Peroral endoscopic myotomy for achalasia: a prospective multicenter study in Japan

Open AccessPublished:November 20, 2019DOI:https://doi.org/10.1016/j.gie.2019.11.020

      Background and Aims

      Peroral endoscopic myotomy (POEM) is an available treatment modalities for achalasia. The reported efficacy of POEM in the only prospective multicenter study was 82%; 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 8 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 patients (10.3%), none of whom required surgical intervention. In the 207 patients satisfying the inclusion criteria, the efficacy rate of POEM, defined by an Eckardt score ≤3 at 1 year, was 97.4% (95% CI, 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 GERD 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 number: UMIN 000021550.)

      Abbreviations:

      ASA-PS (American Society of Anesthesiologist physical status), IRP (integrated relaxation pressure), LES (lower esophageal sphincter), POEM (peroral endoscopic myotomy), PPI (proton pump inhibitor)
      Achalasia is an esophageal motility disorder of unknown etiology with an estimated incidence rate of 1 per 100,000 person-years.
      • Sato H.
      • Yokomichi H.
      • Takahashi K.
      • et al.
      Epidemiological analysis of achalasia in Japan using a large-scale claims database.
      It is characterized by failure of the lower esophageal sphincter (LES) to relax, along with impaired peristalsis of the esophageal body.
      • Richter J.E.
      Oesophageal motility disorders.
      • Vaezi M.F.
      • Pandolfino J.E.
      • Vela M.F.
      ACG clinical guideline: diagnosis and management of achalasia.
      • Japan Esophageal S.
      Descriptive rules for achalasia of the esophagus, June 2012: 4th edition.
      • Sato H.
      • Takahashi K.
      • Mizuno K.I.
      • et al.
      Esophageal motility disorders: new perspectives from high-resolution manometry and histopathology.
      Peroral endoscopic myotomy (POEM) is a minimally invasive treatment for achalasia first reported by Inoue et al in 2010.
      • Inoue H.
      • Minami H.
      • Kobayashi Y.
      • et al.
      Peroral endoscopic myotomy (POEM) for esophageal achalasia.
      Several facilities worldwide have reported the therapeutic efficacy of POEM
      • Inoue H.
      • Sato H.
      • Ikeda H.
      • et al.
      Per-oral endoscopic myotomy: a series of 500 patients.
      • Shiwaku H.
      • Inoue H.
      • Yamashita K.
      • et al.
      Peroral endoscopic myotomy for esophageal achalasia: outcomes of the first over 100 patients with short-term follow-up.
      • Minami H.
      • Inoue H.
      • Haji A.
      • et al.
      Per-oral endoscopic myotomy: emerging indications and evolving techniques.
      • Sato H.
      • Takahashi K.
      • Mizuno K.I.
      • 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.
      • Tanaka S.
      • Toyonaga T.
      • Kawara F.
      • et al.
      Peroral endoscopic myotomy using FlushKnife BT: a single-center series.
      • Akintoye E.
      • Kumar N.
      • Obaitan I.
      • et al.
      Peroral endoscopic myotomy: a meta-analysis.
      ; however, only 1 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%
      • Von Renteln D.
      • Fuchs K.H.
      • Fockens P.
      • et al.
      Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study.
      ; however, a multicenter retrospective study involving over 1300 patients from Japan reported an efficacy of POEM after 1 year of 95%.
      • 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 patients at eight facilities in Japan.
      We expected equally 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 April 1, 2016 to March 31, 2018 (Supplementary Table 1, available online at www.giejournal.org). Institutional review board approval was obtained at each institution. One or more members of the public participated in each ethics committee of the 8 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 University Hospital Medical Information Network. The doctors and clinical staff at 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 age 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 8 facilities participating in this study. Analysis 1 was performed to compare the primary outcomes of our study with those of Von Renteln et al.
      • Von Renteln D.
      • Fuchs K.H.
      • Fockens P.
      • et al.
      Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study.
      Inclusion and exclusion criteria were set according to the study by Von Renteln et al.
      • Von Renteln D.
      • Fuchs K.H.
      • Fockens P.
      • et al.
      Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study.
      In analysis 1 we included patients with a preoperative Eckardt score ≥4 because the primary outcome in the study by Von Renteln et al
      • Von Renteln D.
      • Fuchs K.H.
      • Fockens P.
      • et al.
      Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study.
      was a postoperative Eckardt score ≤3. We excluded patients with achalasia who were younger than age 18 years (Supplementary Table 2, available online at www.giejournal.org). Analysis 2 included all patients with achalasia who underwent POEM, including all patients in analysis 1 plus those satisfying the less-restrictive criteria (Fig. 1).
      Figure thumbnail gr1
      Figure 1Flow chart of patient enrolment in this prospective study of peroral endoscopic myotomy for achalasia. POEM, Peroral endoscopic myotomy; PPI, proton pump inhibitor.

