Dig Dis Sci DOI 10.1007/s10620-014-3117-3
ORIGINAL ARTICLE
Preprocedural Rabeprazole Treatment Before Endoscopic Submucosal Dissection for Gastric Neoplasms Myong Ki Baeg • Myung-Gyu Choi • Seong Jin Moon • Chul-Hyun Lim • Jin Su Kim • Yu Kyung Cho • Jae Myung Park • In Seok Lee • Sang Woo Kim Kyu Yong Choi
•
Received: 15 January 2014 / Accepted: 13 March 2014 Ó Springer Science+Business Media New York 2014
Abstract Background The maximal effect of proton pump inhibitors (PPI) is reported to take 5 days. However, most current protocols start PPI on the day of gastric endoscopic submucosal dissection (ESD). Aims We aimed to evaluate the benefit of 5 days pretreatment with oral PPI before ESD to prevent bleeding. Methods This was a prospective randomized controlled trial. Patients were administered oral rabeprazole 20 mg or placebo twice daily for 5 days before ESD. Intravenous pantoprazole 40 mg was administered 2 h before ESD and at postprocedure day 1, and then oral rabeprazole 20 mg was administered once daily. Follow-up endoscopy was performed on days 1 and 30. Forty-eight-hour measurement of intragastric pH was performed in 26 patients. The primary endpoint was major bleeding related to ESD. Results One-hundred and twenty patients were enrolled. Of these, 45 in the pretreatment and 53 in the placebo group were analyzed. Each group had three cases of major bleeding. There were no significant differences in the ulcer healing rate. Intragastric pH percentage times greater than 4, 5, and 6 were 86.61 ± 19.45 %, 83.30 ± 22.06 %, and 76.86 ± 25.35 %, respectively, in the pretreatment and 85.54 ± 19.45 %, 84.08 ± 27.11 %, and 81.53 ± 27.81 %, respectively, in the placebo group, without significant differences.
M. K. Baeg M.-G. Choi (&) S. J. Moon C.-H. Lim J. S. Kim Y. K. Cho J. M. Park I. S. Lee S. W. Kim K. Y. Choi Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, # 505, Banpo-Dong, Seocho-Gu, Seoul 137-701, South Korea e-mail: [email protected]
Conclusions Preprocedural administration of rabeprazole offers no additional benefit over postprocedural administration alone in preventing major bleeding after gastric ESD. Keywords Proton pump inhibitor Endoscopic submucosal dissection Gastric neoplasms Intragastric pH monitoring
Introduction Endoscopic submucosal dissection (ESD) is an effective alternative to surgery for the treatment of early gastric cancer and gastric adenoma [1–3]. Though ESD is a safe procedure, bleeding is still a common complication. Its incidence is reported to be 2–18 %, and it may require surgical intervention [1, 4–8]. Increasing intragastric pH to prevent clot lysis has been reported to reduce postESD bleeding [9, 10]. Histamine 2 receptor antagonists (H2RA) and proton pump inhibitors (PPI) have been used to treat peptic ulcer bleeding [11]. Their effectiveness in preventing postESD bleeding and accelerating postESD ulcer healing has been the subject of many studies. Several studies have advocated the use of PPIs rather than H2RAs after ESD [12–14]. However, other studies have reported conflicting results [15, 16]. Protocols to ascertain the optimal medication, dosage, and duration have been investigated. PPIs produce a high gastric pH by irreversibly binding to the proton pumps on gastric parietal cells [17]. However, the optimal time for the full effect of PPI is reported to be 5 days [18, 19]. This has been raised as an issue, as most current regimens apply PPI on the day of ESD. We hypothesized that oral PPI therapy for 5 days prior to ESD
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and intravenous PPI administered 2 h before ESD would maximize gastric pH and would be more effective in reducing postESD bleeding than postoperative treatment alone. The aim of this study was to evaluate the benefit of 5 days pretreatment with oral PPI before ESD to prevent bleeding.
Methods This was a prospective, randomized, double-blind, placebo-controlled trial performed at a tertiary referral hospital. Patients who had been referred for ESD were enrolled on an outpatient basis. The patients were randomly given either placebo or 20-mg oral rabeprazole (Janssen-Cilag, Beerse, Belgium) twice daily for 5 days before the ESD. On the day of the ESD, 2 h before the procedure, patients were administered 40 mg of intravenous pantoprazole (Takeda Chemical Industries Ltd., Osaka, Japan). Patients were instructed to fast for 48 h after the procedure, during which intravenous pantoprazole was administered once on the day after the ESD. If there was no postESD bleeding, they commenced eating on the third day and once-daily oral rabeprazole was started and given for 28 days. Follow-up endoscopies were carried out at 1 and 30 days after the ESD. A selected group of patients who had consented to 48-h gastric pH monitoring had a radiotelemetric 48-h intragastric pH BRAVOTM capsule (Medtronic, Inc., Shoreview, MN) attached to the greater curvature of the mid-body [20]. This study was approved by the Institutional Review Board of the Seoul St. Mary’s Hospital and registered with Clinicaltrial.gov (NCT00844675). Participants The participants consisted of patients who were scheduled for ESD. The exclusion criteria were: under 18 years of age, severe concomitant disease including liver cirrhosis, chronic kidney disease, malignancies, or vascular diseases that could affect endoscopic resection or study medication, history of upper gastrointestinal surgery or vagotomy, patients with gastrointestinal bleeding, mechanical ileus or perforation, pregnant or lactating women, patients taking medication known to cause ulcers such as corticosteroids, NSAIDs, aspirin or anticoagulants, patients taking antiulcer medication or other treatments that may affect the study within 7 days prior to study commencement, severe psychological illness, patients currently enrolled in another study or those that had another study medication administered within 30 days of study commencement, and those who did not give informed consent.
