Digestive Endoscopy 2015; 27: 295–297
doi: 10.1111/den.12441
Editorial
Toward further prevention of bleeding after gastric endoscopic submucosal dissection Satoshi Mochizuki,1 Yuichi Ikeda,2 Takehiro Arai1 and Keigo Matsuo1 1
Gastroenterology Division, Tokatsu-Tsujinaka Hospital, Chiba and 2Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
E
bs_bs_banner
NDOSCOPIC SUBMUCOSAL DISSECTION (ESD) is a standard treatment for lymph node-negative early gastric neoplasms, at least in Japan. Owing to its minimal invasiveness, the ‘made-in-Japan’ procedure has spread worldwide during last decade. However the substantial risks of complications are still unresolved. One of the major complications is post-ESD bleeding which is reported in approximately 5% of cases. So far, some effective methods to prevent post-ESD bleeding have been reported such as post-ESD coagulation immediately after completion of ESD and giving proton pump inhibitors (PPI) perioperatively. Second-look endoscopy (SLE) is also considered to lessen post-ESD bleeding and is carried out routinely in the daily practice of most hospitals. In the current issue of the Journal, to clarify the role of SLE, Nishizawa et al.1 carried out a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the incidence of post-ESD bleeding with or without SLE after gastric ESD. After searching the electronic databases, finally three RCTs were found. First, Ryu et al.2 reported a single-center RCT on the efficacy of SLE for post-ESD bleeding. Post-ESD bleeding occurred in 12 (16.2%) patients in the SLE group, and in nine (11.1%) patients in the non-SLE group. There was no statistically significant difference (P = 0.66). However, the sample size was not sufficient and only provided 38% power to detect a 10% difference in post-ESD bleeding rate between the groups. Second, Kim et al.3 reported another single-center RCT showing that the incidence of post-ESD bleeding was not significantly different between the SLE group with eight (3.6%) bleeding cases, and the non-SLE group with six (2.8%) bleeding cases (P = 0.787). Third, a multicenter RCT was reported by a study group in Japan.4 This is the only multicenter RCT with non-inferiority design showing that post-ESD bleeding occurred in seven (5.4%) patients in the SLE group and in five (3.8%) patients in the non-SLE group (P non-inferiority = 0.0003).
All of the three RCTs were at low risk of bias for most of the aspects evaluated by Nishizawa et al.1 Among 854 patients of the three RCTs in total, post-ESD bleeding was observed in 20 (4.7%) out of 430 patients in the non-SLE group and in 27 (6.4%) out of 424 patients in the SLE group (OR 0.69, 95% CI: 0.38–1.26), and there was no significant different between the two groups. In the group with large tumor size (>20 mm), post-ESD bleeding was observed in four (7.1%) out of 56 patients in the non-SLE group and in three (4.8%) out of 63 patients in the SLE group (OR 1.39, 95% CI: 0.31–3.21), with a non-statistically significant difference. There is no advantage of SLE after gastric ESD for patients without high bleeding risks such as taking antithrombotics during the perioperative period. Therefore, SLE after gastric ESD, which is carried out empirically so far, is not routinely recommended. Without unnecessary SLE after gastric ESD, a substantial amount of the burden on patients and the workload of endoscopists will be decreased and, moreover, health-care costs will be reduced. However, a big clinical question of how to reduce postESD bleeding remains. Gastric acid is one of the aggressive factors inhibiting gastric mucosal healing. Giving standarddose PPI is effective for reducing gastric acid secretion and is routinely used in daily practice for the prevention of postESD bleeding. In cases of peptic ulcer bleeding, strong evidence demonstrates the efficacy of high-dose i.v. PPI therapy. In fact, international consensus on the management of patients with non-variceal upper gastrointestinal bleeding recommends an i.v. bolus followed by continuous-infusion PPI therapy to decrease rebleeding and mortality in patients with high-risk stigmata who have undergone successful endoscopic therapy. Therefore, the adequate dosage of PPI for prevention of post-ESD bleeding should be further evaluated. Oral intake is another aggressive factor inducing postESD bleeding. According to Japanese guidelines for the management of gastric ulcer, fasting for 3 days after peptic ulcer bleeding is recommended, although the evidence is
© 2015 The Authors Digestive Endoscopy © 2015 Japan Gastroenterological Endoscopy Society
295
296
Editorial
