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Peroral endoscopic myotomy for achalasia: a prospective multicenter study in Japan
Journal Pre-proof Peroral endoscopic myotomy for achalasia: a prospective multicenter study in Japan Hironari Shiwaku, MD, PhD, Haruhiro Inoue, MD, PhD, Hiroki Sato, MD, PhD, Manabu Onimaru, MD, PhD, Hitomi Minami, MD, PhD, Shinwa Tanaka, MD, PhD, Chiaki Sato, MD, PhD, Ryo Ogawa, MD PhD, Norihiko Okushima, MD PhD, Hiroshi Yokomichi, MD PhD, MPH, DPH PII:
S0016-5107(19)32470-8
DOI:
https://doi.org/10.1016/j.gie.2019.11.020
Reference:
YMGE 11838
To appear in:
Gastrointestinal Endoscopy
Received Date: 1 August 2019 Accepted Date: 4 November 2019
Please cite this article as: Shiwaku H, Inoue H, Sato H, Onimaru M, Minami H, Tanaka S, Sato C, Ogawa R, Okushima N, Yokomichi H, Peroral endoscopic myotomy for achalasia: a prospective multicenter study in Japan, Gastrointestinal Endoscopy (2019), doi: https://doi.org/10.1016/ j.gie.2019.11.020. 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 © 2019 by the American Society for Gastrointestinal Endoscopy
1
Title:
Peroral endoscopic myotomy for achalasia: a prospective multicenter study in Japan Authors: Hironari Shiwaku1, MD, PhD Haruhiro Inoue2, MD, PhD Hiroki Sato3, MD, PhD Manabu Onimaru2, MD, PhD Hitomi Minami4, MD, PhD Shinwa Tanaka5, MD, PhD Chiaki Sato6, MD, PhD Ryo Ogawa7, MD PhD Norihiko Okushima8, MD PhD Hiroshi Yokomichi9, MD PhD, MPH, DPH
1
Department of Gastroenterological Surgery, Fukuoka University Faculty of Medicine, Fukuoka,
Japan 2
Digestive Diseases Center, Showa University Koto-Toyosu Hospital, Tokyo, Japan
3
Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital,
Niigata, Japan 4
Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
5
Department of Gastroenterology, Kobe University Hospital, Hyogo, Japan
6
Department of Surgery, Tohoku University School of Medicine, Miyagi, Japan
2
7
Department of Gastroenterology, Oita University Faculty of Medicine, Oita, Japan
8
Heart Life Hospital, Okinawa, Japan
9
Division of Medicine, Graduate School Department of Interdisciplinary Research, University of
Yamanashi, Yamanashi, Japan
Submitting author: Hironari Shiwaku Department of Gastroenterological Surgery, Fukuoka University Faculty of Medicine 7-45-1, Nanakuma, Jyounan-ku, Fukuoka, 814-0180, Japan TEL: +81-92-801-1011; FAX: +81-92-863-9759 E-mail: [email protected] Corresponding author: Haruhiro Inoue Digestive Diseases Center, Showa University Koto-Toyosu Hospital Toyosu5-1-38, Koto-Ku, Tokyo, 135-8577, Japan Tel: +81-3-6204-6064; FAX: 03-6204-6396 email: [email protected] Guarantor of the article: Hironari Shiwaku and Haruhiro Inoue are guarantor of the article.
Specific author contributions:
3
Study concept and design: Hiroki Sato, Hironari Shiwaku, and Haruhiro Inoue Acquisition of data: Hironari Shiwaku, Hiroki Sato, Manabu Onimaru, Hitomi Minami, Shinwa Tanaka, Chiaki Sato, Ryo Ogawa, and Norihiko Okushima Analysis and interpretation of data: Hiroki Sato and Hiroshi Yokomichi Drafting the manuscript: Hironari Shiwaku and Hiroki Sato Critically revising the manuscript for important intellectual content: Haruhiro Inoue, Hironari Shiwaku, Hiroki Sato, Manabu Onimaru, Hitomi Minami, Shinwa Tanaka, Chiaki Sato, Ryo Ogawa, and Norihiko Okushima Statistical analysis: Hiroshi Yokomichi Administrative, technical, or material support: Hironari Shiwaku, Hiroki Sato, and Haruhiro Inoue Study supervision: Haruhiro Inoue
Financial support: This study received no particular funding.
Potential competing interests: Dr. Inoue reports grants from Olympus Co. and grants from Boston Scientific Co., outside the submitted work; the other authors have nothing to disclose.
1
Title Peroral endoscopic myotomy for achalasia: a prospective multicenter study in Japan
Abstract Background and Aims Peroral endoscopic myotomy (POEM) is one of the available treatment modalities for achalasia. The reported efficacy of POEM in the only prospective multicenter study was 82%, reported by Von Renteln et al; however, a retrospective multicenter study in Japan reported a higher efficacy rate of
95%. The aim of this study was to prospectively verify treatment outcomes after POEM at multiple facilities in Japan. Methods This was a prospective single-arm trial of POEM for achalasia at eight facilities in Japan between April 2016 and March 2018 to evaluate its safety and efficacy. Patients were re-evaluated at 3 months and up to 1 year after POEM. Results Among the 233 patients with achalasia who underwent POEM, procedure-related adverse events occurred in 24 (10.3%) patients, none of whom required surgical intervention. In the 207 patients satisfying the inclusion criteria after the study by Von Renteln et al, the efficacy rate of POEM, defined by an Eckardt score ≤3 at 1 year, was 97.4% (95.3%–99.7%). The Eckardt score decreased significantly from 6.6 ± 2.0 preoperatively to 1.1 ± 1.1, 1 year after POEM. Postoperative reflux esophagitis, severe reflux esophagitis, and symptomatic gastroesophageal reflux disease were reported in 54.2%, 5.6%, and 14.7%, respectively, and proton pump inhibitors were administered in 21.1%. Conclusions Our prospective multicenter study in Japan showed greater efficacy of POEM for achalasia compared with the results of a previous prospective multicenter study. POEM is safe and highly effective for at least 1 year.
Clinical trial registration The study was registered in the University Hospital Medical Information Network Clinical Trial Registry (https://www.umin.ac.jp/ctr/) number: UMIN000021550.
Keywords: Peroral endoscopic myotomy, Achalasia, Prospective single-arm trial, Multicenter study, Gastroesophageal reflux disease
2
INTRODUCTION Achalasia is an esophageal motility disorder of unknown etiology with an estimated incidence rate of 1 per 100,000 person-years. 1 It is characterized by failure of the lower esophageal sphincter (LES) to relax, along with impaired peristalsis of the esophageal body.
2 3 4 5
Peroral endoscopic myotomy
(POEM) is a minimally invasive treatment for achalasia first reported by Inoue et al in 2010. 6 Several facilities worldwide have reported the therapeutic efficacy of POEM;
7 8-12
however, only one
prospective multicenter study evaluating the outcomes of POEM has been published. The authors reported an overall efficacy (Eckardt score ≤3) after 1 year of 82%;13 however, a multicenter retrospective study involving over 1300 patients from Japan reported an efficacy of POEM after 1 year of 95%14. We expected equal satisfactory treatment outcomes for a multicenter prospective study performed in Japan; therefore, the aim of this study was to prospectively verify the treatment outcomes after POEM at multiple facilities in Japan.
METHODS Study design, setting, and study period This prospective multicenter study was performed at 8 facilities in Japan from 1 April 2016 to 31 March 2018 (Supplementary Table 1). Institutional review board approval was obtained at each institution. One or more members of the public participated in each ethics committee of the eight facilities participating in this research, and this information was published on each facility's website. The study was also registered at the University Hospital Medical Information Network Clinical Trial Registry (trial number: UMIN000021550). The progress of the research was published without delay through UMIN. Informed consent was obtained from all patients. The doctors and clinical staff in each facility explained the study to patients diagnosed with achalasia who met the indications for POEM. Before enrollment, several important study-related items were explained directly to each patient, and voluntary consent was obtained in writing from each patient. Informed consent was obtained from the parents of patients under the age of 18 years. All authors had access to the study data and reviewed and approved the final manuscript.
Inclusion and exclusion criteria We analyzed the data of all patients undergoing POEM for achalasia at the eight facilities participating in this study. Analysis 1 was performed to compare the primary outcomes of our study with those of Von Renteln et al.
13
The inclusion and exclusion criteria were set according to the study by Von
Renteln et al.13 In Analysis 1, we included patients with a preoperative Eckardt score of ≥4 because
3
the primary outcome in the study by Von Renteln et al13 was a postoperative Eckardt score of ≤3. We excluded patients with achalasia aged <18 years (Supplementary Table 2). Analysis 2 included all patients with achalasia who underwent POEM, including all of the patients in Analysis 1 plus those satisfying the less-restrictive criteria (Fig. 1).
Clinical assessment before and after POEM Clinical symptoms were assessed using the Eckardt score, which is commonly used to evaluate the severity of symptoms of achalasia and responses to treatment.
15
The Eckardt score comprises four
components: dysphagia, chest pain, regurgitation, and weight loss. Each component is assigned a score from 0 to 3 based on the patient’s self-reported assessment, with a total score ranging from 0 to 12. Higher Eckardt scores reflect more severe symptoms of achalasia, whereas lower scores postoperatively indicate improved symptoms. Preoperative tests included manometry, endoscopy, barium swallow, and computed tomography (CT). The type of achalasia was determined according to the findings on barium esophagography and was classified as straight or sigmoid.
4
Sigmoid achalasia was defined as a significantly tortuous
esophagus on barium esophagography and was classified into 2 subtypes based on CT findings: sigmoid (S1) and advanced sigmoid (S2) 6. The presence of a double lumen on some CT slices was defined as S2, whereas only a single lumen is present in S1. In patients for whom high-resolution manometry could be performed, we classified the type of achalasia according to the Chicago classification.
