of bleeding from ulcer after endoscopic submucosal
17
dissection of early gastric cancer: a prospective randomized controlled trial. Am J Gastroenterol 2007;102:1610–1616. 14. Hamada K, Uedo N, Tonai Y, Arao M, Suzuki S, Iwatsubo T, et al. Efficacy of vonoprazan in prevention of bleeding from endoscopic submucosal dissection-induced gastric ulcers: a prospective randomized phase II study. J Gastroenterol 2019;54:122–130. 15. Takizawa K, Oda I, Gotoda T, Yokoi C, Matsuda T, Saito Y, et al. Routine coagulation of visible vessels may prevent delayed bleeding after endoscopic submucosal dissection—an analysis of risk factors. Endoscopy 2008;40:179–183. 16. Choi KD, Jung HY, Lee GH, Oh TH, Jo JY, Song HJ, et al. Application of metal hemoclips for closure of endoscopic mucosal resection-induced ulcers of the stomach to prevent delayed bleeding. Surg Endosc 2008;22:1882–1886. 17. Maekawa S, Nomura R, Murase T, Ann Y, Harada M. Complete closure of artificial gastric ulcer after endoscopic submucosal dissection by combined use of a single over-the-scope clip and through-the-scope clips (with videos). Surg Endosc 2015;29:500–504. 18. Kantsevoy SV, Bitner M, Mitrakov AA, Thuluvath PJ. Endoscopic suturing closure of large mucosal defects after endoscopic submucosal dissection is technically feasible, fast, and eliminates the need for hospitalization (with videos). Gastrointest Endosc 2014;79:503–507. 19. Goto O, Sasaki M, Ishii H, Horii J, Uraoka T, Takeuchi H, et al. A new endoscopic closure method for gastric mucosal defects: feasibility of endoscopic hand suturing in an ex vivo porcine model (with video).
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Endosc Int Open 2014;2:E111–116. 20. Goto O, Sasaki M, Akimoto T, Ochiai Y, Kiguchi Y, Mitsunaga Y, et al. Endoscopic hand-suturing for defect closure after gastric endoscopic submucosal dissection: a pilot study in animals and in humans. Endoscopy 2017;49:792–797. 21. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer 2017;20:1–19. 22. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649–655. 23. Maruyama K, Itoh I, Miwa K, Kitajima M, Hashimoto M, Tabata T, et al. Prevention of leakage of gastro-intestinal anastomosis principles obtained from pathologic, microamgiraphic and biochemical studies [in Japanese]. Nihon Shokaki Geka Gakkai zasshi 1974;7:18–25. 24. Fujimoto K, Fujishiro M, Kato M, Higuchi K, Iwakiri R, Sakamoto C, et al. Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Dig Endosc 2014;26:1– 14. 25. Kotzev AI, Yang D, Draganov PV. How to master endoscopic submucosal dissection in the USA. Dig Endosc 2019;31:94–100.
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FIGURE LEGENDS
Figure 1. Endoscopic hand-suturing after gastric endoscopic submucosal dissection. A, A mucosal defect on the greater curvature in the mid stomach is created by endoscopic submucosal dissection. B, An absorbable barbed suture is gently delivered into the stomach through an overtube by grasping the suture close to the tail of the needle. C, Suturing is initiated at the distal edge of the defect with the needle firmly grasped by the flexible needle holder. D, Continuous suturing is performed linearly. E, The mucosal defect is completely closed. F, Sutured site on postoperative day 3. The defect is closed without dehiscence.
Figure 2. Flow chart of patients in this study. Out of 32 patients enrolled, 30 who underwent endoscopic submucosal dissection (ESD) followed by endoscopic hand suturing (EHS) and were evaluated endoscopically on postoperative day 3 were analyzed. They were divided into 2 groups according to whether or not they were taking antithrombotic agents.
Video 1. Endoscopic hand-suturing for a gastric mucosal defect A barbed suture is delivered with the flexible needle holder through on overture. Continuous suturing is performed in a linear fashion. The needle is removed by cutting the remaining suture and retrieved transorally through the overtube by grasping the suture with the needle holder.
