Peroral Endoscopic Myotomy for Treatment of Esophageal Achalasia - CAM 20191

Description
Esophageal achalasia is characterized by reduced numbers of neurons in the esophageal myenteric plexuses and reduced peristaltic activity, making it difficult for patients to swallow food and possibly leading to complications such as regurgitation, coughing, choking, aspiration pneumonia, esophagitis, ulceration, and weight loss. Peroral endoscopic myotomy (POEM) is a novel endoscopic procedure that uses the oral cavity as a natural orifice entry point to perform myotomy of the lower esophageal sphincter. This procedure is intended to reduce the total number of incisions needed and thus the overall invasiveness of surgery.

Summary of Evidence
For adults who have achalasia who receive POEM, the evidence includes systematic reviews of observational studies, 2 randomized controlled trials, nonrandomized comparative studies, and case series. Relevant outcomes are symptoms, functional outcomes, health status measures, resource utilization, and treatment-related morbidity. Compared with pneumatic dilation or laparoscopic Heller myotomy (LHM), findings from RCTs demonstrated that POEM had a similar or greater treatment success rate based on the Eckardt score and similar or fewer overall adverse event rates. However, POEM had significantly higher rates of endoscopically confirmed reflux esophagitis and more daily proton-pump inhibitor use at 24 months. An important conduct limitation of the RCTs is that blinded assessment of outcomes was not used. Given that the primary outcome was based on subjective patient report of symptoms, this is a potential source of bias. Additionally, a potential relevance limitation is that the RCTs did not include any US sites. The comparative observational studies have primarily reported similar outcomes for POEM and for Heller myotomy in symptom relief, as assessed by the Eckardt score. Some studies have shown a shorter length of stay and less postoperative pain with POEM. However, potential imbalances in patient characteristics in these nonrandomized studies might have biased the treatment comparisons. In the case series, treatment success at short follow-up periods was reported for a high proportion of patients treated with POEM. However, the incidence of adverse events was relatively high, with POEM-specific complications, including subcutaneous emphysema, pneumothorax, and thoracic effusion, reported across studies. Additionally, a substantial proportion of patients undergoing POEM developed gastroesophageal reflux disease and esophagitis and required treatment. Case series do not permit conclusions about the efficacy of POEM relative to established treatment, and long-term outcomes of the procedure are not well described in the literature.

For pediatric patients who have achalasia who receive POEM, the evidence includes several nonrandomized studies and a systematic review. Relevant outcomes are symptoms, functional outcomes, health status measures, resource utilization, and treatment-related morbidity. The studies reported treatment success for POEM based on decreases in Eckardt scores and lower esophageal sphincter pressure. No randomized clinical trials have been reported.

Additional Information
Not applicable.

Background 
ESOPHAGEAL ACHALASIA 
Esophageal achalasia is characterized by reduced numbers of neurons in the esophageal myenteric plexuses and reduced peristaltic activity, making it difficult for patients to swallow food and possibly leading to complications such as regurgitation, coughing, choking, aspiration pneumonia, esophagitis, ulceration, and weight loss. The estimated U.S. prevalence of achalasia is 10 cases per 100,000, and the estimated incidence is 0.6 cases per 100,000 per year.1

Treatment 
Treatment options for achalasia have included pharmacotherapy (e.g., injections with botulinum toxin), pneumatic dilation, and laparoscopic Heller myotomy.1,2, Although the latter 2 are considered the standard treatments because of higher success rates and relatively long-term efficacy compared with pharmacotherapy, both are associated with a perforation risk of about 1%. Heller myotomy is the most invasive of the procedures, requiring laparoscopy and surgical dissection of the esophagogastric junction.2, One-year response rates of 86% and major mucosal tear rates requiring the subsequent intervention of 0.6% have been reported.3,

Peroral endoscopic myotomy (POEM) is a novel endoscopic procedure developed in Japan.2,4 POEM is performed with the patient under general anesthesia.5 After tunneling an endoscope down the esophagus toward the esophageal-gastric junction, a surgeon performs the myotomy by cutting only the inner, circular lower esophageal sphincter muscles through a submucosal tunnel created in the proximal esophageal mucosa. POEM differs from laparoscopic surgery, which involves the complete division of both circular and longitudinal lower esophageal sphincter muscle layers. Cutting the dysfunctional muscle fibers that prevent the lower esophageal sphincter from opening allows food to enter the stomach more easily.2,5

Note that the acronym POEM in this review refers to peroral endoscopic myotomy. POEMS syndrome, which has a similar acronym, is discussed in evidence review 8.01.17.

Regulatory Status
POEM uses available laparoscopic instrumentation and, as a surgical procedure, is not subject to regulation by the U.S. Food and Drug Administration (FDA).

Related Policies
20138 Transesophageal Endoscopic Therapies for Gastroesophageal Reflux Disease
701137 Magnetic Esophageal Ring to Treat Gastroesophageal Reflux Disease (GERD)

Policy 

I.   POEM for Type III Achalasia 

Peroral endoscopic myotomy (POEM) may be considered MEDICALLY NECESSARY  for patients who meet ALL of the following criteria: 

  • Diagnosis of type III achalasia confirmed by esophageal manometry; AND
  • Chronic, active symptoms due to type III achalasia, including, but not limited to:
  • Dysphagia;
  • Regurgitation;
  • Chest pain

II.   NOT MEDICALLY NECESSARY USES 

  • Peroral endoscopic myotomy (POEM) is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for all other indications, including but not limited to type I and type II esophageal achalasia, due to the lack of clinical evidence demonstrating an impact on improved health outcomes. 
  • Endoscopic pyloromyotomy (G-POEM) is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for all indications, including but not limited to gastroparesis, due to the lack of clinical evidence demonstrating an impact on improved health outcomes. 

Policy Guidelines
See Codes table for details..

Benefit Application
BlueCard/National Account Issues
No applicable information.

Rationale 
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Peroral Endoscopic Myotomy for Adult Patients with Achalasia
Clinical Context and Therapy Purpose
The purpose of POEM in patients who have esophageal achalasia is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of POEM improve the net health outcome of patients with esophageal achalasia?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with esophageal achalasia. Esophageal achalasia is characterized by reduced numbers of neurons in the esophageal myenteric plexuses and reduced peristaltic activity, making it difficult for patients to swallow food and possibly leading to complications such as regurgitation, coughing, choking, aspiration pneumonia, esophagitis, ulceration, and weight loss.

Interventions
The therapy being considered is POEM. The POEM procedure involves tunneling an endoscope down the esophagus toward the esophageal-gastric junction. A surgeon performs the myotomy by cutting only the inner, circular lower esophageal sphincter (LES) muscles through a submucosal tunnel created in the proximal esophageal mucosa.

Patients receive general anesthesia during the POEM procedure, which is conducted in tertiary care facilities.

Comparators
Comparators of interest include esophageal dilation, laparoscopic Heller myotomy (LHM), and botulinum toxin injection.

Esophageal dilation is performed in a graded approach, starting with a small balloon (typically 30 mm), then progressing to larger balloons (35-40 mm) 2 to 4 weeks later. The balloons are placed at the level of the gastroesophageal junction and inflated slowly, in order to tear the muscle fibers in a controlled manner. Esophageal perforations are a potential complication. Long-term studies have estimated that approximately one-third of patients may need a repeat procedure.

LHM is a minimally invasive procedure in which the thick muscle of the lower esophagus and the upper stomach is cut to open the tight LES. The procedure involves 5 small incisions to insert the camera and surgical instruments. Reported success rates are high (>90%), with a 5-year follow-up study showing an 8% rate of symptom recurrence.

Endoscopic botulinum toxin is injected with a sclerotherapy needle approximately 1 cm above the esophagogastric junction. The complication rate is low and approximately 80% of patients experience immediate symptom relief. The effect diminishes over time, with more than 60% of patients reporting recurrent symptoms at 1 year.

Outcomes
The general outcomes of interest are symptom relief and treatment-related morbidity.

Symptom relief may be measured by the Eckardt score, which is comprised of 4 major symptoms of achalasia: dysphagia, regurgitation, retrosternal pain, weight loss. Each symptom receives a score from 0 (none) to 3 (severe), for a maximum score of 12. Total scores of 4 or greater represent treatment failure.6

Treatment-related morbidity of concern is the development of gastroesophageal reflux disease (GERD). GERD risk is high with this procedure because POEM involves ablating the LES without adding any type of anti-reflux mechanism. Additional complications include thoracic effusion, subcutaneous emphysema, and esophagitis.

