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Efficacy and Safety of Peroral Endoscopic Myotomy in Achalasia Patients with Failed Previous Intervention: A Systematic Review and Meta-Analysis

Shali Tan1 , Chunyu Zhong1 , Yutang Ren2 , Xujuan Luo1 , Jin Xu1 , Xiangsheng Fu3 , Yan Peng1 , and Xiaowei Tang1

1Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, 2Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, Tsinghua University School of Clinical Medicine, Beijing, and 3Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China

Correspondence to:Xiaowei Tang
ORCID https://orcid.org/0000-0001-9947-0720
E-mail solitude5834@hotmail.com
Shali Tan, Chunyu Zhong, and Yutang Ren contributed equally to this work as first authors.

Received: July 9, 2019; Revised: October 4, 2019; Accepted: November 4, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut and Liver 2021; 15(2): 153-167

Published online March 15, 2021 https://doi.org/10.5009/gnl19234

Copyright © Gut and Liver.

Peroral endoscopic myotomy (POEM) has emerged as a rescue treatment for recurrent or persistent achalasia after failed initial management. Therefore, we aimed to investigate the efficacy and safety of POEM in achalasia patients with failed previous intervention. We searched the MEDLINE, Embase, Cochrane, and PubMed databases using the queries “achalasia,” “peroral endoscopic myotomy,” and related terms in March 2019. Data on technical and clinical success, adverse events, Eckardt score and lower esophageal sphincter (LES) pressure were collected. The pooled event rates, mean differences (MDs) and risk ratios (RR) were calculated. A total of 15 studies with 2,276 achalasia patients were included. Overall, the pooled technical success, clinical success and adverse events rate of rescue POEM were 98.0% (95% confidence interval [CI], 96.6% to 98.8%), 90.8% (95% CI, 88.8% to 92.4%) and 10.3% (95% CI, 6.6% to 15.8%), respectively. Seven studies compared the clinical outcomes of POEM between previous failed treatment and the treatment naïve patients. The RR for technical success, clinical success, and adverse events were 1.00 (95% CI, 0.98 to 1.01), 0.98 (95% CI, 0.92 to 1.04), and 1.17 (95% CI, 0.78 to 1.76), respectively. Overall, there was significant reduction in the pre- and post-Eckardt score (MD, 5.77; p<0.001) and LES pressure (MD, 18.3 mm Hg; p<0.001) for achalasia patients with failed previous intervention after POEM. POEM appears to be a safe, effective and feasible treatment for individuals who have undergone previous failed intervention. It has similar outcomes in previously treated and treatment-naïve achalasia patients.

Keywords: Esophageal achalasia, Meta-analysis, Pyloromyotomy, Safety, Treatment failure

Achalasia is an esophageal motility disorder, caused by the absence of myenteric neurons and the subsequent impaired lower esophageal sphincter (LES) relaxation. Patients present with dysphagia, regurgitation, chest pain, and weight loss.1 Treatment options include Heller myotomy (HM), pneumatic balloon dilation (PBD), and botulinum toxin injection (BTI). Although HM is considered the first-line therapy due to its superior long-term outcomes, a failure rate of approximately 10% to 20% is observed.2,3 Similarly, despite a 90% PBD success rate, recurrence of symptoms occurs post-procedure in 20%, 30%, and 40% of patients in 2, 5 and 10 years, respectively.4-6 Lastly, BTI is safety and efficacious in the majority of patients; however, symptomatic relief is short term with only 29% of patients reporting continued success during intermediate follow-up.7 In cases of symptom recurrence after primary intervention, surgical myotomy is often technically challenging. Additionally, a high risk of adverse events is documented. Reported rates of gastrointestinal perforation range from 1.5% to 20% and are typically due to the formation of scars, fibrosis and adhesions resulting from previous surgical or endoscopic interventions.8- PBD and BTI are also rescue management strategies for recurrent achalasia. However, the durability of both interventions is limited. Repeat treatment for relapsing symptoms is required in up to 45% of patients after 2 years., Furthermore, previous myotomy is considered to be a relative contraindication to PBD., Recently, peroral endoscopic myotomy (POEM) has emerged as a treatment for recurrent or persistent achalasia after failed initial management. It can avoid shortcomings of other treatments mentioned above. Several studies have demonstrated a promising clinical success rate of greater than 90%.- However, some of these studies in this setting are limited by their small numbers. Therefore, the aim of this systematic review and meta-analysis was to determine the efficacy and safety of POEM as a therapy in those who have undergone failed endoscopic or surgical treatments. We also compared the efficacy and safety of POEM in patients who had previously failed endoscopic or surgical therapies with those who underwent the POEM as a primary treatment.

1. Search strategy and study selection

Utilizing Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines,31 the following databases were searched from interception to March 2019: MEDLINE, Embase, Cochrane, and PubMed. The keywords “achalasia,” “esophageal achalasia,” “peroral endoscopic myotomy,” “per-oral endoscopic myotomy,” “Heller myotomy,” “POEM,” “Pneumatic dilation,” “HM,” and the related terms provided in Supplementary Table 1 were used. The references of published articles were also manually reviewed to ensure the inclusion of all relevant studies. Articles published in the Chinese language were reviewed by coauthor X.T. However, none met our inclusion criteria. Two authors (S.T. and C.Z.) screened all titles, abstracts and full texts independently. Any discrepancies were discussed with a third investigator (X.T.).

2. Eligibility criteria and data collection

Two reviewers (X.F. and Y.R.) assessed the articles independently based on the predefined inclusion criteria and exclusion criteria. All prospective, retrospective, case-control and cohort studies and other clinical trials were included if they featured patients: (1) diagnosed with achalasia and (2) who had undergone POEM after failed previous treatment(s). Manuscripts were excluded if: (1) they described non-human studies, (2) were single-arm studies with treatment-naïve patients undergoing POEM or (3) were case-reports less than five patients, commentaries, reviews, editorials, conference abstracts or surveys. For overlapping publications from the same center, only the most recent and comprehensive publication was considered for inclusion.

Two reviewers (Y.P. and X.T.) collected the following data independently: baseline characteristics (author name, year of publication, country, study design, study duration, group, sample size, patient age, and sex distribution); clinical characteristics (initial achalasia treatment, achalasia subtype, myotomy orientation, myotomy length, procedure time, and length of hospital stay) and clinical outcomes (technical success, clinical success, incidence of symptomatic reflux and reflux esophagitis). Also, major and minor adverse events were recorded to determine the safety of POEM. Pre- and post-procedure Eckardt scores and LES pressures were also included.

3. Quality assessment

The Newcastle-Ottawa Quality Assessment Scale for non-randomized studies was used by two investigators (X.L. and J.X.) to assess the risk of bias in the included studies.32,33 This scale rates three study aspects: selection, comparability and outcome. The maximum attainable score is 9. Each study was rated as “high quality” (score ≥7), “medium quality” (score of 5 or 6) or “low quality” (score ≤4).

4. Endpoint definition and statistical analysis

The primary outcomes were efficacy (as measured by technical and clinical success) and safety (indicated by presence and severity of adverse events) of POEM after failure of endoscopic or surgical intervention for achalasia. Technical success was defined as successful completion of the entire procedure. Clinical success was defined as an Eckardt score ≤3 during the study follow-up period. Procedure-related and post-procedure adverse events were included. Adverse events were divided into major and minor according to the NOSCAR white paper.34 Major adverse events were defined as events requiring additional intervention during or after POEM including endoscopic or surgical interventions, bleeding requiring transfusion, readmission within 30 days, prolonged hospital stay (>5 days) and clinical inflammation. Air-related outcomes and fluid collections were considered to be major adverse events when requiring drainage. Adverse events which were managed conservatively were defined as minor adverse events. The secondary endpoints of the study were the mean reduction in Eckardt scores and LES pressures, the difference in procedure time and hospital stay between the patients with and without previous intervention(s), and gastroesophageal reflux disease (GERD) incidence during follow-up. All statistical analyses were conducted using Comprehensive Meta-Analysis version 2 (Biostat, Englewood, NJ, USA), Cochrane Review Manager 5.3 (London, UK) and GraphPad Prism version 5.00 (San Diego, CA, USA). Pooled effects with 95% confidence intervals (CI) were calculated for technical success, clinical success and adverse events. The mean difference (MD) was calculated for Eckardt score, LES pressure, procedure time and length of hospital stay. We also compared the efficacy and safety of POEM in patients who had previously failed endoscopic or surgical therapies with those who underwent POEM as a primary treatment for achalasia. Risk ratios (RR) were derived for technical success, clinical success and adverse events. The heterogeneity between the studies was assessed using the I2 test and Cochran’s Q statistic in which a p<0.1 indicates substantial heterogeneity. I2 values of around 25%, 50% and 75% were considered as low, moderate and high heterogeneity, respectively. When I2 was greater than 50% and/or the Cochran’s Q test provided a p<0.1, we ran analyses with the random-effect model, otherwise we used the fixed-effect model. Publication bias was assessed using funnel plots and the Egger’s regression test. In addition, we performed subgroup analyses according to follow-up time and adverse events (major and minor adverse events), and a sensitivity analysis to confirm whether a single study caused an effect. A two-sided p<0.05 was regarded as statistically significant.

1. Study characteristics and quality

Using the search strategy, 3,330 records were identified. After exclusion criteria, 15 studies were eligible (Fig. 1). The baseline characteristics of the included studies are summarized in Table 1. The 15 studies were all conducted between September 2008 and January 2017. Three multicenter studies, all lead by USA investigators, were included. The 12 single-center studies were conducted in Japan (n=1), USA (n=5), China (n=4), Denmark (n=1), and India (n=1). Among these studies, six were prospective. No randomized control trials met inclusion criteria.

A total of 2,276 patients were included in our study. One thousand-fifteen were treatment-naïve and 1,261 patients had undergone previous treatment(s) for achalasia. The mean ages of patients ranged from 34.9 to 69.6 years. Overall, five studies were single arm studies with failed endoscopic or/and surgical interventions. Seven studies compared the clinical outcomes of POEM between previous failed treatment and the treatment naïve patients.