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ESD All patients underwent ESD procedures under sedation with intravenous administration of midazolam (3–5 mg, Bukwang Pharm. Co., Ltd., Seoul, Korea) and pethidine (50 mg, Myungmoon Pharm. Co., Ltd., Seoul, Korea). The ESD procedure was carried out using a forward-viewing endoscope (GIF-Q240/Q260J; Olympus Optical Co., Ltd., Tokyo, Japan) with a transparent disposable attachment (D201-11804; Olympus) fitted to the tip of the endoscope for a fixed endoscopic view. Several spots 5–10 mm outside the margin of the lesion were marked with a needle knife or a hook knife. After the injection of normal saline with 0.0025 % epinephrine into the submucosa, mucosal resection and submucosal dissection were performed with an insulated tip (IT) knife (KD-610L; Olympus) or a hook knife (KD-620LR; Olympus). Injections were repeated as needed, and further resection was carried out to ensure total removal of the lesion. An electrosurgical current was applied for cutting and coagulation using a high-frequency generator with an automatically controlled system (ERBE200D; ERBE Elektromedizin GmbH, Tu¨bingen, Germany). After ESD, meticulous coagulation of all exposed vessels was done by Coagrasper (FD-410LR; Olympus Medical Systems Corp., Tokyo, Japan) in the soft coagulation mode with an 80-W current. ESD procedures were performed by two experienced endoscopists who had performed more than 200 ESD procedures before treating these patients. pH Monitoring Forty-eight-hour intragastric pH monitoring was performed on selected patients who had agreed to endoscopic BRAVOTM capsule placement. The pH capsule was attached by clips (HX-600-090K; Olympus Medical Systems Corp., Tokyo, Japan) in the manner reported previously [20]. pH was monitored for 48 h with capsule attachment checked at 24 h by endoscopic follow-up and at 48 h by simple X-ray. pH studies were considered to have failed if there was capsule detachment before 24 h or there was evidence of postprocedural bleeding as described below. Outcomes The primary endpoint was the occurrence of major postprocedural bleeding. Major bleeding was defined as follows: (1) the presence of hematemesis or melena, (2) a sudden decrease in systolic blood pressure by more than 30 mmHg, and (3) a rapid decrease in hemoglobin [2 g/ dL. Secondary endpoints were the number of exposed vessels in the ulcer base and the number of exposed vessels per
Dig Dis Sci Fig. 1 Flowchart of patients pretreated with either rabeprazole or placebo 5 days before endoscopic submucosal dissection
ulcer area observed by endoscopy 1 day after the procedure [16, 21], the ulcer healing rate at 30 days after ESD, and the intragastric pH for 48 h after the procedure. Exposed vessels at the ulcer base were defined by the Forrest classification and were evaluated by an endoscopist with extensive experience in ESD who had been blinded to the study medication [22]. The ulcer diameter was measured by an endoscopic measuring device (M2-3U; Olympus Optical Co., Ltd., Tokyo, Japan). Statistics We calculated the expected bleeding rate as 18 % for the placebo group and 14 % in the pretreatment group by referring to a previous similar study, and set the dropout rate as 20 %, alpha error as 0.05, and statistical power as 0.8, which resulted in a requirement for 60 participants per group [16]. In case of intragastric pH monitoring, a previous study reported the incidence of 24-h pH [ 6 after 40 mg intravenous pantoprazole as about 40 % [23]. The pH in the pretreatment group was estimated to be 15 % higher than that in the placebo group. With alpha error of 0.05, statistical power of 0.8, standard deviation of 9.5 %, dropout rate of 20 %, and a technical failure rate of 5 %, at least eight participants were needed per group. Because of a large number of early dropouts, it was decided to recruit twice the expected number of participants, for a total of 32, 16 per group. Continuous data were summarized as mean (95 % confidence interval [CI]). Statistical comparisons of the participants were performed using the v2 test for
categorical data and the Student’s t test for numerical data. The analysis was performed with a statistical software package (SPSS for Windows, SPSS, Chicago, IL, USA). A p value less than 0.05 was accepted as statistically significant.