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Table 1. Baseline patient
characteristics of cases N = 30
and
outcomes
of
endoscopic
Patient's factors Age (years)
73.0 (9.5)
Gender
dissection
Male Female
24 (80) 6 (20)
Past history/Comorbidities* Hypertension
17 (57)
Arrhythmia
6 (20)
Diabetes mellitus
5 (17)
Malignancy Cerebrovascular disease
6 (20) 4 (13)
Ischemic heart disease
4 (13)
Dyslipidemia
3 (10)
Cardiac valvular disease
2 (7)
Antithrombotic agents Administered Not administered
15 (50) 15 (50)
Lesion factors Location Upper
1 (3)
Middle
15 (50)
Lower Remnant
13 (43) 1 (3)
Circumference Lesser curvature
13 (43)
Anterior wall
9 (30)
Posterior wall
6 (20)
Greater curvature Gross type
2 (7)
0-IIa
8 (27)
0-IIb
3 (10)
0-IIc
19 (63)
ESD factors Procedural time (minutes) En-bloc resection
38.5 (21.9) 30 (100)
R0 resection
30 (100)
Perforation
0 (0)
Histology Tumor size (mm)
12.4 (7.7)
Diagnosis Adenoma
2 (6)
Adenocarcinoma
27 (90)
No tumor
1 (3)
Ulceration Present
0 (0)
Absent Lymphovascular infiltration
21
30 (100)
submucosal
Present
0 (0)
Absent
30 (100)
Data presented as mean (SD) or number (%). * There is some overlap. ESD, endoscopic submucosal dissection
22
Table 2. Outcomes of endoscopic hand-suturing
Total N = 30 EHS procedure Completeness of EHS
29 (97)
Defect size (mm)
36.0 (7.1)
Suturing duration (minutes)
49.5 (16.2)
Number of stitches Adverse events during EHS
8.0 (1.6) 1 (3)
Defect closure on POD 3 Sustained
25 (83)
Partially sustained
5 (17)
Unsustained
0 (0)
Major
3 (10)
Minor
1 (3)
Bleeding
Data presented as mean (SD) or number (%). EHS, endoscopic hand suturing; POD, postoperative day
23
Table 3. Comparison of the outcomes according to use of antithrombotic agents
Antithrombotic agents Administered
Not administered
N = 15
N = 15
P value
14 (93)
15 (100)
1.00
Defect size (mm)
35.5 (6.4)
36.5 (8.4)
0.967
Time required for suturing (minutes)
49.1 (13.2)
50.0 (19.1)
0.886
7.5 (1.7)
8.5 (1.5)
0.116
0 (0)
1 (7)
1.00
EHS procedure Completeness of EHS
Number of stitches Adverse events during EHS
1.00
Defect closure on POD 3 Sustained
12 (80)
13 (87)
Partially sustained
3 (20)
2 (13)
Unsustained
0 (0)
0 (0)
Major
2 (13)
1 (7)
1.00
Minor
1 (7)
0(0)
1.00
Bleeding
Data presented as mean (SD) or number (%). EHS, endoscopic hand suturing; POD, postoperative day
24
Table 4. Comparison of the outcomes among institutions
Institution A
B
C
N = 10
N = 10
N = 10
P value
Completeness of EHS
10 (100)
10 (100)
9 (90)
0.355
Defect size (mm)
37.3 (7.0)
37.1 (8.3)
33.5 (6.0)
0.486
Suturing duration (minutes)
46.2 (17.0)
47.1 (8.3)
59.2 (17.8)
0.056
Number of stitches (stitches)
8.7 (1.4)
8.0 (1.2)
7.3 (2.1)
0.296
Adverse events during EHS
1 (10)
0 (0)
0 (0)
0.355
EHS procedure
0.002
Defect closure on POD 3 Sustained
10 (100)
10 (100)
5 (50)
Partially sustained
0 (0)
0 (0)
5 (50)
Unsustained
0 (0)
0 (0)
0 (0)
Major
1 (10)
0 (0)
2 (20)
0.329
Minor
0 (0)
1 (10)
0 (0)
0.355
Bleeding
Data presented as mean (SD) or number (%) EHS, endoscopic hand suturing; POD, postoperative day
25
Acronyms
EHS: endoscopic hand-suturing ESD: endoscopic submucosal dissection POD: postoperative day ATAs: antithrombotic agents
S0016-5107(20)30007-9
DOI:
https://doi.org/10.1016/j.gie.2019.12.046
Reference:
YMGE 11910
To appear in:
Gastrointestinal Endoscopy
Received Date: 25 September 2019 Accepted Date: 22 December 2019
Please cite this article as: Goto O, Oyama T, Ono H, Takahashi A, Fujishiro M, Saito Y, Abe S, Kaise M, Iwakiri K, Yahagi N, Endoscopic hand-suturing is feasible, safe, and might contribute in reducing bleeding risk after gastric endoscopic submucosal dissection: a multicenter pilot study (with video), Gastrointestinal Endoscopy (2020), doi: https://doi.org/10.1016/j.gie.2019.12.046. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020 by the American Society for Gastrointestinal Endoscopy
Original article Endoscopic hand-suturing is feasible, safe, and might contribute in reducing bleeding risk after gastric endoscopic submucosal dissection: a multicenter pilot study (with video)
Osamu Goto,1 Tsuneo Oyama,2 Hiroyuki Ono,3 Akiko Takahashi,2 Mitsuhiro Fujishiro,4 Yukata Saito,5 Seiichiro Abe, 5 Mitsuru Kaise,1 Katsuhiko Iwakiri,1 Naohisa Yahagi6 1. Department of Gastroenterology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan 2. Division of Endoscopy, Saku Central Hospital Advanced Care Center, Saku, Japan 3. Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan 4. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan 5. Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan 6. Division of Research and Department for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan
Correspondence and request for reprints to: Osamu Goto, MD, PhD, Department of Gastroenterology, Nippon Medical School Graduate School of Medicine 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan Tel: +81-3-3822-2131; Fax: +81-3-5814-6289 Email: [email protected]
ABSTRACT Background and Aims: Endoscopic hand-suturing (EHS) provides secure intraluminal mucosal closure and should decrease the risk of adverse events after gastric endoscopic submucosal dissection (ESD). We prospectively investigated the feasibility and safety of EHS after gastric ESD, particularly for preventing post-ESD bleeding. Methods: Patients scheduled for gastric ESD at 3 institutions were prospectively recruited. Just after ESD, the mucosal defect was closed by EHS. The primary outcome was endoscopic assessment of adequately sustained closure of the defect on postoperative day (POD) 3. Endoscopy was performed to assess maintenance of the closure for the primary outcome. During postoperative week 3 to 4, the patients were interviewed as outpatients about any occurrence of delayed bleeding. Results: Data from 30 patients (15 each who did or did not take antithrombotic agents [ATAs]) were analyzed. Mucosal closure by EHS was completed in 29 of 30 cases (97%) and was well maintained on POD 3 in 25 cases (84%). Emergency endoscopy was required for major postoperative bleeding in 3 cases (10%), including the one in which suturing had been incomplete. Excluding one patient with a remnant stomach, the other 24 with sustained closure had no bleeding, regardless of whether they did or did not take ATAs (0/11 and 0/13, respectively). No serious adverse events occurred during EHS. Conclusions: The results show that EHS is feasible and safe with favorable outcomes. Provided that mucosal suturing is successfully completed and sustained, post-ESD bleeding can be decreased even in patients undergoing antithrombotic therapy.