Table 2 shows the clinical characteristics of the included studies. Information on achalasia subtype was available for 2,197 patients (type I n=579, type II n=1,108, type III n=145, and unspecified type n=321). There were 44 patients with other esophageal dysmotility disorders. Submucosal myotomies (534/1,169; 45.7%) were posterior. The mean procedure time, total myotomy length and hospital stay ranged from 36.4 to 139 minutes, 9.0 to 12.7 cm and 1 to 6.2 days, respectively. The assessment of risk of bias of individual studies is shown in the Table 3. Follow-up time ranged from 5 to 28 months (Table 4).

2. Technical success

Thirteen studies with 1,179 patients reported the technical success of POEM for patients with prior endoscopic or/and surgical treatment. Technical success ranged from 97.1% to 100% and was achieved in 1,170 (99.2%) patients (Table 4). Pooled technical success was 98.0% (95% CI, 96.6% to 98.8%) with no statistically significant heterogeneity (Q=9.99, p=0.62, I2=0%) (Fig. 2A). Sensitivity analysis was performed removing one study at a time, and confirmed the same outcomes of the main analyses. There was no publication bias amongst the studies as shown in the Supplementary Fig. 1A (Egger’s regression test p=0.38).

3. Clinical success

Ten studies with 1,095 patients reported the clinical success of POEM for patients with prior endoscopic or/and surgical treatment. Clinical success ranged from 81% to 100% in these studies. Clinical success was achieved in 999 patients (91.2%) at 3-month follow-up (Table 4). The pooled clinical success in patients with greater than three months’ follow-up was 90.8% (95% CI, 88.8% to 92.4%) with a low degree of heterogeneity (Q=10.73, p=0.29, I2=16.14%) as shown in Fig. 2B. Subgroup analysis was undertaken on the basis of duration of follow-up. Four studies reported clinical success with 1-year follow-up. Two studies reported 2- and 3-year follow-ups. The pooled results of clinical success rates for 1-, 2-, and 3-year follow-ups were 89.9% (95% CI, 86.9% to 92.3%), 85.8% (95% CI, 81.7% to 89.1%) and 81.2% (95% CI, 76.2% to 85.4%), respectively (Supplementary Fig. 2). Sensitivity analysis removing one study at a time was performed and confirmed the outcomes of the main analyses. However, when removing either the study by Zhang et al.22 or Ngamruengphong et al.,18 a considerable reduction in heterogeneity occurred, changing the I2 from 16.14% to 0%. There was no publication bias amongst the studies as shown in Supplementary Fig. 1B (Egger’ s regression test p=0.49).

4. Adverse events

Fourteen studies with 1,195 patients reported the adverse events of POEM for patients with prior endoscopic or/and surgical treatment. A total of 83 (6.9%) adverse events occurred (Table 5). The pooled adverse events rate was 10.3% (95% CI, 6.6% to 15.8%) with a high degree of heterogeneity (Q=45.67, p<0.001, I2=71.54%), as shown in Fig. 2C. The pooled major and minor adverse events rates were 6.4% (95% CI, 3.6% to 11.1%) and 7.0% (95% CI, 5.2% to 9.5%) as shown in Supplementary Fig. 3. Sensitivity analysis demonstrated that the largest change occurred when the study conducted by Zhang et al.22 was removed. The heterogeneity decreased from 71.54% to 60.74%. The effect sized changed from 10.3% to 11.8% (95% CI, 7.9% to 17.3%). There was no publication bias amongst the studies as shown in Supplementary Fig. 1C (Egger’ s regression test p=0.39).

5. Meta-analysis

Overall, six studies with 1,548 patients compared the technical success of POEM between achalasia patients with and without previous treatment. The pooled RR for technical success was 1.00 (95% CI, 0.98 to 1.01), p=0.56, Cochran Q test p=0.91, I2=0% (Fig. 3). For clinical success, the pooled RR at 1-year follow-up was 0.98 (95% CI, 0.92 to 1.04), p=0.46, Cochran Q test p=0.10, I2=56% (Fig. 4A). The results for 2- and 3-year follow-ups were 0.93 (95% CI, 0.89 to 0.98) and 0.89 (95% CI, 0.84 to 0.95) (Fig. 4B and C). Seven studies with 1,588 patients compared the safety of POEM in achalasia patients with and without previous treatment. The adverse events rate for patients with prior treatment versus treatment naïve patients were 6.3% and 5.3%. The pooled RR was 1.17 (95% CI, 0.78 to 1.76), p=0.45, Cochran Q test p=0.60, I2=0% (Fig. 5A). There were also no significant difference in major and minor adverse events between the two groups. The RR for major and minor adverse events were 1.14 (95% CI, 0.71 to 1.82; p=0.60) and 0.99 (95% CI, 0.85 to 1.16; p=0.94), respectively (Fig. 5B and C). The presence of GERD diagnosed via esophagogastroduodenoscopy (EGD) was documented for 963 patients. The RR for reflux esophagitis at EGD was 1.18 (95% CI, 0.91 to 1.53), p=0.21, Cochran Q test p=0.51, I2=0% (Table 4, Supplementary Fig. 4A). The RR for GERD symptoms was 1.19 (95% CI, 0.90 to 1.57), p=0.22, Cochran Q test p=0.45, I2=0% (Table 4, Supplementary Fig. 4B). We also compared the procedure time between the patients with and without previous intervention. The MD for procedure time and length of hospital stay were 7.21 minutes (95% CI, 4.04 to 10.39; p<0.001, I2=0%) and 0.09 days (95% CI, –0.53 to 0.71; p=0.77, I2=58%) (Table 2, Supplementary Fig. 5). Thirteen studies reported the change in the Eckardt score in the cohort with previous intervention. Ten studies evaluated the change in LES pressure after POEM. The mean Eckardt score was significantly decreased by 5.77 points (95% CI, 5.07 to 6.47; p<0.001, I2=96%) and LES pressure was significantly reduced by 18.3 mm Hg (95% CI, 12.73 to 23.86; p<0.001, I2=95%) (Fig. 6A and C, Supplementary Table 2). The mean Eckardt score and LES pressure in patients with prior treatment were 7.25±0.14 points and 38.65±1.28 mm Hg, respectively. After POEM, these decreased to 1.07±0.10 and 16.28±0.65, respectively (Fig. 6B and D). When we excluded the studies that did not report the standard deviation. Significant changes in Eckardt score and LES pressure were still found. The overall MDs in Eckardt score and LES pressure were 5.74 (95% CI, 5.04 to 6.44; p<0.001, I2=90%) and 20.16 mm Hg (95% CI, 14.76 to 25.56; p<0.001, I2=87%), respectively.

With the advent of minimally invasive era, POEM has become a promising technique with excellent clinical outcomes for the treatment of achalasia patients with or without failed previous treatment. However, it is technically challenging for several, multifactorial reasons. Irrespective of type of previous intervention for achalasia, endoscopic or surgical, esophageal scarring and fibrosis may result. This may lead to difficulty in delineating tissue planes and reduce the efficacy of submucosal injection, leading to an increased likelihood of complications such as perforation and bleeding. Due to this potentially increased difficulty of POEM after previous interventions for achalasia, we performed this meta-analysis to explore the efficacy and safety of POEM for patients with and without prior treatment. In our present study, we demonstrated that POEM was equally efficacious and safe in achalasia patients with and without previous intervention. We found that POEM achieved high pooled technical (98.0%) and clinical (90.8%) success rates and reduced the Eckardt score (MD: 5.77, p<0.001) and LES pressure (MD: 18.3 mm Hg, p<0.001) significantly in patients who have undergone prior treatment. In addition, our meta-analysis demonstrated that the efficacy of POEM in the patients who had undergone prior intervention was comparable to that of the treatment-naïve patients. Our result is consistent with several published studies.24,28 The favorable results provided by POEM are due to several reasons. POEM is a completely endoscopic and intraluminal approach which is unlikely to be affected by the scars and tissue adhesions resulting from previous treatment. Thus, efficacy is similar to treatment naïve patients. Additionally, POEM provides the opportunity to perform the myotomy in an opposite orientation. Thus, the new myotomy can be performed in a location without scars, resulting in good control of the myotomy length. Conversely, due to the presence of scars, fibrosis and tissue adhesions, the POEM procedure could potentially be more technically challenging, resulting in a longer procedure time and hospital stay. In the Liu et al.,30 a significantly longer hospital stay after POEM was found in patients with prior therapy when compared to the patients without prior treatment (<2 days: 43.7% vs 53.6%, ≥2 days: 56.3% vs 46.4%, p=0.001). Our study failed to demonstrate a longer length of hospital stay (MD: 0.09, p=0.77) after pooling all related data. Importantly, our analysis was performed with only three studies. In view of this small numbers of studies and sample size, we must interpret this outcome with caution.

When comparing the clinical success rate of POEM in patients with a greater than 2-and 3-year follow-ups, we found that results from the group of treatment naïve patients was superior to the that of the patients who had undergone previous endoscopic or/and surgical interventions. However, an individual study by Nabi et al.24 with 502 patients and a greater than 2-year follow-up did not suggest a higher clinical success rate in treatment-naïve patients. Liu et al.30 reviewed 849 patients and demonstrated a superior 5-year clinical success rate in the treatment naïve cohort. They indicated that follow-up duration correlated with the difference in clinical failure between patients with and without prior treatment. They also found patients who had undergone more than one previous intervention had a higher risk than those with only one previous treatment. This may be attributed to severe inflammation and fibrosis formed by prior treatments. This difference may also be due to a difference in “symptom-reporting threshold” of patients whose symptoms recurred after prior treatments. Given this discrepancy in outcomes, systematic evaluation of long-term outcomes between the two groups is necessary in the future.