Results One-hundred twenty patients were recruited, and 60 assigned to each of the two groups. Of these, 11 patients from the rabeprazole group were excluded from initial ESD. Seven patients withdrew consent on the date of ESD. Three patients underwent laparoscopic surgery because of positive lymph nodes discovered during staging via highresolution computed tomography at our hospital. They had been enrolled in our outpatient clinic based on negative lymph nodes on their referral notes. Of the remaining 49 participants in the pretreatment group, four were excluded from final analysis. Of the 60 patients in the placebo group, four withdrew consent on the date of ESD. Of the remaining 56 patients in the placebo group, three were excluded from the final analysis. A detailed flow chart of the study is shown in Fig. 1. Of the 32 participants who agreed to 48-h intragastric pH monitoring, 16 were allocated to each of the pretreatment and placebo groups. Of those in the pretreatment group, five withdrew consent and 11 underwent pH monitoring. Of these 11, three were excluded from the final analysis; one because of early capsule detachment, one
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Dig Dis Sci Table 1 Demographic characteristics of the study population Pretreatment group
Placebo group
Number of subjects
45
53
P value
Pretreatment group
Placebo group
P value
Clinical evidence of bleedinga
1
0
0.658
Fall in hemoglobin level by [2 g/dL
3
3
0.620
Fall in systolic blood pressure [ 30 mmHg
0
0
1.000
Total
3b
3
0.620
Primary endpoints
Age (mean ± SD)
59 ± 8.9
58 ± 10
0.721
Male gender
24 (53.3 %)
42 (79.2 %)
0.009
Smoking
8 (17.9 %)
10 (18.9 %)
1.000
Alcohol
22 (48.9 %)
32 (60.3 %)
0.372
Coffee
29 (64.4 %)
30 (56.6 %)
0.535
Body mass index (kg/m2) Male 23 ± 2.5
24.2 ± 2.7
0.104
Female
23.2 ± 3.1
24.2 ± 2.2
0.331
Helicobacter pylori positivity
21/43 (48.8 %)
28/51 (54.9 %)
0.679
Secondary endpoints Number of exposed vesselsc
1.02 ± 1.37
1.36 ± 1.08
0.178
Ulcer healing rate at 30 days
93.3 %
92.5 %
1.00
a
Location Cardia
2 (4.4 %)
1 (1.9 %)
Body
12 (26.7 %)
11 (20.8 %)
Angle
7 (15.6 %)
3 (5.7 %)
Antrum
24 (53.4 %)
38 (71.7 %)
Adenoma
32 (71.1 %)
42 (79.2 %)
Carcinoma Others
11 (24.4 %) 2 (4.4 %)
8 (15.1 %) 3 (5.7 %)
0.211
Hematemesis or melena
b
One patient was positive for both clinical evidence of bleeding and showed a drop in hemoglobin [2 g/dL
c
Noted during endoscopic follow-up at 1 day after endoscopic submucosal dissection
Pathology 0.481
Procedure time (minute)
36.8 ± 25.9
40.9 ± 32.2
0.495
Resulting ulcer area (cm2)
10.7 ± 6.2
9.6 ± 5.0
0.328
Number of lesions
1.2 ± 0.5
1.2 ± 0.6
0.535
NS nonspecific, SD standard deviation
because of intragastric bleeding, and one who was excluded from the study because of incomplete resection. Of the placebo group, one participant withdrew consent and two had early capsule detachment, leaving 13 participants in the final analysis. The baseline characteristics of the two groups are shown in Table 1. There were no significant differences in age, smoking history, obesity, or Helicobacter pylori status. The placebo group included significantly more men. There were also no significant differences in lesion location, resected ulcer size, or pathology, and the total procedure time was not significantly different. There were no significant differences between the two groups in the incidence of major postprocedural bleeding; there were three cases of bleeding in each group: One patient showed hematemesis on the evening of the procedure and his hemoglobin level fell 2.4 g/dL; Two patients had a fall of [2 g/dL in hemoglobin level without clinical evidence of bleeding. In the placebo group, all three patients showed a reduction in hemoglobin level of [2 g/ dL without clinical evidence of bleeding. Five among six bleeding cases occurred within 48 h after ESD while one
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Table 2 Primary and secondary endpoints
case in the pretreatment group occurred during the 48–72 h period. Second-look endoscopy revealed no difference between the two groups in the number of exposed vessels. Comparisons of the ulcer healing rate between the first endoscopy and the second endoscopy performed at day 30 revealed no significant difference between the two groups (Table 2). The 48-h intragastric pH monitoring revealed no significant difference in the mean pH of the two groups, with the pretreatment group at 6.67 ± 1.72 and the placebo group at 6.45 ± 1.25. The percentage time at pH [ 4, [5, and [6 was 86.61 ± 19.45 %, 83.30 ± 22.06 %, and 76.86 ± 25.35 %, respectively, in the pretreatment group and 85.54 ± 19.45 %, 84.08 ± 27.11 % and 81.53 ± 27.81 %, respectively, in the placebo group.