limited. However, in international consensus recommendations on the management of patients with non-variceal upper gastrointestinal bleeding, the recommendation is that patients at low risk after endoscopy can be fed within 24 h. Furthermore, a RCT to evaluate the pattern of meals after ESD is undergoing (trial registration number UMINCTR000013297). The evidence is lacking in both timing of beginning of meals and pattern of meals; therefore, further studies providing new evidence in this field are required. In terms of mucosal defense factor, although a mucosal protective drug was reported to be effective in healing artificial gastric ulcer,5 there is no positive evidence on its efficacy in the prevention of post-ESD bleeding. Instead of using a mucosal protective drug, Zhang et al.6 recently reported that a medical adhesive spray with the primary ingredient of n-butyl-2-cyanoacrylate was effective in the prevention of post-ESD bleeding in a Chinese prospective study. The incidence of post-ESD bleeding was 0.00% in the spray group and 4.88% in the control group (P = 0.035). In another approach, through a retrospective study, Tsuji et al.7 reported a tissue-shielding method with polyglycolic acid (PGA) sheets and fibrin glue that decreased the incidence of post-ESD bleeding (6.7% in the PGA group vs 22.0% in the control group) in high-risk patients (P = 0.041). Endoscopic tissue-shielding methods are options to prevent post-ESD bleeding, and several RCTs to evaluate the efficacy of PGA sheets and fibrin glue are undergoing (trial registration numbers UMIN-CTR000013990, 000013995 and 000015091). Complete closure of artificial ulcer after ESD was reported by Maekawa et al.8 by using a single over-the-scope clip and through-the-scope clips. In 11 out of 12 cases, complete closure of artificial gastric ulcer after ESD was achieved, and no post-ESD bleeding occurred, although the sample size was small and the target lesions were relatively small. As mentioned above, there are some promising new methods for the prevention of post-ESD bleeding. When considering that approximately 5% of cases experience postESD bleeding, it is necessary to identify risk factors for post-ESD bleeding more clearly. Lesion-related risk factors such as tumor location, resected specimen size, tumor size and ulcerative findings are reported as risk factors for post-ESD bleeding. In respect of tumor location, the lower third of the stomach is reported as a risk factor. Because intraoperative excessive bleeding is rare in this region, coagulation during ESD is not done as often as in other regions. Many viable vessels remain in the submucosal layer and are related to post-ESD bleeding. After recognition of this risk factor, post-ESD coagulation in this region has been carried out more carefully, and tumor
Digestive Endoscopy 2015; 27: 295–297
location has not been reported as a risk factor in recent reports.2–4,9 Resected specimen size >40 mm and tumor size >20 mm were reported as risk factors for post-ESD bleeding, which might be confounding, because, in most cases, resected specimen size should be determined by lesion size. When we compare lesions with the same lesion size, in cases of lesions with ulcerative findings, resection sizes would be much bigger than in those without ulcerative findings, because the mucosal incision should be made outside of the fibrotic area. According to recent reports,4,9 resected specimen size is the sole independent lesion-related risk factor for post-ESD bleeding. In terms of patient-related risk factors, a recent large retrospective study showed that antithrombotics were risk factors for post-ESD bleeding.9 Another multicenter prospective observational cohort study concluded that cautious care after ESD was necessary for patients taking thienopyridine derivatives with aspirin,10 In 2012, Japan Gastroenterological Endoscopy Society published guidelines for gastroenterological endoscopy in patients taking antithrombotics, and stated that post-ESD bleeding is highly expected in cases reinitiating antithrombotics in the early period after ESD and would even occur after the second week of ESD. Because patients who took antithrombotics during the perioperative period were excluded in all three RCTs reviewed in the current systematic review by Nishizawa et al.,1 the evidence for SLE in patients taking antithrombotics is still lacking, and further studies for this patient population are required. The study by Nishizawa et al.1 provides further insight into the management of post-ESD bleeding, although the study did not review a high-risk group such as patients who are taking antithrombotics. The next step to reduce post-ESD bleeding should provide promising preventive methods for patients with higher post-ESD bleeding risk such as resected specimen size >40 mm or who are taking antithrombotic drugs.