1
Trial registration number: UMIN000033988.
Keywords Antithrombotic agents, Endoscopic hand-suturing, Endoscopic submucosal dissection.
INTRODUCTION Owing to the recent development and establishment of therapeutic endoscopy, endoscopic procedures for curative treatment have been expanded. In particular, endoscopic submucosal dissection (ESD), that is, circumferential mucosal incision followed by submucosal dissection, is widely accepted as a less-invasive, potentially curative procedure to treat node-negative, early stage gastrointestinal cancers.1-3 However, compared with other endoscopic treatments, ESD has a relatively high risk of adverse events.4 Effective countermeasures to prevent these events are therefore needed. Postoperative bleeding is a particularly urgent issue to address, especially as the number of patients taking antithrombotic agents (ATAs) for other disorders is increasing.5 The risk of bleeding after gastric ESD is estimated to be 5% in conventional low risk cases, but up to approximately 30% in a high-risk cohort of patients, including those on ATAs.6-9 A previous meta-analysis7 showed that influential factors for post-ESD bleeding included the male sex, cardiopathy, cirrhosis, chronic kidney disease, tumor/resected specimen size, location in the lesser curvature, flat or depressed type, carcinoma, ulceration, long procedure duration, histamine-2 receptor antagonists instead of proton pump inhibitors, and ATAs. Generally, the bleeding risk tends to increase with the increase in the number of ATAs, ie, patients undergoing dual antiplatelet therapy or combined use of antiplatelet agents and anticoagulants appear 2
to be at a higher risk of post-ESD bleeding compared with patients being administered a single agent. If postprocedure bleeding occurs, emergency endoscopy is necessary to identify the site of bleeding in the mucosal defect and to perform endoscopic hemostasis. Such patients often require blood transfusions or rehospitalization to stabilize their condition. In a patient taking ATAs, perioperative discontinuation of these agents would minimize the risk of post-ESD bleeding, but this must be weighed against the risk of potentially lethal thrombotic events for which the ATAs were prescribed in the first place.10-12 Therefore, a method that minimizes the risk of post-ESD bleeding while allowing patients to continue taking their ATAs is greatly needed. Although several measures such as the use of gastric antisecretory agents13-14 or precoagulation of exposed vessels just after resection15 have been attempted, these have not adequately reduced the incidence of postoperative bleeding. As long as the mucosal defect remains open, exposure to various stimuli such as gastric acid, reflux bile, food, and peristalsis still poses substantial risk. The most effective means of decreasing the chance of bleeding would seem to be closure of the mucosal defect. However, conventional endoscopic methods of tissue apposition with endoclips are often unsuccessful due to the thickness of the mucosal layer. Dehiscence easily occurs despite temporary closure of the defect.16 Therefore, a tight and long-lasting closure method is mandated to successfully prevent postoperative bleeding.17,18 Endoscopic hand-suturing (EHS) appears to be a suitable technique to address this problem. It involves continuous linear suturing endoscopically by using a commercially available absorbable barbed suture and a prototype of a through-the-scope flexible needle holder.19,20 We successfully demonstrated the
3
feasibility and safety of this technique ex vivo,19 in vivo, and in a small number of clinical cases.20 However, evidence is still lacking in terms of indications, technical ability to access the lesion, and whether it in fact reduces the incidence of post-ESD bleeding. Therefore, we prospectively investigated the feasibility, safety, and efficacy of this new suturing technique in a multicenter study to evaluate its value in routine clinical settings. METHODS
Participants This phase I pilot study was approved by the Institutional Review Board at all 3 participating institutions and registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000033988). Participants were prospectively recruited according to the following criteria: individuals were eligible if (1) aged ≥20 years with a single clinically or histologically diagnosed early gastric cancer of ≤3 cm, which fulfilled criteria for ESD in the Japanese gastric cancer treatment guidelines21; (2) they were scheduled to undergo gastric ESD at one of the participating institutions; and (3) they had an Eastern Cooperative Oncology Group performance status score of 0 or 1.22 All patients provided written informed consent, both to participate in the trial and to undergo ESD.
Endoscopic submucosal dissection Patients were admitted and underwent ESD under intravenous sedation in a conventional manner described elsewhere.1-3 Briefly, after placing an overtube from the mouth to the upper esophagus, the 4
endoscope was introduced, the stomach was cleaned, and the location of the lesion was confirmed. The mucosa was marked circumferentially approximately 5 mm outside the margin of the neoplasm using the tip of the electrocautery device, followed by submucosal injection to elevate the lesion appropriately. Using an electrocautery knife specially designed for ESD, we made a circumferential mucosal incision outside the markings, followed by submucosal dissection to remove the lesion en-bloc with endoscopically negative surgical margins. Intraoperative bleeding was stopped with electrocautery knives or hemostatic forceps. After transoral retrieval of the lesion, the mucosal defect was closely observed and exposed visible vessels in the defect were ablated with electrocautery.