16 17
The integrated relaxation pressure (IRP) as
assessed by high-resolution manometry is the most important parameter for evaluating LES relaxation. IRP is measured after deglutitive upper sphincter relaxation from the anticipation of esophagogastric junction relaxation until arrival of the peristaltic wave. Patients' general status was classified according to the American Society of Anesthesiologists (ASA) physical status classification system. 18 Adverse events related to the POEM procedure were evaluated according to the American Society for Gastrointestinal Endoscopy severity grade for adverse events. 19 Patients were reassessed at 3 months and 1 year after POEM. Evaluation was based on an interview, including a calculation of the Eckardt score, and endoscopy and manometry. Erosive esophagitis on endoscopy was evaluated according to the Los Angeles classification. 20
POEM procedures POEM was performed using the methods described by Inoue et al. (Fig. 2A–D). 6 7 21 22 All procedures
4
were performed or supervised by surgeons from each of the facilities who received POEM procedural and technique training from Dr Inoue. POEM was performed under general anesthesia with endotracheal intubation and with the patient lying in a supine position to reflect preoperative CT images. CO2 insufflation was performed through the endoscope. The electrosurgical Triangle Tip Knife with integrated water-jet function (KD-645L, Olympus Corp, Tokyo, Japan) was the preferred surgical device, and myotomy was performed in either an anterior or posterior direction. The starting point for the myotomy was on the oral side of abnormal luminal obstructive contractions in the esophageal body, and the endpoint was the incision from the LES to the gastric side of the sphincter. The length and direction of the myotomy and the method used to confirm the adequacy of the LES incision were left to the judgment of the surgeons at each facility. Confirmation of the LES incision was determined by one of the following 3 methods: 1) Double-scope method:
23
A second endoscope was inserted into the stomach to examine the
cardiac region. If the procedure reached the gastric side, the light from the main endoscope within the submucosal space was visible through the second scope in the stomach (Fig. 2D). 2) Injection method: 9 Indocyanine green solution was injected into the lesser curvature of the gastric cardia before the POEM procedure. If the procedure reached the gastric side, the dye was visible within the submucosal space. 3) Conventional method: 22 The procedure reaching the gastric side was confirmed by the endoscope insertion depth, anatomical landmarks, and/or scope resistance.
Anatomical landmarks The distance from the incisors to the esophagogastric junction was measured before POEM. This measurement was used to gauge how far the scope had been inserted within the submucosal tunnel. The intramucosal or submucosal blood vessels were visible inside the submucosal tunnel, and we noted the transition from the palisade vessels, corresponding anatomically to the LES, to the spindle veins seen on the gastric side. Spindle veins in the gastric cardia are a specific anatomical landmark in the stomach. Depending on the orientation of the submucosal tunnel, it was possible to observe a part of the oblique muscle and the large branch of the left gastric artery in some patients, indicating that the scope was within the lesser curvature of the stomach 24.
Endoscope resistance When creating the submucosal tunnel, it is possible to note the narrowing of the esophageal lumen closer to the LES, which then opens wide into the stomach. When the endoscope is inserted into the
5
stomach cavity after the myotomy is completed, it is possible to feel decreased resistance at the LES.
Outcomes and sample size To compare our results with those of Von Renteln et al, 13 we set the primary outcome as the efficacy of POEM 1 year postoperatively, defined as an Eckardt score ≤3. This was the outcome used in Analysis 1, which included patients meeting the limited criteria, similar to the criteria in Von Renteln et al's study.
13
The efficacy of POEM for all patients with achalasia was assessed in Analysis 2. In
Analysis 2, a lower postoperative Eckardt score was defined as effective POEM surgery in patients with a pre-POEM Eckardt score ≤3. To further assess the results in our multicenter study, we defined the following secondary outcomes: efficacy 3 months postoperatively, adverse events, postoperative gastroesophageal reflux disease (GERD) (including erosive esophagitis and symptomatic GERD), oral administration of proton pump inhibitors (PPIs), and factors associated with erosive esophagitis after POEM. With a 2-sided alpha of 5% and an 80% detection power, we calculated that 144 patients were necessary for Analysis 1 to show the significance of the efficacy of our procedure compared with that of Von Renteln et al.13 Expecting a drop-out rate of 10% in 1 year, nearly 160 patients were required. Based on the number of patients treated with POEM annually in the preceding years at the eight participating facilities, we set the study period at 2 years (patient registration during the first year followed by a 1-year follow-up after POEM).
Statistical analysis Figure 1 is a flowchart of patient enrollment in our study. Patients' characteristics and the details of the POEM procedures are presented as means ± standard deviations (interquartile ranges) for continuous variables and numbers (percentages) for categorical variables. We presented proportions (standard errors) for data for patients with an Eckardt score ≤3, 3 months, and 1 year after POEM, for patients meeting the Analysis 1 and 2 criteria (Supplementary Table 2). We explored the risk factors for reflux esophagitis for Los Angeles classification grades A, B, C, or D in univariable and multivariable logistic regressions. Referring to previous results, we compared odds ratios and their p-values for reflux esophagitis with sex, age, degree of esophageal dilation, type of achalasia on the Chicago classification, direction and length of the myotomy, and IRP 1 year after POEM.
25 26 27
Statistical analyses were performed using SAS V.9.4 statistical software (SAS Institute, Cary, NC, USA). Reported p-values sere 2-sided, and we considered p <0.05 statistically significant. All data were sent to and analyzed at an independent facility (University of Yamanashi, Japan).
6
RESULTS Patient demographics POEM was performed for a total of 233 patients (130 women and 103 men with a mean age of 52.0 ± 17.5 years) between April 2016 and March 2017. (At Tohoku University, institutional review board approval was obtained, but patients were not registered.) Patients' clinical data are summarized in Table 1. Straight achalasia was present in 191 (82%) patients, and sigmoid achalasia in the remaining 42 (18%), including 10 (4%) patients with advanced sigmoid achalasia. Previous procedures included pneumatic dilation in 43 (18 %) patients and Heller–Dor operation in 8 (3 %) patients. 28 29 30 31 We assessed each patient's American Society of Anesthesiologists physical status (ASA-PS) and classified 157 (67%) patients as ASA-PS class I, 72 (31%) as ASA-PS class II, and 4 (2%) as ASA-PS class III (Table 1). Among the 233 patients undergoing POEM, 223 were evaluated 1 year after POEM and were included in Analysis 2. A total of 207 patients satisfied the inclusion and exclusion criteria reported by Von Renteln et al13, and their data were included in Analysis 1 (Fig. 1).
POEM outcomes The details of the POEM procedure are summarized in Table 2. POEM was successfully completed in all patients (technical success rate: 100%) with a mean procedural time of 94.1 ± 44.6 minutes. The mean length of the esophageal myotomy was 10.5 ± 3.3 cm, and the mean length of the gastric myotomy was 2.8 ± 1.1 cm. To confirm the LES incision, we used the double-scope method in 80% of the patients (Table 2 and Supplementary Table 1). Adverse events occurred in 24 of 233 patients (10.3%) and comprised 11 mucosal perforations, 9 mucosal injuries without perforation, 3 hematomas in the submucosal space, 1 case of pleurisy, and 1 case of peritonitis (1 patient had both mucosal perforation and peritonitis). According to the American Society for Gastrointestinal Endoscopy severity grade for adverse events, 15 and 9 adverse events were classified as mild and moderate, respectively. No adverse events were severe or fatal. 19 All adverse events were treated conservatively.
Short- and long-term efficacy of POEM The primary outcome (efficacy) (Analysis 1) 1 year after POEM in 207 patients was 97.4% (95.2%– 99.7%). Patients' Eckardt scores decreased significantly from 6.6 ± 2.0 preoperatively to 1.0 ± 1.1 at 3 months postoperatively and to 1.1 ± 1.1 at 1 year after POEM. The short-term efficacy at 3 months was 97.1% (94.8%–99.4%), indicating durable efficacy after 1 year (Fig. 3). For all 223 patients
7
(Analysis 2), the efficacy rate at 1 year was 97.5% (95.3%–99.7%). The efficacy 1 year after POEM according to the achalasia subtype (Chicago classification) was Type I: 96.2%, Type II: 98.7%, and Type III: 100%.
16, 17
The efficacy of anterior myotomy was 96.8%, and the efficacy of posterior
myotomy was 97.9%; the difference was not statistically significant.
GERD and PPI use Among the 223 patients who could be evaluated at 1 year, 10 had received PPIs before POEM and were excluded from the analysis for GERD. Among the remaining 213 patients, symptomatic GERD was present postoperatively in 14.7% (9.5%–19.9%) of the patients, and 21.1% (15.2%–27.0%) had been prescribed PPIs within the first year after POEM. One year after POEM, 142 patients underwent endoscopy. Los Angeles grade A to D erosive esophagitis was present in 54.2% (46.0%–62.4%, 77/142) of the patients, and severe erosive esophagitis (Los Angeles grade C or D) was seen in 5.6% (8/142) of the patients. We performed univariable and multivariable analyses to evaluate the factors associated with erosive esophagitis (Los Angeles grades A–D) after POEM, including sex, age, degree of dilation, type of achalasia (straight or sigmoid), Chicago classification for the manometry results, direction of the myotomy, length of the myotomy on the esophageal and gastric sides, and IRP after POEM. Among these factors, the length of the myotomy on the esophageal side was a significant factor on univariate analysis (odds ratio, 1.63; 95% confidence interval [CI], 1.04–2.56), but not on multivariate analysis (Table 3). DISCUSSION This prospective multicenter study reported a higher efficacy rate (97.4%; 95.2%–99.7%) for POEM compared with the results of the previous prospective multicenter study reported by Von Renteln et al13 (82.4%) involving patients meeting similar inclusion criteria. When we included all of the patients with achalasia, the efficacy rate remained high (97.5%; 95.3%–99.7%) in our study. There are 2 possible reasons for this high efficacy rate: (1) most of the surgeons in our study learned the POEM procedure over at least a 1-year period from its originator, Dr. Inoue, and used consistent techniques; and (2) all procedures were performed by these trained surgeons or under their supervision. Based on our results, we believe that POEM is potentially curative for most patients with achalasia, with durable results up to at least 1 year after the procedure. The efficacy rate of 97.4% (95.2%–99.7%) in this prospective multicenter study was also higher than the 94.7% efficacy found in our previous retrospective multicenter analysis of 1300 patients.
14
Therefore, the current study demonstrated that
POEM may be adequately taught and used safely and effectively at different institutions in Japan.
8
However, even if POEM is performed at a certain technical level, incomplete LES incisions can occur during large series 8. The most reliable method to prevent incomplete LES incisions is confirmation using the double-scope method.