In our study, the most common adverse events related to the POEM procedure in patients with prior treatments were mucosal injury, bleeding, pneumothorax, and pneumoperitoneum. Theoretically, patients who have undergone surgical or/and endoscopic treatment are more prone to incur adverse events because of inflammation and fibrosis. Nevertheless, in the current study, the adverse event rate was not significantly higher in those who had undergone previous interventions when compared to those without interventions. This may be due to all the POEM procedures being performed by experienced operators in our included studies.30 When evaluating the GERD rate during follow-ups, we found that the incidence of GERD diagnosed via EGD or questionnaires was not significantly different between the two groups (Supplementary Fig. 4). However, our result may be affected by various factors. For example, the GERD measurement results were only available in a minority of the total patients’ number. Additionally, previous fundoplication may have an influence on preventing postoperative reflux. Importantly, there were no procedure-related deaths in any of the included studies. Our study confirmed the safety of POEM for patients with previous interventions.

To our knowledge, this is the first systematic review and meta-analysis comparing the efficacy and safety of POEM in patients with and without previous treatments. There are a few limitations in the current study. First, only retrospective and prospective studies were included. No randomized controlled studies were found. Second, owing to the paucity of data in the included studies, we were unable to assess the efficacy and safety of POEM for patients with previous surgical or endoscopic interventions separately. Third, some studies included pediatric patients with achalasia and some patients with other esophageal dysmotility disorders. However, these patients accounted for a small percentage and our outcomes were unchanged after removing these studies. Fourth, we were unable to assess the quality of life in patients with prior treatments after POEM due to the limited number of studies reporting this results. Last, long-term (greater than 2 years) differences between the patients with and without prior intervention should be interpreted carefully as only two study reported these outcomes.

POEM appears to be a safe, effective and feasible treatment for those who have undergone previous failed endoscopic or surgical intervention. It has similar outcomes in previously treated and treatment-naïve achalasia patients. It may be an attractive option for the treatment of patients with this difficult condition. However, further studies with a long-term follow-up to determine the durability of rescue POEM are still warranted.

This study is independent research funded by the following grants: Medical Science and Technology Plan Projects of Zhejiang Province (No. 2017196257), Youth Foundation of Southwest Medical University (No. 0903-00031099), Doctoral Research Start-up Funding Project of Affiliated Hospital of Southwest Medical University (No. 16229).

Study conception and design: X.T., Y.R. Acquisition of data and critical revision: X.L., J.X. Drafting of manuscript: S.T., C.Z. Revision of manuscript, and final approval of manuscript: X.F., Y.P., X.T.

Fig. 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart.
Fig. 2.Overall efficacy and safety of peroral endoscopic myotomy in patients with previous intervention(s). (A) Technical success; (B) clinical success (less than 12 months of follow-up); (C) adverse events.
CI, confidence interval.
Fig. 3.Meta-analysis of technical success between patients with and without previous intervention(s).
M-H, Mantel-Haenszel; CI, confidence interval.
Fig. 4.Meta-analysis of clinical success between patients with and without previous intervention(s). (A) One-year follow-up; (B) 2-year follow-up; (3) 3-year follow-up.
M-H, Mantel-Haenszel; CI, confidence interval.
Fig. 5.Meta-analysis of adverse events between patients with and without previous intervention(s). (A) Overall adverse events; (B) major adverse events; (3) minor adverse events.
M-H, Mantel-Haenszel; CI, confidence interval.
Fig. 6.Changes in the mean Eckardt score and lower esophageal sphincter (LES) pressure before and after peroral endoscopic myotomy (POEM) in patients with previous endoscopic or/and surgical intervention. (A) Change in the mean Eckardt score. (B) Changes in the mean Eckardt score before and after POEM: the diamond corresponds to the mean Eckardt score, and the lines extending from them indicate the standard error above and below the mean. (C) Change in the mean LES pressure. (D) Changes in the mean LES pressure before and after POEM.
IV, inverse variance; CI, confidence interval.

Baseline Characteristics of Included Studies

Author (year) Country Design Duration No. of patients Group Age, yr Male sex, No. (%)
Tyberg et al. (2016)16 USA Prospective Mar 2014–Aug 2015 46 46 PTF 49.3±16.78 20 (45.0)
Tyberg et al. (2018)21 USA Prospective Jan 2012–Jan 2017 51 51 PTF 54.2 24 (47.0)
Onimaru et al. (2013)25 Japan Prospective Sep 2008–Dec 2012 10 10 PTF 52 5 (50.0)
Vigneswaran et al. (2014)26 USA Prospective Oct 2010–Jun 2013 5 5 PTF 69.6 4 (80.0)
Zhou et al. (2013)28 China Prospective Mar 2011–Dec 2011 12 12 PTF 51.1 5 (41.7)
Ling et al. (2014)17 China Prospective May 2010–Sep 2012 51 21 PTF 43.2±12.7 8 (38.1)
30 Naïve 42.5±11.3 10 (33.3)
Ngamruengphong et al. (2017)18 USA Retrospective Dec 2009–Sep 2015 180 90 PTF with HM 54±15 44 (48.9)
90 PTF without HM 53±14 38 (42.2)
Tang et al. (2017)19 China Retrospective Jul 2011–Jan 2014 61 22 PTF 34.9±7.7 14 (63.6)
39 Naïve 38.5±11.3 20 (51.3)
Kristensen et al. (2017)20 Denmark Retrospective Jan 2012–May 2016 66 14 PTF with HM 43.5 (22–75) 7 (50.0)
52 PTF without HM 49.5 (18–77) 26 (50.0)
Orenstein et al. (2015)23 USA Retrospective May 2011–Sep 2013 40 16 PTF NA NA
24 Naïve NA NA
Nabi et al. (2018)24 India Retrospective Jan 2013–Nov 2016 502 242 PTF 42.4±13.6 137 (56.6)
260 Naïve 38.0±13.6 142 (54.6)
Sharata et al. (2013)27 USA Retrospective Oct 2010–May 2012 40 12 PTF 55±17 5 (41.7)
28 Naïve 48±21 12 (42.9)
Zhang et al. (2018)22 USA Retrospective Oct 2009–Oct 2016 318 46 PTF* 55 (17–85) 24 (52.2)
272 PTF 54 (10–94) 155 (57.0)
Jones et al. (2015)29 USA Retrospective Aug 2012–Oct 2014 45 15 PTF 64.4±12 3 (20.0)
30 Naïve 46.2±17.2 25 (83.3)
Liu et al. (2019)30 China Retrospective Aug 2010–Dec 2014 849 245 PTF 38 (6–98) 132 (53.9)
604 Naïve 38 (8–77) 291 (48.2)

Data are presented as mean±SD or median (range).

PTF, previous treatment failure; HM, Heller myotomy.

*Previous surgical and endoscopic treatment failure; Previous endoscopic treatment failure.


Clinical Characteristics of Included Studies

Author Group Previous treatment Subtype* Direction of myotomy Procedure time, mean±SD, min Myotomy length, mean±SD, cm Hospital stay, mean±SD, day

E G T
Tyberg et al.16 46 PTF 46 POEM 10 I, 16 II, 5 III, 15 other EDD NA 90 NA NA NA NA
Tyberg et al.21 51 PTF 43 LHM, 8 laparotomy HM 13 I, 29 II, 6 III, 3 other EDD 51 Posterior NA NA NA NA NA
Onimaru et al. 25 10 PTF 10 LHM+PBD 6 II, 4 III 7 Posterior 118.2 9.2 3.2 12.4 NA
1 Right anterior
2 Right
Vigneswaran et al.26 5 PTF 5 LHM NA NA 139.0±29.6 NA NA 9.0 1.6±0.2
Zhou et al.28 12 PTF 3 Laparotomy HM, 3 open thoracotomy HM, 6 LHM NA 12 Posterior 36.4±9.3 8.0 (6–10) 2.1 (2–3) 10.1 (8–13) 4.1±1.3
Ling et al.17 21 PTF 21 PBD 5 I, 13 II, 3 III 21 Posterior 42.4±8.3 NA NA 10.3±1.5 NA
30 Naïve None 6 I, 22 II, 2 III 30 Posterior 34.3±7.4 NA NA 9.6±1.2 NA
Ngamruengphong
et al.18
90 PTF with HM 40 PBD, 10 BTI 26 I, 23 II, 10 III, 31 unspecified 2 Anterior
86 Posterior
2 Missing data
102.8±41 8.7±4.4 2.9±1.2 11.6 3.54±1.7
90 PTF without HM 23 PBD, 7 BTI 20 I, 29 II, 10 III, 31 unspecified 42 Anterior
48 Posterior
102.6±61 9.7±3.9 3±1.3 12.7 3.59±2.5
Tang et al.19 22 PTF 18 PBD, 2 BTI, 2 BTI+PBD 5 I, 17 II NA 60.8±30.9 6.7±2.6 3.1±1.1 9.8±2.9 6.2±1.3
39 Naïve None 13 I, 26 II NA 62.0±21.0 7.4±3.3 3.1±1.6 10.5±3.9 6.5±1.6
Kristensen et al.20 14 PTF with HM 13 BTI or PBD 9 I, 5 missing data NA 74 (35–149) 9 (6–13) 3 (2–5) NA 2 (1–4)
52 PTF without HM 15 BTI or PBD 7 I, 25 II, 3 III, 17 missing data NA 61 (35–126) 9.5 (6–13) 4 (2–5) NA 2 (1–4)
Orenstein et al.23 16 PTF 6 BTI, 4 PBD, 3 BTI+PBD, 3 LHM NA NA 102 NA NA NA NA
24 Naïve None NA NA 118 NA NA NA NA
Nabi et al.24 242 PTF 205 PBD, 30 LHM, 4 BTI, 3 POEM 91 I, 140 II, 11 III 186 Anterior
56 Posterior
74.9±30.6 9.4±2.4 3.1±0.5 12.5 3 (2-5)
260 Naïve None 82 I, 169 II, 9 III 210 Anterior
50 Posterior
67.0±27.1 9.0±2.5 3.08±0.5 12.08 3 (2-5)
Sharata et al.27 12 PTF 10 BTI, 2 PBD 9 Unspecified , 3 other EDD NA 134±43 NA NA NA NA
28 Naïve None 22 Unspecified, 6 other EDD NA 131±41 NA NA NA NA
Zhang et al.22 46 PTF§ 14 HM+PBD, 19 HM+BTI 30 I, 5 II, 6 III, 5 unspecified 8 Anterior
38 Posterior
82 (32–166) NA NA 11 (5–23) 1 (1–5)
272 PTFΙΙ 29 PBD, 54 BTI 53 I, 147 II, 32 III, 26 unspecified, 14 other EDD 137 Anterior
135 Posterior
72 (21–240) NA NA 12 (3–27) 2 (1–30)
Jones et al.29 15 PTF
30 Naïve
7 BTI, 5 PBD, 3 HM
None
42 Unspecified, 3 other EDD (total) 15 Anterior
30 Anterior
102±29
103±27
NA
NA
NA
NA
NA
NA
1 (0–12)
1 (0–1)
Liu et al.30 245 PTF 165 PBD, 28 HM, 6 POEM,
45 esophageal stent, 46 BTI
65 I, 132 II, 13 III, 35 unspecified NA <60, 166
≥60, 79
NA NA NA <2, 107
≥2, 138
604 Naïve None 144 I, 309 II, 31 III, 120 unspecified NA <60, 441
≥60, 163
NA NA NA <2, 324
≥2, 280