      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.
      • Eckardt V.F.
      Clinical presentations and complications of achalasia.
      The Eckardt score comprises 4 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 CT. The type of achalasia was determined according to the findings on barium esophagography and was classified as straight or sigmoid.
      • Japan Esophageal S.
      Descriptive rules for achalasia of the esophagus, June 2012: 4th edition.
      Sigmoid achalasia was defined as a significantly tortuous esophagus on barium esophagography and was classified into 2 subtypes based on CT findings: sigmoid and advanced sigmoid.
      • Inoue H.
      • Minami H.
      • Kobayashi Y.
      • et al.
      Peroral endoscopic myotomy (POEM) for esophageal achalasia.
      The presence of a double lumen on some CT slices was defined as advanced sigmoid, whereas only a single lumen is present in sigmoid.
      In patients for whom high-resolution manometry could be performed, we classified the type of achalasia according to the Chicago classification.
      • Pandolfino J.E.
      • Kwiatek M.A.
      • Nealis T.
      • et al.
      Achalasia: a new clinically relevant classification by high-resolution manometry.
      ,
      • Kahrilas P.J.
      • Bredenoord A.J.
      • Fox M.
      • et al.
      The Chicago classification of esophageal motility disorders, v3.0.
      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 physical status (ASA-PS) classification system.
      American Society of Anesthesiologists.
      Adverse events related to the POEM procedure were evaluated according to the American Society for Gastrointestinal Endoscopy severity grade for adverse events.
      • Cotton P.B.
      • Eisen G.M.
      • Aabakken L.
      • et al.
      A lexicon for endoscopic adverse events: report of an ASGE workshop.
      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.
      • Armstrong D.
      • Bennett J.R.
      • Blum A.L.
      • et al.
      The endoscopic assessment of esophagitis: a progress report on observer agreement.

      POEM procedures

      POEM was performed using the methods described by Inoue et al
      • Inoue H.
      • Minami H.
      • Kobayashi Y.
      • et al.
      Peroral endoscopic myotomy (POEM) for esophageal achalasia.
      ,
      • Inoue H.
      • Sato H.
      • Ikeda H.
      • et al.
      Per-oral endoscopic myotomy: a series of 500 patients.
      ,
      • Inoue H.
      • Tianle K.M.
      • Ikeda H.
      • et al.
      Peroral endoscopic myotomy for esophageal achalasia: technique, indication, and outcomes.
      ,
      • Inoue H.
      • Shiwaku H.
      • Iwakiri K.
      • et al.
      Clinical practice guidelines for peroral endoscopic myotomy.
      (Fig. 2A-D). All procedures were performed or supervised by surgeons from each facility who received POEM procedural and technique training from Dr Inoue. POEM was performed with the patient under general anesthesia with endotracheal intubation and 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 1 of the following 3 methods:
      • 1.
        Double-scope method
        • Baldaque-Silva F.
        • Marques M.
        • Vilas-Boas F.
        • et al.
        New transillumination auxiliary technique for peroral endoscopic myotomy.
        : 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
        • Minami H.
        • Inoue H.
        • Haji A.
        • et al.
        Per-oral endoscopic myotomy: emerging indications and evolving techniques.
        : 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
        • Inoue H.
        • Shiwaku H.
        • Iwakiri K.
        • et al.
        Clinical practice guidelines for peroral endoscopic myotomy.
        : The procedure reaching the gastric side was confirmed by the endoscope insertion depth, anatomic landmarks, and/or scope resistance.
        • Anatomic 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 anatomic 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.
          • Tanaka S.
          • Kawara F.
          • Toyonaga T.
          • et al.
          Two penetrating vessels as a novel indicator of the appropriate distal end of peroral endoscopic myotomy.
        • 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 stomach cavity after the myotomy is completed, it is possible to feel decreased resistance at the LES.
      Figure thumbnail gr2
      Figure 2A, Peroral endoscopic myotomy procedure (posterior myotomy) after creating the submucosal tunnel. B, Selective myotomy of the inner circular muscle using the triangle tip knife J (Olympus). C, After myotomy. D, 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.