Discussion We hypothesized that 5 days of oral PPI pretreatment with intravenous PPI administration 2 h before ESD would be effective in reducing postESD bleeding by maximizing gastric acid suppression. However, preprocedural administration of rabeprazole offered no additional benefit over postprocedural administration alone in preventing major bleeding after gastric ESD. This was most likely because the mean pH in both groups was C6. PPIs function by irreversibly binding to the proton pump, resulting in potent acid inhibition throughout the 24 h postdose period [17]. However, the first dose of PPI inhibits only the activated H?/K?-ATPase located in the
Dig Dis Sci
canalicular membrane, with maximum acid inhibition achieved on day 5 after PPI administration [18, 19, 24, 25].However, the placebo group also achieved maximal acid inhibition and pH [ 6.4, comparable with the pretreatment group. This might be because all patients with gastric neoplasms are more likely to have atrophic gastritis [26–28]. As corpus atrophy results in a reduced number of acid-producing parietal cells, the stomach becomes hypochlorhydric [29]. The reduced number of parietal cells would have needed less PPI to be fully inhibited, resulting in no clinically significant differences in pH and postESD bleeding rate between the two groups. Six percent of our participants reported bleeding which was lower than our expectations, within the previous reported postESD bleeding rates of 2–15 % [1, 4–8]. As this study was designed in the early days of ESD, we had expected a high bleeding rate. Therefore, this study should be interpreted with in mind that it could have been insufficiently powered. The low bleeding rate could be explained by the following. First, the improvement in ESD materials such as use of the water-jet scope, procedure methods, and operator skills [30] during the study period most likely led to a decrease in the bleeding rates of our study. Second, our endoscopists performed meticulous electrocautery procedures on exposed vessels during and after ESD which may have reduced the bleeding [10]. Third, intravenous pantoprazole 40 mg once daily might be enough to inhibit gastric acid secretion during ESD. Fourth, the strict exclusion criteria prevented individuals at higher risk of bleeding such as patients taking aspirin, NSAIDs, or anticoagulants or those with severe comorbid diseases, from inclusion. The ulcer healing rates noted by endoscopic follow-up at 30 days after ESD were about 95 %. Even though a large iatrogenic ulcer was created by ESD, a 4-week treatment with oral PPI was sufficient to heal this postESD ulcer. There have been few studies on preprocedural administration of antisecretory agents. A randomized controlled trial involving 1 week of preprocedural once-daily oral administration of 30 mg lansoprazole in patients undergoing endoscopic mucosa resection (EMR) reported that this treatment improved ulcer healing. In this study, there were no cases of postprocedural bleeding in the PPI group and only three in the nonpremedicated group, but there were too few cases to infer a significant difference. Intragastric pH, which was measured by collecting gastric juice during EMR, was significantly higher in the PPI group with all preEMR participants in the PPI group reporting a pH C 5.4 [31]. Another study compared PPI administration begun 1 day prior to ESD with PPI administration only after ESD. In this study, no additional benefit was noted, with a rate of postESD bleeding of about 7 % in both groups. This study also reported sufficient acid suppression after intravenous PPI administration, with postESD day 1 intragastric pH
similar in both groups at pH [ 6 [21]. Our study suggests that low-dose intravenous PPI administration without pretreatment achieves sufficient gastric acid inhibition to prevent postprocedural bleeding. There have been many protocols used to reduce postESD/EMR bleeding. A recent meta-analysis showed that postESD/EMR treatment with PPI was significantly superior to treatment with H2RA in bleeding prevention [14]. However, other studies have reported little difference in postprocedural bleeding rates between PPI- and H2RAtreated groups, especially when second-look endoscopy was performed [16, 32]. Protocols involving the administration of mucoprotective agents together with PPIs have also been suggested [33, 34]. However, further studies are needed to determine the appropriate regimen and risk criteria to identify high-risk patients who will benefit from tailored regimens. In order to account for nonobvious postprocedural bleeding, the decrease in hemoglobin and newly formed vessels on follow-up endoscopy were measured as secondary parameters [16, 21]. However, the fall in hemoglobin may have been related to bleeding during the procedure as well as postprocedural bleeding. In addition, the inclusion of newly formed vessels could have been dependent on postprocedural coagulation. Therefore, these should be carefully considered. To summarize, preprocedural administration of rabeprazole offers no additional benefit over postprocedural administration alone in preventing major bleeding after gastric ESD. This might be related to the hypochlorhydria resulting from the underlying atrophic gastric mucosa. Acknowledgments The authors would like to respectfully dedicate this paper to the memory of Dr. Chung In-Sik, a beloved mentor who did so much for the progress of Korean Gastroenterology and Endoscopy. This study was supported by Janssen Korea. Conflict of interest
None.