E, esophageal; G, gastric; T, total; PTF, previous treatment failure; POEM, peroral endoscopic myotomy; EDD, esophageal dysmotility disorder; NA, not available; LHM, laparoscopic Heller myotomy; HM, Heller myotomy; PBD, pneumatic balloon dilation; BTI, botulinum toxin injection.

*Chicago classification; Mean (range); Median (range); §Previous surgical and endoscopic treatment failure; ΙΙPrevious endoscopic treatment failure.


Newcastle-Ottawa Quality Assessment Scale for Included Studies

Study Selection Outcome assessment Comparability Quality of study



1 2 3 4 1 2 3 1 2
Tyberg et al.16 + + + + + + Medium quality
Ling et al.17 + + + + + + + + High quality
Tang et al.19 + + + + + + + + + High quality
Ngamruengphong et al.18 + + + + + + + + High quality
Kristensen et al.20 + + + + + + + + High quality
Tyberg et al.21 + + + + + + Medium quality
Orenstein et al.23 + + + + + + + High quality
Nabi et al.24 + + + + + + + + High quality
Onimaru et al.25 + + + + + + Medium quality
Vigneswaran et al.26 + + + + + Medium quality
Sharata et al.27 + + + + + + + + + High quality
Zhang et al.22 + + + + + + + + High quality
Zhou et al.28 + + + + + + Medium quality
Jones et al.29 + + + + + + + + High quality
Liu et al.30 + + + + + + + + High quality

Selection: 1, representativeness of the exposed cohort; 2, selection of the nonexposed cohort; 3, ascertainment of exposure; 4, outcome of interest not present at start of study. Outcome assessment: 1, assessment of outcome; 2, adequacy of duration of follow-up; 3, adequacy of completeness of follow-up. Comparability: 1, study controls for confounder; 2, study controls for any additional factors.


Clinical Outcomes of Included Studies during Follow-up

Author Group % (No./No.) Follow-up, mean (range), mo

Technical
success
Clinical success Symptomatic reflux and
reflux esophagitis
Tyberg et al.16 46 PTF 100 (46/46) 85 (41/46) (3-mo FU) NA 12.2 (1–32)
Tyberg et al.21 51 PTF 100 (51/51) 94 (48/51) (1-yr FU) NA 24.4 (12–52)
Onimaru et al.25 10 PTF 100 (10/10) NA NA 18.3
Vigneswaran et al.26 5 PTF 100 (5/5) NA NA 4.9
Zhou et al.28 12 PTF 100 (12/12) 91.7 (11/12) (5–14 mo FU) Reflux esophagitis 8.3 (1/12) 10.4 (5–14)
Ling et al.17 21 PTF 100 (21/21) 92.3 (19/21) (postoperative), Reflux esophagitis 19.0 (4/21) 13.2
87.5 (18/21) 1-yr FU
30 Naïve 100 (30/30) NA NA 14.4
Ngamruengphong et al.18 90 PTF (with HM) 98 (88/90) 81.2 (69/85) Symptomatic reflux 30 (21/70) 9 (4–14)*
Reflux esophagitis 44 (18/41)
90 PTF (without HM) 100 (90/90) 94.8 (77/82) (total n=167)
(≥3-mo FU)
Symptomatic reflux 32 (24/76) 8.5 (1.3–18.5)*
Reflux esophagitis 52 (23/44)
Tang et al.19 22 PTF 100 (22/22) 95.5 (21/22) Reflux esophagitis 23.5 (4/17) 12
39 Naïve 100 (39/39) 92.3 (36/39) (1-yr FU) Reflux esophagitis 20 (7/35) 12
Kristensen et al.20 14 PTF (with HM) NA NA NA 24
52 PTF (without HM) NA NA NA 24
Orenstein et al.23 16 PTF NA NA NA 9.0
24 Naïve NA NA NA 10.1
Nabi et al.24 242 PTF 97.1 (235/242) 92.5 (186/201) (6-mo FU) Symptomatic reflux 17.8 (26/146) 20 (1–45)
91.2 (145/159) (1-yr FU)
84.2 (85/101) (2-yr FU) Reflux esophagitis 20.7 (24/116)
76.3 (29/38) (3-yr FU)
260 Naïve 98.1 (255/260) 92.4 (206/223) (6-mo FU) Symptomatic reflux 16.4 (22/134) 20 (1–45)
90.7 (166/183) (1-yr FU)
87.5 (112/128) (2-yr FU) Reflux esophagitis 22.1 (29/131)
87.1 (27/31) (3-yr FU)
Sharata et al.27 12 PTF 100 (12/12) 100 (12/12) NA 6
28 Naïve 100 (28/28) 100 (28/28) (postoperative) NA 6
Zhang et al.22 46 PTF 100 (46/46) 95.7 (44/46) Reflux esophagitis 46.2 (12/26) 28 (3–46)
272 PTF§ 100 (272/272) 95.1 (255/272) (>3 mo) Reflux esophagitis 34.0 (50/147) 23 (3–78)
Jones et al.29 15 PTF 100 (15/15) NA NA 12
30 Naïve 100 (30/30) NA NA 10
Liu et al.30 245 PTF 100 (245/245) 88.6 (217/245) (1-yr FU) Symptomatic reflux 18.8 (46/245) 23 (1–71)
86.5 (212/245) (2-yr FU) Reflux esophagitis 22.8 (46/202)
82 (201/245) (5-yr FU) Symptomatic reflux 14.7 (89/604)
604 Naïve 100 (604/604) 95.0 (574/604) (1-yr FU) Reflux esophagitis 17.3 (80/462) 23 (1–71)
93.5 (565/604) (2-yr FU)
91.7 (554/604) (5-yr FU)

PTF, previous treatment failure, FU, follow-up; NA, not available; HM, Heller myotomy.

*Median (interquartile range); †Median (range); ‡Previous surgical and endoscopic treatment failure; §Previous endoscopic treatment failure.


Safety of Peroral Endoscopic Myotomy

Author Major adverse events Minor adverse events


PTF Naïve PTF Naïve
Tyberg et al.16 0 - 8 Bleeding -
Tyberg et al.21 2 Mediastinitis - 6 Mucosal defects -
Onimaru et al.25 0 - 0 -
Vigneswaran et al.26 1 Esophageal leak and mediastinal abscess - 0 -
Zhou et al.28 1 Pneumothorax - 1 Mucosal perforation -
1 Pneumoperitoneum
Ling et al.17 0 0 0 0
Ngamruengphong et al.18 1 Pneumonia - 7 Mucosotomy -
1 Mediastinitis 1 Delayed bleeding
5 Symptomatic pneumoperitoneum 1 Submucosal hematoma
1 Symptomatic pneumothorax
1 Symptomatic subcutaneous emphysema
1 Pleural effusion requiring chest drain
Tang et al.19 0 0 1 Bleeding 2 Bleeding
Kristensen et al.20 NA - NA -
Orenstein et al.23 1 Capnoperitoneum alleviated with angiocatheter evacuation 1 Capnoperitoneum alleviated with angiocatheter evacuation 0 1 Mucosal tear
1 Mallory-Weiss tear requiring blood transfusion
1 Mucosal tear requiring a stent
Nabi et al.24 1 Capnothorax requiring decompression 2 Capnopericardium 11 Mucosal injury 8 Mucosal injury
2 Enlargement of mucosal incision 1 Capnothorax requiring decompression
1 Enlargement of mucosal incision
1 30-Day readmission
Sharata et al.27 1 Bleeding requiring endoscopic re-intervention 1 Full-thickness esophageal perforation requring endoscopic and surgical re-intervention 0 0
1 Mucosotomy dehiscence needing endoscopic suture 1 Capnoperitoneum needed Veress needle decompression
1 Capnoperitoneum needed Veress needle decompression
Zhang et al.22 5 Prolonged stay >5 day - NA -
3 Readmission within 30 days related to POEM (1 diarrhea; 1 bleeding; 1 fever)
Jones et al.29 4 Pneumoperitoneum needed needle decompression 12 Pneumoperitoneum needed needle decompression NA NA
Liu et al.30 6 Pneumothorax requiring drainage 13 Pneumothorax requiring drainage NA NA
2 Hydrothorax requiring drainage 4 Hydrothorax requiring drainage
1 Delayed mucosa barrier failure 3 Delayed mucosa barrier failure
1 Delayed bleeding requiring intervention or transfusion 1 Delayed bleeding requiring intervention or transfusion
1 Other miscellaneous major adverse event 2 Other miscellaneous major adverse events

PTF, previous treatment failure; NA, not available; POEM, peroral endoscopic myotomy.