REFERENCES 1 Nishizawa T, Suzuki H, Kinoshita S, Goto O, Kanai T, Yahagi N. Second-look endoscopy after endoscopic submucosal dissection for gastric neoplasms. Dig. Endosc. Published online: 15 Dec 2014; DOI: 10.1111/den.12410 [Epub ahead of print]. 2 Ryu HY, Kim JW, Kim HS et al. Second-look endoscopy is not associated with better clinical outcomes after gastric endoscopic submucosal dissection: A prospective, randomized, clinical trial analyzed on an as-treated basis. Gastrointest. Endosc. 2013; 78: 285–94. 3 Kim JS, Chung MW, Chung CY et al. The need for second-look endoscopy to prevent delayed bleeding after endoscopic
© 2015 The Authors Digestive Endoscopy © 2015 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2015; 27: 295–297
4
5
6
7
Editorial 297
submucosal dissection for gastric neoplasms: a prospective randomized trial. Gut Liver 2014; 8: 480–6. Mochizuki S, Uedo N, Oda I et al. Scheduled second-look endoscopy is not recommended after endoscopic submucosal dissection for gastric neoplasms (the SAFE trial): a multicentre prospective randomised controlled non-inferiority trial. Gut 2015; 64: 397–405. Wang J, Guo X, Ye C et al. Efficacy and safety of proton pump inhibitors (PPIs) plus rebamipide for endoscopic submucosal dissection-induced ulcers: a meta-analysis. Intern. Med. 2014; 53: 1243–8. Zhang Y, Chen Y, Qu CY et al. Effects of medical adhesives in prevention of complications after endoscopic submucosal dissection. World J. Gastroenterol. 2013; 19: 2704–8. Tsuji Y, Fujishiro M, Kodashima S et al. Polyglycolic acid sheets and fibrin glue decrease the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms (with video).
Gastrointest. Endosc. Published online: 29 Oct 2014; DOI: 10.1016/j.gie.2014.08.028. [Epub ahead of print]. 8 Maekawa S, Nomura R, Murase T et al. Complete closure of artificial gastric ulcer after endoscopic submucosal dissection by combined use of a single over-the-scope clip and throughthe-scope clips (with videos). Surg. Endosc. 2015 Feb; 29: 500–4. 9 Koh R, Hirasawa K, Yahara S et al. Antithrombotic drugs are risk factors for delayed postoperative bleeding after endoscopic submucosal dissection for gastric neoplasms. Gastrointest. Endosc. 2013; 78: 476–83. 10 Ono S, Fujishiro M, Yoshida N et al. Thienopyridine derivatives as risk factors for bleeding following high risk endoscopic treatments: Safe Treatment on Antiplatelets (STRAP) study. Endoscopy. Published online: 15 Jan 2015; DOI: 10.1055/s0034-1391354. [Epub ahead of print].
© 2015 The Authors Digestive Endoscopy © 2015 Japan Gastroenterological Endoscopy Society
doi: 10.1111/den.12441
Editorial
Toward further prevention of bleeding after gastric endoscopic submucosal dissection Satoshi Mochizuki,1 Yuichi Ikeda,2 Takehiro Arai1 and Keigo Matsuo1 1
Gastroenterology Division, Tokatsu-Tsujinaka Hospital, Chiba and 2Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
E
bs_bs_banner
NDOSCOPIC SUBMUCOSAL DISSECTION (ESD) is a standard treatment for lymph node-negative early gastric neoplasms, at least in Japan. Owing to its minimal invasiveness, the ‘made-in-Japan’ procedure has spread worldwide during last decade. However the substantial risks of complications are still unresolved. One of the major complications is post-ESD bleeding which is reported in approximately 5% of cases. So far, some effective methods to prevent post-ESD bleeding have been reported such as post-ESD coagulation immediately after completion of ESD and giving proton pump inhibitors (PPI) perioperatively. Second-look endoscopy (SLE) is also considered to lessen post-ESD bleeding and is carried out routinely in the daily practice of most hospitals. In the current issue of the Journal, to clarify the role of SLE, Nishizawa et al.1 carried out a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the incidence of post-ESD bleeding with or without SLE after gastric ESD. After searching the electronic databases, finally three RCTs were found. First, Ryu et al.2 reported a single-center RCT on the efficacy of SLE for post-ESD bleeding. Post-ESD bleeding occurred in 12 (16.2%) patients in the SLE group, and in nine (11.1%) patients in the non-SLE group. There was no statistically significant difference (P = 0.66). However, the sample size was not sufficient and only provided 38% power to detect a 10% difference in post-ESD bleeding rate between the groups. Second, Kim et al.3 reported another single-center RCT showing that the incidence of post-ESD bleeding was not significantly different between the SLE group with eight (3.6%) bleeding cases, and the non-SLE group with six (2.8%) bleeding cases (P = 0.787). Third, a multicenter RCT was reported by a study group in Japan.4 This is the only multicenter RCT with non-inferiority design showing that post-ESD bleeding occurred in seven (5.4%) patients in the SLE group and in five (3.8%) patients in the non-SLE group (P non-inferiority = 0.0003).