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21. Ono S, Kato M, Ono Y, et al. Effects of preoperative administration of omeprazole on bleeding after endoscopic submucosal dissection: a prospective randomized controlled trial. Endoscopy. 2009;41:299–303. 22. Forrest JA, Finlayson ND, Shearman DJ. Endoscopy in gastrointestinal bleeding. Lancet. 1974;2:394–397. 23. Choi KD, Kim N, Jang IJ, et al. Optimal dose of intravenous pantoprazole in patients with peptic ulcer bleeding requiring endoscopic hemostasis in Korea. J Gastroenterol Hepatol. 2009;24:1617–1624. 24. Saitoh T, Fukushima Y, Otsuka H, et al. Effects of rabeprazole, lansoprazole and omeprazole on intragastric pH in CYP2C19 extensive metabolizers. Aliment Pharmacol Ther. 2002;16: 1811–1817. 25. Muller P, Goksu MA, Fuchs W, Schluter F, Simon B. Initial potency of lansoprazole and omeprazole tablets on pentagastrinstimulated gastric acid secretion-a placebo-controlled study in healthy volunteers. Aliment Pharmacol Ther. 2000;14: 1225–1229. 26. Kakushima N, Fujishiro M, Yahagi N, Kodashima S, Nakamura M, Omata M. Helicobacter pylori status and the extent of gastric atrophy do not affect ulcer healing after endoscopic submucosal dissection. J Gastroenterol Hepatol. 2006;21:1586–1589. 27. Iino C, Shimoyama T, Sasaki Y, Sawaya M, Hanabata N, Fukuda S. Influence of endoscopic submucosal dissection on serum levels of pepsinogens in patients with early gastric cancer. Dig Endosc. 2012;24:339–342. 28. Pezzicoli G, Tucci FA, Ummarino A, et al. Perendoscopic realtime assessment of pH improves detection of gastric preneoplastic conditions. Minerva Gastroenterol Dietol. 2013;59: 97–105. 29. Agreus L, Kuipers EJ, Kupcinskas L, et al. Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers. Scand J Gastroenterol. 2012;47:136–147. 30. Sakurazawa N, Kato S, Fujita I, Kanazawa Y, Onodera H, Uchida E. Supportive techniques and devices for endoscopic submucosal dissection of gastric cancer. World J Gastrointest Endosc. 2012;4:231–235. 31. Watanabe Y, Kato N, Maehata T, et al. Safer endoscopic gastric mucosal resection: preoperative proton pump inhibitor administration. J Gastroenterol Hepatol. 2006;21:1675–1680. 32. Imaeda H, Hosoe N, Suzuki H, et al. Effect of lansoprazole versus roxatidine on prevention of bleeding and promotion of ulcer healing after endoscopic submucosal dissection for superficial gastric neoplasia. J Gastroenterol. 2011;46:1267–1272. 33. Shin WG, Kim SJ, Choi MH, et al. Can rebamipide and proton pump inhibitor combination therapy promote the healing of endoscopic submucosal dissection-induced ulcers? A randomized, prospective, multicenter study. Gastrointest Endosc. 2012; 75:739–747. 34. Asakuma Y, Kudo M, Matsui S, et al. Comparison of an ecabet sodium and proton pump inhibitor (PPI) combination therapy with PPI alone in the treatment of endoscopic submucosal dissection (ESD)–induced ulcers in early gastric cancer: prospective randomized study. Hepatogastroenterology. 2009;56:1270–1273.
ORIGINAL ARTICLE
Preprocedural Rabeprazole Treatment Before Endoscopic Submucosal Dissection for Gastric Neoplasms Myong Ki Baeg • Myung-Gyu Choi • Seong Jin Moon • Chul-Hyun Lim • Jin Su Kim • Yu Kyung Cho • Jae Myung Park • In Seok Lee • Sang Woo Kim Kyu Yong Choi
•
Received: 15 January 2014 / Accepted: 13 March 2014 Ó Springer Science+Business Media New York 2014
Abstract Background The maximal effect of proton pump inhibitors (PPI) is reported to take 5 days. However, most current protocols start PPI on the day of gastric endoscopic submucosal dissection (ESD). Aims We aimed to evaluate the benefit of 5 days pretreatment with oral PPI before ESD to prevent bleeding. Methods This was a prospective randomized controlled trial. Patients were administered oral rabeprazole 20 mg or placebo twice daily for 5 days before ESD. Intravenous pantoprazole 40 mg was administered 2 h before ESD and at postprocedure day 1, and then oral rabeprazole 20 mg was administered once daily. Follow-up endoscopy was performed on days 1 and 30. Forty-eight-hour measurement of intragastric pH was performed in 26 patients. The primary endpoint was major bleeding related to ESD. Results One-hundred and twenty patients were enrolled. Of these, 45 in the pretreatment and 53 in the placebo group were analyzed. Each group had three cases of major bleeding. There were no significant differences in the ulcer healing rate. Intragastric pH percentage times greater than 4, 5, and 6 were 86.61 ± 19.45 %, 83.30 ± 22.06 %, and 76.86 ± 25.35 %, respectively, in the pretreatment and 85.54 ± 19.45 %, 84.08 ± 27.11 %, and 81.53 ± 27.81 %, respectively, in the placebo group, without significant differences.
M. K. Baeg M.-G. Choi (&) S. J. Moon C.-H. Lim J. S. Kim Y. K. Cho J. M. Park I. S. Lee S. W. Kim K. Y. Choi Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, # 505, Banpo-Dong, Seocho-Gu, Seoul 137-701, South Korea e-mail: [email protected]
Conclusions Preprocedural administration of rabeprazole offers no additional benefit over postprocedural administration alone in preventing major bleeding after gastric ESD. Keywords Proton pump inhibitor Endoscopic submucosal dissection Gastric neoplasms Intragastric pH monitoring
Introduction Endoscopic submucosal dissection (ESD) is an effective alternative to surgery for the treatment of early gastric cancer and gastric adenoma [1–3]. Though ESD is a safe procedure, bleeding is still a common complication. Its incidence is reported to be 2–18 %, and it may require surgical intervention [1, 4–8]. Increasing intragastric pH to prevent clot lysis has been reported to reduce postESD bleeding [9, 10]. Histamine 2 receptor antagonists (H2RA) and proton pump inhibitors (PPI) have been used to treat peptic ulcer bleeding [11]. Their effectiveness in preventing postESD bleeding and accelerating postESD ulcer healing has been the subject of many studies. Several studies have advocated the use of PPIs rather than H2RAs after ESD [12–14]. However, other studies have reported conflicting results [15, 16]. Protocols to ascertain the optimal medication, dosage, and duration have been investigated. PPIs produce a high gastric pH by irreversibly binding to the proton pumps on gastric parietal cells [17]. However, the optimal time for the full effect of PPI is reported to be 5 days [18, 19]. This has been raised as an issue, as most current regimens apply PPI on the day of ESD. We hypothesized that oral PPI therapy for 5 days prior to ESD
123
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and intravenous PPI administered 2 h before ESD would maximize gastric pH and would be more effective in reducing postESD bleeding than postoperative treatment alone. The aim of this study was to evaluate the benefit of 5 days pretreatment with oral PPI before ESD to prevent bleeding.