Symptom relief may be experienced shortly following the procedure. Assessment of durability of relief requires a follow-up of months to years of follow-up.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;

  • To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Multiple systematic reviews and meta-analyses have been published to evaluate POEM as a treatment for achalasia. They are heterogenous in whether they assessed data on POEM alone or compared POEM to LHM, which outcomes they assessed, which studies they included, and in the statistical methods they used. The majority addressed the comparison of POEM to LHM. No systematic review has included either of the 2 published RCTs summarized below.

Results of systematic reviews that primarily relied on data from noncomparative case series studies are not comprehensively summarized herein.7-11 This is because conclusions on comparative effects cannot be determined from their findings. Some systematic reviews of noncomparative case series did not calculate comparative treatment effects. Others that did had important limitations in their statistical methods, including use of unadjusted indirect comparison approaches which are subject to a variety of confounding factors that may bias the effect estimate. For example, Andolfi et al. (2019) published a meta-analysis of success rates based on manometric subtypes.11 They calculated pooled success rates for POEM, LHM, and PD in type I, II, and III achalasia, respectively, based primarily on data from noncomparative case series studies. Pooled success rates for POEM in types I, II, and III were 94% (95% confidence interval [CI], 89% to 98%), 97% (95% CI, 93% to 99%), and 93% (95% CI, 88% to 97%), respectively, which were significantly higher compared to LHM for type I (odds ratio [OR]=2.97; 95% CI, 1.09 to 8.03) and type III (OR=3.50; 95% CI, 1.39 to 8.77), but not type II. However, the use of an unadjusted indirect comparison approach in this analysis precludes drawing conclusions based on these findings.

Peroral Endoscopic Myotomy Versus Laparoscopic Heller Myotomy
Below are summarized the most recent systematic reviews (published on or after 2015) that address the comparison of POEM to LHM using data from comparative observational studies. Table 1 provides a crosswalk of the comparative observational studies included in those systematic reviews.

Table 1. Comparison of Observational Studies of POEM versus LHM Included in SR & M-A 

Study Martins et al (2020)12 Aiolfi et al (2020)13 Schlottmann et al (2018)14 Awaiz et al (2017)15 Marano et al (2016)16 Zhang et al (2016)17
Hungness et al (2013)5  
Teitelbaum et al (2013)18    
Ujiki et al (2013)19  
Von Renteln et al (2013)20          
Bhayani et al (2014)21  
Vigneswaran et al (2014)22          
Kumagai et al (2015)23    
Kumbhari et al (2015)24    
Teitelbaum et al (2015)25          
Chan et al (2016)26      
Sanaka et al (2016)27          
Schneider et al (2016)28        
Kashab et al (2017)29          
Leeds et al (2017)30          
de Pascale et al (2017)31          
Peng et al (2017)32          
Ward et al (2017)33          
Hanna et al (2018)34          
Ramirez et al (2018)35          

POEM: Peroral Endoscopic Myotomy; LHM: Laparoscopic Heller Myotomy; SR: systematic review; M-A: meta-analysis

Tables 2 and 3 summarize characteristics and results of the included systematic reviews published or or after 2015 that address the comparison of POEM to LHM using data from comparative observational studies. The included comparative observational studies are heterogenous in their patient populations, proportions of patients with any previous treatments (ie, none versus prior pneumatic dilation or botulinum toxin, or prior pneumatic dilation and botulinum toxin), and proportions of each achalasia subtype I-III, follow-up duration, and definition of treatment success. These differences limit interpretation of their findings.

Martins et al. (2020) conducted a systematic review and meta-analysis of the largest number of comparative observational studies and patients treated with POEM (n=359) or LHM (n=534).12 Study quality was assessed using the Modified New Castle Ottawa Scale and all included studies were considered to be adequate for analysis. POEM demonstrated small improvements in Eckardt scores and reduced length of stay, comparable operative time, but more major adverse events. Most of the major adverse events were described as being related to unrecognized intraoperative mucosal perforation. An important limitation of this meta-analysis is that it did not take into account between-group differences in pre-operative Eckardt score levels at baseline.

Aiolfi et al. (2020) conducted a systematic review and Bayesian random-effects network meta-analysis that compared POEM to LHM and pneumatic dilation.13 Overall, 19 studies of 4,407 patients were included. Of those, 10 studies of 645 patients directly compared POEM and LHM and none directly compared POEM and pneumatic dilation. POEM was associated with improved dysphasia remission and Eckardt scores, but higher risk of GERD compared to LHM. Results of the comparison to pneumatic dilation are discussed below Table 3. Important limitations of this network meta-analysis include its inclusion of arm-based indirect comparisons and the inherent bias of its reliance on observational studies.

Schlottmann et al. (2018) conducted a systematic review and meta-analysis of 53 studies using LHM (5,834 patients) and 21 studies using POEM (1,958 patients) for the treatment of esophageal achalasia.14 Data was combined from noncomparative and comparative studies and analyzed using linear regression. Potential variation in risk of bias of the individual studies was not considered. The probability for improvement in dysphagia at 24 months was significantly greater for patients receiving POEM, but POEM was associated with significantly greater risk of pathological GERD and a longer hospital length of stay. Important limitations of this meta-analysis include that it combined data from noncomparative and comparative studies and did not take into account differences in patient characteristics and follow-up. The POEM studies had significantly shorter follow-up periods, which could have influenced the results.

Awaiz et al. (2017) conducted a systematic review and meta-analysis of 7 studies that compared LHM (N=250) to POEM (N=233) for the treatment of esophageal achalasia.15 Study quality was assessed using the Modified New Castle Ottawa Scale and was found to be moderate to high. Meta-analysis results found POEM and LHM to be comparable on operative time (weighted mean difference [WMD]=26.28; 95% CI, -11.20 to 63.70), overall complication rate (OR=1.25; 95% CI, 0.56 to 2.77), postoperative GERD, long-term GERD, length of hospital stay, and postoperative pain score (WMD=-0.26; 95% CI, -1.58 to 1.06). LHM was associated with a significantly higher short-term clinical treatment failure rate (OR=9.82; 95% CI, 2.06 to 46.80). However, as there was no standard definition of treatment failure across studies, findings from this meta-analysis are unreliable. Meta-analysis of dysphasia, Eckardt scores, clinical success and serious/major complications was not undertaken. An important relevance limitation of this meta-analysis is that because the follow-up periods in all the studies were short-term, no conclusions can be drawn about long-term comparative effectiveness of the 2 interventions.

Marano et al. (2016) evaluated outcomes for 486 patients (196 receiving POEM, 290 receiving LHM) from 7 studies.16 None of the studies was randomized. Reviewers rated all studies as having a moderate risk of bias. No information on differences in disease severity between treatment groups was provided. There were no significant differences in the reduction of Eckardt scores, postoperative pain scores, or requirements for analgesics between procedures. Hospital lengths of stay were shorter for POEM. Risk of symptomatic GERD was higher for POEM, however. Important limitations of this meta-analysis included high between-study heterogeneity, imprecision evidenced by wide confidence intervals, and lack of studies with follow-up beyond 1 year.

The meta-analysis by Zhang et al. (2016) included only 4 observational studies that compared POEM to LHM..17 OEM was associated with improved postoperative Eckardt scores, but no other differences compared to the LHM group. An important limitation of this meta-analysis is that it did not take into account that patients in the POEM group were older at baseline than those in the LHM group.