      Outcomes and sample size

      To compare our results with those of Von Renteln et al,
      • Von Renteln D.
      • Fuchs K.H.
      • Fockens P.
      • et al.
      Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study.
      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.
      • Von Renteln D.
      • Fuchs K.H.
      • Fockens P.
      • et al.
      Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study.
      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 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.
      • Von Renteln D.
      • Fuchs K.H.
      • Fockens P.
      • et al.
      Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study.
      Expecting a dropout 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 8 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 flow chart of patient enrollment in our study. Patient 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 Pvalues 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.
      • Shiwaku H.
      • Inoue H.
      • Sasaki T.
      • et al.
      A prospective analysis of GERD after POEM on anterior myotomy.
      • 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.
      • Kumbhari V.
      • Familiari P.
      • Bjerregaard N.C.
      • et al.
      Gastroesophageal reflux after peroral endoscopic myotomy: a multicenter case-control study.
      Statistical analyses were performed using SAS version 9.4 statistical software (SAS Institute, Cary, NC, USA). Reported Pvalues were 2-sided, and we considered P < .05 statistically significant. All data were sent to and analyzed at an independent facility (University of Yamanashi, Japan).

      Results

      Patient demographics

      POEM was performed for 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.) Patient clinical data are summarized in Table 1. Straight achalasia was present in 191 patients (82%) and sigmoid achalasia in the remaining 42 (18%), including 10 patients (4%) with advanced sigmoid achalasia. Previous procedures included pneumatic dilation in 43 patients (18 %) and Heller-Dor operation in 8 (3%).
      • Heller E.
      Extramukose Kardioplastik beim chronischen Kardiospasmus mit Dilatation des Oesophagus.
      • Cox J.
      • Buckton G.K.
      • Bennett J.R.
      Balloon dilatation in achalasia: a new dilator.
      • Boeckxstaens G.E.
      • Annese V.
      • des Varannes S.B.
      • et al.
      Pneumatic dilation versus laparoscopic Heller's myotomy for idiopathic achalasia.
      • Campos G.M.
      • Vittinghoff E.
      • Rabl C.
      • et al.
      Endoscopic and surgical treatments for achalasia: a systematic review and meta-analysis.
      We assessed each patient's ASA-PS and classified 157 patients (67%) 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. Two hundred seven patients satisfied the inclusion and exclusion criteria reported by Von Renteln et al,
      • Von Renteln D.
      • Fuchs K.H.
      • Fockens P.
      • et al.
      Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study.
      and their data were included in analysis 1 (Fig. 1).
      Table 1Characteristics of 233 patients with achalasia who underwent peroral endoscopic myotomy
      CharacteristicValue
      Age, y, mean ± SD (range)52.0 ± 17.5 (13-93)
      Sex, female/male130/103
      Type of achalasia
       Straight191 (82)
       Sigmoid32 (14)
       Advanced sigmoid10 (4)
      Chicago classification
       Type I108 (46)
       Type II80 (34)
       Type III13 (6)
      Previous procedure
      Balloon dilatation43 (18)
      Heller-Dor operation8 (3)
      ASA-PS
       I157 (67)
       II72 (31)
       III4 (2)
      Values are n (%) unless otherwise defined. SD, Standard deviation; ASA-PS, American Society of Anesthesiologists physical status.