Methods This was a prospective, randomized, double-blind, placebo-controlled trial performed at a tertiary referral hospital. Patients who had been referred for ESD were enrolled on an outpatient basis. The patients were randomly given either placebo or 20-mg oral rabeprazole (Janssen-Cilag, Beerse, Belgium) twice daily for 5 days before the ESD. On the day of the ESD, 2 h before the procedure, patients were administered 40 mg of intravenous pantoprazole (Takeda Chemical Industries Ltd., Osaka, Japan). Patients were instructed to fast for 48 h after the procedure, during which intravenous pantoprazole was administered once on the day after the ESD. If there was no postESD bleeding, they commenced eating on the third day and once-daily oral rabeprazole was started and given for 28 days. Follow-up endoscopies were carried out at 1 and 30 days after the ESD. A selected group of patients who had consented to 48-h gastric pH monitoring had a radiotelemetric 48-h intragastric pH BRAVOTM capsule (Medtronic, Inc., Shoreview, MN) attached to the greater curvature of the mid-body [20]. This study was approved by the Institutional Review Board of the Seoul St. Mary’s Hospital and registered with Clinicaltrial.gov (NCT00844675). Participants The participants consisted of patients who were scheduled for ESD. The exclusion criteria were: under 18 years of age, severe concomitant disease including liver cirrhosis, chronic kidney disease, malignancies, or vascular diseases that could affect endoscopic resection or study medication, history of upper gastrointestinal surgery or vagotomy, patients with gastrointestinal bleeding, mechanical ileus or perforation, pregnant or lactating women, patients taking medication known to cause ulcers such as corticosteroids, NSAIDs, aspirin or anticoagulants, patients taking antiulcer medication or other treatments that may affect the study within 7 days prior to study commencement, severe psychological illness, patients currently enrolled in another study or those that had another study medication administered within 30 days of study commencement, and those who did not give informed consent.
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ESD All patients underwent ESD procedures under sedation with intravenous administration of midazolam (3–5 mg, Bukwang Pharm. Co., Ltd., Seoul, Korea) and pethidine (50 mg, Myungmoon Pharm. Co., Ltd., Seoul, Korea). The ESD procedure was carried out using a forward-viewing endoscope (GIF-Q240/Q260J; Olympus Optical Co., Ltd., Tokyo, Japan) with a transparent disposable attachment (D201-11804; Olympus) fitted to the tip of the endoscope for a fixed endoscopic view. Several spots 5–10 mm outside the margin of the lesion were marked with a needle knife or a hook knife. After the injection of normal saline with 0.0025 % epinephrine into the submucosa, mucosal resection and submucosal dissection were performed with an insulated tip (IT) knife (KD-610L; Olympus) or a hook knife (KD-620LR; Olympus). Injections were repeated as needed, and further resection was carried out to ensure total removal of the lesion. An electrosurgical current was applied for cutting and coagulation using a high-frequency generator with an automatically controlled system (ERBE200D; ERBE Elektromedizin GmbH, Tu¨bingen, Germany). After ESD, meticulous coagulation of all exposed vessels was done by Coagrasper (FD-410LR; Olympus Medical Systems Corp., Tokyo, Japan) in the soft coagulation mode with an 80-W current. ESD procedures were performed by two experienced endoscopists who had performed more than 200 ESD procedures before treating these patients. pH Monitoring Forty-eight-hour intragastric pH monitoring was performed on selected patients who had agreed to endoscopic BRAVOTM capsule placement. The pH capsule was attached by clips (HX-600-090K; Olympus Medical Systems Corp., Tokyo, Japan) in the manner reported previously [20]. pH was monitored for 48 h with capsule attachment checked at 24 h by endoscopic follow-up and at 48 h by simple X-ray. pH studies were considered to have failed if there was capsule detachment before 24 h or there was evidence of postprocedural bleeding as described below. Outcomes The primary endpoint was the occurrence of major postprocedural bleeding. Major bleeding was defined as follows: (1) the presence of hematemesis or melena, (2) a sudden decrease in systolic blood pressure by more than 30 mmHg, and (3) a rapid decrease in hemoglobin [2 g/ dL. Secondary endpoints were the number of exposed vessels in the ulcer base and the number of exposed vessels per
Dig Dis Sci Fig. 1 Flowchart of patients pretreated with either rabeprazole or placebo 5 days before endoscopic submucosal dissection
ulcer area observed by endoscopy 1 day after the procedure [16, 21], the ulcer healing rate at 30 days after ESD, and the intragastric pH for 48 h after the procedure. Exposed vessels at the ulcer base were defined by the Forrest classification and were evaluated by an endoscopist with extensive experience in ESD who had been blinded to the study medication [22]. The ulcer diameter was measured by an endoscopic measuring device (M2-3U; Olympus Optical Co., Ltd., Tokyo, Japan). Statistics We calculated the expected bleeding rate as 18 % for the placebo group and 14 % in the pretreatment group by referring to a previous similar study, and set the dropout rate as 20 %, alpha error as 0.05, and statistical power as 0.8, which resulted in a requirement for 60 participants per group [16]. In case of intragastric pH monitoring, a previous study reported the incidence of 24-h pH [ 6 after 40 mg intravenous pantoprazole as about 40 % [23]. The pH in the pretreatment group was estimated to be 15 % higher than that in the placebo group. With alpha error of 0.05, statistical power of 0.8, standard deviation of 9.5 %, dropout rate of 20 %, and a technical failure rate of 5 %, at least eight participants were needed per group. Because of a large number of early dropouts, it was decided to recruit twice the expected number of participants, for a total of 32, 16 per group. Continuous data were summarized as mean (95 % confidence interval [CI]). Statistical comparisons of the participants were performed using the v2 test for
categorical data and the Student’s t test for numerical data. The analysis was performed with a statistical software package (SPSS for Windows, SPSS, Chicago, IL, USA). A p value less than 0.05 was accepted as statistically significant.