Table 2. SR & M-A Characteristics 

Systematic Review Dates Included Comparative Observational Studies Participants N (Range) Design Duration
Martins et al (2020)12 2012-2017 12 All adult patients (≥18 years of age) with 1 of 3 subtypes of achalasia, with or without prior history of therapy for achalasia 893 (31-178) Observational 9 to 260 weeks
Aiolfi et al (2020)13 2012-2018 10 Esophageal achalasia 645 (23-101) Observational NR
Schlottmann et al (2018)14 2015-2016 3a Esophageal achalasia 116 (25-49)a Observational 9 to 12 months
Awaiz et al (2017)15 2013-2016 7 All adult patients (≥18 years of age) with all grades and subtypes of achalasia, whether or not they had previously undergone other interventions for achalasia 483 (range NR) Observational NR
Marano et al (2016)16 2012-2015 7 Adult patients with diagnosis of achalasia 486 (8-180) Observational 2 to 12 months
Zhang et al (2016)17 2012-2015 4 Esophageal achalasia 317 (39-101) Observational 2 to 12 months

a Overall number of studies was 21 and overall N=1958, including noncomparative studies
SR: systematic review; M-A: Meta-Analysis; N: sample size; NR: Not reported

Table 3. SR & M-A Results  

Systematic Review Dysphasia Eckardt Score GERD Length of Hospital Stay Overall major / severe adverse events
Martins et al (2020)12
Total N N/A 249 354 451 Total N
Pooled effect (95% CI) NR MD=-0.257 (-0.512 to -0.002) RD=0.00 (-0.09 to 0.09)
I2: 0%
MD=-0.6 (-1.11 to -0.09)
I2=70%
"Major events (CD III a and IIIb)
were more common in the POEM group"; analysis NR
Aiolfi et al (2020)13
Total N NR NR NR N/A N/A
Pooled effect (95% CI) Remission RR=1.21 (1.04 to 1.47)
I2=0.0%
MD=-0.6 (-1.4 to -0.2)
I2=17.5%
RR=1.75 (1.35 to 2.03)
I2=6.3%
NR NR
Schlottmann et al (2018)14
Total N NR N/A NR NR N/A
Pooled effect (95% CI) Probability for improvement in dysphagia at 24 months:
LHM=90% vs POEM=93%; p=.01
NR
  • GERD symptoms OR=1.69 ( 1.33 to 2.14)
  • GERD evidenced by erosive esophagitis OR=9.31 (4.71 to 18.85)
  • GERD evidenced by pH monitoring OR=4.30 (2.96 to 6.27)
1.03 days longer after POEM (p=0.04) NR
Awaiz et al (2017)15
Total N N/A N/A 315 427 N/A
Pooled effect (95% CI)

NR

NR

  • Postoperative GERD OR=1.27 (0.70 to 2.30)
    I2=0%
  • Long-term GERD WMD=1.06 (0.27 to 4.1)
    I2=NR
MD=0.30 (-0.24 to 0.85)
I2=57.95%
NR
Marano et al (2016)[Marano L, Pallabazzer G, Solito B, et al. Surgery.... ; 95(10): e3001. PMID 26962813]
Total N N/A 384 375 221 NR
Pooled effect (95% CI) NR MD=-0.66 (-1.70 to.39)
I2=94.33%
Post-procedure symptomatic GERD OR=1.81 (1.11 to 2.95)
I2=0%
MD=-0.63 (-1.26 to -0.00)
I2=72%
Major complications OR=1.33 (0.24 to 7.35)
I2 NR
Zhang et al (2016)17
Total N N/A 143 N/A 317 216
Pooled effect (95% CI) NR MD=-0.30 (-0.42 to -0.18)
I2=0%
NR MD=-0.42 (-1.26 to 0.43)
I2=80%
Overall complications OR 1.53 (0.65 to 3.59)
I2=0.0%

CD: Clavien-Dindo; CI: confidence interval; GERD: Gastroesophageal Reflux Disease; LHM: laparoscopic Heller myotomy; MD: Mean Difference; N: sample size; N/A: Not applicable; NR: Not reported; OR=Odds Ratio; POEM: Peroral Endoscopic Myotomy; RD: Risk Difference; RR=Risk Ratio; WMD: weighted mean difference;

Peroral Endoscopic Myotomy Versus Pneumatic Dilation
Zhong et al. (2020) conducted a meta-analysis of 7 observational studies comparing POEM (n=298) to pneumatic dilation (n=321).36 Achalasia type varied, with 33% type I, 55% type II, and 12% type III. The mean age of the patients in the included studies ranged from 14 to 69 years; thus, including 2 pediatric studies and 2 studies of older adults. Follow-up ranged from 2 to 49.23 months. POEM improved the clinical success rate (24-month RR=1.35; 95% CI, 1.10 to 1.65; I2=70%) and change in Eckardt scores (MD 1.19, 95% CI 0.78 to 1.60, I2=70%); however, the risk of GERD and other complications was higher for POEM compared with pneumatic dilation (RR=4.17, 95% CI, 1.52 to 11.45, and RR=3.78; 95% CI, 1.41 to 10.16, respectively). Important limitations of this meta-analysis include the inherent bias of reliance on observational studies and the high between-study clinical and statistical heterogeneity.

Aiolfi et al. (2020) conducted a systematic review and Bayesian random-effects network meta-analysis that compared POEM to LHM and pneumatic dilation.13 Overall, 19 studies of 4,407 patients were included. Of those, none directly compared POEM and pneumatic dilation. Therefore, data from the POEM and pneumatic dilation arms of studies that compared them each, respectively, to LHM, were indirectly compared in the network meta-analysis. Compared to pneumatic dilation, POEM was associated with improved dysphasia remission (RR=1.40; 95% CI, 1.14 to 1.79) and Eckardt scores (MD=-1.2; 95% CI, -2.3 to -0.2), but higher risk of GERD (RR=1.36; 95% CI, 1.18 to 1.68). Important limitations of this network meta-analysis include its inclusion of arm-based indirect comparisons and the inherent bias of its reliance on observational studies.

Section Summary: Systematic Reviews
The systematic reviews evaluating comparative studies only assessed nonrandomized studies and did not appear to have taken into account differences in patient characteristics.

Randomized Controlled Trials
Ponds et al. (2019) published a randomized clinical trial comparing POEM and pneumatic dilation for treatment-naïve patients with achalasia.37 Between 2012 and 2015, patients from 6 sites in 5 countries were randomized to receive either POEM or pneumatic dilation (Tables 4 and 5 ). The primary outcome was o verall treatment success at 2 years, defined as an Eckardt score < 3 and the absence of severe complications or retreatment. Based on previously reported success rates, the power calculation for the primary outcome was based on a difference of at least 20%. Treatment success at 2 years was significantly higher in the POEM group. However, POEM had higher rates of reflux esophagitis than pneumatic dilation. Two serious adverse events (including 1 perforation) occurred after pneumatic dilation; no serious adverse events occurred after POEM. The study was limited by the lack of blinding, lack of intention-to-treat analysis, and by the follow-up time starting at treatment initiation rather than at randomization.

Werner et al. (2019) published a randomized, noninferiority trial that compared POEM to LHM plus Dor's fundoplication in patients with idiopathic achalasia.38 The primary outcome was clinical success at 2 years, defined as an Eckardt score < 3, without the use of additional treatments. A noninferiority margin of -12.5 percentage points was prespecified as "clinically acceptable" for the primary end point, based on input from the interventional gastroenterologists and surgeons involved in the trial. Analyses were primarily performed in a modified intention-to-treat population of 221 patients, which excluded 20 (8%) of patients who withdrew consent, had exclusion criteria discovered post-randomization, or did not undergo treatment. Among the modified intention-to-treat population, the mean age was 48.6 years, 64.2% had no previous therapy, 26.2% had a previous endoscopic pneumatic dilation, and their mean Eckardt symptom score was 6.8. POEM was noninferior to LHM plus Dor's fundoplication for clinical success at 2 years, but rates of reflux esophagitis were higher for POEM. This resulted in more patients in the POEM group receiving daily low-dose proton-pump inhibitors at 24 months. Although a higher rate of serious adverse events was reported in the LHM group, the difference was not statistically significant. This was likely owing to insufficient statistical power for measuring differences in rare outcomes. The most common serious adverse event in the LHM group was mucosal perforation (n=3, 2.7%). The RCT was limited by the lack of blinding of outcome assessment. 

Table 4. Summary of Key RCT Characteristics 

Study Countries Sites Dates Participants Interventions
          Active Comparator
Ponds et al (2019)37 Netherlands, Germany, Italy, Hong Kong 6 2012-2015 Treatment naïve adults with newly diagnosed achalasia and Eckardt score ≥3 POEM (N=64) Pneumatic dilation
Initial with 30 mm balloon
Subsequent with 35 mm balloon if Eckardt score ≥3 at 3 weeks
(N=66)
Werner et al (2019)38 Belgium, Czech Republic, Germany, Italy, Netherlands, Sweden 8 2012-2015 Adults with symptomatic achalasia and Eckardt score ≥3 POEM (N=120) LHM plus Dor's fundoplication (N=121)

LHM: laparoscopic Heller's myotomy; POEM: peroral endoscopic myotomy; RCT: randomized controlled trial.