All of the three RCTs were at low risk of bias for most of the aspects evaluated by Nishizawa et al.1 Among 854 patients of the three RCTs in total, post-ESD bleeding was observed in 20 (4.7%) out of 430 patients in the non-SLE group and in 27 (6.4%) out of 424 patients in the SLE group (OR 0.69, 95% CI: 0.38–1.26), and there was no significant different between the two groups. In the group with large tumor size (>20 mm), post-ESD bleeding was observed in four (7.1%) out of 56 patients in the non-SLE group and in three (4.8%) out of 63 patients in the SLE group (OR 1.39, 95% CI: 0.31–3.21), with a non-statistically significant difference. There is no advantage of SLE after gastric ESD for patients without high bleeding risks such as taking antithrombotics during the perioperative period. Therefore, SLE after gastric ESD, which is carried out empirically so far, is not routinely recommended. Without unnecessary SLE after gastric ESD, a substantial amount of the burden on patients and the workload of endoscopists will be decreased and, moreover, health-care costs will be reduced. However, a big clinical question of how to reduce postESD bleeding remains. Gastric acid is one of the aggressive factors inhibiting gastric mucosal healing. Giving standarddose PPI is effective for reducing gastric acid secretion and is routinely used in daily practice for the prevention of postESD bleeding. In cases of peptic ulcer bleeding, strong evidence demonstrates the efficacy of high-dose i.v. PPI therapy. In fact, international consensus on the management of patients with non-variceal upper gastrointestinal bleeding recommends an i.v. bolus followed by continuous-infusion PPI therapy to decrease rebleeding and mortality in patients with high-risk stigmata who have undergone successful endoscopic therapy. Therefore, the adequate dosage of PPI for prevention of post-ESD bleeding should be further evaluated. Oral intake is another aggressive factor inducing postESD bleeding. According to Japanese guidelines for the management of gastric ulcer, fasting for 3 days after peptic ulcer bleeding is recommended, although the evidence is
© 2015 The Authors Digestive Endoscopy © 2015 Japan Gastroenterological Endoscopy Society
295
296
Editorial
limited. However, in international consensus recommendations on the management of patients with non-variceal upper gastrointestinal bleeding, the recommendation is that patients at low risk after endoscopy can be fed within 24 h. Furthermore, a RCT to evaluate the pattern of meals after ESD is undergoing (trial registration number UMINCTR000013297). The evidence is lacking in both timing of beginning of meals and pattern of meals; therefore, further studies providing new evidence in this field are required. In terms of mucosal defense factor, although a mucosal protective drug was reported to be effective in healing artificial gastric ulcer,5 there is no positive evidence on its efficacy in the prevention of post-ESD bleeding. Instead of using a mucosal protective drug, Zhang et al.6 recently reported that a medical adhesive spray with the primary ingredient of n-butyl-2-cyanoacrylate was effective in the prevention of post-ESD bleeding in a Chinese prospective study. The incidence of post-ESD bleeding was 0.00% in the spray group and 4.88% in the control group (P = 0.035). In another approach, through a retrospective study, Tsuji et al.7 reported a tissue-shielding method with polyglycolic acid (PGA) sheets and fibrin glue that decreased the incidence of post-ESD bleeding (6.7% in the PGA group vs 22.0% in the control group) in high-risk patients (P = 0.041). Endoscopic tissue-shielding methods are options to prevent post-ESD bleeding, and several RCTs to evaluate the efficacy of PGA sheets and fibrin glue are undergoing (trial registration numbers UMIN-CTR000013990, 000013995 and 000015091). Complete closure of artificial ulcer after ESD was reported by Maekawa et al.8 by using a single over-the-scope clip and through-the-scope clips. In 11 out of 12 cases, complete closure of artificial gastric ulcer after ESD was achieved, and no post-ESD bleeding occurred, although the sample size was small and the target lesions were relatively small. As mentioned above, there are some promising new methods for the prevention of post-ESD bleeding. When considering that approximately 5% of cases experience postESD bleeding, it is necessary to identify risk factors for post-ESD bleeding more clearly. Lesion-related risk factors such as tumor location, resected specimen size, tumor size and ulcerative findings are reported as risk factors for post-ESD bleeding. In respect of tumor location, the lower third of the stomach is reported as a risk factor. Because intraoperative excessive bleeding is rare in this region, coagulation during ESD is not done as often as in other regions. Many viable vessels remain in the submucosal layer and are related to post-ESD bleeding. After recognition of this risk factor, post-ESD coagulation in this region has been carried out more carefully, and tumor