23 32 33
In the present study, the double-scope method was routinely
performed at Showa University, Fukuoka University, and Kobe University (80% of all patients) (Table 2 and Supplementary Table 1). In addition, all patients with advanced sigmoid type achalasia (10 cases) that was likely to cause incomplete myotomy of the LES were included in these 3 institutions, and the efficacy at these institutions remained high. These results indicate that the double-scope method may help to avoid incomplete myotomy of the LES during large series. Because the double-scope method requires 2 endoscope systems, it is difficult to perform routinely in all facilities. In the present study, 3 facilities (Niigata University, Oita University, and Heart Life Hospital) confirmed incision of the LES by the conventional method and the efficacy at these institutions was also high. The reason for this may be that 1 or 2 fixed surgeons with substantial experience performed the POEM procedure. In facilities with multiple surgeons, a method for confirming the LES incision (double-scope method or injection method) tended to be used (Supplementary Table 1). We believe that differences in skill level between surgeons can be appropriately addressed by objectively confirming the LES incision. We performed POEM safely and effectively in a wide range of patients, based on ASA-PS (class II: 31%, class III: 2%), which suggests that POEM is not invasive in patients with relatively poor physical condition. We also performed POEM in younger patients, 2 of whom were less than 17 years old. Additionally, we performed the POEM procedure effectively regardless of the type of achalasia (according to the Chicago classification). GERD after POEM is a major adverse event. In this study, 54.2% (46.0%–62.4%) of the patients experienced reflux esophagitis after POEM, although severe esophagitis (Los Angeles class C or D) occurred only in 5.6% of those who underwent follow-up endoscopy. These results were similar to findings in a previous report.
14
Only 142 out of 213 patients underwent follow-up endoscopy,
whereas the remaining patients declined the procedure. Assuming that the remaining patients had no symptoms of GERD after POEM and, therefore, had normal endoscopic findings, it is possible that erosive esophagitis was overestimated in the first year. None of the factors we assessed were significantly associated with erosive esophagitis after POEM on multivariate analysis, possibly because the number of patients in this study was too small to yield statistically significant results; therefore, further studies involving a large sample size are warranted. Several limitations of this study were the following. We did not include patients with other esophageal motility disorders. Furthermore, the number of patients with Type III achalasia was relatively small,
9
and the POEM procedure, including the myotomy direction, was not uniform in this study. Although the short-term and 1-year outcomes were almost equivalent, efficacy over a relatively longer term remains to be investigated. In conclusion, our prospective multicenter study showed greater efficacy of POEM for achalasia compared with the results of a previous prospective multicenter study. POEM is durably effective for at least 1 year, and is considered safe and highly effective.
Acknowledgments The authors thank all patients and clinical staff for their participation and contribution to this study.
Data sharing All data relevant to the study are included in the article. Data are available upon reasonable request.
10
Table 1. Characteristics of the 233 patients with achalasia who underwent peroral endoscopic myotomy Age, years, mean ± SD (range)
52.0 ± 17.5 (13–93)
Sex (female, male)
130, 103
Type of achalasia, n (%) Straight
191 (82)
Sigmoid
32 (14)
Advanced sigmoid
10 (4)
Chicago classification, n (%) Type I
108 (46)
Type II
80 (34)
Type III
13 (6)
Previous procedure, n (%) Balloon dilatation
43 (18)
Heller–Dor operation
8 (3)
ASA-PS, n (%) I
157 (67)
II
72 (31)
III
4 (2)
SD, standard deviation; ASA-PS, American Society of Anesthesiologists physical status classification
Table 2. Details of the 233 peroral endoscopic myotomy procedures for achalasia Length of procedure, mean ± SD (range), min
94.1 ± 44.6 (34–460)
Direction of myotomy, n (%)
Anterior
32 (14)
Posterior
201 (86)
Myotomy length, mean (range), cm
11
Esophageal
10.5 ± 3.3 (3–25)
Gastric
2.8 ± 1.1 (0–6)
Confirmation of LES incision, n (%)
Double-scope method
185 (80)
Conventional method
42 (18)
Injection method
6 (2)
SD, standard deviation; LES, lower esophageal sphincter
Table 3. Odds ratios for Los Angeles grade A–D erosive esophagitis 1 year after peroral endoscopic myotomy (POEM) for achalasia Variables
Univariate analysis
p value
OR (95% CI)
Multivariate
p value
analysis OR (95% CI)
Male vs. female
1.54 (0.76–3.12)
0.23
1.12 (0.42–
0.82
3.00)
Age per 10 years
0.88 (0.71–1.09)
0.25
0.67 (0.48–
0.02
0.94)
Degree of dilatation II or III (vs. I)
0.78 (0.39–1.57)
0.48
1.57 (0.55– 4.49)
0.40
12
Achalasia type: sigmoid (vs.
1.23 (0.47–3.20)
0.68
2.06 (0.54–
straight)
Chicago classification type Ⅱ
7.86)
1.24 (0.60–2.57)
0.56
1.21 (0.43–
0.88 (0.25–3.04)
0.84
0.16 (0.01–
vs. posterior)
Length of myotomy on the
1.63 (1.04–2.56)
0.03
1.61 (0.88–
0.12
2.96)
2.05 (0.91–4.62)
0.08
3.02 (0.97–
gastric side per 2 cm
IRP (1 year after POEM) per 5
0.19
2.41)
esophageal side per 5 cm
Length of myotomy on the
0.72
3.40)
or Ⅲ (vs. type Ⅰ)
Direction of myotomy (anterior
0.29
0.06
9.39)
1.20 (0.84–1.72)
0.31
1.18 (0.79–
mmHg
0.41
1.77)
IRP, integrated relaxation pressure
Figure Legends Figure 1. Flow chart of patient enrolment in this prospective study of peroral endoscopic myotomy for achalasia Figure 2A. Figure showing the peroral endoscopic myotomy procedure (posterior myotomy) after creating the submucosal tunnel Figure 2B. Selective myotomy of the inner circular muscle using the Triangle Tip Knife J (Olympus Medical Systems Corp., Tokyo, Japan) Figure 2C. After myotomy Figure 2D. Double-scope endoscopy. A second endoscope is inserted into the stomach to examine the cardiac region. If the myotomy procedure reached the gastric side, the light from the main scope in the submucosal space is visible through the second scope in the stomach. Figure 3. Efficacy rates 3 months and 1 year after peroral endoscopic myotomy in this study compared with a previous prospective study
13
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Kahrilas PJ, Bredenoord AJ, Fox M, et al. The Chicago Classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil 2015;27:160-74.
18.
American Society of Anesthesiologists. ASA Physical Status Classification System. 2014:https://www.asahq.org/standards-and-guidelines/asa-physical-status-classificat ion-system.
19.
Cotton PB, Eisen GM, Aabakken L, et al. A lexicon for endoscopic adverse events: report of an ASGE workshop. Gastrointest Endosc 2010;71:446-54.
20.
Armstrong D, Bennett JR, Blum AL, et al. The endoscopic assessment of esophagitis: a progress report on observer agreement. Gastroenterology 1996;111:85-92.
21.
Inoue H, Tianle KM, Ikeda H, et al. Peroral endoscopic myotomy for esophageal achalasia: technique, indication, and outcomes. Thorac Surg Clin 2011;21:519-25.
22.
Inoue H, Shiwaku H, Iwakiri K, et al. Clinical practice guidelines for peroral endoscopic myotomy. Dig Endosc 2018;30:563-579.
23.
Baldaque-Silva F, Marques M, Vilas-Boas F, et al. New transillumination auxiliary technique for peroral endoscopic myotomy. Gastrointest Endosc 2014;79:544-5.
24.
Tanaka S, Kawara F, Toyonaga T, et al. Two penetrating vessels as a novel indicator of the appropriate distal end of peroral endoscopic myotomy. Dig Endosc 2018;30:206-211.
25.
Shiwaku H, Inoue H, Sasaki T, et al. A prospective analysis of GERD after POEM on anterior myotomy. Surg Endosc 2016;30:2496-504.
26.
Familiari P, Greco S, Gigante G, et al. Gastroesophageal reflux disease after peroral endoscopic myotomy: Analysis of clinical, procedural and functional factors, associated with gastroesophageal reflux disease and esophagitis. Dig Endosc 2016;28:33-41.
27.
Kumbhari V, Familiari P, Bjerregaard NC, et al. Gastroesophageal reflux after peroral endoscopic myotomy: a multicenter case-control study. Endoscopy 2017;49:634-642.
28.
Heller.E. Extramukose Kardioplastik beim chronischen Kardiospasmus mit Dilatation des Oesophagus. Mitteilungen aus den Grenzgebieten der Medizin und Chirurgie 1914;27:141.
29.
Cox J, Buckton GK, Bennett JR. Balloon dilatation in achalasia: a new dilator. Gut 1986;27:986-9.
30.
Boeckxstaens GE, Annese V, des Varannes SB, et al. Pneumatic dilation versus laparoscopic
15
Heller's myotomy for idiopathic achalasia. N Engl J Med 2011;364:1807-16. 31.
Campos GM, Vittinghoff E, Rabl C, et al. Endoscopic and surgical treatments for achalasia: a systematic review and meta-analysis. Ann Surg 2009;249:45-57.
32.
Grimes KL, Inoue H, Onimaru M, et al. Double-scope per oral endoscopic myotomy (POEM): a prospective randomized controlled trial. Surg Endosc 2016;30:1344-51.
33.
Inoue H, Shiwaku H, Kobayashi Y, et al. Statement for gastroesophageal reflux disease after peroral endoscopic myotomy from an international multicenter experience. Esophagus 2019.
Supplementary Table 1: Details of all POEM procedures and the surgeons in each facility
Number of Surgeon Facility
No.
From surgical
From internal
department
medicine
Each experience of over 15 cases of POEM as
Each experience of ESD
Trained POEM procedure from Dr.