Results One-hundred twenty patients were recruited, and 60 assigned to each of the two groups. Of these, 11 patients from the rabeprazole group were excluded from initial ESD. Seven patients withdrew consent on the date of ESD. Three patients underwent laparoscopic surgery because of positive lymph nodes discovered during staging via highresolution computed tomography at our hospital. They had been enrolled in our outpatient clinic based on negative lymph nodes on their referral notes. Of the remaining 49 participants in the pretreatment group, four were excluded from final analysis. Of the 60 patients in the placebo group, four withdrew consent on the date of ESD. Of the remaining 56 patients in the placebo group, three were excluded from the final analysis. A detailed flow chart of the study is shown in Fig. 1. Of the 32 participants who agreed to 48-h intragastric pH monitoring, 16 were allocated to each of the pretreatment and placebo groups. Of those in the pretreatment group, five withdrew consent and 11 underwent pH monitoring. Of these 11, three were excluded from the final analysis; one because of early capsule detachment, one
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Dig Dis Sci Table 1 Demographic characteristics of the study population Pretreatment group
Placebo group
Number of subjects
45
53
P value
Pretreatment group
Placebo group
P value
Clinical evidence of bleedinga
1
0
0.658
Fall in hemoglobin level by [2 g/dL
3
3
0.620
Fall in systolic blood pressure [ 30 mmHg
0
0
1.000
Total
3b
3
0.620
Primary endpoints
Age (mean ± SD)
59 ± 8.9
58 ± 10
0.721
Male gender
24 (53.3 %)
42 (79.2 %)
0.009
Smoking
8 (17.9 %)
10 (18.9 %)
1.000
Alcohol
22 (48.9 %)
32 (60.3 %)
0.372
Coffee
29 (64.4 %)
30 (56.6 %)
0.535
Body mass index (kg/m2) Male 23 ± 2.5
24.2 ± 2.7
0.104
Female
23.2 ± 3.1
24.2 ± 2.2
0.331
Helicobacter pylori positivity
21/43 (48.8 %)
28/51 (54.9 %)
0.679
Secondary endpoints Number of exposed vesselsc
1.02 ± 1.37
1.36 ± 1.08
0.178
Ulcer healing rate at 30 days
93.3 %
92.5 %
1.00
a
Location Cardia
2 (4.4 %)
1 (1.9 %)
Body
12 (26.7 %)
11 (20.8 %)
Angle
7 (15.6 %)
3 (5.7 %)
Antrum
24 (53.4 %)
38 (71.7 %)
Adenoma
32 (71.1 %)
42 (79.2 %)
Carcinoma Others
11 (24.4 %) 2 (4.4 %)
8 (15.1 %) 3 (5.7 %)
0.211
Hematemesis or melena
b
One patient was positive for both clinical evidence of bleeding and showed a drop in hemoglobin [2 g/dL
c
Noted during endoscopic follow-up at 1 day after endoscopic submucosal dissection
Pathology 0.481
Procedure time (minute)
36.8 ± 25.9
40.9 ± 32.2
0.495
Resulting ulcer area (cm2)
10.7 ± 6.2
9.6 ± 5.0
0.328
Number of lesions
1.2 ± 0.5
1.2 ± 0.6
0.535
NS nonspecific, SD standard deviation
because of intragastric bleeding, and one who was excluded from the study because of incomplete resection. Of the placebo group, one participant withdrew consent and two had early capsule detachment, leaving 13 participants in the final analysis. The baseline characteristics of the two groups are shown in Table 1. There were no significant differences in age, smoking history, obesity, or Helicobacter pylori status. The placebo group included significantly more men. There were also no significant differences in lesion location, resected ulcer size, or pathology, and the total procedure time was not significantly different. There were no significant differences between the two groups in the incidence of major postprocedural bleeding; there were three cases of bleeding in each group: One patient showed hematemesis on the evening of the procedure and his hemoglobin level fell 2.4 g/dL; Two patients had a fall of [2 g/dL in hemoglobin level without clinical evidence of bleeding. In the placebo group, all three patients showed a reduction in hemoglobin level of [2 g/ dL without clinical evidence of bleeding. Five among six bleeding cases occurred within 48 h after ESD while one
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Table 2 Primary and secondary endpoints
case in the pretreatment group occurred during the 48–72 h period. Second-look endoscopy revealed no difference between the two groups in the number of exposed vessels. Comparisons of the ulcer healing rate between the first endoscopy and the second endoscopy performed at day 30 revealed no significant difference between the two groups (Table 2). The 48-h intragastric pH monitoring revealed no significant difference in the mean pH of the two groups, with the pretreatment group at 6.67 ± 1.72 and the placebo group at 6.45 ± 1.25. The percentage time at pH [ 4, [5, and [6 was 86.61 ± 19.45 %, 83.30 ± 22.06 %, and 76.86 ± 25.35 %, respectively, in the pretreatment group and 85.54 ± 19.45 %, 84.08 ± 27.11 % and 81.53 ± 27.81 %, respectively, in the placebo group.