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Article

Review Article

Gut and Liver 2021; 15(2): 153-167

Published online March 15, 2021 https://doi.org/10.5009/gnl19234

Copyright © Gut and Liver.

Efficacy and Safety of Peroral Endoscopic Myotomy in Achalasia Patients with Failed Previous Intervention: A Systematic Review and Meta-Analysis

Shali Tan1 , Chunyu Zhong1 , Yutang Ren2 , Xujuan Luo1 , Jin Xu1 , Xiangsheng Fu3 , Yan Peng1 , and Xiaowei Tang1

1Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, 2Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, Tsinghua University School of Clinical Medicine, Beijing, and 3Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China

Correspondence to:Xiaowei Tang
ORCID https://orcid.org/0000-0001-9947-0720
E-mail solitude5834@hotmail.com
Shali Tan, Chunyu Zhong, and Yutang Ren contributed equally to this work as first authors.

Received: July 9, 2019; Revised: October 4, 2019; Accepted: November 4, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Peroral endoscopic myotomy (POEM) has emerged as a rescue treatment for recurrent or persistent achalasia after failed initial management. Therefore, we aimed to investigate the efficacy and safety of POEM in achalasia patients with failed previous intervention. We searched the MEDLINE, Embase, Cochrane, and PubMed databases using the queries “achalasia,” “peroral endoscopic myotomy,” and related terms in March 2019. Data on technical and clinical success, adverse events, Eckardt score and lower esophageal sphincter (LES) pressure were collected. The pooled event rates, mean differences (MDs) and risk ratios (RR) were calculated. A total of 15 studies with 2,276 achalasia patients were included. Overall, the pooled technical success, clinical success and adverse events rate of rescue POEM were 98.0% (95% confidence interval [CI], 96.6% to 98.8%), 90.8% (95% CI, 88.8% to 92.4%) and 10.3% (95% CI, 6.6% to 15.8%), respectively. Seven studies compared the clinical outcomes of POEM between previous failed treatment and the treatment naïve patients. The RR for technical success, clinical success, and adverse events were 1.00 (95% CI, 0.98 to 1.01), 0.98 (95% CI, 0.92 to 1.04), and 1.17 (95% CI, 0.78 to 1.76), respectively. Overall, there was significant reduction in the pre- and post-Eckardt score (MD, 5.77; p<0.001) and LES pressure (MD, 18.3 mm Hg; p<0.001) for achalasia patients with failed previous intervention after POEM. POEM appears to be a safe, effective and feasible treatment for individuals who have undergone previous failed intervention. It has similar outcomes in previously treated and treatment-naïve achalasia patients.

Keywords: Esophageal achalasia, Meta-analysis, Pyloromyotomy, Safety, Treatment failure

INTRODUCTION

Achalasia is an esophageal motility disorder, caused by the absence of myenteric neurons and the subsequent impaired lower esophageal sphincter (LES) relaxation. Patients present with dysphagia, regurgitation, chest pain, and weight loss.1 Treatment options include Heller myotomy (HM), pneumatic balloon dilation (PBD), and botulinum toxin injection (BTI). Although HM is considered the first-line therapy due to its superior long-term outcomes, a failure rate of approximately 10% to 20% is observed.2,3 Similarly, despite a 90% PBD success rate, recurrence of symptoms occurs post-procedure in 20%, 30%, and 40% of patients in 2, 5 and 10 years, respectively.4-6 Lastly, BTI is safety and efficacious in the majority of patients; however, symptomatic relief is short term with only 29% of patients reporting continued success during intermediate follow-up.7 In cases of symptom recurrence after primary intervention, surgical myotomy is often technically challenging. Additionally, a high risk of adverse events is documented. Reported rates of gastrointestinal perforation range from 1.5% to 20% and are typically due to the formation of scars, fibrosis and adhesions resulting from previous surgical or endoscopic interventions.8- PBD and BTI are also rescue management strategies for recurrent achalasia. However, the durability of both interventions is limited. Repeat treatment for relapsing symptoms is required in up to 45% of patients after 2 years., Furthermore, previous myotomy is considered to be a relative contraindication to PBD., Recently, peroral endoscopic myotomy (POEM) has emerged as a treatment for recurrent or persistent achalasia after failed initial management. It can avoid shortcomings of other treatments mentioned above. Several studies have demonstrated a promising clinical success rate of greater than 90%.- However, some of these studies in this setting are limited by their small numbers. Therefore, the aim of this systematic review and meta-analysis was to determine the efficacy and safety of POEM as a therapy in those who have undergone failed endoscopic or surgical treatments. We also compared the efficacy and safety of POEM in patients who had previously failed endoscopic or surgical therapies with those who underwent the POEM as a primary treatment.

METHODS

1. Search strategy and study selection

Utilizing Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines,31 the following databases were searched from interception to March 2019: MEDLINE, Embase, Cochrane, and PubMed. The keywords “achalasia,” “esophageal achalasia,” “peroral endoscopic myotomy,” “per-oral endoscopic myotomy,” “Heller myotomy,” “POEM,” “Pneumatic dilation,” “HM,” and the related terms provided in Supplementary Table 1 were used. The references of published articles were also manually reviewed to ensure the inclusion of all relevant studies. Articles published in the Chinese language were reviewed by coauthor X.T. However, none met our inclusion criteria. Two authors (S.T. and C.Z.) screened all titles, abstracts and full texts independently. Any discrepancies were discussed with a third investigator (X.T.).

2. Eligibility criteria and data collection

Two reviewers (X.F. and Y.R.) assessed the articles independently based on the predefined inclusion criteria and exclusion criteria. All prospective, retrospective, case-control and cohort studies and other clinical trials were included if they featured patients: (1) diagnosed with achalasia and (2) who had undergone POEM after failed previous treatment(s). Manuscripts were excluded if: (1) they described non-human studies, (2) were single-arm studies with treatment-naïve patients undergoing POEM or (3) were case-reports less than five patients, commentaries, reviews, editorials, conference abstracts or surveys. For overlapping publications from the same center, only the most recent and comprehensive publication was considered for inclusion.

Two reviewers (Y.P. and X.T.) collected the following data independently: baseline characteristics (author name, year of publication, country, study design, study duration, group, sample size, patient age, and sex distribution); clinical characteristics (initial achalasia treatment, achalasia subtype, myotomy orientation, myotomy length, procedure time, and length of hospital stay) and clinical outcomes (technical success, clinical success, incidence of symptomatic reflux and reflux esophagitis). Also, major and minor adverse events were recorded to determine the safety of POEM. Pre- and post-procedure Eckardt scores and LES pressures were also included.

3. Quality assessment

The Newcastle-Ottawa Quality Assessment Scale for non-randomized studies was used by two investigators (X.L. and J.X.) to assess the risk of bias in the included studies.32,33 This scale rates three study aspects: selection, comparability and outcome. The maximum attainable score is 9. Each study was rated as “high quality” (score ≥7), “medium quality” (score of 5 or 6) or “low quality” (score ≤4).

4. Endpoint definition and statistical analysis

The primary outcomes were efficacy (as measured by technical and clinical success) and safety (indicated by presence and severity of adverse events) of POEM after failure of endoscopic or surgical intervention for achalasia. Technical success was defined as successful completion of the entire procedure. Clinical success was defined as an Eckardt score ≤3 during the study follow-up period. Procedure-related and post-procedure adverse events were included. Adverse events were divided into major and minor according to the NOSCAR white paper.34 Major adverse events were defined as events requiring additional intervention during or after POEM including endoscopic or surgical interventions, bleeding requiring transfusion, readmission within 30 days, prolonged hospital stay (>5 days) and clinical inflammation. Air-related outcomes and fluid collections were considered to be major adverse events when requiring drainage. Adverse events which were managed conservatively were defined as minor adverse events. The secondary endpoints of the study were the mean reduction in Eckardt scores and LES pressures, the difference in procedure time and hospital stay between the patients with and without previous intervention(s), and gastroesophageal reflux disease (GERD) incidence during follow-up. All statistical analyses were conducted using Comprehensive Meta-Analysis version 2 (Biostat, Englewood, NJ, USA), Cochrane Review Manager 5.3 (London, UK) and GraphPad Prism version 5.00 (San Diego, CA, USA). Pooled effects with 95% confidence intervals (CI) were calculated for technical success, clinical success and adverse events. The mean difference (MD) was calculated for Eckardt score, LES pressure, procedure time and length of hospital stay. We also compared the efficacy and safety of POEM in patients who had previously failed endoscopic or surgical therapies with those who underwent POEM as a primary treatment for achalasia. Risk ratios (RR) were derived for technical success, clinical success and adverse events. The heterogeneity between the studies was assessed using the I2 test and Cochran’s Q statistic in which a p<0.1 indicates substantial heterogeneity. I2 values of around 25%, 50% and 75% were considered as low, moderate and high heterogeneity, respectively. When I2 was greater than 50% and/or the Cochran’s Q test provided a p<0.1, we ran analyses with the random-effect model, otherwise we used the fixed-effect model. Publication bias was assessed using funnel plots and the Egger’s regression test. In addition, we performed subgroup analyses according to follow-up time and adverse events (major and minor adverse events), and a sensitivity analysis to confirm whether a single study caused an effect. A two-sided p<0.05 was regarded as statistically significant.

RESULTS

1. Study characteristics and quality

Using the search strategy, 3,330 records were identified. After exclusion criteria, 15 studies were eligible (Fig. 1). The baseline characteristics of the included studies are summarized in Table 1. The 15 studies were all conducted between September 2008 and January 2017. Three multicenter studies, all lead by USA investigators, were included. The 12 single-center studies were conducted in Japan (n=1), USA (n=5), China (n=4), Denmark (n=1), and India (n=1). Among these studies, six were prospective. No randomized control trials met inclusion criteria.