How to confirm
the primary surgeon or
over 20 cases
Inoue
incision of LES
as an assistant 1
Showa University Koto-Toyosu Hospital, Tokyo
4
6
〇
〇
〇
Double scope method
2
Fukuoka University Faculty of Medicine, Fukuoka
2
0
〇
〇
〇
Double scope method
3
Kobe University Hospital, Hyogo
0
2
〇
〇
〇
Double scope method
0
1
〇
〇
〇
Conventional method
Niigata University Medical and Dental Hospital,
4 Niigata
5
Oita University Faculty of Medicine, Oita
0
2
〇
〇
〇
Conventional method
6
Heart Life Hospital, Okinawa
1
0
〇
〇
〇
Conventional method
7
Nagasaki University Hospital, Nagasaki
0
4
〇
〇
〇
Injection method
POEM, peroral endoscopic myotomy; ESD, endoscopic submucosal dissection; LES, lower esophageal sphincter
Supplementary Table 2. Inclusion and exclusion criteria for analysis 1 and 2
Analysis 1: Inclusion and exclusion criteria were made to compare the efficacy of POEM with that reported by the previous prospective study. Inclusion criteria
Exclusion criteria
・Symptomatic achalasia
・Eosinophilic esophagitis
・Preoperative ES ≥ 4
・Barrett esophagus
・Preoperative barium swallow, manometry, and ・Pregnancy esophagogastroduodenoscopy
results
were
suggestive of achalasia ・Age >18 years
・ Malignant or premalignant esophageal lesion ・Severe candida esophagitis ・ Extensive,
tortuous
dilatation
of
the
esophagus (luminal diameter >7 cm, S shape) ・Patients with preoperative ES ≤3 Analysis 2 All patients with achalasia plus those aged ≤18 years or with a preoperative ES ≤3
POEM, peroral endoscopic myotomy; ES, Eckardt score
Title: Peroral endoscopic myotomy for the treatment of achalasia: a prospective multicenter study in Japan Principal Investigator: Hironari Shiwaku 1, MD, PhD Other Investigators: Haruhiro Inoue 2, MD, PhD Hiroki Sato3, MD, PhD Manabu Onimaru2, MD, PhD Hitomi Minami4, MD, PhD Shinwa Tanaka5, MD, PhD Chiaki Sato6, MD, PhD Ryo Ogawa7, MD PhD Norihiko Okushima8, MD PhD Hiroshi Yokomichi9, MD PhD, MPH, DPH Institutional affiliations: Department of Gastroenterological Surgery, Fukuoka University Faculty of Medicine, Fukuoka 2 Digestive Diseases Center, Showa University Koto-Toyosu Hospital, Tokyo 1
3
Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, Niigata 4 Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki 5 Department of Gastroenterology, Kobe University Hospital, Hyogo 6
Division of Advanced Surgical Science and Technology, Tohoku University School of Medicine, Miyagi 7 Department of Gastroenterology, Faculty of Medicine, Oita University, Oita 8 9
Heart Life Hospital, Okinawa Division of Medicine, Graduate School Department of Interdisciplinary Research, University of Yamanashi, Yamanashi
I. BACKGROUND AND SIGNIFICANCE Peroral endoscopic myotomy (POEM) is the standard treatment for esophageal achalasia. A single-center study in Japan reported a higher efficacy rate than that reported in other previous reports. The aim of this study is to examine treatment outcomes of POEM at multiple facilities in Japan. II.
STUDY
OBJECTIVE(S),
INCLUDING
SPECIFIC
AIMS
AND/OR
HYPOTHESES Esophageal achalasia is an esophageal motility disorder of unknown etiology with an estimated incidence rate of 1 per 100,000 person-years. It is characterized by failure of the lower esophageal sphincter relaxation along with impaired peristalsis of the esophageal body. Peroral endoscopic myotomy (POEM) is a minimally invasive treatment for esophageal achalasia, as reported first by Inoue et al. in 2010. Several facilities worldwide have reported the therapeutic efficacy of POEM. However, prospective multicenter studies assessing the outcomes have only been reported from the European and North American group (Germany, the Netherlands, Switzerland, and Canada), with an overall efficacy [Eckardt score (ES) ≤ 3] of POEM of 82.4% after 1 year. A single-center study of 500 cases from Japan reported an efficacy (ES ≤ 2 or ES improved by ≥4 points) of 91.0%. If multicenter studies are to be conducted in Japan, equal satisfactory treatment outcomes can be expected. The aim of this prospective research is to evaluate the treatment outcomes of POEM at multiple facilities in Japan.
III. METHODS Study subjects Patients diagnosed with esophageal achalasia or related diseases, who were deemed suitable for myotomy Inclusion criterion Patients capable of providing written informed consent by themselves or by their legal representative *** *** The legal representative will be the person with parental authority for patients younger than 20 years of age, and the closest family member or relative in the event of patients who have lost the ability to understand and make judgments owing to mental disorder or intellectual disability. Exclusion criteria • •
Patients in whom general anesthesia is difficult Patients deemed unsuitable by the attending physician
Explanation and consent Before conducting this study, as a rule, the items listed below will be explained directly to the patient, and voluntary consent will be obtained in writing from the patient. 1) Background, purpose, and significance of the study 2) Treatment methods 3) Anticipated results 4) Expected side effects/ethical issues 5) Costs involved 6) Human rights and privacy 7) Refusal to consent 8) Withdrawal of consent 9) Changes may occur as medically needed
10) Freedom to ask questions and availability of an enquiry desk Patient enrolment 1) Patient enrolment will commence after obtaining approval from the ethical review board. 2) Informed consent is required for all patients to participate in this study. Patients will sign the relevant documents only after voluntary consent is obtained from patients. 3) Patient enrolment will be reported on a regular basis to the institution responsible for enrolments (coordinating center in Showa University Koto Toyosu Hospital). 4) POEM will be performed at each institution in accordance with instructions from the coordinating center, and follow-up of specified items will be performed up to one year after surgery. Preoperative
At 3 months
At 1 year
Symptom score (Eckardt score)
○
○
○
Endoscopic examination
○
○
○
Intraesophageal pressure measurement
○
○
○
GERD score
○
○
○
Presence or absence of ○ oral antacids
○
○
Expected adverse events Procedural accidents associated with POEM, general anesthesia, and pre- and postoperative tests will be considered as adverse events. In Japan, to this day, more than 1,300 patients have undergone POEM without serious complications of Clavien-Dindo grade IIIb or greater. Cases of mild-to-moderate procedural accidents of Clavien-Dindo grade IIIa or below were resolved with conservative treatment. Expected adverse events are listed below. Mucosal damage of the esophagus and stomach, esophagitis, mediastinitis, peritonitis,
inflammation of the lesser omentum, intra- and postoperative bleeding, submucosal hematoma, atelectasis, pneumonia, pneumothorax, pneumoperitoneum, subcutaneous emphysema, mediastinal emphysema, retroperitoneal emphysema, pleural effusion, ascites, etc.
Endpoints
Primary endpoint
Effectiveness at one year after POEM Eckardt score of 3 or less is considered effective.
Secondary endpoints
• • •
The presence or absence of POEM-related procedural accidents Effectiveness at three months after POEM Postoperative GERD (Analysis-2)
•
Lower esophageal sphincter pressure
• •
Operative duration Oral PPI therapy
Analysis of this study All patients undergoing POEM for achalasia were analyzed in this study. Analysis 1 was performed to compare the primary outcomes with that of multicenter studies from European and North American group. In Analysis 1, patients with preoperative ES ≥4 were included because primary outcome was set to ES ≤3 postoperatively, and patients with achalasia aged <18 years were excluded. Analysis 2 was performed for all patients with achalasia who underwent POEM, including all patients in Analysis 1 plus others satisfying the less restrictive criteria.
Discontinuation criteria The trial investigators will discontinue the trial for subjects in whom any of the following events occur during the trial period. Furthermore, when investigators decide to discontinue or terminate the trial, they will administer appropriate treatment to the subject, and an annual written report will be submitted to the director of the hospital. 1. Subject (or legal representative) requests discontinuation 2. Trial is terminated owing to the subject’s circumstances (home relocation, change of physician, change of hospital, being too busy, and follow-up is impossible) 3. After trial commencement, when it is judged that the subject is not eligible 4. Event of a procedural accident 5. Occurrence of adverse events (including exacerbation of the underlying disease, exacerbation of complications, and procedural accidents), prompting trial investigator to discontinue the trial 6. Insufficient response or deterioration of symptoms hinders continuation of the trial. 7. Major protocol deviations 8. Lack of compliance with the medication 9. Trial investigator decides to discontinue the trial Planned number of enrolments and subject recruitment period 1) Sample size The planned sample size for this study is 160 patients. The rationale is as follows. To demonstrate a higher rate of effectiveness than that in a European multicenter trial (*) with a statistical significance, 144 subjects are required to provide 80% power at a two-tailed p-value of 0.05. With an attrition rate of 10% per year, a total of 160 subjects are required to be enrolled. 2) Subject recruitment period The planned subject recruitment period was from April 1, 2016 to March 31, 2017. Anonymization of personal information and data privacy
1. Personal information, including subject name and address, will be deleted from data submitted and associated medical information to be anonymized, and a new code will be allocated. 2. Documents related to study implementation, such as the code correspondence table, will be strictly managed by the principal investigator. 3. Computerized data pertaining to study subjects will be password-protected at the Department of Gastrointestinal Surgery and retained for ten years after trial completion, following which the electronic data will be anonymized and destroyed. Paper-based trial data will be retained for ten years after trial completion, following which they will be destroyed. Monetary compensation for health care Subjects will not be provided compensation, and the details will be explained prior to obtaining consent. In the event of illness including hospitalization owing to adverse effects as a result of the procedure, appropriate treatment will be provided as per normal medical care. In such instances, the medical costs will be covered by the patient’s health insurance, and there may be certain co-payments stipulated by the insurance provider. Treatment in the event of serious adverse event Reports of serious adverse events (SAE) will be analyzed by qualified personnel, and appropriate measures will be adopted without delay. Upon being notified of an SAE, the principal investigator will provide a written report of SAE to the hospital director without delay. Information related to SAE will also be communicated to the principal investigator of the central institution and principal investigators of collaborating institutions via the central institution. Funding It is expected that the patient’s health insurance will cover all the pre- and post-POEM tests and the POEM procedure. Conflict of interest
Conflicts of interest indicate an advantageous or disadvantageous relationship that could affect the study results, including financial and personal relationships. There are no possible conflicts of interest regarding the planning, implementation, and announcement of the trial. Periodic reporting to the hospital director Annual reports describing the status of the study’s implementation, sample/information storage status, and adverse events will be submitted in writing to the hospital director. Disclosure of information pertaining to the study The results of the present study will be submitted as a research article for publication.