Table 5. Summary of Key RCTs: 2-Year Results 

Study Treatment success, n (%) PPI use Endoscopic Reflux Esophagitis Retreatment Treatment-related SAE
Ponds et al (2019)37 126 92 92 126 126
POEM



58 (92%)
58
Median(IQR) SD
24(41) 6.5
54
No.(%) SD
22(41) 6.5
63
No.(%) SD
5 (8) 3.4
63
No.(%) SD
0
Pneumatic dilation


34 (54%)
34
Median(IQR) SD
7(21) 7
29
No.(%) SD
2(7) 4.7
63
No.(%) SD
26 (41) 10.5
63
No.(%) SD
1(1.6) 1.7
Comparative treatment effects 1.71 (1.34 to 2.17)a 20 (1 to 38)b 34 (12 to 49)b 33 (17 to 47)b 1.6 (-5 to 10)b
Werner et al (2019)38 221 221 165   221
POEM 93 (83.0) n (%)
41 (38.7)
n (%)
38 (44)
NR n (%)
3 (2.7)
LHM 89 (81.7) n (%)
21 (19.4)
n (%)
23 (29)
NR n (%)
8 (7.3)
Comparative treatment effects 1.4 (-8.7 to 11.4)a NR 2.00 (1.03 to 3.85)c NR 4.6 (-1.1 to 10.4)a

a Unadjusted Risk Ratio (95% confidence interval[CI])
b Unadjusted Absolute Difference (95% CI)
c Odds Ratio (95% CI)
IQR: interquartile range; LHM: laparoscopic Heller's myotomy; NR: not reported; POEM: peroral endoscopic myotomy; PPI: proton pump inhibitor; RCT: randomized controlled trial; SAE: severe adverse even; SD: standard deviation

Tables 6 and 7 summarize the important limitations of the RCTs discussed above.

Table 6. Study Relevance Limitations  

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Ponds et al (2019)37     2. Pneumatic dilation protocol limited to 1-2 dilations as compared to clinical practice
2. Optimal comparator would be laparoscopic Heller myotomy
4. Eckardt score not validated symptom assessment  
Werner et al (2019)38 4. Non-US   2. Laparoscopic Heller's myotomy plus Dor's fundoplication    

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 7. Study Design and Conduct Limitations 

Study Allocationa Blindingb Selective Reportingc Follow-Upd Powere Statisticalf
Ponds et al (2019)37   1. Blinding not possible due to different technical approaches to each procedure 6. Per protocol analysis 6. Not intent to treat analysis
6. Follow-up insufficient to define long-term effects
  3. Inadequate statistical analysis and reporting
Werner et al (2019)38   1. Not blinded outcome assessment        

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Follow-Up key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Randomized Controlled Trials
Findings from 2 RCTs demonstrated that, compared with pneumatic dilation or LHM, POEM had a similar or greater treatment success rate based on the Eckardt score and similar or lower rates of overall adverse events. However, POEM had significantly higher rates of endoscopically confirmed reflux esophagitis, which led to more patients using daily proton pump inhibitors. An important conduct limitation of the RCTs is that blinded assessment of outcomes was not used. Given that the primary outcome was based on subjective patient report of symptoms, this is a potential source of bias. Additionally, a potential relevance limitation is that the RCTs did not include any US sites. Larger RCTs are still needed to confirm these findings and to explore potential differences in subgroups based on achalasia subtype and previous therapy status. Longer-term RCT data is also needed to examine GERD-related consequences, such as development of Barrett's esophagus and durability and need for retreatment.

Nonrandomized Comparative Studies
Numerous nonrandomized comparative studies have compared POEM and LHM in adults with achalasia. The majority of these studies are included in the systematic reviews described above and will not be comprehensively summarized herein. Those that were not included in previous systematic reviews or that have notable characteristics (i.e., focus on important subpopulations, have long-term follow-up) are summarized below.

Docimo et al. (2016) published a retrospective study comparing POEM and LHM for individuals with achalasia that was not included in any above-described systematic review.39 Patients who underwent POEM (n=44) or LHM (n=122) between 2006 and 2015 were included. There was no difference in average pain scores for POEM and LHM after the first 24 hours (2.7±2.067 vs 3.29±1.980, p=0.472) or at time of discharge (1.6±2.420 vs 2.09±2.157, p=0.0657). The POEM group required significantly fewer narcotics while hospitalized than the LHM group (35.8mg vs 101.8mg, p<0.001), and fewer POEM patients needed a prescription for a narcotic analgesic at discharge (6.81% vs 92.4%, p<0.001). Also, the average length of stay was 31.2 hours for POEM and 55.79 for LHM (p<0.001). The study was limited by its retrospective nature and its lack of randomization and blinding.

Wang et al. (2016) retrospectively reviewed outcomes for POEM (n=21) and pneumatic dilation (n=10) in patients ages 65 years and older.40 All were treated successfully, with decreases in Eckardt scores. At a mean follow-up of 21.8 months for POEM and 35 months for pneumatic dilation patients, 1 POEM case failed, and 2 pneumatic dilation procedures failed.

In a retrospective study of patients with type III achalasia, Kumbhari et al. (2015) compared outcomes for 49 patients who underwent POEM across 8 centers between 2011 and 2013, and a historical control groups of 25 patients who underwent LHM between 2000 and 2013.24 Defining clinical response as a reduction in Eckardt score of no more than 1, clinical response was more frequent in the POEM group (98.0%) than the LHM group (80.8%; p=0.01). On multivariable analysis, there was no statistically significant difference in the odds of failure between procedures, although the point estimate of the odds favored POEM (OR= 11.32; p=0.06). Procedure times were shorter with POEM. There was no difference in length of stay. The overall rate of adverse events was lower in the POEM group (6% vs 27%, p=0.01). However, an important limitation of this study is that LHM patients had a more severe disease at baseline by several different measures (ie, higher Eckardt symptom stage, prior endoscopic interventions). Also, the LHM and POEM groups differed in the achalasia diagnostic criteria used, with the LHM group lacking use of the current gold standard of high-resolution esophageal manometry to diagnose type III because it was not yet available at that time.

Section Summary: Nonrandomized Comparative Studies
The nonrandomized studies comparing POEM with other procedures are retrospective and involved patients who might not have been comparable in terms of age and severity of the disease. Although outcomes were generally similar between POEM and the comparator treatments (LHM, pneumatic dilation), potential confounding and selection bias makes outcome comparisons uncertain. The comparative studies did not report long-term outcomes.

Case Series
Several case series have evaluated the use of POEM. Evaluation of case series with 50 or more cases founded consistent improvements in symptoms of achalasia after POEM.41,42,43,18,44,20,20,45,46 These reports have also highlighted short- and long-term complications and adverse events. For example, across 3 studies with up to 3 years of follow-up,41,43,20 GERD was reported in 16.8% to 40% of patients. A sampling of other case series with noteworthy characteristics are highlighted below.

Li et al. (2017) published the largest case series to-date. In a single-center study assessing POEM for the treatment of achalasia,46 between 2010 and 2012, 564 consecutive patients were included with a median follow-up of 49 months. Mean Eckardt score decreased from 8 to 2 (p<0.05) and the median lower esophageal sphincter pressure decreased from 29.7 mm Hg to 11.9 mm Hg (p<0.05). Fifteen failures occurred within 3 months, 23 between 3 months and 3 years, and 10 after 3 years. Major perioperative adverse events (AEs) occurred in 36 (6.4%) patients, including delayed mucosal barrier failure (n=3), delayed bleeding (n=3), hydrothorax (n=6), and pneumothorax (n=21). Ninety-three (16.5%) patients experienced mucosal injuries, and 48 patients required nasogastric tube placement at the end of the procedure. Other minor AEs included estimated blood loss >200mL (n=3), subcutaneous emphysema (n=1), and pneumoperitoneum (n=1). The study was limited by a high loss to follow-up and poor patient compliance at diagnostic tests. Also, late initiation of CO2 insufflation may have made the AE rate unrealistically high.

Ling et al. (2014) reported on the quality of life outcomes in 2 patient cohorts (probably overlapping) who underwent POEM for achalasia at a single-center in China.44 Quality of life was assessed at pretreatment and at 1-year follow-up using the 36-Item Short-Form Health Survey; Physical Component Summary and Mental Component Summary raw scores were transformed to a 0 (poor health) to 100 (good health) scale. In a group of 21 patients who had failed previous pneumatic dilation, mean Physical Component Summary scores improved from 30 to 65, and mean Mental Component Summary scores improved from 43 to 67 (p<0.001 for both comparisons). Incidences of intraoperative subcutaneous emphysema and pneumothorax were 14% and 5%, respectively; postoperative esophagitis developed in 19%. In 87 previously untreated patients, mean Physical Component Summary scores improved from 33 to 69 (p<0.001), and mean Mental Component Summary scores improved from 44 to 67 (p=0.003).47 Incidence rates of intraoperative subcutaneous emphysema and pneumothorax were 12% and 1%, respectively; postoperative esophagitis developed in 6%.