A total of 2,276 patients were included in our study. One thousand-fifteen were treatment-naïve and 1,261 patients had undergone previous treatment(s) for achalasia. The mean ages of patients ranged from 34.9 to 69.6 years. Overall, five studies were single arm studies with failed endoscopic or/and surgical interventions. Seven studies compared the clinical outcomes of POEM between previous failed treatment and the treatment naïve patients.

Table 2 shows the clinical characteristics of the included studies. Information on achalasia subtype was available for 2,197 patients (type I n=579, type II n=1,108, type III n=145, and unspecified type n=321). There were 44 patients with other esophageal dysmotility disorders. Submucosal myotomies (534/1,169; 45.7%) were posterior. The mean procedure time, total myotomy length and hospital stay ranged from 36.4 to 139 minutes, 9.0 to 12.7 cm and 1 to 6.2 days, respectively. The assessment of risk of bias of individual studies is shown in the Table 3. Follow-up time ranged from 5 to 28 months (Table 4).

2. Technical success

Thirteen studies with 1,179 patients reported the technical success of POEM for patients with prior endoscopic or/and surgical treatment. Technical success ranged from 97.1% to 100% and was achieved in 1,170 (99.2%) patients (Table 4). Pooled technical success was 98.0% (95% CI, 96.6% to 98.8%) with no statistically significant heterogeneity (Q=9.99, p=0.62, I2=0%) (Fig. 2A). Sensitivity analysis was performed removing one study at a time, and confirmed the same outcomes of the main analyses. There was no publication bias amongst the studies as shown in the Supplementary Fig. 1A (Egger’s regression test p=0.38).

3. Clinical success

Ten studies with 1,095 patients reported the clinical success of POEM for patients with prior endoscopic or/and surgical treatment. Clinical success ranged from 81% to 100% in these studies. Clinical success was achieved in 999 patients (91.2%) at 3-month follow-up (Table 4). The pooled clinical success in patients with greater than three months’ follow-up was 90.8% (95% CI, 88.8% to 92.4%) with a low degree of heterogeneity (Q=10.73, p=0.29, I2=16.14%) as shown in Fig. 2B. Subgroup analysis was undertaken on the basis of duration of follow-up. Four studies reported clinical success with 1-year follow-up. Two studies reported 2- and 3-year follow-ups. The pooled results of clinical success rates for 1-, 2-, and 3-year follow-ups were 89.9% (95% CI, 86.9% to 92.3%), 85.8% (95% CI, 81.7% to 89.1%) and 81.2% (95% CI, 76.2% to 85.4%), respectively (Supplementary Fig. 2). Sensitivity analysis removing one study at a time was performed and confirmed the outcomes of the main analyses. However, when removing either the study by Zhang et al.22 or Ngamruengphong et al.,18 a considerable reduction in heterogeneity occurred, changing the I2 from 16.14% to 0%. There was no publication bias amongst the studies as shown in Supplementary Fig. 1B (Egger’ s regression test p=0.49).

4. Adverse events

Fourteen studies with 1,195 patients reported the adverse events of POEM for patients with prior endoscopic or/and surgical treatment. A total of 83 (6.9%) adverse events occurred (Table 5). The pooled adverse events rate was 10.3% (95% CI, 6.6% to 15.8%) with a high degree of heterogeneity (Q=45.67, p<0.001, I2=71.54%), as shown in Fig. 2C. The pooled major and minor adverse events rates were 6.4% (95% CI, 3.6% to 11.1%) and 7.0% (95% CI, 5.2% to 9.5%) as shown in Supplementary Fig. 3. Sensitivity analysis demonstrated that the largest change occurred when the study conducted by Zhang et al.22 was removed. The heterogeneity decreased from 71.54% to 60.74%. The effect sized changed from 10.3% to 11.8% (95% CI, 7.9% to 17.3%). There was no publication bias amongst the studies as shown in Supplementary Fig. 1C (Egger’ s regression test p=0.39).

5. Meta-analysis

Overall, six studies with 1,548 patients compared the technical success of POEM between achalasia patients with and without previous treatment. The pooled RR for technical success was 1.00 (95% CI, 0.98 to 1.01), p=0.56, Cochran Q test p=0.91, I2=0% (Fig. 3). For clinical success, the pooled RR at 1-year follow-up was 0.98 (95% CI, 0.92 to 1.04), p=0.46, Cochran Q test p=0.10, I2=56% (Fig. 4A). The results for 2- and 3-year follow-ups were 0.93 (95% CI, 0.89 to 0.98) and 0.89 (95% CI, 0.84 to 0.95) (Fig. 4B and C). Seven studies with 1,588 patients compared the safety of POEM in achalasia patients with and without previous treatment. The adverse events rate for patients with prior treatment versus treatment naïve patients were 6.3% and 5.3%. The pooled RR was 1.17 (95% CI, 0.78 to 1.76), p=0.45, Cochran Q test p=0.60, I2=0% (Fig. 5A). There were also no significant difference in major and minor adverse events between the two groups. The RR for major and minor adverse events were 1.14 (95% CI, 0.71 to 1.82; p=0.60) and 0.99 (95% CI, 0.85 to 1.16; p=0.94), respectively (Fig. 5B and C). The presence of GERD diagnosed via esophagogastroduodenoscopy (EGD) was documented for 963 patients. The RR for reflux esophagitis at EGD was 1.18 (95% CI, 0.91 to 1.53), p=0.21, Cochran Q test p=0.51, I2=0% (Table 4, Supplementary Fig. 4A). The RR for GERD symptoms was 1.19 (95% CI, 0.90 to 1.57), p=0.22, Cochran Q test p=0.45, I2=0% (Table 4, Supplementary Fig. 4B). We also compared the procedure time between the patients with and without previous intervention. The MD for procedure time and length of hospital stay were 7.21 minutes (95% CI, 4.04 to 10.39; p<0.001, I2=0%) and 0.09 days (95% CI, –0.53 to 0.71; p=0.77, I2=58%) (Table 2, Supplementary Fig. 5). Thirteen studies reported the change in the Eckardt score in the cohort with previous intervention. Ten studies evaluated the change in LES pressure after POEM. The mean Eckardt score was significantly decreased by 5.77 points (95% CI, 5.07 to 6.47; p<0.001, I2=96%) and LES pressure was significantly reduced by 18.3 mm Hg (95% CI, 12.73 to 23.86; p<0.001, I2=95%) (Fig. 6A and C, Supplementary Table 2). The mean Eckardt score and LES pressure in patients with prior treatment were 7.25±0.14 points and 38.65±1.28 mm Hg, respectively. After POEM, these decreased to 1.07±0.10 and 16.28±0.65, respectively (Fig. 6B and D). When we excluded the studies that did not report the standard deviation. Significant changes in Eckardt score and LES pressure were still found. The overall MDs in Eckardt score and LES pressure were 5.74 (95% CI, 5.04 to 6.44; p<0.001, I2=90%) and 20.16 mm Hg (95% CI, 14.76 to 25.56; p<0.001, I2=87%), respectively.

DISCUSSION

With the advent of minimally invasive era, POEM has become a promising technique with excellent clinical outcomes for the treatment of achalasia patients with or without failed previous treatment. However, it is technically challenging for several, multifactorial reasons. Irrespective of type of previous intervention for achalasia, endoscopic or surgical, esophageal scarring and fibrosis may result. This may lead to difficulty in delineating tissue planes and reduce the efficacy of submucosal injection, leading to an increased likelihood of complications such as perforation and bleeding. Due to this potentially increased difficulty of POEM after previous interventions for achalasia, we performed this meta-analysis to explore the efficacy and safety of POEM for patients with and without prior treatment. In our present study, we demonstrated that POEM was equally efficacious and safe in achalasia patients with and without previous intervention. We found that POEM achieved high pooled technical (98.0%) and clinical (90.8%) success rates and reduced the Eckardt score (MD: 5.77, p<0.001) and LES pressure (MD: 18.3 mm Hg, p<0.001) significantly in patients who have undergone prior treatment. In addition, our meta-analysis demonstrated that the efficacy of POEM in the patients who had undergone prior intervention was comparable to that of the treatment-naïve patients. Our result is consistent with several published studies.24,28 The favorable results provided by POEM are due to several reasons. POEM is a completely endoscopic and intraluminal approach which is unlikely to be affected by the scars and tissue adhesions resulting from previous treatment. Thus, efficacy is similar to treatment naïve patients. Additionally, POEM provides the opportunity to perform the myotomy in an opposite orientation. Thus, the new myotomy can be performed in a location without scars, resulting in good control of the myotomy length. Conversely, due to the presence of scars, fibrosis and tissue adhesions, the POEM procedure could potentially be more technically challenging, resulting in a longer procedure time and hospital stay. In the Liu et al.,30 a significantly longer hospital stay after POEM was found in patients with prior therapy when compared to the patients without prior treatment (<2 days: 43.7% vs 53.6%, ≥2 days: 56.3% vs 46.4%, p=0.001). Our study failed to demonstrate a longer length of hospital stay (MD: 0.09, p=0.77) after pooling all related data. Importantly, our analysis was performed with only three studies. In view of this small numbers of studies and sample size, we must interpret this outcome with caution.

When comparing the clinical success rate of POEM in patients with a greater than 2-and 3-year follow-ups, we found that results from the group of treatment naïve patients was superior to the that of the patients who had undergone previous endoscopic or/and surgical interventions. However, an individual study by Nabi et al.24 with 502 patients and a greater than 2-year follow-up did not suggest a higher clinical success rate in treatment-naïve patients. Liu et al.30 reviewed 849 patients and demonstrated a superior 5-year clinical success rate in the treatment naïve cohort. They indicated that follow-up duration correlated with the difference in clinical failure between patients with and without prior treatment. They also found patients who had undergone more than one previous intervention had a higher risk than those with only one previous treatment. This may be attributed to severe inflammation and fibrosis formed by prior treatments. This difference may also be due to a difference in “symptom-reporting threshold” of patients whose symptoms recurred after prior treatments. Given this discrepancy in outcomes, systematic evaluation of long-term outcomes between the two groups is necessary in the future.