ASA-PS: American Society of Anesthesiologist physical status ES: Eckardt score HRM: High resolution manometry IRP: Integrated relaxation pressure LA: Los Angels LES: Lower esophageal sphincter GERD: Gastroesophageal reflux disease POEM: Peroral endoscopic myotomy PPI: Proton pump inhibitor
S0016-5107(19)32470-8
DOI:
https://doi.org/10.1016/j.gie.2019.11.020
Reference:
YMGE 11838
To appear in:
Gastrointestinal Endoscopy
Received Date: 1 August 2019 Accepted Date: 4 November 2019
Please cite this article as: Shiwaku H, Inoue H, Sato H, Onimaru M, Minami H, Tanaka S, Sato C, Ogawa R, Okushima N, Yokomichi H, Peroral endoscopic myotomy for achalasia: a prospective multicenter study in Japan, Gastrointestinal Endoscopy (2019), doi: https://doi.org/10.1016/ j.gie.2019.11.020. 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 © 2019 by the American Society for Gastrointestinal Endoscopy
1
Title:
Peroral endoscopic myotomy for achalasia: a prospective multicenter study in Japan Authors: Hironari Shiwaku1, MD, PhD Haruhiro Inoue2, MD, PhD Hiroki Sato3, MD, PhD Manabu Onimaru2, MD, PhD Hitomi Minami4, MD, PhD Shinwa Tanaka5, MD, PhD Chiaki Sato6, MD, PhD Ryo Ogawa7, MD PhD Norihiko Okushima8, MD PhD Hiroshi Yokomichi9, MD PhD, MPH, DPH
1
Department of Gastroenterological Surgery, Fukuoka University Faculty of Medicine, Fukuoka,
Japan 2
Digestive Diseases Center, Showa University Koto-Toyosu Hospital, Tokyo, Japan
3
Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital,
Niigata, Japan 4
Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
5
Department of Gastroenterology, Kobe University Hospital, Hyogo, Japan
6
Department of Surgery, Tohoku University School of Medicine, Miyagi, Japan
2
7
Department of Gastroenterology, Oita University Faculty of Medicine, Oita, Japan
8
Heart Life Hospital, Okinawa, Japan
9
Division of Medicine, Graduate School Department of Interdisciplinary Research, University of
Yamanashi, Yamanashi, Japan
Submitting author: Hironari Shiwaku Department of Gastroenterological Surgery, Fukuoka University Faculty of Medicine 7-45-1, Nanakuma, Jyounan-ku, Fukuoka, 814-0180, Japan TEL: +81-92-801-1011; FAX: +81-92-863-9759 E-mail: [email protected] Corresponding author: Haruhiro Inoue Digestive Diseases Center, Showa University Koto-Toyosu Hospital Toyosu5-1-38, Koto-Ku, Tokyo, 135-8577, Japan Tel: +81-3-6204-6064; FAX: 03-6204-6396 email: [email protected] Guarantor of the article: Hironari Shiwaku and Haruhiro Inoue are guarantor of the article.
Specific author contributions:
3
Study concept and design: Hiroki Sato, Hironari Shiwaku, and Haruhiro Inoue Acquisition of data: Hironari Shiwaku, Hiroki Sato, Manabu Onimaru, Hitomi Minami, Shinwa Tanaka, Chiaki Sato, Ryo Ogawa, and Norihiko Okushima Analysis and interpretation of data: Hiroki Sato and Hiroshi Yokomichi Drafting the manuscript: Hironari Shiwaku and Hiroki Sato Critically revising the manuscript for important intellectual content: Haruhiro Inoue, Hironari Shiwaku, Hiroki Sato, Manabu Onimaru, Hitomi Minami, Shinwa Tanaka, Chiaki Sato, Ryo Ogawa, and Norihiko Okushima Statistical analysis: Hiroshi Yokomichi Administrative, technical, or material support: Hironari Shiwaku, Hiroki Sato, and Haruhiro Inoue Study supervision: Haruhiro Inoue
Financial support: This study received no particular funding.
Potential competing interests: Dr. Inoue reports grants from Olympus Co. and grants from Boston Scientific Co., outside the submitted work; the other authors have nothing to disclose.
1
Title Peroral endoscopic myotomy for achalasia: a prospective multicenter study in Japan
Abstract Background and Aims Peroral endoscopic myotomy (POEM) is one of the available treatment modalities for achalasia. The reported efficacy of POEM in the only prospective multicenter study was 82%, reported by Von Renteln et al; however, a retrospective multicenter study in Japan reported a higher efficacy rate of
95%. The aim of this study was to prospectively verify treatment outcomes after POEM at multiple facilities in Japan. Methods This was a prospective single-arm trial of POEM for achalasia at eight facilities in Japan between April 2016 and March 2018 to evaluate its safety and efficacy. Patients were re-evaluated at 3 months and up to 1 year after POEM. Results Among the 233 patients with achalasia who underwent POEM, procedure-related adverse events occurred in 24 (10.3%) patients, none of whom required surgical intervention. In the 207 patients satisfying the inclusion criteria after the study by Von Renteln et al, the efficacy rate of POEM, defined by an Eckardt score ≤3 at 1 year, was 97.4% (95.3%–99.7%). The Eckardt score decreased significantly from 6.6 ± 2.0 preoperatively to 1.1 ± 1.1, 1 year after POEM. Postoperative reflux esophagitis, severe reflux esophagitis, and symptomatic gastroesophageal reflux disease were reported in 54.2%, 5.6%, and 14.7%, respectively, and proton pump inhibitors were administered in 21.1%. Conclusions Our prospective multicenter study in Japan showed greater efficacy of POEM for achalasia compared with the results of a previous prospective multicenter study. POEM is safe and highly effective for at least 1 year.
Clinical trial registration The study was registered in the University Hospital Medical Information Network Clinical Trial Registry (https://www.umin.ac.jp/ctr/) number: UMIN000021550.
Keywords: Peroral endoscopic myotomy, Achalasia, Prospective single-arm trial, Multicenter study, Gastroesophageal reflux disease
2
INTRODUCTION Achalasia is an esophageal motility disorder of unknown etiology with an estimated incidence rate of 1 per 100,000 person-years. 1 It is characterized by failure of the lower esophageal sphincter (LES) to relax, along with impaired peristalsis of the esophageal body.
2 3 4 5
Peroral endoscopic myotomy
(POEM) is a minimally invasive treatment for achalasia first reported by Inoue et al in 2010. 6 Several facilities worldwide have reported the therapeutic efficacy of POEM;
7 8-12
however, only one
prospective multicenter study evaluating the outcomes of POEM has been published. The authors reported an overall efficacy (Eckardt score ≤3) after 1 year of 82%;13 however, a multicenter retrospective study involving over 1300 patients from Japan reported an efficacy of POEM after 1 year of 95%14. We expected equal satisfactory treatment outcomes for a multicenter prospective study performed in Japan; therefore, the aim of this study was to prospectively verify the treatment outcomes after POEM at multiple facilities in Japan.
METHODS Study design, setting, and study period This prospective multicenter study was performed at 8 facilities in Japan from 1 April 2016 to 31 March 2018 (Supplementary Table 1). Institutional review board approval was obtained at each institution. One or more members of the public participated in each ethics committee of the eight facilities participating in this research, and this information was published on each facility's website. The study was also registered at the University Hospital Medical Information Network Clinical Trial Registry (trial number: UMIN000021550). The progress of the research was published without delay through UMIN. Informed consent was obtained from all patients. The doctors and clinical staff in each facility explained the study to patients diagnosed with achalasia who met the indications for POEM. Before enrollment, several important study-related items were explained directly to each patient, and voluntary consent was obtained in writing from each patient. Informed consent was obtained from the parents of patients under the age of 18 years. All authors had access to the study data and reviewed and approved the final manuscript.
Inclusion and exclusion criteria We analyzed the data of all patients undergoing POEM for achalasia at the eight facilities participating in this study. Analysis 1 was performed to compare the primary outcomes of our study with those of Von Renteln et al.
13
The inclusion and exclusion criteria were set according to the study by Von
Renteln et al.13 In Analysis 1, we included patients with a preoperative Eckardt score of ≥4 because
3
the primary outcome in the study by Von Renteln et al13 was a postoperative Eckardt score of ≤3. We excluded patients with achalasia aged <18 years (Supplementary Table 2). Analysis 2 included all patients with achalasia who underwent POEM, including all of the patients in Analysis 1 plus those satisfying the less-restrictive criteria (Fig. 1).
Clinical assessment before and after POEM Clinical symptoms were assessed using the Eckardt score, which is commonly used to evaluate the severity of symptoms of achalasia and responses to treatment.
15
The Eckardt score comprises four
components: dysphagia, chest pain, regurgitation, and weight loss. Each component is assigned a score from 0 to 3 based on the patient’s self-reported assessment, with a total score ranging from 0 to 12. Higher Eckardt scores reflect more severe symptoms of achalasia, whereas lower scores postoperatively indicate improved symptoms. Preoperative tests included manometry, endoscopy, barium swallow, and computed tomography (CT). The type of achalasia was determined according to the findings on barium esophagography and was classified as straight or sigmoid.
4
Sigmoid achalasia was defined as a significantly tortuous
esophagus on barium esophagography and was classified into 2 subtypes based on CT findings: sigmoid (S1) and advanced sigmoid (S2) 6. The presence of a double lumen on some CT slices was defined as S2, whereas only a single lumen is present in S1. In patients for whom high-resolution manometry could be performed, we classified the type of achalasia according to the Chicago classification.
16 17
The integrated relaxation pressure (IRP) as
assessed by high-resolution manometry is the most important parameter for evaluating LES relaxation. IRP is measured after deglutitive upper sphincter relaxation from the anticipation of esophagogastric junction relaxation until arrival of the peristaltic wave. Patients' general status was classified according to the American Society of Anesthesiologists (ASA) physical status classification system. 18 Adverse events related to the POEM procedure were evaluated according to the American Society for Gastrointestinal Endoscopy severity grade for adverse events. 19 Patients were reassessed at 3 months and 1 year after POEM. Evaluation was based on an interview, including a calculation of the Eckardt score, and endoscopy and manometry. Erosive esophagitis on endoscopy was evaluated according to the Los Angeles classification. 20
POEM procedures POEM was performed using the methods described by Inoue et al. (Fig. 2A–D). 6 7 21 22 All procedures
4
were performed or supervised by surgeons from each of the facilities who received POEM procedural and technique training from Dr Inoue. POEM was performed under general anesthesia with endotracheal intubation and with the patient lying in a supine position to reflect preoperative CT images. CO2 insufflation was performed through the endoscope. The electrosurgical Triangle Tip Knife with integrated water-jet function (KD-645L, Olympus Corp, Tokyo, Japan) was the preferred surgical device, and myotomy was performed in either an anterior or posterior direction. The starting point for the myotomy was on the oral side of abnormal luminal obstructive contractions in the esophageal body, and the endpoint was the incision from the LES to the gastric side of the sphincter. The length and direction of the myotomy and the method used to confirm the adequacy of the LES incision were left to the judgment of the surgeons at each facility. Confirmation of the LES incision was determined by one of the following 3 methods: 1) Double-scope method:
23
A second endoscope was inserted into the stomach to examine the
cardiac region. If the procedure reached the gastric side, the light from the main endoscope within the submucosal space was visible through the second scope in the stomach (Fig. 2D). 2) Injection method: 9 Indocyanine green solution was injected into the lesser curvature of the gastric cardia before the POEM procedure. If the procedure reached the gastric side, the dye was visible within the submucosal space. 3) Conventional method: 22 The procedure reaching the gastric side was confirmed by the endoscope insertion depth, anatomical landmarks, and/or scope resistance.