Endoscopic hand-suturing EHS to close the mucosal defect was then performed by a single endoscopist at each institution who had sufficient experience in gastric ESD (at least 500 cases; Figure 1, Video 1). For EHS, a V-loc 180 absorbable barbed suture (VLOCL0604; Covidien, Mansfield, Mass, USA) and a through-the-scope flexible needle holder (Olympus, Tokyo, Japan) were prepared.19,20 The suture was grasped with the needle holder close to the tail of the needle so that the needle dangled freely as it was carefully delivered into the stomach through the overtube. After freeing the suture and grasping the needle at the optimal site (one-third to one-fourth the distance from the tail of the needle), the first stitch was placed on either mucosal margin of the defect. The needle was extracted and passed through a loop on the tail of the suture. After tightening the first suture, continuous suturing was performed in a linear fashion at an interval of approximately 5 mm and a bite
5
of more than 8 mm. To facilitate suturing, grasping forceps (FG-21L-1; Olympus) were inserted through another working channel of an endoscope mounted with dual working channels (GIF-2TQ260M; Olympus) and used for assistance as needed. After obtaining complete closure, an endoclip (HX-610-090S; Olympus) was placed at the final stitch to bind the bottom of the suture and the mucosal surface. The needle was then removed by cutting the remaining suture with a prototype of scissors forceps (Olympus). The procedure was finished with retrieval of the needle transorally through the overtube by grasping the suture with the needle holder.
Postprocedural management Antisecretory agents (proton-pump inhibitors or a potassium-competitive acid blocker) were administered from the day of the procedure for at least 14 weeks. On postoperative day (POD) 1, after confirming the absence of symptoms or of abnormal findings on chest radiograph and laboratory tests, the patients not taking an ATA were allowed to have soft food, whereas those on ATAs were given a liquid diet. For the latter, the diet was gradually advanced to soft food while they were monitored for signs of bleeding. On POD 3, based on the presumed minimal tensile strength of a sutured site in an animal model,23 follow-up endoscopy was performed to judge whether the sutured mucosal defect remained closed without dehiscence. Patients were discharged on POD 4 or later depending on their condition, with an outpatient visit scheduled during postoperative week 3 to 4. They were asked about signs of postoperative bleeding after discharge. When major postoperative bleeding (as defined below) was suspected, emergency endoscopy was performed.
6
If active bleeding or any signs of recent bleeding from exposed vessels was seen, endoscopic hemostasis was performed mechanically with endoclips or using electrocautery with hemostatic forceps. Perioperative management of ATAs was determined by the endoscopist based on guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment.24
Outcome measures The primary outcome of the study was closure of the sutured site on POD 3. Closure was defined as sustained if the mucosal defect remained closed without dehiscence, partially sustained if there was partial opening with dehiscence, or unsustained if the defect was completely open. Technical aspects of EHS assessed included completeness of suturing, time required for suturing (minutes), and number of stitches. Completeness was defined as suturing with no discontinuities. The time required was measured from the first insertion of the needle in the mucosa to cutting the remaining suture to freeing the needle. To assess safety, adverse events associated with EHS were recorded. To evaluate the efficacy of EHS, postoperative bleeding, major or minor, was analyzed. Major bleeding was defined as endoscopically diagnosed bleeding or stigma of bleeding at the post-ESD mucosal defect on emergency endoscopy, which was performed in cases of hematemesis or melena or for a decrease in the serum hemoglobin level of >2 g/dL. Minor bleeding was defined as clinically irrelevant bleeding, such as transient melena with spontaneous bleeding or incidental bleeding seen on the follow-up endoscopy on POD 3.
7
Bleeding was compared between patients who were or were not taking ATAs. The technical aspects were compared among the participating institutions.
Sample size Because this was a phase I pilot study, we did not calculate a required sample size. Based on projected enrollment at each institution, we aimed to recruit a total of 30 participants (10 per institution), equally divided between those who were or were not taking ATAs.