A study by Ren et al. (2012) highlighted POEM-specific complications.45 In this series of 119 cases, 23% of patients developed subcutaneous emphysema intraoperatively and another 56%, postoperatively. Three of these patients required subcutaneous needle decompression. Additionally, 3% of patients developed a pneumothorax intraoperatively and another 25% postoperatively. Postoperatively, the incidence of thoracic effusion was 49%; the incidence of mild inflammation or segmental atelectasis of the lungs was 50%. All complications were resolved with conservative treatment.

At least 2 other small case series (both 2013) have evaluated the efficacy and feasibility of POEM for patients with failed LHM/achalasia recurrence; success rates have been reported in over 90% of cases up to 10 months after rescue POEM.48,49 Studies also have compared different POEM techniques; comparable outcomes have been reported between patients undergoing full-thickness and circular myotomy.50

However, these case series do not permit comparison with other established treatments.

Section Summary: Case Series
Case series have shown improvements in symptoms of achalasia after POEM. These reports also point to defined short- and long-term complications and adverse events. Such studies do not permit comparison with other established treatments.

Section Summary: Peroral Endoscopic Myotomy for Adult Patients with Achalasia
Studies on POEM for adults with achalasia included systematic reviews of nonrandomized studies, nonrandomized studies, case series, and 2 RCTs. Conclusions on comparative efficacy cannot be determined from the systematic reviews because they did not appear to have accounted for differences in patient characteristics in the nonrandomized studies. Findings from RCT's demonstrated that POEM had a similar or greater treatment success rate based on the Eckardt score, similar or fewer adverse events compared with pneumatic dilation or LHM. However, POEM had significantly higher rates of endoscopically confirmed reflux esophagitis. An important conduct limitation of the RCTs is that blinded assessment of outcomes was not used. Given that the primary outcome was based on subjective patient report of symptoms, this is a potential source of bias. Additionally, a potential relevance limitation is that the RCTs did not include any US sites. The nonrandomized studies comparing POEM with other procedures were retrospective and involved patients who might not be comparable in terms of age and severity of the disease. Although outcomes were generally similar between POEM and the comparator treatments (LHM, pneumatic dilation), potential confounding and selection bias makes outcomes comparisons uncertain. The comparative studies did not report long-term outcomes. Case series have shown improvements in symptoms of achalasia after POEM. These reports also point to defined short-term and long-term complications and adverse events. Such studies do not permit comparison with other established treatments.

Peroral Endoscopic Myotomy for Pediatric Patients with Achalasia
Clinical Context and Therapy Purpose
The purpose of POEM in patients who have esophageal achalasia is to provide a treatment option that is an alternative to or an improvement on existing therapies. 

The question addressed in this evidence review is: Does the use of POEM improve the net health outcome of pediatric patients with esophageal achalasia?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest are pediatric patients with esophageal achalasia. Esophageal achalasia is characterized by reduced numbers of neurons in the esophageal myenteric plexuses and reduced peristaltic activity, making it difficult for patients to swallow food and possibly leading to complications such as regurgitation, coughing, choking, aspiration pneumonia, esophagitis, ulceration, and weight loss.

Interventions
The therapy being considered is POEM. The POEM procedure involves tunneling an endoscope down the esophagus toward the esophageal-gastric junction. A surgeon performs the myotomy by cutting only the inner, circular LES muscles through a submucosal tunnel created in the proximal esophageal mucosa.

Patients receive general anesthesia during the POEM procedure, which is conducted in tertiary care facilities.

Comparators
Comparators of interest include esophageal dilation, LHM, and botulinum toxin injection.

Esophageal dilation is performed in a graded approach, starting with a small balloon (typically 30 mm), then progressing to larger balloons (35-40 mm) 2 to 4 weeks later. The balloons are placed at the level of the gastroesophageal junction and inflated slowly, in order to tear the muscle fibers in a controlled manner. Esophageal perforations are a potential complication. Long-term studies have estimated that approximately one-third of patients may need a repeat procedure.

Heller laparoscopic myotomy is a minimally invasive procedure in which the thick muscle of the lower esophagus and the upper stomach is cut to open the tight LES. The procedure involves 5 small incisions to insert the camera and surgical instruments. Reported success rates are high (>90%), with a 5-year follow-up study showing an 8% rate of symptom recurrence.

Endoscopic botulinum toxin is injected with a sclerotherapy needle approximately 1 cm above the esophagogastric junction. The complication rate is low and approximately 80% of patients experience immediate symptom relief. The effect diminishes over time, with more than 60% of patients reporting recurrent symptoms at 1 year.

Outcomes
The general outcomes of interest are symptom relief and treatment-related morbidity.

Symptom relief may be measured by the Eckardt score, which is comprised of 4 major symptoms of achalasia: dysphagia, regurgitation, retrosternal pain, weight loss. Each symptom receives a score from 0 (none) to 3 (severe), for a maximum score of 12. Total scores of 4 or greater represent treatment failure.9

A treatment-related morbidity of concern is the development of GERD. GERD risk is high with this procedure because POEM involves ablating the LES without adding any type of anti-reflux mechanism. Additional complications include thoracic effusion, subcutaneous emphysema, and esophagitis.

Symptom relief may be experienced shortly following the procedure. Duration of relief is measured after months to years of follow-up.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;

  • To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Lee et al. (2019) published a systematic review and meta-analysis evaluating POEM for the treatment of pediatric achalasia.51 Twelve studies, published between 2013 and 2018, with a total of 146 patients (53.68% female), were included in the analysis. There was a reduction in the Eckardt score of 6.88 points (mean difference 6.88, 95% CI 6.28–7.48, p<0.001) and a reduction in LES pressure of 20.73 mmHg (mean difference 20.73, 95% CI 15.76–25.70, p<0.001). Improvement or resolution of short- and long-term achalasia symptoms was experienced in 93% of patients. The study was limited by several of the including studies being case series (5/12) with no control groups or comparators, all of the studies having a sample size of <30, and by most studies only reporting follow-up of ≤2 years. 

Nonrandomized Studies
Nabi et al. (2019) published a retrospective study assessing POEM for the treatment of children with achalasia.52 Forty-four patients ≤18 years old and weighing ≥10kg who were diagnosed with achalasia between 2013 and 2018 were included. POEM was successfully performed in 43 patients (technical success 97.72%). Eleven (25.6%) children experienced intra-operative AEs, including retroperitoneal CO2 (n=7), capnoperitoneum (n=3), and mucosal injury (n=1). Clinical success at 1, 2, 3, and 4 years follow-up was 92.8%, 94.4%, 92.3%, and 83.3%, respectively. The study was limited by its retrospective design, the lack of confirmation of GERD in about half the patients, and the small number of patients who completed 3 or more years of follow-up.

Miao et al. (2017) published a retrospective, single-center study of POEM for the treatment of pediatric achalasia.53 Twenty-one children (aged 11 months –18 years) diagnosed with achalasia and treated between 2014 and 2016 were included. Mean follow-up time was 13.2 months. No severe AEs were reported, and for all patients, difficulty in feeding or swallowing was significantly alleviated or resolved. By 1 month after POEM, all Eckardt scores were <3 and by 6 months were 0.75 on average (average pre-operative score 7.18; p<0.001). At 6 months, an average weight gain of 2.7kg was observed. Four patients had gastroesophageal reflux and 2 had concomitant gastroesophageal reflux and reflux esophagitis at 3 months follow-up. No limitations to the study were reported.

Section Summary: Peroral Endoscopic Myotomy for Pediatric Patients with Achalasia
One systematic review and meta-analysis available evaluating POEM for the treatment of pediatric achalasia was identified. A significant decrease was observed in both Eckardt scores and LES pressure, as well as improvement in symptoms; however, no RCTs were included and all of the included studies had sample sizes <30. Two comparative observational studies were available evaluating POEM for the treatment of pediatric achalasia. Both studies reported high rates of success for POEM and alleviation of achalasia symptoms.