      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 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.
      • Cotton P.B.
      • Eisen G.M.
      • Aabakken L.
      • et al.
      A lexicon for endoscopic adverse events: report of an ASGE workshop.
      All adverse events were treated conservatively.
      Table 2Details of 233 peroral endoscopic myotomy procedures for achalasia
      CharacteristicValue
      Length of procedure, min, mean ± SD (range)94.1 ± 44.6 (34-460)
      Direction of myotomy
       Anterior32 (14)
       Posterior201 (86)
      Myotomy length, cm mean ± SD (range)
       Esophageal10.5 ± 3.3 (3-25)
       Gastric2.8 ± 1.1 (0-6)
      Confirmation of LES incision
       Double-scope method185 (80)
       Conventional method42 (18)
       Injection method6 (2)
      Values are n (%) unless otherwise defined. SD, Standard deviation; LES, lower esophageal sphincter.

      Short- and long-term efficacy of POEM

      The primary outcome (efficacy; analysis 1) 1 year after POEM in 207 patients was 97.4% (95% CI, 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 (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%.
      • Pandolfino J.E.
      • Kwiatek M.A.
      • Nealis T.
      • et al.
      Achalasia: a new clinically relevant classification by high-resolution manometry.
      ,
      • Kahrilas P.J.
      • Bredenoord A.J.
      • Fox M.
      • et al.
      The Chicago classification of esophageal motility disorders, v3.0.
      The efficacy of anterior myotomy was 96.8% and the efficacy of posterior myotomy 97.9%; the difference was not statistically significant.
      Figure thumbnail gr3
      Figure 3Efficacy rates 3 months and 1 year after peroral endoscopic myotomy in this study compared with a previous prospective study.

      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% of patients (9.5%-19.9%), 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 grades A to D erosive esophagitis was present in 54.2% of patients (46.0%-62.4%, 77/142) and severe erosive esophagitis (Los Angeles grade C or D) was seen in 5.6% (8/142).
      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 length of the myotomy on the esophageal side was a significant factor on univariate analysis (odds ratio, 1.63; 95% CI, 1.04-2.56), but not on multivariate analysis (Table 3).
      Table 3Odds ratios for Los Angeles grades A-D erosive esophagitis 1 year after peroral endoscopic myotomy for achalasia
      VariablesUnivariate analysisMultivariate analysis
      Odds ratio (95% confidence interval)PvalueOdds ratio (95% confidence interval)Pvalue
      Male vs female1.54 (.76-3.12).231.12 (.42-3.00).82
      Age per 10 years.88 (.71-1.09).25.67 (.48-.94).02
      Degree of dilatation II or III (vs I).78 (.39-1.57).481.57 (.55-4.49).40
      Achalasia type: sigmoid (vs straight)1.23 (.47-3.20).682.06 (.54-7.86).29
      Chicago classification type Ⅱ or Ⅲ (vs type Ⅰ)1.24 (.60-2.57).561.21 (.43-3.40).72
      Direction of myotomy (anterior vs posterior).88 (.25-3.04).84.16 (.01-2.41).19
      Length of myotomy on the esophageal side per 5 cm1.63 (1.04-2.56).031.61 (.88-2.96).12
      Length of myotomy on the gastric side per 2 cm2.05 (.91-4.62).083.02 (.97-9.39).06
      IRP (1 year after POEM) per 5 mm Hg1.20 (.84-1.72).311.18 (.79-1.77).41
      IRP, Integrated relaxation pressure.