Statistical analysis For the 2 groups with or without ATAs, categorical data were compared using the Fisher exact test and continuous data using the t-test or Mann–Whitney U test for data with a normal or non-normal distribution, respectively. For comparisons among the 3 institutions, categorical data were analyzed using the Pearson chi-squared test and continuous data using one-way analysis of variance or the Kruskal–Wallis test, depending on the data distribution. All analyses were performed by with IBM SPSS statistics version 25 (IBM Corp., Armonk, NY, USA), and a P-value <0.05 was considered significant. RESULTS Enrollment and procedures Between December 2018 and June 2019, 32 patients were enrolled in the study. One was excluded when ESD had to be discontinued due to severe bradycardia requiring resuscitation. This left 31 patients who
8
underwent ESD with EHS. However, one erroneously underwent follow-up endoscopy on POD 1. Therefore, 30 patients (10 from each institution), underwent the complete study protocol and were analyzed (Figure 2, Table 1). One patient had previously undergone distal gastrectomy for gastric cancer and therefore had only a remnant stomach. ATAs that were administered to 15 patients (5 from each institution) were aspirin (n = 3), apixaban (n = 2), ethyl icosapentate (n = 2), clopidogrel sulfate (n = 2), omega-3-acid ethyl esters (n = 1), prasugrel hydrochloride (n = 1), ticlopidine hydrochloride (n = 1), aspirin and clopidogrel sulfate (n = 1), aspirin and prasugrel hydrochloride (n = 1), and clopidogrel sulfate, rivaroxaban, and ethyl icosapentate (n = 1). Antiplatelet agents were the predominant ATA (13 patients, 87%). In all 15 cases, the ATAs were continued periprocedurally. In all 30 cases, ESD was successfully performed without adverse events (Table 1). The lesions were completely resected, as evaluated both endoscopically and histologically. Overall outcomes Feasibility and safety The mean defect size created by ESD was 37.3 ± 7.0 mm (Table 2). EHS was successfully completed in 29 of the 30 cases (97%). The mean time needed for suturing was 46.2 ± 17.0 minutes, and a mean of 8.7 ± 1.4 stitches were placed, indicating an average of 5.3 minutes/stitch. One patient had a 20-mm mucosal defect in the lesser curvature at the upper third of the stomach, and EHS was discontinued due to technical difficulty. In this case, the defect was partially closed with 3 stitches, requiring 75 minutes. Follow-up endoscopy on POD 3 showed sustained closure in 25 patients (83%) and partially sustained closure in 5 (17%, including the 1 patient with incomplete EHS). In all of the latter cases, the defect
9
was in the lesser curvature. None of the closures were unsustained. Discounting the case in which EHS was discontinued after 3 stitches, complete closure was sustained in 25 of 29 cases (86%). In one case, minor arterial bleeding occurred from the puncture site when the tip of the needle was inserted into the mucosa but then removed to correct the direction of insertion. This bleeding was easily stopped endoscopically by electrocoagulation with hemostatic forceps and EHS was continued thereafter. No other adverse events occurred during EHS.
Efficacy Major postoperative bleeding occurred in 3 patients (10%), 2 on POD 1 and 1 on POD 6. Of those 3, 2 had a partially sustained closure and one was the patient with a remnant stomach. Consequently, of the 24 patients with a surgery-naïve stomach who had sustained closure, no major bleeding occurred. One patient who was not on an ATA had hematemesis on POD 1. A 30-mm mucosal defect on the lesser curvature in the mid stomach had been closed with 9 stitches in 72 minutes. Emergency endoscopy revealed bleeding from a partially dehisced closure site. The other patient with bleeding on POD 1 was the one in whom EHS was discontinued as mentioned above. This patient was taking aspirin for ischemic heart disease. The patient who bled on POD 6 reported melena and dizziness and was readmitted the next day. This was the patient with the remnant stomach who was also being treated with clopidogrel sulfate for valvular heart disease. The 35-mm mucosal defect on the lesser curvature below the cardia was successfully sutured, a closure which was sustained on the POD 3 follow-up endoscopy. On rehospitalization on POD 7, the patient’s
10
hemoglobin level had dropped, requiring transfusion. On emergency endoscopy, however, there was no apparent active bleeding or blood in the stomach. The sutured site remained closed with only slight black stigmata seen. Although no definite evidence of bleeding could be detected at the sutured site, we still counted the patient as having delayed postoperative bleeding. One case of minor bleeding occurred in a patient taking apixaban, which was incidentally found at a scheduled endoscopy on 3POD. Bleeding was easily stopped endoscopically.
Comparison of groups with or without antithrombotic agents In terms of the technical aspects of EHS, there were no apparent differences between patients taking or not taking ATAs (Table 3). The sustainability of closure was equivalent. Major postoperative bleeding occurred in 2 patients taking and one not taking ATAs. The one case of minor bleeding occurred in a patient taking ATAs. None of these differences were statistically significant.
Comparison of institutions The technical outcomes of EHS did not differ significantly among the 3 participating institutions (Table 4). However, all 5 cases of partially sustained closure on POD 3 were at C (a significant difference), as were 2 of the 3 cases of major bleeding. DISCUSSION This prospective multicenter pilot study demonstrated that EHS for closure of mucosal defects after
11
gastric ESD was safe regardless of administration of ATAs. There was a high rate of sustained closure on POD 3. The postoperative bleeding rate was considered acceptable, and the data suggest that successful EHS with sustained closure might decrease the risk of bleeding, particularly in patients being administered ATAs. In closing mucosal defects created by gastric ESD, the following 2 issues must be addressed: technical feasibility and sustainability of the closure. The technical challenge arises because the gastric mucosa is thick and quite firm compared with other parts of the tract such as the esophagus or colon. Therefore, conventional endoclips easily slip on the mucosal surface when attaching the edges of the defect to each other. Even if closure is initially obtained, sustainability is a problem. Outward traction on the defect facilitates dehiscence. Indeed, sustained closure using endoclips has been reported in only about 60% of humans.16 That may be because the remnant seromuscular layer continuously gives the outward traction to the suturing site. Therefore, even though mucosal closure can be completed, the sustainability of the closure is in jeopardy. In EHS, these 2 problems can be overcome with secure and tight suturing. By using a surgically proven suture with a curved needle and a needle holder to firmly grasp the needle, endoscopists can suture the mucosal rims as necessary. The edges can be tightly opposed by pulling on the slack part of the suture. This hand suturing method is similar to that in routine surgical practice and should provide secure and long-lasting closure of a gastric mucosal defect. In this study, we successfully demonstrated good results with EHS, completely closing the mucosal defect in 97% of cases, a complete closure that was sustained in 86%. EHS thus may be an ideal technique for endoscopic tissue apposition, although more evidence must be accumulated in humans on the frequency of dehiscence according to the location of the defect.