Anatomical landmarks The distance from the incisors to the esophagogastric junction was measured before POEM. This measurement was used to gauge how far the scope had been inserted within the submucosal tunnel. The intramucosal or submucosal blood vessels were visible inside the submucosal tunnel, and we noted the transition from the palisade vessels, corresponding anatomically to the LES, to the spindle veins seen on the gastric side. Spindle veins in the gastric cardia are a specific anatomical landmark in the stomach. Depending on the orientation of the submucosal tunnel, it was possible to observe a part of the oblique muscle and the large branch of the left gastric artery in some patients, indicating that the scope was within the lesser curvature of the stomach 24.
Endoscope resistance When creating the submucosal tunnel, it is possible to note the narrowing of the esophageal lumen closer to the LES, which then opens wide into the stomach. When the endoscope is inserted into the
5
stomach cavity after the myotomy is completed, it is possible to feel decreased resistance at the LES.
Outcomes and sample size To compare our results with those of Von Renteln et al, 13 we set the primary outcome as the efficacy of POEM 1 year postoperatively, defined as an Eckardt score ≤3. This was the outcome used in Analysis 1, which included patients meeting the limited criteria, similar to the criteria in Von Renteln et al's study.
13
The efficacy of POEM for all patients with achalasia was assessed in Analysis 2. In
Analysis 2, a lower postoperative Eckardt score was defined as effective POEM surgery in patients with a pre-POEM Eckardt score ≤3. To further assess the results in our multicenter study, we defined the following secondary outcomes: efficacy 3 months postoperatively, adverse events, postoperative gastroesophageal reflux disease (GERD) (including erosive esophagitis and symptomatic GERD), oral administration of proton pump inhibitors (PPIs), and factors associated with erosive esophagitis after POEM. With a 2-sided alpha of 5% and an 80% detection power, we calculated that 144 patients were necessary for Analysis 1 to show the significance of the efficacy of our procedure compared with that of Von Renteln et al.13 Expecting a drop-out rate of 10% in 1 year, nearly 160 patients were required. Based on the number of patients treated with POEM annually in the preceding years at the eight participating facilities, we set the study period at 2 years (patient registration during the first year followed by a 1-year follow-up after POEM).
Statistical analysis Figure 1 is a flowchart of patient enrollment in our study. Patients' characteristics and the details of the POEM procedures are presented as means ± standard deviations (interquartile ranges) for continuous variables and numbers (percentages) for categorical variables. We presented proportions (standard errors) for data for patients with an Eckardt score ≤3, 3 months, and 1 year after POEM, for patients meeting the Analysis 1 and 2 criteria (Supplementary Table 2). We explored the risk factors for reflux esophagitis for Los Angeles classification grades A, B, C, or D in univariable and multivariable logistic regressions. Referring to previous results, we compared odds ratios and their p-values for reflux esophagitis with sex, age, degree of esophageal dilation, type of achalasia on the Chicago classification, direction and length of the myotomy, and IRP 1 year after POEM.
25 26 27
Statistical analyses were performed using SAS V.9.4 statistical software (SAS Institute, Cary, NC, USA). Reported p-values sere 2-sided, and we considered p <0.05 statistically significant. All data were sent to and analyzed at an independent facility (University of Yamanashi, Japan).
6
RESULTS Patient demographics POEM was performed for a total of 233 patients (130 women and 103 men with a mean age of 52.0 ± 17.5 years) between April 2016 and March 2017. (At Tohoku University, institutional review board approval was obtained, but patients were not registered.) Patients' clinical data are summarized in Table 1. Straight achalasia was present in 191 (82%) patients, and sigmoid achalasia in the remaining 42 (18%), including 10 (4%) patients with advanced sigmoid achalasia. Previous procedures included pneumatic dilation in 43 (18 %) patients and Heller–Dor operation in 8 (3 %) patients. 28 29 30 31 We assessed each patient's American Society of Anesthesiologists physical status (ASA-PS) and classified 157 (67%) patients as ASA-PS class I, 72 (31%) as ASA-PS class II, and 4 (2%) as ASA-PS class III (Table 1). Among the 233 patients undergoing POEM, 223 were evaluated 1 year after POEM and were included in Analysis 2. A total of 207 patients satisfied the inclusion and exclusion criteria reported by Von Renteln et al13, and their data were included in Analysis 1 (Fig. 1).
POEM outcomes The details of the POEM procedure are summarized in Table 2. POEM was successfully completed in all patients (technical success rate: 100%) with a mean procedural time of 94.1 ± 44.6 minutes. The mean length of the esophageal myotomy was 10.5 ± 3.3 cm, and the mean length of the gastric myotomy was 2.8 ± 1.1 cm. To confirm the LES incision, we used the double-scope method in 80% of the patients (Table 2 and Supplementary Table 1). Adverse events occurred in 24 of 233 patients (10.3%) and comprised 11 mucosal perforations, 9 mucosal injuries without perforation, 3 hematomas in the submucosal space, 1 case of pleurisy, and 1 case of peritonitis (1 patient had both mucosal perforation and peritonitis). According to the American Society for Gastrointestinal Endoscopy severity grade for adverse events, 15 and 9 adverse events were classified as mild and moderate, respectively. No adverse events were severe or fatal. 19 All adverse events were treated conservatively.
Short- and long-term efficacy of POEM The primary outcome (efficacy) (Analysis 1) 1 year after POEM in 207 patients was 97.4% (95.2%– 99.7%). Patients' Eckardt scores decreased significantly from 6.6 ± 2.0 preoperatively to 1.0 ± 1.1 at 3 months postoperatively and to 1.1 ± 1.1 at 1 year after POEM. The short-term efficacy at 3 months was 97.1% (94.8%–99.4%), indicating durable efficacy after 1 year (Fig. 3). For all 223 patients
7
(Analysis 2), the efficacy rate at 1 year was 97.5% (95.3%–99.7%). The efficacy 1 year after POEM according to the achalasia subtype (Chicago classification) was Type I: 96.2%, Type II: 98.7%, and Type III: 100%.
16, 17
The efficacy of anterior myotomy was 96.8%, and the efficacy of posterior
myotomy was 97.9%; the difference was not statistically significant.
GERD and PPI use Among the 223 patients who could be evaluated at 1 year, 10 had received PPIs before POEM and were excluded from the analysis for GERD. Among the remaining 213 patients, symptomatic GERD was present postoperatively in 14.7% (9.5%–19.9%) of the patients, and 21.1% (15.2%–27.0%) had been prescribed PPIs within the first year after POEM. One year after POEM, 142 patients underwent endoscopy. Los Angeles grade A to D erosive esophagitis was present in 54.2% (46.0%–62.4%, 77/142) of the patients, and severe erosive esophagitis (Los Angeles grade C or D) was seen in 5.6% (8/142) of the patients. We performed univariable and multivariable analyses to evaluate the factors associated with erosive esophagitis (Los Angeles grades A–D) after POEM, including sex, age, degree of dilation, type of achalasia (straight or sigmoid), Chicago classification for the manometry results, direction of the myotomy, length of the myotomy on the esophageal and gastric sides, and IRP after POEM. Among these factors, the length of the myotomy on the esophageal side was a significant factor on univariate analysis (odds ratio, 1.63; 95% confidence interval [CI], 1.04–2.56), but not on multivariate analysis (Table 3). DISCUSSION This prospective multicenter study reported a higher efficacy rate (97.4%; 95.2%–99.7%) for POEM compared with the results of the previous prospective multicenter study reported by Von Renteln et al13 (82.4%) involving patients meeting similar inclusion criteria. When we included all of the patients with achalasia, the efficacy rate remained high (97.5%; 95.3%–99.7%) in our study. There are 2 possible reasons for this high efficacy rate: (1) most of the surgeons in our study learned the POEM procedure over at least a 1-year period from its originator, Dr. Inoue, and used consistent techniques; and (2) all procedures were performed by these trained surgeons or under their supervision. Based on our results, we believe that POEM is potentially curative for most patients with achalasia, with durable results up to at least 1 year after the procedure. The efficacy rate of 97.4% (95.2%–99.7%) in this prospective multicenter study was also higher than the 94.7% efficacy found in our previous retrospective multicenter analysis of 1300 patients.
14
Therefore, the current study demonstrated that
POEM may be adequately taught and used safely and effectively at different institutions in Japan.
8
However, even if POEM is performed at a certain technical level, incomplete LES incisions can occur during large series 8. The most reliable method to prevent incomplete LES incisions is confirmation using the double-scope method.
23 32 33
In the present study, the double-scope method was routinely
performed at Showa University, Fukuoka University, and Kobe University (80% of all patients) (Table 2 and Supplementary Table 1). In addition, all patients with advanced sigmoid type achalasia (10 cases) that was likely to cause incomplete myotomy of the LES were included in these 3 institutions, and the efficacy at these institutions remained high. These results indicate that the double-scope method may help to avoid incomplete myotomy of the LES during large series. Because the double-scope method requires 2 endoscope systems, it is difficult to perform routinely in all facilities. In the present study, 3 facilities (Niigata University, Oita University, and Heart Life Hospital) confirmed incision of the LES by the conventional method and the efficacy at these institutions was also high. The reason for this may be that 1 or 2 fixed surgeons with substantial experience performed the POEM procedure. In facilities with multiple surgeons, a method for confirming the LES incision (double-scope method or injection method) tended to be used (Supplementary Table 1). We believe that differences in skill level between surgeons can be appropriately addressed by objectively confirming the LES incision. We performed POEM safely and effectively in a wide range of patients, based on ASA-PS (class II: 31%, class III: 2%), which suggests that POEM is not invasive in patients with relatively poor physical condition. We also performed POEM in younger patients, 2 of whom were less than 17 years old. Additionally, we performed the POEM procedure effectively regardless of the type of achalasia (according to the Chicago classification). GERD after POEM is a major adverse event. In this study, 54.2% (46.0%–62.4%) of the patients experienced reflux esophagitis after POEM, although severe esophagitis (Los Angeles class C or D) occurred only in 5.6% of those who underwent follow-up endoscopy. These results were similar to findings in a previous report.