Summary of Evidence
For adults who have achalasia who receive POEM, the evidence includes systematic reviews of observational studies, 2 randomized controlled trials, nonrandomized comparative studies, and case series. Relevant outcomes are symptoms, functional outcomes, health status measures, resource utilization, and treatment-related morbidity. Compared with pneumatic dilation or laparoscopic Heller myotomy (LHM), findings from RCTs demonstrated that POEM had a similar or greater treatment success rate based on the Eckardt score and similar or fewer overall adverse event rates. However, POEM had significantly higher rates of endoscopically confirmed reflux esophagitis and more daily proton-pump inhibitor use at 24 months. An important conduct limitation of the RCTs is that blinded assessment of outcomes was not used. Given that the primary outcome was based on subjective patient report of symptoms, this is a potential source of bias. Additionally, a potential relevance limitation is that the RCTs did not include any US sites. The comparative observational studies have primarily reported similar outcomes for POEM and for Heller myotomy in symptom relief, as assessed by the Eckardt score. Some studies have shown a shorter length of stay and less postoperative pain with POEM. However, potential imbalances in patient characteristics in these nonrandomized studies might have biased the treatment comparisons. In the case series, treatment success at short follow-up periods was reported for a high proportion of patients treated with POEM. However, the incidence of adverse events was relatively high, with POEM-specific complications, including subcutaneous emphysema, pneumothorax, and thoracic effusion, reported across studies. Additionally, a substantial proportion of patients undergoing POEM developed gastroesophageal reflux disease and esophagitis and required treatment. Case series do not permit conclusions about the efficacy of POEM relative to established treatment, and long-term outcomes of the procedure are not well described in the literature.

For pediatric patients who have achalasia who receive POEM, the evidence includes several nonrandomized studies and a systematic review. Relevant outcomes are symptoms, functional outcomes, health status measures, resource utilization, and treatment-related morbidity. The studies reported treatment success for POEM based on decreases in Eckardt scores and lower esophageal sphincter pressure. No randomized clinical trials have been reported. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements
American College of Gastroenterology
In 2020, the American College of Gastroenterology (ACG) issued evidence-based clinical guidelines on the diagnosis and management of achalasia.54 The quality of the evidence and the strength of recommendations were rated based on the GRADE framework. The evidence review includes the 2 RCTs of POEM compared to LHM or pneumatic dilation. Based on their evaluation, the ACG made the following recommendations:  

  • "In patients with achalasia who are candidates for definite therapy, PD, LHM, and POEM are comparable effective therapies for type I or type II achalasia and POEM would be a better treatment option in those with type III achalasia.
  • "We suggest that POEM or PD result in comparable symptomatic improvement in patients with types I or II achalasia." (GRADE quality=Low, Recommendation strength=Conditional)

  • "We recommend that POEM and LHM result in comparable symptomatic improvement in patients with achalasia." (GRADE quality=Moderate; Recommendation strength=Strong)

  • "We recommend that tailored POEM or LHM for type III achalasia as a more efficacious alternative disruptive therapy at the lower esophageal sphincter compared to PD." (GRADE quality=Moderate; Recommendation strength=Strong)

  • "We suggest that in patients with achalasia, POEM compared with LHM with fundoplication or PD is associated with a higher incidence of GERD." (GRADE quality=Moderate; Recommendation strength=Strong)

  • "We suggest that POEM is a safe option in patients with achalasia who have previously undergone PD or LHM." (GRADE quality=Low; Recommendation strength=Strong)

American Gastroenterological Association Institute
In 2017, the American Gastroenterological Association Institute published a clinical practice update on the use of peroral endoscopic myotomy (POEM) for the treatment of achalasia.55 Based on the expert review, the Institute made the following recommendations:  

  • POEM should be performed by experienced physicians in high-volume centers (competence achieved after an estimated 20 to 40 procedures)

  • If expertise is available, POEM should be considered primary therapy for type III achalasia

  • If expertise is available, POEM should be considered comparable to Heller myotomy for any achalasia syndromes

  • Patients receiving POEM should be considered high-risk to develop reflux esophagitis and be advised of management considerations (eg, proton pump inhibitor therapy and/or surveillance endoscopy) prior to undergoing POEM.

American Society of Gastrointestinal and Endoscopic Surgeons
In 2014, the American Society of Gastrointestinal and Endoscopic Surgeons (ASGE) issued evidence-based, consensus guidelines on the use of endoscopy in the evaluation and management of dysphagia, including esophageal achalasia.56 The Society recommended that:

"....Endoscopic and surgical treatment options for achalasia should be discussed with the patient. In patients who opt for endoscopic management and are good surgical candidates, pneumatic dilation with large-caliber balloon dilators for the endoscopic treatment of achalasia was recommended....Long-term data and randomized trials comparing peroral endoscopic myotomy to conventional modalities of management are necessary before it can be adopted into clinical practice, but the procedure is becoming more widely used in expert centers."

In 2020, ASGE issued an evidence-based guideline on the management of achalasia.57 The methodologic quality of systematic reviews was assessed using the Methodological Quality of Systematic Reviews-2 (AMSTAR-2) tool and the certainty of the body of evidence was rated as very low to high based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. ASGE rated the strength of individual recommendation based on the aggregate evidence quality and an assessment of the anticipated benefits and harms. ASGE used the phrase "we suggest" to indicate weaker recommendations and "we recommend" to indicate stronger recommendations. This guideline did not include either of the 2 available RCTs of POEM. Based on their evaluation, ASGE issued the following recommendations:  

  • "We suggest POEM as the preferred treatment for management of patients with type III achalasia." (Very low quality evidence)

  • "In patients with failed initial myotomy (POEM or laparoscopic Heller myotomy), we suggest pneumatic dilation or redo myotomy using either the same or an alternative myotomy technique (POEM or laparoscopic Heller myotomy)." (Very low quality evidence)

  • "We suggest that patients undergoing POEM are counseled regarding the increased risk of postprocedure reflux compared with pneumatic dilation and laparoscopic Heller myotomy. Based on patient preferences and physician expertise, postprocedure management options include objective testing for esophageal acid exposure, long-term acid suppressive therapy, and surveillance upper endoscopy." (Low quality evidence)

  • We suggest that POEM and laparoscopic Heller myotomy are comparable treatment options for management of patients with achalasia types I and II, and the treatment option should be based on shared decision-making between the patient and provider." (Low quality evidence)

These 2020 ASGE guidelines were endorsed by the American Neurogastroenterology and Motility Society and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES).

International Society for Diseases of the Esophagus
In 2018, the International Society for Diseases of the Esophagus published guidelines on the diagnosis and management of achalasia.58 The Society convened 51 experts from 11 countries, including several from the U. S., to systematically review evidence, assess recommendations using the GRADE system, and vote to integrate the recommendations into the guidelines (>80% approval required for inclusion). Table 8 summarizes POEM recommendations. 

Table 8. Recommendations for the Treatment of Achalasia 

Recommendation LOR GOR
POEM is an effective therapy for achalasia both in short- and medium-term follow-up with results comparable to Heller myotomy. Conditional Very low
POEM is an effective therapy for achalasia both in short- and medium-term follow-up with results comparable to pneumatic dilations. Conditional Low
Pretreatment information on GERD, nonsurgical options (pneumatic dilation), and surgical options with lower GERD risk (Heller myotomy) should be provided to patient. Good practice NA
POEM is feasible and effective for symptom relief in patients previously treated with endoscopic therapies. Conditional Very low
POEM may be considered an option for treating recurrent symptoms after laparoscopic Heller myotomy. Conditional Low
Appropriate training (in vivo/in vitro animal model) and proctorship should be considered prior to a clinical program of POEM. Good practice NA

GERD: gastroesophageal reflux disease; GOR: grade of recommendation; LOR: level of recommendation; NA: not applicable; POEM: peroral endoscopic myotomy.

Society of American Gastrointestinal and Endoscopic Surgeons
In 2012, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) issued evidence-based, consensus guidelines on the surgical management of esophageal achalasia. The guidelines stated that the POEM technique "is in its infancy and further experience is needed before providing recommendations."59

In 2020, SAGES endorsed the guideline on the management of achalasia issued by ASGE (2020) as described above.57

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 9.

Table 9. Summary of Key Trials  

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing      
NCT01832779 Prospective Evaluation of the Clinical Utility of Peroral Endoscopic Myotomy (POEM) 600 Dec 2022
NCT01793922 A Prospective Randomized Multi-center Study Comparing Endoscopic Pneumodilation and Per Oral Endoscopic Myotomy (POEM) as Treatment of Idiopathic Achalasia 150 Jan 2023
Unpublished      
NCT02138643 Laparoscopy Heller Myotomy With Fundoplication Associated Versus Peroral Endoscopic Myotomy (POEM) 30 Dec 2017 (last update posted April 2017)
NCT03228758 Efficacy of Anterior Versus Posterior Myotomy Approach in Peroral Endoscopic Myotomy (POEM) for the Treatment of Achalasia - a Single Operator Analysis 89 May 2019 (last update posted May 2020)

 NCT: national clinical trial.