Discussion We hypothesized that 5 days of oral PPI pretreatment with intravenous PPI administration 2 h before ESD would be effective in reducing postESD bleeding by maximizing gastric acid suppression. However, preprocedural administration of rabeprazole offered no additional benefit over postprocedural administration alone in preventing major bleeding after gastric ESD. This was most likely because the mean pH in both groups was C6. PPIs function by irreversibly binding to the proton pump, resulting in potent acid inhibition throughout the 24 h postdose period [17]. However, the first dose of PPI inhibits only the activated H?/K?-ATPase located in the
Dig Dis Sci
canalicular membrane, with maximum acid inhibition achieved on day 5 after PPI administration [18, 19, 24, 25].However, the placebo group also achieved maximal acid inhibition and pH [ 6.4, comparable with the pretreatment group. This might be because all patients with gastric neoplasms are more likely to have atrophic gastritis [26–28]. As corpus atrophy results in a reduced number of acid-producing parietal cells, the stomach becomes hypochlorhydric [29]. The reduced number of parietal cells would have needed less PPI to be fully inhibited, resulting in no clinically significant differences in pH and postESD bleeding rate between the two groups. Six percent of our participants reported bleeding which was lower than our expectations, within the previous reported postESD bleeding rates of 2–15 % [1, 4–8]. As this study was designed in the early days of ESD, we had expected a high bleeding rate. Therefore, this study should be interpreted with in mind that it could have been insufficiently powered. The low bleeding rate could be explained by the following. First, the improvement in ESD materials such as use of the water-jet scope, procedure methods, and operator skills [30] during the study period most likely led to a decrease in the bleeding rates of our study. Second, our endoscopists performed meticulous electrocautery procedures on exposed vessels during and after ESD which may have reduced the bleeding [10]. Third, intravenous pantoprazole 40 mg once daily might be enough to inhibit gastric acid secretion during ESD. Fourth, the strict exclusion criteria prevented individuals at higher risk of bleeding such as patients taking aspirin, NSAIDs, or anticoagulants or those with severe comorbid diseases, from inclusion. The ulcer healing rates noted by endoscopic follow-up at 30 days after ESD were about 95 %. Even though a large iatrogenic ulcer was created by ESD, a 4-week treatment with oral PPI was sufficient to heal this postESD ulcer. There have been few studies on preprocedural administration of antisecretory agents. A randomized controlled trial involving 1 week of preprocedural once-daily oral administration of 30 mg lansoprazole in patients undergoing endoscopic mucosa resection (EMR) reported that this treatment improved ulcer healing. In this study, there were no cases of postprocedural bleeding in the PPI group and only three in the nonpremedicated group, but there were too few cases to infer a significant difference. Intragastric pH, which was measured by collecting gastric juice during EMR, was significantly higher in the PPI group with all preEMR participants in the PPI group reporting a pH C 5.4 [31]. Another study compared PPI administration begun 1 day prior to ESD with PPI administration only after ESD. In this study, no additional benefit was noted, with a rate of postESD bleeding of about 7 % in both groups. This study also reported sufficient acid suppression after intravenous PPI administration, with postESD day 1 intragastric pH
similar in both groups at pH [ 6 [21]. Our study suggests that low-dose intravenous PPI administration without pretreatment achieves sufficient gastric acid inhibition to prevent postprocedural bleeding. There have been many protocols used to reduce postESD/EMR bleeding. A recent meta-analysis showed that postESD/EMR treatment with PPI was significantly superior to treatment with H2RA in bleeding prevention [14]. However, other studies have reported little difference in postprocedural bleeding rates between PPI- and H2RAtreated groups, especially when second-look endoscopy was performed [16, 32]. Protocols involving the administration of mucoprotective agents together with PPIs have also been suggested [33, 34]. However, further studies are needed to determine the appropriate regimen and risk criteria to identify high-risk patients who will benefit from tailored regimens. In order to account for nonobvious postprocedural bleeding, the decrease in hemoglobin and newly formed vessels on follow-up endoscopy were measured as secondary parameters [16, 21]. However, the fall in hemoglobin may have been related to bleeding during the procedure as well as postprocedural bleeding. In addition, the inclusion of newly formed vessels could have been dependent on postprocedural coagulation. Therefore, these should be carefully considered. To summarize, preprocedural administration of rabeprazole offers no additional benefit over postprocedural administration alone in preventing major bleeding after gastric ESD. This might be related to the hypochlorhydria resulting from the underlying atrophic gastric mucosa. Acknowledgments The authors would like to respectfully dedicate this paper to the memory of Dr. Chung In-Sik, a beloved mentor who did so much for the progress of Korean Gastroenterology and Endoscopy. This study was supported by Janssen Korea. Conflict of interest
None.
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