14
Only 142 out of 213 patients underwent follow-up endoscopy,
whereas the remaining patients declined the procedure. Assuming that the remaining patients had no symptoms of GERD after POEM and, therefore, had normal endoscopic findings, it is possible that erosive esophagitis was overestimated in the first year. None of the factors we assessed were significantly associated with erosive esophagitis after POEM on multivariate analysis, possibly because the number of patients in this study was too small to yield statistically significant results; therefore, further studies involving a large sample size are warranted. Several limitations of this study were the following. We did not include patients with other esophageal motility disorders. Furthermore, the number of patients with Type III achalasia was relatively small,
9
and the POEM procedure, including the myotomy direction, was not uniform in this study. Although the short-term and 1-year outcomes were almost equivalent, efficacy over a relatively longer term remains to be investigated. In conclusion, our prospective multicenter study showed greater efficacy of POEM for achalasia compared with the results of a previous prospective multicenter study. POEM is durably effective for at least 1 year, and is considered safe and highly effective.
Acknowledgments The authors thank all patients and clinical staff for their participation and contribution to this study.
Data sharing All data relevant to the study are included in the article. Data are available upon reasonable request.
10
Table 1. Characteristics of the 233 patients with achalasia who underwent peroral endoscopic myotomy Age, years, mean ± SD (range)
52.0 ± 17.5 (13–93)
Sex (female, male)
130, 103
Type of achalasia, n (%) Straight
191 (82)
Sigmoid
32 (14)
Advanced sigmoid
10 (4)
Chicago classification, n (%) Type I
108 (46)
Type II
80 (34)
Type III
13 (6)
Previous procedure, n (%) Balloon dilatation
43 (18)
Heller–Dor operation
8 (3)
ASA-PS, n (%) I
157 (67)
II
72 (31)
III
4 (2)
SD, standard deviation; ASA-PS, American Society of Anesthesiologists physical status classification
Table 2. Details of the 233 peroral endoscopic myotomy procedures for achalasia Length of procedure, mean ± SD (range), min
94.1 ± 44.6 (34–460)
Direction of myotomy, n (%)
Anterior
32 (14)
Posterior
201 (86)
Myotomy length, mean (range), cm
11
Esophageal
10.5 ± 3.3 (3–25)
Gastric
2.8 ± 1.1 (0–6)
Confirmation of LES incision, n (%)
Double-scope method
185 (80)
Conventional method
42 (18)
Injection method
6 (2)
SD, standard deviation; LES, lower esophageal sphincter
Table 3. Odds ratios for Los Angeles grade A–D erosive esophagitis 1 year after peroral endoscopic myotomy (POEM) for achalasia Variables
Univariate analysis
p value
OR (95% CI)
Multivariate
p value
analysis OR (95% CI)
Male vs. female
1.54 (0.76–3.12)
0.23
1.12 (0.42–
0.82
3.00)
Age per 10 years
0.88 (0.71–1.09)
0.25
0.67 (0.48–
0.02
0.94)
Degree of dilatation II or III (vs. I)
0.78 (0.39–1.57)
0.48
1.57 (0.55– 4.49)
0.40
12
Achalasia type: sigmoid (vs.
1.23 (0.47–3.20)
0.68
2.06 (0.54–
straight)
Chicago classification type Ⅱ
7.86)
1.24 (0.60–2.57)
0.56
1.21 (0.43–
0.88 (0.25–3.04)
0.84
0.16 (0.01–
vs. posterior)
Length of myotomy on the
1.63 (1.04–2.56)
0.03
1.61 (0.88–
0.12
2.96)
2.05 (0.91–4.62)
0.08
3.02 (0.97–
gastric side per 2 cm
IRP (1 year after POEM) per 5
0.19
2.41)
esophageal side per 5 cm
Length of myotomy on the
0.72
3.40)
or Ⅲ (vs. type Ⅰ)
Direction of myotomy (anterior
0.29
0.06
9.39)
1.20 (0.84–1.72)
0.31
1.18 (0.79–
mmHg
0.41
1.77)
IRP, integrated relaxation pressure
Figure Legends Figure 1. Flow chart of patient enrolment in this prospective study of peroral endoscopic myotomy for achalasia Figure 2A. Figure showing the peroral endoscopic myotomy procedure (posterior myotomy) after creating the submucosal tunnel Figure 2B. Selective myotomy of the inner circular muscle using the Triangle Tip Knife J (Olympus Medical Systems Corp., Tokyo, Japan) Figure 2C. After myotomy Figure 2D. Double-scope endoscopy. A second endoscope is inserted into the stomach to examine the cardiac region. If the myotomy procedure reached the gastric side, the light from the main scope in the submucosal space is visible through the second scope in the stomach. Figure 3. Efficacy rates 3 months and 1 year after peroral endoscopic myotomy in this study compared with a previous prospective study
13
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Vaezi MF, Pandolfino JE, Vela MF. ACG clinical guideline: diagnosis and management of achalasia. Am J Gastroenterol 2013;108:1238-49; quiz 1250.
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Sato H, Takahashi K, Mizuno KI, et al. A clinical study of peroral endoscopic myotomy reveals that impaired lower esophageal sphincter relaxation in achalasia is not only defined by high-resolution manometry. PLoS One 2018;13:e0195423.
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Von Renteln D, Fuchs KH, Fockens P, et al. Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study. Gastroenterology 2013;145:309-11 e1-3.
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Shiwaku H, Inoue H, Onimaru M, et al. Multicenter collaborative retrospective evaluation of peroral endoscopic myotomy for esophageal achalasia : analysis of data from more than 1300
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Eckardt VF. Clinical presentations and complications of achalasia. Gastrointest Endosc Clin N Am 2001;11:281-92, vi.
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Pandolfino JE, Kwiatek MA, Nealis T, et al. Achalasia: a new clinically relevant classification by high-resolution manometry. Gastroenterology 2008;135:1526-33.
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Kahrilas PJ, Bredenoord AJ, Fox M, et al. The Chicago Classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil 2015;27:160-74.
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American Society of Anesthesiologists. ASA Physical Status Classification System. 2014:https://www.asahq.org/standards-and-guidelines/asa-physical-status-classificat ion-system.
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Cotton PB, Eisen GM, Aabakken L, et al. A lexicon for endoscopic adverse events: report of an ASGE workshop. Gastrointest Endosc 2010;71:446-54.
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Armstrong D, Bennett JR, Blum AL, et al. The endoscopic assessment of esophagitis: a progress report on observer agreement. Gastroenterology 1996;111:85-92.
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Inoue H, Tianle KM, Ikeda H, et al. Peroral endoscopic myotomy for esophageal achalasia: technique, indication, and outcomes. Thorac Surg Clin 2011;21:519-25.
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Inoue H, Shiwaku H, Iwakiri K, et al. Clinical practice guidelines for peroral endoscopic myotomy. Dig Endosc 2018;30:563-579.
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Baldaque-Silva F, Marques M, Vilas-Boas F, et al. New transillumination auxiliary technique for peroral endoscopic myotomy. Gastrointest Endosc 2014;79:544-5.
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Tanaka S, Kawara F, Toyonaga T, et al. Two penetrating vessels as a novel indicator of the appropriate distal end of peroral endoscopic myotomy. Dig Endosc 2018;30:206-211.
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Shiwaku H, Inoue H, Sasaki T, et al. A prospective analysis of GERD after POEM on anterior myotomy. Surg Endosc 2016;30:2496-504.
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Familiari P, Greco S, Gigante G, et al. Gastroesophageal reflux disease after peroral endoscopic myotomy: Analysis of clinical, procedural and functional factors, associated with gastroesophageal reflux disease and esophagitis. Dig Endosc 2016;28:33-41.
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Kumbhari V, Familiari P, Bjerregaard NC, et al. Gastroesophageal reflux after peroral endoscopic myotomy: a multicenter case-control study. Endoscopy 2017;49:634-642.
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Heller.E. Extramukose Kardioplastik beim chronischen Kardiospasmus mit Dilatation des Oesophagus. Mitteilungen aus den Grenzgebieten der Medizin und Chirurgie 1914;27:141.
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Cox J, Buckton GK, Bennett JR. Balloon dilatation in achalasia: a new dilator. Gut 1986;27:986-9.
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Boeckxstaens GE, Annese V, des Varannes SB, et al. Pneumatic dilation versus laparoscopic
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Heller's myotomy for idiopathic achalasia. N Engl J Med 2011;364:1807-16. 31.
Campos GM, Vittinghoff E, Rabl C, et al. Endoscopic and surgical treatments for achalasia: a systematic review and meta-analysis. Ann Surg 2009;249:45-57.
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Grimes KL, Inoue H, Onimaru M, et al. Double-scope per oral endoscopic myotomy (POEM): a prospective randomized controlled trial. Surg Endosc 2016;30:1344-51.
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Inoue H, Shiwaku H, Kobayashi Y, et al. Statement for gastroesophageal reflux disease after peroral endoscopic myotomy from an international multicenter experience. Esophagus 2019.
Supplementary Table 1: Details of all POEM procedures and the surgeons in each facility
Number of Surgeon Facility
No.
From surgical
From internal
department
medicine
Each experience of over 15 cases of POEM as
Each experience of ESD
Trained POEM procedure from Dr.