      Discussion

      This prospective multicenter study reported a higher efficacy rate (97.4%; 95% CI, 95.2%-99.7%) for POEM compared with the results of the previous prospective multicenter study reported by Von Renteln et al
      • Von Renteln D.
      • Fuchs K.H.
      • Fockens P.
      • et al.
      Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study.
      (82.4%) involving patients meeting similar inclusion criteria. When we included all patients with achalasia, the efficacy rate remained high (97.5%; 95% CI, 95.3%-99.7%) in our study. There are 2 possible reasons for this high efficacy rate: (1) most 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% CI, 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.
      • 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 patients at eight facilities in Japan.
      Therefore, the current study demonstrated that POEM may be adequately taught and used safely and effectively at different institutions in Japan. However, even if POEM is performed at a certain technical level, incomplete LES incisions can occur during large series.
      • Shiwaku H.
      • Inoue H.
      • Yamashita K.
      • et al.
      Peroral endoscopic myotomy for esophageal achalasia: outcomes of the first over 100 patients with short-term follow-up.
      The most reliable method to prevent incomplete LES incisions is confirmation using the double-scope method.
      • Baldaque-Silva F.
      • Marques M.
      • Vilas-Boas F.
      • et al.
      New transillumination auxiliary technique for peroral endoscopic myotomy.
      ,
      • Grimes K.L.
      • Inoue H.
      • Onimaru M.
      • et al.
      Double-scope per oral endoscopic myotomy (POEM): a prospective randomized controlled trial.
      ,
      • Inoue H.
      • Shiwaku H.
      • Kobayashi Y.
      • et al.
      Statement for gastroesophageal reflux disease after peroral endoscopic myotomy from an international multicenter experience.
      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 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% (95% CI, 46.0%-62.4%) of 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.
      • 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 patients at eight facilities in Japan.
      Only 142 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 was 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.
      There were several limitations in this study. We did not include patients with other esophageal motility disorders. Furthermore, the number of patients with type III achalasia was relatively small, 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.

      Acknowledgment

      We thank all patients and clinical staff for their participation and contribution to this study. All data relevant to the study are included in the article. Data are available upon reasonable request.

      Appendix

      Supplementary Table 1Details of all POEM procedures and the surgeons in each facility
      No.FacilityNo. of surgeonsEach experience of over 15 cases of POEM as the primary surgeon or as an assistantEach experience of ESD over 20 casesTrained POEM procedure from Dr InoueHow to confirm incision of LES
      From surgical departmentFrom internal medicine
      1Showa University Koto-Toyosu Hospital, Tokyo46Double-scope method
      2Fukuoka University Faculty of Medicine, Fukuoka20Double-scope method
      3Kobe University Hospital, Hyogo02Double-scope method
      4Niigata University Medical and Dental Hospital, Niigata01Conventional method
      5Oita University Faculty of Medicine, Oita02Conventional method
      6Heart Life Hospital, Okinawa10Conventional method
      7Nagasaki University Hospital, Nagasaki04Injection method
      POEM, Peroral endoscopic myotomy; ESD, endoscopic submucosal dissection; LES, lower esophageal sphincter.
      Supplementary Table 2Inclusion and exclusion criteria for analyses 1 and 2
      Analysis 1: Inclusion and exclusion criteria were made to compare the efficacy of peroral endoscopic myotomy with that reported by the previous prospective study.
      Inclusion criteriaExclusion criteria
      • Symptomatic achalasia
      • Eosinophilic esophagitis
      • Preoperative Eckardt score ≥4
      • Barrett’s esophagus
      • Preoperative barium swallow, manometry, and EGD results were suggestive of achalasia
      • Pregnancy
      • Age >18 y
      • Malignant or premalignant esophageal lesion
      • Severe candida esophagitis
      • Extensive, tortuous dilatation of the esophagus (luminal diameter >7 cm, S shape)
      • Patients with preoperative Eckardt score ≤3
      Analysis 2

      All patients with achalasia plus those aged ≤18 years or with a preoperative Eckardt score ≤3

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      Linked Article

      • POEM for achalasia: endoscopic myotomy enters its golden age, and we are taking NOTES
        Gastrointestinal EndoscopyVol. 91Issue 5
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          Achalasia is an uncommon primary motor disorder of the esophagus, characterized by disorganized peristalsis and insufficient relaxation of the lower esophageal sphincter (LES).1 These abnormalities impede food passage across the LES into the stomach, causing symptoms that include dysphagia, regurgitation, and/or chest pain. Treatment targeting disruption of the LES leads to improvement or resolution of symptoms in the vast majority of patients.2 Currently, 3 main LES-directed treatments are offered to patients with achalasia: pneumatic dilation (PD), laparoscopic Heller myotomy (LHM), and peroral endoscopic myotomy (POEM).
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