12
No severe adverse events occurred in this study. To avoid injury to the esophagus with the tip of the needle, we placed the overtube in the throat and held the suture rather than the needle itself, allowing the needle to dangle freely during delivery. Bleeding during EHS suturing was not serious. Even the one case of arterial bleeding we encountered was easily managed. This is not surprising as arterial bleeding frequently occurs during ESD and experienced endoscopists are equipped to manage it with endoscopic hemostasis. Complete and sustained closure of mucosal defects after gastric ESD would be expected to prevent postoperative bleeding. We found no bleeding in 24 cases of a completely sutured, sustained closure of a mucosal defect in a normal stomach. In contrast, among 5 cases with a partially sustained closure (including one incomplete closure), bleeding occurred in 2. It suggests that exposure of the mucosal defect inside the stomach will cause delayed bleeding. In the patient with a remnant stomach, bleeding occurred on POD 6 despite complete and sustained closure. The reason for this delayed bleeding is unclear, although the nature of the remnant stomach may be a possible cause. Vascularity in the remnant stomach is generally poor compared with the normal stomach due to systematic lymphadenectomy accompanied with removal of several major feeding arteries in gastrectomy. Relatively diminished blood flow may worsen healing of the mucosal defect. Therefore, a post-ESD bleeding in the remnant stomach may be more likely than in a surgically naïve stomach. Prevention of post-ESD bleeding by adequate defect closure is particularly important in patients with a high risk of bleeding. A meta-analysis reported a risk of delayed bleeding after gastric ESD of 5.0% in patients not on ATAs compared with 23.4% in those who continued taking ATAs perioperatively.8 Effective
13
means to prevent delayed bleeding in such individuals are desired. EHS appears to be a promising technique for this purpose, and we found it to have essentially the same efficacy regardless of whether patients were or were not taking ATAs. EHS may also reduce the length of hospital stay for patients at low risk of bleeding. In this study, the patients not taking ATAs tolerated an essentially normal diet the day after ESD. It is conceivable that same-day surgery may eventually be possible. A major drawback of EHS is that it is time-consuming. In the present study, EHS for mucosal defects approximately 4 cm in size required three-quarters of an hour for placement of n9 stitches. Even for endoscopists skilled in ESD, EHS is technically demanding. Furthermore, the time required and sustainability of the closure varied among endoscopists. This may be due to differences in the length of the bites as well as the degree of tightening, which would be difficult to standardize. However, over time, accumulating clinical experience may help overcome these technical drawbacks as is the case with other advanced endoscopic techniques such as ESD.25 Overstitch is a leading device among currently available endoscopic suturing methods.18 It can provide reliable mechanical suturing in a short time but is more complex and expensive. In contrast, EHS is manual and simple but time consuming. It enables endoscopists to suture the mucosa as desired by using a regular curved needle, although gentle maneuvering is required, which takes time. Every suturing technique has advantages and disadvantages, and combined use of different techniques might be a good alternative for complete and secure suturing. For example, Overstitch is difficult to use in some locations and angles. In these cases, additional use of EHS can complement Overstitch.
14
There are several limitations in this study. First, this is a single-arm study with a relatively small number of participants and therefore a possible selection bias because we designed it as a multicenter phase I study. On the basis of our results, to demonstrate the clinical utility of EHS in patients being administered ATAs, in the near future, we will conduct a prospective, multicenter, single-arm phase II study that sets the post-ESD bleeding rate as a primary outcome measure. Second, the sustainability of defect closure was only evaluated on POD 3. Therefore, we still have no data regarding the condition of the sutured site later than that, although we expected sustained closure on POD 3 based on an animal study investigating the tensile strength of the closure of a site surgically sutured in a layer-to-layer manner.23 Third, the endoscopists involved in this study were experienced and skilled in therapeutic endoscopy. Therefore, we are not sure whether our results are generally reproducible. Understanding the learning curve for EHS will be important. In conclusion, the findings in our multicenter study suggest that EHS is feasible, safe, and potentially effective in decreasing the risk of postoperative bleeding after gastric ESD. Complete and sustained closure of a post-ESD mucosal defect by EHS might reduce the risk of delayed bleeding, even in patients at high risk of bleeding because of antithrombotic treatment. Further prospective investigation is required to confirm the efficacy of EHS for this purpose.
Acknowledgments This study was supported by a grant-in-aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology in Japan in 2018–2020 (Grant No. 18K07919).
15
Conflicts of interest The flexible needle holder and the scissors forceps which were used in this study were complimentarily provided by Olympus Co Ltd. REFERENCES
1.
Ono H, Kondo H, Gotoda T, Shirao K, Yamaguchi H, Saito D, et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001;48:225–229.
2.
Oyama T, Tomori A, Hotta K, Morita S, Kominato K, Tanaka M, et al. Endoscopic submucosal dissection of early esophageal cancer. Clin Gastroenterol Hepatol 2005;3:S67–70.
3.
Yahagi N, Uraoka T, Ida Y, Hosoe N, Nakamura R, Kitagawa Y, et al. Endoscopic submucosal dissection using the Flex and the Dual knives. Tech Gastrointest Endosc 2011;13:74–78.