How to confirm
the primary surgeon or
over 20 cases
Inoue
incision of LES
as an assistant 1
Showa University Koto-Toyosu Hospital, Tokyo
4
6
〇
〇
〇
Double scope method
2
Fukuoka University Faculty of Medicine, Fukuoka
2
0
〇
〇
〇
Double scope method
3
Kobe University Hospital, Hyogo
0
2
〇
〇
〇
Double scope method
0
1
〇
〇
〇
Conventional method
Niigata University Medical and Dental Hospital,
4 Niigata
5
Oita University Faculty of Medicine, Oita
0
2
〇
〇
〇
Conventional method
6
Heart Life Hospital, Okinawa
1
0
〇
〇
〇
Conventional method
7
Nagasaki University Hospital, Nagasaki
0
4
〇
〇
〇
Injection method
POEM, peroral endoscopic myotomy; ESD, endoscopic submucosal dissection; LES, lower esophageal sphincter
Supplementary Table 2. Inclusion and exclusion criteria for analysis 1 and 2
Analysis 1: Inclusion and exclusion criteria were made to compare the efficacy of POEM with that reported by the previous prospective study. Inclusion criteria
Exclusion criteria
・Symptomatic achalasia
・Eosinophilic esophagitis
・Preoperative ES ≥ 4
・Barrett esophagus
・Preoperative barium swallow, manometry, and ・Pregnancy esophagogastroduodenoscopy
results
were
suggestive of achalasia ・Age >18 years
・ Malignant or premalignant esophageal lesion ・Severe candida esophagitis ・ Extensive,
tortuous
dilatation
of
the
esophagus (luminal diameter >7 cm, S shape) ・Patients with preoperative ES ≤3 Analysis 2 All patients with achalasia plus those aged ≤18 years or with a preoperative ES ≤3
POEM, peroral endoscopic myotomy; ES, Eckardt score
Title: Peroral endoscopic myotomy for the treatment of achalasia: a prospective multicenter study in Japan Principal Investigator: Hironari Shiwaku 1, MD, PhD Other Investigators: Haruhiro Inoue 2, MD, PhD Hiroki Sato3, MD, PhD Manabu Onimaru2, MD, PhD Hitomi Minami4, MD, PhD Shinwa Tanaka5, MD, PhD Chiaki Sato6, MD, PhD Ryo Ogawa7, MD PhD Norihiko Okushima8, MD PhD Hiroshi Yokomichi9, MD PhD, MPH, DPH Institutional affiliations: Department of Gastroenterological Surgery, Fukuoka University Faculty of Medicine, Fukuoka 2 Digestive Diseases Center, Showa University Koto-Toyosu Hospital, Tokyo 1
3
Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, Niigata 4 Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki 5 Department of Gastroenterology, Kobe University Hospital, Hyogo 6
Division of Advanced Surgical Science and Technology, Tohoku University School of Medicine, Miyagi 7 Department of Gastroenterology, Faculty of Medicine, Oita University, Oita 8 9
Heart Life Hospital, Okinawa Division of Medicine, Graduate School Department of Interdisciplinary Research, University of Yamanashi, Yamanashi
I. BACKGROUND AND SIGNIFICANCE Peroral endoscopic myotomy (POEM) is the standard treatment for esophageal achalasia. A single-center study in Japan reported a higher efficacy rate than that reported in other previous reports. The aim of this study is to examine treatment outcomes of POEM at multiple facilities in Japan. II.
STUDY
OBJECTIVE(S),
INCLUDING
SPECIFIC
AIMS
AND/OR
HYPOTHESES Esophageal achalasia is an esophageal motility disorder of unknown etiology with an estimated incidence rate of 1 per 100,000 person-years. It is characterized by failure of the lower esophageal sphincter relaxation along with impaired peristalsis of the esophageal body. Peroral endoscopic myotomy (POEM) is a minimally invasive treatment for esophageal achalasia, as reported first by Inoue et al. in 2010. Several facilities worldwide have reported the therapeutic efficacy of POEM. However, prospective multicenter studies assessing the outcomes have only been reported from the European and North American group (Germany, the Netherlands, Switzerland, and Canada), with an overall efficacy [Eckardt score (ES) ≤ 3] of POEM of 82.4% after 1 year. A single-center study of 500 cases from Japan reported an efficacy (ES ≤ 2 or ES improved by ≥4 points) of 91.0%. If multicenter studies are to be conducted in Japan, equal satisfactory treatment outcomes can be expected. The aim of this prospective research is to evaluate the treatment outcomes of POEM at multiple facilities in Japan.
III. METHODS Study subjects Patients diagnosed with esophageal achalasia or related diseases, who were deemed suitable for myotomy Inclusion criterion Patients capable of providing written informed consent by themselves or by their legal representative *** *** The legal representative will be the person with parental authority for patients younger than 20 years of age, and the closest family member or relative in the event of patients who have lost the ability to understand and make judgments owing to mental disorder or intellectual disability. Exclusion criteria • •
Patients in whom general anesthesia is difficult Patients deemed unsuitable by the attending physician
Explanation and consent Before conducting this study, as a rule, the items listed below will be explained directly to the patient, and voluntary consent will be obtained in writing from the patient. 1) Background, purpose, and significance of the study 2) Treatment methods 3) Anticipated results 4) Expected side effects/ethical issues 5) Costs involved 6) Human rights and privacy 7) Refusal to consent 8) Withdrawal of consent 9) Changes may occur as medically needed
10) Freedom to ask questions and availability of an enquiry desk Patient enrolment 1) Patient enrolment will commence after obtaining approval from the ethical review board. 2) Informed consent is required for all patients to participate in this study. Patients will sign the relevant documents only after voluntary consent is obtained from patients. 3) Patient enrolment will be reported on a regular basis to the institution responsible for enrolments (coordinating center in Showa University Koto Toyosu Hospital). 4) POEM will be performed at each institution in accordance with instructions from the coordinating center, and follow-up of specified items will be performed up to one year after surgery. Preoperative
At 3 months
At 1 year
Symptom score (Eckardt score)
○
○
○
Endoscopic examination
○
○
○
Intraesophageal pressure measurement
○
○
○
GERD score
○
○
○
Presence or absence of ○ oral antacids
○
○
Expected adverse events Procedural accidents associated with POEM, general anesthesia, and pre- and postoperative tests will be considered as adverse events. In Japan, to this day, more than 1,300 patients have undergone POEM without serious complications of Clavien-Dindo grade IIIb or greater. Cases of mild-to-moderate procedural accidents of Clavien-Dindo grade IIIa or below were resolved with conservative treatment. Expected adverse events are listed below. Mucosal damage of the esophagus and stomach, esophagitis, mediastinitis, peritonitis,
inflammation of the lesser omentum, intra- and postoperative bleeding, submucosal hematoma, atelectasis, pneumonia, pneumothorax, pneumoperitoneum, subcutaneous emphysema, mediastinal emphysema, retroperitoneal emphysema, pleural effusion, ascites, etc.
Endpoints
Primary endpoint
Effectiveness at one year after POEM Eckardt score of 3 or less is considered effective.
Secondary endpoints
• • •
The presence or absence of POEM-related procedural accidents Effectiveness at three months after POEM Postoperative GERD (Analysis-2)
•
Lower esophageal sphincter pressure
• •
Operative duration Oral PPI therapy
Analysis of this study All patients undergoing POEM for achalasia were analyzed in this study. Analysis 1 was performed to compare the primary outcomes with that of multicenter studies from European and North American group. In Analysis 1, patients with preoperative ES ≥4 were included because primary outcome was set to ES ≤3 postoperatively, and patients with achalasia aged <18 years were excluded. Analysis 2 was performed for all patients with achalasia who underwent POEM, including all patients in Analysis 1 plus others satisfying the less restrictive criteria.
Discontinuation criteria The trial investigators will discontinue the trial for subjects in whom any of the following events occur during the trial period. Furthermore, when investigators decide to discontinue or terminate the trial, they will administer appropriate treatment to the subject, and an annual written report will be submitted to the director of the hospital. 1. Subject (or legal representative) requests discontinuation 2. Trial is terminated owing to the subject’s circumstances (home relocation, change of physician, change of hospital, being too busy, and follow-up is impossible) 3. After trial commencement, when it is judged that the subject is not eligible 4. Event of a procedural accident 5. Occurrence of adverse events (including exacerbation of the underlying disease, exacerbation of complications, and procedural accidents), prompting trial investigator to discontinue the trial 6. Insufficient response or deterioration of symptoms hinders continuation of the trial. 7. Major protocol deviations 8. Lack of compliance with the medication 9. Trial investigator decides to discontinue the trial Planned number of enrolments and subject recruitment period 1) Sample size The planned sample size for this study is 160 patients. The rationale is as follows. To demonstrate a higher rate of effectiveness than that in a European multicenter trial (*) with a statistical significance, 144 subjects are required to provide 80% power at a two-tailed p-value of 0.05. With an attrition rate of 10% per year, a total of 160 subjects are required to be enrolled. 2) Subject recruitment period The planned subject recruitment period was from April 1, 2016 to March 31, 2017. Anonymization of personal information and data privacy
1. Personal information, including subject name and address, will be deleted from data submitted and associated medical information to be anonymized, and a new code will be allocated. 2. Documents related to study implementation, such as the code correspondence table, will be strictly managed by the principal investigator. 3. Computerized data pertaining to study subjects will be password-protected at the Department of Gastrointestinal Surgery and retained for ten years after trial completion, following which the electronic data will be anonymized and destroyed. Paper-based trial data will be retained for ten years after trial completion, following which they will be destroyed. Monetary compensation for health care Subjects will not be provided compensation, and the details will be explained prior to obtaining consent. In the event of illness including hospitalization owing to adverse effects as a result of the procedure, appropriate treatment will be provided as per normal medical care. In such instances, the medical costs will be covered by the patient’s health insurance, and there may be certain co-payments stipulated by the insurance provider. Treatment in the event of serious adverse event Reports of serious adverse events (SAE) will be analyzed by qualified personnel, and appropriate measures will be adopted without delay. Upon being notified of an SAE, the principal investigator will provide a written report of SAE to the hospital director without delay. Information related to SAE will also be communicated to the principal investigator of the central institution and principal investigators of collaborating institutions via the central institution. Funding It is expected that the patient’s health insurance will cover all the pre- and post-POEM tests and the POEM procedure. Conflict of interest
Conflicts of interest indicate an advantageous or disadvantageous relationship that could affect the study results, including financial and personal relationships. There are no possible conflicts of interest regarding the planning, implementation, and announcement of the trial. Periodic reporting to the hospital director Annual reports describing the status of the study’s implementation, sample/information storage status, and adverse events will be submitted in writing to the hospital director. Disclosure of information pertaining to the study The results of the present study will be submitted as a research article for publication.
ASA-PS: American Society of Anesthesiologist physical status ES: Eckardt score HRM: High resolution manometry IRP: Integrated relaxation pressure LA: Los Angels LES: Lower esophageal sphincter GERD: Gastroesophageal reflux disease POEM: Peroral endoscopic myotomy PPI: Proton pump inhibitor