In our study, the most common adverse events related to the POEM procedure in patients with prior treatments were mucosal injury, bleeding, pneumothorax, and pneumoperitoneum. Theoretically, patients who have undergone surgical or/and endoscopic treatment are more prone to incur adverse events because of inflammation and fibrosis. Nevertheless, in the current study, the adverse event rate was not significantly higher in those who had undergone previous interventions when compared to those without interventions. This may be due to all the POEM procedures being performed by experienced operators in our included studies.30 When evaluating the GERD rate during follow-ups, we found that the incidence of GERD diagnosed via EGD or questionnaires was not significantly different between the two groups (Supplementary Fig. 4). However, our result may be affected by various factors. For example, the GERD measurement results were only available in a minority of the total patients’ number. Additionally, previous fundoplication may have an influence on preventing postoperative reflux. Importantly, there were no procedure-related deaths in any of the included studies. Our study confirmed the safety of POEM for patients with previous interventions.

To our knowledge, this is the first systematic review and meta-analysis comparing the efficacy and safety of POEM in patients with and without previous treatments. There are a few limitations in the current study. First, only retrospective and prospective studies were included. No randomized controlled studies were found. Second, owing to the paucity of data in the included studies, we were unable to assess the efficacy and safety of POEM for patients with previous surgical or endoscopic interventions separately. Third, some studies included pediatric patients with achalasia and some patients with other esophageal dysmotility disorders. However, these patients accounted for a small percentage and our outcomes were unchanged after removing these studies. Fourth, we were unable to assess the quality of life in patients with prior treatments after POEM due to the limited number of studies reporting this results. Last, long-term (greater than 2 years) differences between the patients with and without prior intervention should be interpreted carefully as only two study reported these outcomes.

CONCLUSION

POEM appears to be a safe, effective and feasible treatment for those who have undergone previous failed endoscopic or surgical intervention. It has similar outcomes in previously treated and treatment-naïve achalasia patients. It may be an attractive option for the treatment of patients with this difficult condition. However, further studies with a long-term follow-up to determine the durability of rescue POEM are still warranted.

Supplemental Materials

ACKNOWLEDGEMENTS

This study is independent research funded by the following grants: Medical Science and Technology Plan Projects of Zhejiang Province (No. 2017196257), Youth Foundation of Southwest Medical University (No. 0903-00031099), Doctoral Research Start-up Funding Project of Affiliated Hospital of Southwest Medical University (No. 16229).

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Study conception and design: X.T., Y.R. Acquisition of data and critical revision: X.L., J.X. Drafting of manuscript: S.T., C.Z. Revision of manuscript, and final approval of manuscript: X.F., Y.P., X.T.

Fig 1.

Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart.
Gut and Liver 2021; 15: 153-167https://doi.org/10.5009/gnl19234

Fig 2.

Figure 2.Overall efficacy and safety of peroral endoscopic myotomy in patients with previous intervention(s). (A) Technical success; (B) clinical success (less than 12 months of follow-up); (C) adverse events.
CI, confidence interval.
Gut and Liver 2021; 15: 153-167https://doi.org/10.5009/gnl19234

Fig 3.

Figure 3.Meta-analysis of technical success between patients with and without previous intervention(s).
M-H, Mantel-Haenszel; CI, confidence interval.
Gut and Liver 2021; 15: 153-167https://doi.org/10.5009/gnl19234

Fig 4.

Figure 4.Meta-analysis of clinical success between patients with and without previous intervention(s). (A) One-year follow-up; (B) 2-year follow-up; (3) 3-year follow-up.
M-H, Mantel-Haenszel; CI, confidence interval.
Gut and Liver 2021; 15: 153-167https://doi.org/10.5009/gnl19234

Fig 5.

Figure 5.Meta-analysis of adverse events between patients with and without previous intervention(s). (A) Overall adverse events; (B) major adverse events; (3) minor adverse events.
M-H, Mantel-Haenszel; CI, confidence interval.
Gut and Liver 2021; 15: 153-167https://doi.org/10.5009/gnl19234

Fig 6.

Figure 6.Changes in the mean Eckardt score and lower esophageal sphincter (LES) pressure before and after peroral endoscopic myotomy (POEM) in patients with previous endoscopic or/and surgical intervention. (A) Change in the mean Eckardt score. (B) Changes in the mean Eckardt score before and after POEM: the diamond corresponds to the mean Eckardt score, and the lines extending from them indicate the standard error above and below the mean. (C) Change in the mean LES pressure. (D) Changes in the mean LES pressure before and after POEM.
IV, inverse variance; CI, confidence interval.
Gut and Liver 2021; 15: 153-167https://doi.org/10.5009/gnl19234

Table 1 Baseline Characteristics of Included Studies

Author (year)CountryDesignDurationNo. of patientsGroupAge, yrMale sex, No. (%)
Tyberg et al. (2016)16USAProspectiveMar 2014–Aug 20154646 PTF49.3±16.7820 (45.0)
Tyberg et al. (2018)21USAProspectiveJan 2012–Jan 20175151 PTF54.224 (47.0)
Onimaru et al. (2013)25JapanProspectiveSep 2008–Dec 20121010 PTF525 (50.0)
Vigneswaran et al. (2014)26USAProspectiveOct 2010–Jun 201355 PTF69.64 (80.0)
Zhou et al. (2013)28ChinaProspectiveMar 2011–Dec 20111212 PTF51.15 (41.7)
Ling et al. (2014)17ChinaProspectiveMay 2010–Sep 20125121 PTF43.2±12.78 (38.1)
30 Naïve42.5±11.310 (33.3)
Ngamruengphong et al. (2017)18USARetrospectiveDec 2009–Sep 201518090 PTF with HM54±1544 (48.9)
90 PTF without HM53±1438 (42.2)
Tang et al. (2017)19ChinaRetrospectiveJul 2011–Jan 20146122 PTF34.9±7.714 (63.6)
39 Naïve38.5±11.320 (51.3)
Kristensen et al. (2017)20DenmarkRetrospectiveJan 2012–May 20166614 PTF with HM43.5 (22–75)7 (50.0)
52 PTF without HM49.5 (18–77)26 (50.0)
Orenstein et al. (2015)23USARetrospectiveMay 2011–Sep 20134016 PTFNANA
24 NaïveNANA
Nabi et al. (2018)24IndiaRetrospectiveJan 2013–Nov 2016502242 PTF42.4±13.6137 (56.6)
260 Naïve38.0±13.6142 (54.6)
Sharata et al. (2013)27USARetrospectiveOct 2010–May 20124012 PTF55±175 (41.7)
28 Naïve48±2112 (42.9)
Zhang et al. (2018)22USARetrospectiveOct 2009–Oct 201631846 PTF*55 (17–85)24 (52.2)
272 PTF54 (10–94)155 (57.0)
Jones et al. (2015)29USARetrospectiveAug 2012–Oct 20144515 PTF64.4±123 (20.0)
30 Naïve46.2±17.225 (83.3)
Liu et al. (2019)30ChinaRetrospectiveAug 2010–Dec 2014849245 PTF38 (6–98)132 (53.9)
604 Naïve38 (8–77)291 (48.2)

Data are presented as mean±SD or median (range).

PTF, previous treatment failure; HM, Heller myotomy.

*Previous surgical and endoscopic treatment failure; Previous endoscopic treatment failure.


Table 2 Clinical Characteristics of Included Studies

AuthorGroupPrevious treatmentSubtype*Direction of myotomyProcedure time, mean±SD, minMyotomy length, mean±SD, cmHospital stay, mean±SD, day

EGT
Tyberg et al.1646 PTF46 POEM10 I, 16 II, 5 III, 15 other EDDNA90NANANANA
Tyberg et al.2151 PTF43 LHM, 8 laparotomy HM13 I, 29 II, 6 III, 3 other EDD51 PosteriorNANANANANA
Onimaru et al. 2510 PTF10 LHM+PBD6 II, 4 III7 Posterior118.29.23.212.4NA
1 Right anterior
2 Right
Vigneswaran et al.265 PTF5 LHMNANA139.0±29.6NANA9.01.6±0.2
Zhou et al.2812 PTF3 Laparotomy HM, 3 open thoracotomy HM, 6 LHMNA12 Posterior36.4±9.38.0 (6–10)2.1 (2–3)10.1 (8–13)4.1±1.3
Ling et al.1721 PTF21 PBD5 I, 13 II, 3 III21 Posterior42.4±8.3NANA10.3±1.5NA
30 NaïveNone6 I, 22 II, 2 III30 Posterior34.3±7.4NANA9.6±1.2NA
Ngamruengphong et al.1890 PTF with HM40 PBD, 10 BTI26 I, 23 II, 10 III, 31 unspecified2 Anterior86 Posterior2 Missing data102.8±418.7±4.42.9±1.211.63.54±1.7
90 PTF without HM23 PBD, 7 BTI20 I, 29 II, 10 III, 31 unspecified42 Anterior48 Posterior102.6±619.7±3.93±1.312.73.59±2.5
Tang et al.1922 PTF18 PBD, 2 BTI, 2 BTI+PBD5 I, 17 IINA60.8±30.96.7±2.63.1±1.19.8±2.96.2±1.3
39 NaïveNone13 I, 26 IINA62.0±21.07.4±3.33.1±1.610.5±3.96.5±1.6
Kristensen et al.2014 PTF with HM13 BTI or PBD9 I, 5 missing dataNA74 (35–149)9 (6–13)3 (2–5)NA2 (1–4)
52 PTF without HM15 BTI or PBD7 I, 25 II, 3 III, 17 missing dataNA61 (35–126)9.5 (6–13)4 (2–5)NA2 (1–4)
Orenstein et al.2316 PTF6 BTI, 4 PBD, 3 BTI+PBD, 3 LHMNANA102NANANANA
24 NaïveNoneNANA118NANANANA
Nabi et al.24242 PTF205 PBD, 30 LHM, 4 BTI, 3 POEM91 I, 140 II, 11 III186 Anterior56 Posterior74.9±30.69.4±2.43.1±0.512.53 (2-5)
260 NaïveNone82 I, 169 II, 9 III210 Anterior50 Posterior67.0±27.19.0±2.53.08±0.512.083 (2-5)
Sharata et al.2712 PTF10 BTI, 2 PBD9 Unspecified , 3 other EDDNA134±43NANANANA
28 NaïveNone22 Unspecified, 6 other EDDNA131±41NANANANA
Zhang et al.2246 PTF§14 HM+PBD, 19 HM+BTI30 I, 5 II, 6 III, 5 unspecified8 Anterior38 Posterior82 (32–166)NANA11 (5–23)1 (1–5)
272 PTFΙΙ29 PBD, 54 BTI53 I, 147 II, 32 III, 26 unspecified, 14 other EDD137 Anterior135 Posterior72 (21–240)NANA12 (3–27)2 (1–30)
Jones et al.2915 PTF30 Naïve7 BTI, 5 PBD, 3 HMNone42 Unspecified, 3 other EDD (total)15 Anterior30 Anterior102±29103±27NANANANANANA1 (0–12)1 (0–1)
Liu et al.30245 PTF165 PBD, 28 HM, 6 POEM, 45 esophageal stent, 46 BTI65 I, 132 II, 13 III, 35 unspecifiedNA<60, 166≥60, 79NANANA<2, 107≥2, 138
604 NaïveNone144 I, 309 II, 31 III, 120 unspecifiedNA<60, 441≥60, 163NANANA<2, 324≥2, 280