4.
Park YM, Cho E, Kang HY, Kim JM. The effectiveness and safety of endoscopic submucosal dissection compared with endoscopic mucosal resection for early gastric cancer: a systematic review and metaanalysis. Surg Endosc 2011;25:2666–2677.
5.
Hallas J, Dall M, Andries A, Andersen BS, Aalykke C, Hansen JM, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ 2006;333:726.
6.
Ono S, Fujishiro M, Yoshida N, Doyama H, Kamoshida T, Hirai S, et al. Thienopyridine derivatives as
16
risk factors for bleeding following high risk endoscopic treatments: Safe Treatment on Antiplatelets (STRAP) study. Endoscopy 2015;47:632–637. 7.
Libânio D, Costa MN, Pimentel-Nunes P, Dinis-Ribeiro M. Risk factors for bleeding after gastric endoscopic submucosal dissection: A systematic review and meta-analysis. Gastrointest Endosc 2016;84:572–586.
8.
Dong J, Wei K, Deng J, Zhou X, Huang X, Deng M, et al. Effects of antithrombotic therapy on bleeding after endoscopic submucosal dissection. Gastrointest Endosc 2017;86:807–816.
9.
Koh R, Hirasawa K, Yahara S, Oka H, Sugimori K, Morimoto M, et al. Antithrombotic drugs are risk factors for delayed postoperative bleeding after endoscopic submucosal dissection for gastric neoplasms. Gastrointest Endosc 2013;78:476–483.
10. Fujishiro M, Oda I, Yamamoto Y, Akiyama J, Ishii N, Kakushima N, et al. Multi-center survey regarding the management of anticoagulation and antiplatelet therapy for endoscopic procedures in Japan. J Gastroenterol Hepatol 2009;24:214–218. 11. Sibon I, Orgogozo JM. Antiplatelet drug discontinuation is a risk factor for ischemic stroke. Neurology 2004;62:1187–1189. 12. Blacker DJ, Wijdicks EF, McClelland RL. Stroke risk in anticoagulated patients with atrial fibrillation undergoing endoscopy. Neurology 2003;61:964–968. 13. Uedo N, Takeuchi Y, Yamada T, Ishihara R, Ogiyama H, Yamamoto S, et al. Effect of a proton pump inhibitor or an H2-receptor antagonist on prevention of bleeding from ulcer after endoscopic submucosal
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dissection of early gastric cancer: a prospective randomized controlled trial. Am J Gastroenterol 2007;102:1610–1616. 14. Hamada K, Uedo N, Tonai Y, Arao M, Suzuki S, Iwatsubo T, et al. Efficacy of vonoprazan in prevention of bleeding from endoscopic submucosal dissection-induced gastric ulcers: a prospective randomized phase II study. J Gastroenterol 2019;54:122–130. 15. Takizawa K, Oda I, Gotoda T, Yokoi C, Matsuda T, Saito Y, et al. Routine coagulation of visible vessels may prevent delayed bleeding after endoscopic submucosal dissection—an analysis of risk factors. Endoscopy 2008;40:179–183. 16. Choi KD, Jung HY, Lee GH, Oh TH, Jo JY, Song HJ, et al. Application of metal hemoclips for closure of endoscopic mucosal resection-induced ulcers of the stomach to prevent delayed bleeding. Surg Endosc 2008;22:1882–1886. 17. Maekawa S, Nomura R, Murase T, Ann Y, Harada M. Complete closure of artificial gastric ulcer after endoscopic submucosal dissection by combined use of a single over-the-scope clip and through-the-scope clips (with videos). Surg Endosc 2015;29:500–504. 18. Kantsevoy SV, Bitner M, Mitrakov AA, Thuluvath PJ. Endoscopic suturing closure of large mucosal defects after endoscopic submucosal dissection is technically feasible, fast, and eliminates the need for hospitalization (with videos). Gastrointest Endosc 2014;79:503–507. 19. Goto O, Sasaki M, Ishii H, Horii J, Uraoka T, Takeuchi H, et al. A new endoscopic closure method for gastric mucosal defects: feasibility of endoscopic hand suturing in an ex vivo porcine model (with video).
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Endosc Int Open 2014;2:E111–116. 20. Goto O, Sasaki M, Akimoto T, Ochiai Y, Kiguchi Y, Mitsunaga Y, et al. Endoscopic hand-suturing for defect closure after gastric endoscopic submucosal dissection: a pilot study in animals and in humans. Endoscopy 2017;49:792–797. 21. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer 2017;20:1–19. 22. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649–655. 23. Maruyama K, Itoh I, Miwa K, Kitajima M, Hashimoto M, Tabata T, et al. Prevention of leakage of gastro-intestinal anastomosis principles obtained from pathologic, microamgiraphic and biochemical studies [in Japanese]. Nihon Shokaki Geka Gakkai zasshi 1974;7:18–25. 24. Fujimoto K, Fujishiro M, Kato M, Higuchi K, Iwakiri R, Sakamoto C, et al. Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Dig Endosc 2014;26:1– 14. 25. Kotzev AI, Yang D, Draganov PV. How to master endoscopic submucosal dissection in the USA. Dig Endosc 2019;31:94–100.