Digestive Endoscopy 2015; 27: 295–297
location has not been reported as a risk factor in recent reports.2–4,9 Resected specimen size >40 mm and tumor size >20 mm were reported as risk factors for post-ESD bleeding, which might be confounding, because, in most cases, resected specimen size should be determined by lesion size. When we compare lesions with the same lesion size, in cases of lesions with ulcerative findings, resection sizes would be much bigger than in those without ulcerative findings, because the mucosal incision should be made outside of the fibrotic area. According to recent reports,4,9 resected specimen size is the sole independent lesion-related risk factor for post-ESD bleeding. In terms of patient-related risk factors, a recent large retrospective study showed that antithrombotics were risk factors for post-ESD bleeding.9 Another multicenter prospective observational cohort study concluded that cautious care after ESD was necessary for patients taking thienopyridine derivatives with aspirin,10 In 2012, Japan Gastroenterological Endoscopy Society published guidelines for gastroenterological endoscopy in patients taking antithrombotics, and stated that post-ESD bleeding is highly expected in cases reinitiating antithrombotics in the early period after ESD and would even occur after the second week of ESD. Because patients who took antithrombotics during the perioperative period were excluded in all three RCTs reviewed in the current systematic review by Nishizawa et al.,1 the evidence for SLE in patients taking antithrombotics is still lacking, and further studies for this patient population are required. The study by Nishizawa et al.1 provides further insight into the management of post-ESD bleeding, although the study did not review a high-risk group such as patients who are taking antithrombotics. The next step to reduce post-ESD bleeding should provide promising preventive methods for patients with higher post-ESD bleeding risk such as resected specimen size >40 mm or who are taking antithrombotic drugs.
REFERENCES 1 Nishizawa T, Suzuki H, Kinoshita S, Goto O, Kanai T, Yahagi N. Second-look endoscopy after endoscopic submucosal dissection for gastric neoplasms. Dig. Endosc. Published online: 15 Dec 2014; DOI: 10.1111/den.12410 [Epub ahead of print]. 2 Ryu HY, Kim JW, Kim HS et al. Second-look endoscopy is not associated with better clinical outcomes after gastric endoscopic submucosal dissection: A prospective, randomized, clinical trial analyzed on an as-treated basis. Gastrointest. Endosc. 2013; 78: 285–94. 3 Kim JS, Chung MW, Chung CY et al. The need for second-look endoscopy to prevent delayed bleeding after endoscopic
© 2015 The Authors Digestive Endoscopy © 2015 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2015; 27: 295–297
4
5
6
7
Editorial 297
submucosal dissection for gastric neoplasms: a prospective randomized trial. Gut Liver 2014; 8: 480–6. Mochizuki S, Uedo N, Oda I et al. Scheduled second-look endoscopy is not recommended after endoscopic submucosal dissection for gastric neoplasms (the SAFE trial): a multicentre prospective randomised controlled non-inferiority trial. Gut 2015; 64: 397–405. Wang J, Guo X, Ye C et al. Efficacy and safety of proton pump inhibitors (PPIs) plus rebamipide for endoscopic submucosal dissection-induced ulcers: a meta-analysis. Intern. Med. 2014; 53: 1243–8. Zhang Y, Chen Y, Qu CY et al. Effects of medical adhesives in prevention of complications after endoscopic submucosal dissection. World J. Gastroenterol. 2013; 19: 2704–8. Tsuji Y, Fujishiro M, Kodashima S et al. Polyglycolic acid sheets and fibrin glue decrease the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms (with video).
Gastrointest. Endosc. Published online: 29 Oct 2014; DOI: 10.1016/j.gie.2014.08.028. [Epub ahead of print]. 8 Maekawa S, Nomura R, Murase T et al. Complete closure of artificial gastric ulcer after endoscopic submucosal dissection by combined use of a single over-the-scope clip and throughthe-scope clips (with videos). Surg. Endosc. 2015 Feb; 29: 500–4. 9 Koh R, Hirasawa K, Yahara S et al. Antithrombotic drugs are risk factors for delayed postoperative bleeding after endoscopic submucosal dissection for gastric neoplasms. Gastrointest. Endosc. 2013; 78: 476–83. 10 Ono S, Fujishiro M, Yoshida N et al. Thienopyridine derivatives as risk factors for bleeding following high risk endoscopic treatments: Safe Treatment on Antiplatelets (STRAP) study. Endoscopy. Published online: 15 Jan 2015; DOI: 10.1055/s0034-1391354. [Epub ahead of print].
© 2015 The Authors Digestive Endoscopy © 2015 Japan Gastroenterological Endoscopy Society