E, esophageal; G, gastric; T, total; PTF, previous treatment failure; POEM, peroral endoscopic myotomy; EDD, esophageal dysmotility disorder; NA, not available; LHM, laparoscopic Heller myotomy; HM, Heller myotomy; PBD, pneumatic balloon dilation; BTI, botulinum toxin injection.

*Chicago classification; Mean (range); Median (range); §Previous surgical and endoscopic treatment failure; ΙΙPrevious endoscopic treatment failure.


Table 3 Newcastle-Ottawa Quality Assessment Scale for Included Studies

StudySelectionOutcome assessmentComparabilityQuality of study



123412312
Tyberg et al.16++++++Medium quality
Ling et al.17++++++++High quality
Tang et al.19+++++++++High quality
Ngamruengphong et al.18++++++++High quality
Kristensen et al.20++++++++High quality
Tyberg et al.21++++++Medium quality
Orenstein et al.23+++++++High quality
Nabi et al.24++++++++High quality
Onimaru et al.25++++++Medium quality
Vigneswaran et al.26+++++Medium quality
Sharata et al.27+++++++++High quality
Zhang et al.22++++++++High quality
Zhou et al.28++++++Medium quality
Jones et al.29++++++++High quality
Liu et al.30++++++++High quality

Selection: 1, representativeness of the exposed cohort; 2, selection of the nonexposed cohort; 3, ascertainment of exposure; 4, outcome of interest not present at start of study. Outcome assessment: 1, assessment of outcome; 2, adequacy of duration of follow-up; 3, adequacy of completeness of follow-up. Comparability: 1, study controls for confounder; 2, study controls for any additional factors.


Table 4 Clinical Outcomes of Included Studies during Follow-up

AuthorGroup% (No./No.)Follow-up, mean (range), mo

Technical successClinical successSymptomatic reflux and reflux esophagitis
Tyberg et al.1646 PTF100 (46/46)85 (41/46) (3-mo FU)NA12.2 (1–32)
Tyberg et al.2151 PTF100 (51/51)94 (48/51) (1-yr FU)NA24.4 (12–52)
Onimaru et al.2510 PTF100 (10/10)NANA18.3
Vigneswaran et al.265 PTF100 (5/5)NANA4.9
Zhou et al.2812 PTF100 (12/12)91.7 (11/12) (5–14 mo FU)Reflux esophagitis 8.3 (1/12)10.4 (5–14)
Ling et al.1721 PTF100 (21/21)92.3 (19/21) (postoperative),Reflux esophagitis 19.0 (4/21)13.2
87.5 (18/21) 1-yr FU
30 Naïve100 (30/30)NANA14.4
Ngamruengphong et al.1890 PTF (with HM)98 (88/90)81.2 (69/85)Symptomatic reflux 30 (21/70)9 (4–14)*
Reflux esophagitis 44 (18/41)
90 PTF (without HM)100 (90/90)94.8 (77/82) (total n=167)(≥3-mo FU)Symptomatic reflux 32 (24/76)8.5 (1.3–18.5)*
Reflux esophagitis 52 (23/44)
Tang et al.1922 PTF100 (22/22)95.5 (21/22)Reflux esophagitis 23.5 (4/17)12
39 Naïve100 (39/39)92.3 (36/39) (1-yr FU)Reflux esophagitis 20 (7/35)12
Kristensen et al.2014 PTF (with HM)NANANA24
52 PTF (without HM)NANANA24
Orenstein et al.2316 PTFNANANA9.0
24 NaïveNANANA10.1
Nabi et al.24242 PTF97.1 (235/242)92.5 (186/201) (6-mo FU)Symptomatic reflux 17.8 (26/146)20 (1–45)
91.2 (145/159) (1-yr FU)
84.2 (85/101) (2-yr FU)Reflux esophagitis 20.7 (24/116)
76.3 (29/38) (3-yr FU)
260 Naïve98.1 (255/260)92.4 (206/223) (6-mo FU)Symptomatic reflux 16.4 (22/134)20 (1–45)
90.7 (166/183) (1-yr FU)
87.5 (112/128) (2-yr FU)Reflux esophagitis 22.1 (29/131)
87.1 (27/31) (3-yr FU)
Sharata et al.2712 PTF100 (12/12)100 (12/12)NA6
28 Naïve100 (28/28)100 (28/28) (postoperative)NA6
Zhang et al.2246 PTF100 (46/46)95.7 (44/46)Reflux esophagitis 46.2 (12/26)28 (3–46)
272 PTF§100 (272/272)95.1 (255/272) (>3 mo)Reflux esophagitis 34.0 (50/147)23 (3–78)
Jones et al.2915 PTF100 (15/15)NANA12
30 Naïve100 (30/30)NANA10
Liu et al.30245 PTF100 (245/245)88.6 (217/245) (1-yr FU)Symptomatic reflux 18.8 (46/245)23 (1–71)
86.5 (212/245) (2-yr FU)Reflux esophagitis 22.8 (46/202)
82 (201/245) (5-yr FU)Symptomatic reflux 14.7 (89/604)
604 Naïve100 (604/604)95.0 (574/604) (1-yr FU)Reflux esophagitis 17.3 (80/462)23 (1–71)
93.5 (565/604) (2-yr FU)
91.7 (554/604) (5-yr FU)

PTF, previous treatment failure, FU, follow-up; NA, not available; HM, Heller myotomy.

*Median (interquartile range); †Median (range); ‡Previous surgical and endoscopic treatment failure; §Previous endoscopic treatment failure.


Table 5 Safety of Peroral Endoscopic Myotomy

AuthorMajor adverse eventsMinor adverse events


PTFNaïvePTFNaïve
Tyberg et al.160-8 Bleeding-
Tyberg et al.212 Mediastinitis-6 Mucosal defects-
Onimaru et al.250-0-
Vigneswaran et al.261 Esophageal leak and mediastinal abscess-0-
Zhou et al.281 Pneumothorax-1 Mucosal perforation-
1 Pneumoperitoneum
Ling et al.170000
Ngamruengphong et al.181 Pneumonia-7 Mucosotomy-
1 Mediastinitis1 Delayed bleeding
5 Symptomatic pneumoperitoneum1 Submucosal hematoma
1 Symptomatic pneumothorax
1 Symptomatic subcutaneous emphysema
1 Pleural effusion requiring chest drain
Tang et al.19001 Bleeding2 Bleeding
Kristensen et al.20NA-NA-
Orenstein et al.231 Capnoperitoneum alleviated with angiocatheter evacuation1 Capnoperitoneum alleviated with angiocatheter evacuation01 Mucosal tear
1 Mallory-Weiss tear requiring blood transfusion
1 Mucosal tear requiring a stent
Nabi et al.241 Capnothorax requiring decompression2 Capnopericardium11 Mucosal injury8 Mucosal injury
2 Enlargement of mucosal incision1 Capnothorax requiring decompression
1 Enlargement of mucosal incision
1 30-Day readmission
Sharata et al.271 Bleeding requiring endoscopic re-intervention1 Full-thickness esophageal perforation requring endoscopic and surgical re-intervention00
1 Mucosotomy dehiscence needing endoscopic suture1 Capnoperitoneum needed Veress needle decompression
1 Capnoperitoneum needed Veress needle decompression
Zhang et al.225 Prolonged stay >5 day-NA-
3 Readmission within 30 days related to POEM (1 diarrhea; 1 bleeding; 1 fever)
Jones et al.294 Pneumoperitoneum needed needle decompression12 Pneumoperitoneum needed needle decompressionNANA
Liu et al.306 Pneumothorax requiring drainage13 Pneumothorax requiring drainageNANA
2 Hydrothorax requiring drainage4 Hydrothorax requiring drainage
1 Delayed mucosa barrier failure3 Delayed mucosa barrier failure
1 Delayed bleeding requiring intervention or transfusion1 Delayed bleeding requiring intervention or transfusion
1 Other miscellaneous major adverse event2 Other miscellaneous major adverse events

PTF, previous treatment failure; NA, not available; POEM, peroral endoscopic myotomy.


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Gut and Liver

Vol.15 No.6
November, 2021

pISSN 1976-2283
eISSN 2005-1212

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