References 

  1. Cheatham JG, Wong RK. Current approach to the treatment of achalasia. Curr Gastroenterol Rep. Jun 2011; 13(3): 219-25. PMID 21424734
  2. Pandolfino JE, Kahrilas PJ. Presentation, diagnosis, and management of achalasia. Clin Gastroenterol Hepatol. Aug 2013; 11(8): 887-97. PMID 23395699
  3. Yaghoobi M, Mayrand S, Martel M, et al. Laparoscopic Heller's myotomy versus pneumatic dilation in the treatment of idiopathic achalasia: a meta-analysis of randomized, controlled trials. Gastrointest Endosc. Sep 2013; 78(3): 468-75. PMID 23684149
  4. Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy. Apr 2010; 42(4): 265-71. PMID 20354937
  5. Hungness ES, Teitelbaum EN, Santos BF, et al. Comparison of perioperative outcomes between peroral esophageal myotomy (POEM) and laparoscopic Heller myotomy. J Gastrointest Surg. Feb 2013; 17(2): 228-35. PMID 23054897
  6. Eckardt AJ, Eckardt VF. Treatment and surveillance strategies in achalasia: an update. Nat Rev Gastroenterol Hepatol. Jun 2011; 8(6): 311-9. PMID 21522116
  7. Li H, Peng W, Huang S, et al. The 2 years' long-term efficacy and safety of peroral endoscopic myotomy for the treatment of achalasia: a systematic review. J Cardiothorac Surg. Jan 03 2019; 14(1): 1. PMID 30606216
  8. Crespin OM, Liu LWC, Parmar A, et al. Safety and efficacy of POEM for treatment of achalasia: a systematic review of the literature. Surg Endosc. May 2017; 31(5): 2187-2201. PMID 27633440
  9. Akintoye E, Kumar N, Obaitan I, et al. Peroral endoscopic myotomy: a meta-analysis. Endoscopy. Dec 2016; 48(12): 1059-1068. PMID 27617421
  10. Patel K, Abbassi-Ghadi N, Markar S, et al. Peroral endoscopic myotomy for the treatment of esophageal achalasia: systematic review and pooled analysis. Dis Esophagus. Oct 2016; 29(7): 807-819. PMID 26175119
  11. Andolfi C, Fisichella PM. Meta-analysis of clinical outcome after treatment for achalasia based on manometric subtypes. Br J Surg. Mar 2019; 106(4): 332-341. PMID 30690706
  12. Martins RK, Ribeiro IB, DE Moura DTH, et al. PERORAL (POEM) OR SURGICAL MYOTOMY FOR THE TREATMENT OF ACHALASIA: A SYSTEMATIC REVIEW AND META-ANALYSIS. Arq Gastroenterol. Jan-Mar 2020; 57(1): 79-86. PMID 32294740
  13. Aiolfi A, Bona D, Riva CG, et al. Systematic Review and Bayesian Network Meta-Analysis Comparing Laparoscopic Heller Myotomy, Pneumatic Dilatation, and Peroral Endoscopic Myotomy for Esophageal Achalasia. J Laparoendosc Adv Surg Tech A. Feb 2020; 30(2): 147-155. PMID 31364910
  14. Schlottmann F, Luckett DJ, Fine J, et al. Laparoscopic Heller Myotomy Versus Peroral Endoscopic Myotomy (POEM) for Achalasia: A Systematic Review and Meta-analysis. Ann Surg. Mar 2018; 267(3): 451-460. PMID 28549006
  15. Awaiz A, Yunus RM, Khan S, et al. Systematic Review and Meta-Analysis of Perioperative Outcomes of Peroral Endoscopic Myotomy (POEM) and Laparoscopic Heller Myotomy (LHM) for Achalasia. Surg Laparosc Endosc Percutan Tech. Jun 2017; 27(3): 123-131. PMID 28472017
  16. Marano L, Pallabazzer G, Solito B, et al. Surgery or Peroral Esophageal Myotomy for Achalasia: A Systematic Review and Meta-Analysis. Medicine (Baltimore). Mar 2016; 95(10): e3001. PMID 26962813
  17. Zhang Y, Wang H, Chen X, et al. Per-Oral Endoscopic Myotomy Versus Laparoscopic Heller Myotomy for Achalasia: A Meta-Analysis of Nonrandomized Comparative Studies. Medicine (Baltimore). Feb 2016; 95(6): e2736. PMID 26871816
  18. Teitelbaum EN, Soper NJ, Santos BF, et al. Symptomatic and physiologic outcomes one year after peroral esophageal myotomy (POEM) for treatment of achalasia. Surg Endosc. Dec 2014; 28(12): 3359-65. PMID 24939164
  19. Ujiki MB, Yetasook AK, Zapf M, et al. Peroral endoscopic myotomy: A short-term comparison with the standard laparoscopic approach. Surgery. Oct 2013; 154(4): 893-7; discussion 897-900. PMID 24074429
  20. Von Renteln D, Fuchs KH, Fockens P, et al. Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study. Gastroenterology. Aug 2013; 145(2): 309-11.e1-3. PMID 23665071
  21. Bhayani NH, Kurian AA, Dunst CM, et al. A comparative study on comprehensive, objective outcomes of laparoscopic Heller myotomy with per-oral endoscopic myotomy (POEM) for achalasia. Ann Surg. Jun 2014; 259(6): 1098-103. PMID 24169175
  22. Vigneswaran Y, Yetasook AK, Zhao JC, et al. Peroral endoscopic myotomy (POEM): feasible as reoperation following Heller myotomy. J Gastrointest Surg. Jun 2014; 18(6): 1071-6. PMID 24658904
  23. Kumagai K, Tsai JA, Thorell A, et al. Per-oral endoscopic myotomy for achalasia. Are results comparable to laparoscopic Heller myotomy?. Scand J Gastroenterol. May 2015; 50(5): 505-12. PMID 25712228
  24. Kumbhari V, Tieu AH, Onimaru M, et al. Peroral endoscopic myotomy (POEM) vs laparoscopic Heller myotomy (LHM) for the treatment of Type III achalasia in 75 patients: a multicenter comparative study. Endosc Int Open. Jun 2015; 3(3): E195-201. PMID 26171430
  25. Teitelbaum EN, Soper NJ, Pandolfino JE, et al. Esophagogastric junction distensibility measurements during Heller myotomy and POEM for achalasia predict postoperative symptomatic outcomes. Surg Endosc. Mar 2015; 29(3): 522-8. PMID 25055891
  26. Chan SM, Wu JC, Teoh AY, et al. Comparison of early outcomes and quality of life after laparoscopic Heller's cardiomyotomy to peroral endoscopic myotomy for treatment of achalasia. Dig Endosc. Jan 2016; 28(1): 27-32. PMID 26108140
  27. Sanaka MR, Hayat U, Thota PN, et al. Efficacy of peroral endoscopic myotomy vs other achalasia treatments in improving esophageal function. World J Gastroenterol. May 28 2016; 22(20): 4918-25. PMID 27239118
  28. Schneider AM, Louie BE, Warren HF, et al. A Matched Comparison of Per Oral Endoscopic Myotomy to Laparoscopic Heller Myotomy in the Treatment of Achalasia. J Gastrointest Surg. Nov 2016; 20(11): 1789-1796. PMID 27514392
  29. Khashab MA, Kumbhari V, Tieu AH, et al. Peroral endoscopic myotomy achieves similar clinical response but incurs lesser charges compared to robotic heller myotomy. Saudi J Gastroenterol. Mar-Apr 2017; 23(2): 91-96. PMID 28361839
  30. Leeds SG, Burdick JS, Ogola GO, et al. Comparison of outcomes of laparoscopic Heller myotomy versus per-oral endoscopic myotomy for management of achalasia. Proc (Bayl Univ Med Cent). Oct 2017; 30(4): 419-423. PMID 28966450
  31. de Pascale S, Repici A, Puccetti F, et al. Peroral endoscopic myotomy versus surgical myotomy for primary achalasia: single-center, retrospective analysis of 74 patients. Dis Esophagus. Aug 01 2017; 30(8): 1-7. PMID 28575245
  32. Peng L, Tian S, Du C, et al. Outcome of Peroral Endoscopic Myotomy (POEM) for Treating Achalasia Compared With Laparoscopic Heller Myotomy (LHM). Surg Laparosc Endosc Percutan Tech. Feb 2017; 27(1): 60-64. PMID 28145968
  33. Ward MA, Gitelis M, Patel L, et al. Outcomes in patients with over 1-year follow-up after peroral endoscopic myotomy (POEM). Surg Endosc. Apr 2017; 31(4): 1550-1557. PMID 27858209
  34. Hanna AN, Datta J, Ginzberg S, et al. Laparoscopic Heller Myotomy vs Per Oral Endoscopic Myotomy: Patient-Reported Outcomes at a Single Institution. J Am Coll Surg. Apr 2018; 226(4): 465-472.e1. PMID 29410262
  35. Ramirez M, Zubieta C, Ciotola F, et al. Per oral endoscopic myotomy vs. laparoscopic Heller myotomy, does gastric extension length matter?. Surg Endosc. Jan 2018; 32(1): 282-288. PMID 28660419
  36. Zhong C, Tan S, Huang S, et al. Peroral endoscopic myotomy versus pneumatic dilation for achalasia: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. Nov 2020; 32(11): 1413-1421. PMID 32516175
  37. Ponds FA, Fockens P, Lei A, et al. Effect of Peroral Endoscopic Myotomy vs Pneumatic Dilation on Symptom Severity and Treatment Outcomes Among Treatment-Naive Patients With Achalasia: A Randomized Clinical Trial. JAMA. Jul 09 2019; 322(2): 134-144. PMID 31287522
  38. Werner YB, Hakanson B, Martinek J, et al. Endoscopic or Surgical Myotomy in Patients with Idiopathic Achalasia. N Engl J Med. Dec 05 2019; 381(23): 2219-2229. PMID 31800987
  39. Docimo S, Mathew A, Shope AJ, et al. Reduced postoperative pain scores and narcotic use favor per-oral endoscopic myotomy over laparoscopic Heller myotomy. Surg Endosc. Feb 2017; 31(2): 795-800. PMID 27338580
  40. Wang X, Tan Y, Lv L, et al. Peroral endoscopic myotomy versus pneumatic dilation for achalasia in patients aged 65 years. Rev Esp Enferm Dig. Oct 2016; 108(10): 637-641. PMID 27649684
  41. Hungness ES, Sternbach JM, Teitelbaum EN, et al. Per-oral Endoscopic Myotomy (POEM) After the Learning Curve: Durable Long-term Results With a Low Complication Rate. Ann Surg. Sep 2016; 264(3): 508-17. PMID 27513156
  42. Ramchandani M, Nageshwar Reddy D, Darisetty S, et al. Peroral endoscopic myotomy for achalasia cardia: Treatment analysis and follow up of over 200 consecutive patients at a single center. Dig Endosc. Jan 2016; 28(1): 19-26. PMID 26018637
  43. Inoue H, Sato H, Ikeda H, et al. Per-Oral Endoscopic Myotomy: A Series of 500 Patients. J Am Coll Surg. Aug 2015; 221(2): 256-64. PMID 26206634
  44. Ling T, Guo H, Zou X. Effect of peroral endoscopic myotomy in achalasia patients with failure of prior pneumatic dilation: a prospective case-control study. J Gastroenterol Hepatol. Aug 2014; 29(8): 1609-13. PMID 24628480
  45. Ren Z, Zhong Y, Zhou P, et al. Perioperative management and treatment for complications during and after peroral endoscopic myotomy (POEM) for esophageal achalasia (EA) (data from 119 cases). Surg Endosc. Nov 2012; 26(11): 3267-72. PMID 22609984
  46. Li QL, Wu QN, Zhang XC, et al. Outcomes of per-oral endoscopic myotomy for treatment of esophageal achalasia with a median follow-up of 49 months. Gastrointest Endosc. Jun 2018; 87(6): 1405-1412.e3. PMID 29108981
  47. Ling TS, Guo HM, Yang T, et al. Effectiveness of peroral endoscopic myotomy in the treatment of achalasia: a pilot trial in Chinese Han population with a minimum of one-year follow-up. J Dig Dis. Jul 2014; 15(7): 352-8. PMID 24739072
  48. Onimaru M, Inoue H, Ikeda H, et al. Peroral endoscopic myotomy is a viable option for failed surgical esophagocardiomyotomy instead of redo surgical Heller myotomy: a single center prospective study. J Am Coll Surg. Oct 2013; 217(4): 598-605. PMID 23891071
  49. Zhou PH, Li QL, Yao LQ, et al. Peroral endoscopic remyotomy for failed Heller myotomy: a prospective single-center study. Endoscopy. 2013; 45(3): 161-6. PMID 23389963
  50. Li QL, Chen WF, Zhou PH, et al. Peroral endoscopic myotomy for the treatment of achalasia: a clinical comparative study of endoscopic full-thickness and circular muscle myotomy. J Am Coll Surg. Sep 2013; 217(3): 442-51. PMID 23891074
  51. Lee Y, Brar K, Doumouras AG, et al. Peroral endoscopic myotomy (POEM) for the treatment of pediatric achalasia: a systematic review and meta-analysis. Surg Endosc. Jun 2019; 33(6): 1710-1720. PMID 30767141
  52. Nabi Z, Ramchandani M, Chavan R, et al. Outcome of peroral endoscopic myotomy in children with achalasia. Surg Endosc. Nov 2019; 33(11): 3656-3664. PMID 30671667
  53. Miao S, Wu J, Lu J, et al. Peroral Endoscopic Myotomy in Children With Achalasia: A Relatively Long-term Single-center Study. J Pediatr Gastroenterol Nutr. Feb 2018; 66(2): 257-262. PMID 28691974
  54. Vaezi MF, Pandolfino JE, Yadlapati RH, et al. ACG Clinical Guidelines: Diagnosis and Management of Achalasia. Am J Gastroenterol. Sep 2020; 115(9): 1393-1411. PMID 32773454
  55. Kahrilas PJ, Katzka D, Richter JE. Clinical Practice Update: The Use of Per-Oral Endoscopic Myotomy in Achalasia: Expert Review and Best Practice Advice From the AGA Institute. Gastroenterology. Nov 2017; 153(5): 1205-1211. PMID 28989059
  56. Pasha SF, Acosta RD, Chandrasekhara V, et al. The role of endoscopy in the evaluation and management of dysphagia. Gastrointest Endosc. Feb 2014; 79(2): 191-201. PMID 24332405
  57. Khashab MA, Vela MF, Thosani N, et al. ASGE guideline on the management of achalasia. Gastrointest Endosc. Feb 2020; 91(2): 213-227.e6. PMID 31839408
  58. Zaninotto G, Bennett C, Boeckxstaens G, et al. The 2018 ISDE achalasia guidelines. Dis Esophagus. Sep 01 2018; 31(9). PMID 30169645
  59. Stefanidis D, Richardson W, Farrell TM, et al. SAGES guidelines for the surgical treatment of esophageal achalasia. Surg Endosc. Feb 2012; 26(2): 296-311. PMID 22044977