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FIGURE LEGENDS
Figure 1. Endoscopic hand-suturing after gastric endoscopic submucosal dissection. A, A mucosal defect on the greater curvature in the mid stomach is created by endoscopic submucosal dissection. B, An absorbable barbed suture is gently delivered into the stomach through an overtube by grasping the suture close to the tail of the needle. C, Suturing is initiated at the distal edge of the defect with the needle firmly grasped by the flexible needle holder. D, Continuous suturing is performed linearly. E, The mucosal defect is completely closed. F, Sutured site on postoperative day 3. The defect is closed without dehiscence.
Figure 2. Flow chart of patients in this study. Out of 32 patients enrolled, 30 who underwent endoscopic submucosal dissection (ESD) followed by endoscopic hand suturing (EHS) and were evaluated endoscopically on postoperative day 3 were analyzed. They were divided into 2 groups according to whether or not they were taking antithrombotic agents.
Video 1. Endoscopic hand-suturing for a gastric mucosal defect A barbed suture is delivered with the flexible needle holder through on overture. Continuous suturing is performed in a linear fashion. The needle is removed by cutting the remaining suture and retrieved transorally through the overtube by grasping the suture with the needle holder.
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Table 1. Baseline patient
characteristics of cases N = 30
and
outcomes
of
endoscopic
Patient's factors Age (years)
73.0 (9.5)
Gender
dissection
Male Female
24 (80) 6 (20)
Past history/Comorbidities* Hypertension
17 (57)
Arrhythmia
6 (20)
Diabetes mellitus
5 (17)
Malignancy Cerebrovascular disease
6 (20) 4 (13)
Ischemic heart disease
4 (13)
Dyslipidemia
3 (10)
Cardiac valvular disease
2 (7)
Antithrombotic agents Administered Not administered
15 (50) 15 (50)
Lesion factors Location Upper
1 (3)
Middle
15 (50)
Lower Remnant
13 (43) 1 (3)
Circumference Lesser curvature
13 (43)
Anterior wall
9 (30)
Posterior wall
6 (20)
Greater curvature Gross type
2 (7)
0-IIa
8 (27)
0-IIb
3 (10)
0-IIc
19 (63)
ESD factors Procedural time (minutes) En-bloc resection
38.5 (21.9) 30 (100)
R0 resection
30 (100)
Perforation
0 (0)
Histology Tumor size (mm)
12.4 (7.7)
Diagnosis Adenoma
2 (6)
Adenocarcinoma
27 (90)
No tumor
1 (3)
Ulceration Present
0 (0)
Absent Lymphovascular infiltration
21
30 (100)
submucosal
Present
0 (0)
Absent
30 (100)
Data presented as mean (SD) or number (%). * There is some overlap. ESD, endoscopic submucosal dissection
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Table 2. Outcomes of endoscopic hand-suturing
Total N = 30 EHS procedure Completeness of EHS
29 (97)
Defect size (mm)
36.0 (7.1)
Suturing duration (minutes)
49.5 (16.2)
Number of stitches Adverse events during EHS
8.0 (1.6) 1 (3)
Defect closure on POD 3 Sustained
25 (83)
Partially sustained
5 (17)
Unsustained
0 (0)
Major
3 (10)
Minor
1 (3)
Bleeding
Data presented as mean (SD) or number (%). EHS, endoscopic hand suturing; POD, postoperative day
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Table 3. Comparison of the outcomes according to use of antithrombotic agents
Antithrombotic agents Administered
Not administered
N = 15
N = 15
P value
14 (93)
15 (100)
1.00
Defect size (mm)
35.5 (6.4)
36.5 (8.4)
0.967
Time required for suturing (minutes)
49.1 (13.2)
50.0 (19.1)
0.886
7.5 (1.7)
8.5 (1.5)
0.116
0 (0)
1 (7)
1.00
EHS procedure Completeness of EHS
Number of stitches Adverse events during EHS
1.00
Defect closure on POD 3 Sustained
12 (80)
13 (87)
Partially sustained
3 (20)
2 (13)
Unsustained
0 (0)
0 (0)
Major
2 (13)
1 (7)
1.00
Minor
1 (7)
0(0)
1.00
Bleeding
Data presented as mean (SD) or number (%). EHS, endoscopic hand suturing; POD, postoperative day
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Table 4. Comparison of the outcomes among institutions
Institution A
B
C
N = 10
N = 10
N = 10
P value
Completeness of EHS
10 (100)
10 (100)
9 (90)
0.355
Defect size (mm)
37.3 (7.0)
37.1 (8.3)
33.5 (6.0)
0.486
Suturing duration (minutes)
46.2 (17.0)
47.1 (8.3)
59.2 (17.8)
0.056
Number of stitches (stitches)
8.7 (1.4)
8.0 (1.2)
7.3 (2.1)
0.296
Adverse events during EHS
1 (10)
0 (0)
0 (0)
0.355
EHS procedure
0.002
Defect closure on POD 3 Sustained
10 (100)
10 (100)
5 (50)
Partially sustained
0 (0)
0 (0)
5 (50)
Unsustained
0 (0)
0 (0)
0 (0)
Major
1 (10)
0 (0)
2 (20)
0.329
Minor
0 (0)
1 (10)
0 (0)
0.355
Bleeding
Data presented as mean (SD) or number (%) EHS, endoscopic hand suturing; POD, postoperative day
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Acronyms
EHS: endoscopic hand-suturing ESD: endoscopic submucosal dissection POD: postoperative day ATAs: antithrombotic agents