Coding Section

Codes

Number

Description

CPT

43497 (code effective on 01/01/2022)

Lower esophageal myotomy, transoral

 

43499

Unlisted procedure, esophagus

ICD-10-CM

 

Investigational for achalasia

 

K22.0

Achalasia of cardia

ICD-10-PCS

 

ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure.

 

0D848ZZ, 0DN48ZZ

Surgery, gastrointestinal system, via natural or artificial opening, endoscopic – codes for division and release

TOS

Medicine 

 

POS

Inpatient/Outpatient 

 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2013 Forward     

11/29/2021 

Updating policy with 2022 coding. Adding code 43497. No other change made 

10/01/2021 

Annual reivew, no change to policy intent. Updating description, background, rationale and references. 

10/20/2020

Interim review adding medical necessity criteria to previously negative position statement. 

10/01/2020 

Annual review, no change to policy intent. Updating guidelines, coding, rationale and references. 

10/01/2019 

Annual review, updated policy verbiage to state: Peroral endoscopic myotomy is investigatonal and/or unproven and is therefore considered NOT MEDICALLY NECESSARY as a treatment for esophageal achalasia. Also updating rationale and references. 

10/09/2018

Annual review, no change to policy intent. Updating background, rationale and references. 

10/05/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

10/11/2016

Annual review, no change to policy intent. Updating background, description, rationale and references. 

10/27/2015 

Annual review, no change to policy intent. Updated background and description. Added guidelines. 

10/20/2014

Annual review. Updated background, rationale and references. Added coding section. No change to policy intent.

10/16/2013

New Policy

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