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.

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 

POEM is considered MEDICALLY NECESSARY when ALL of the following criteria are met:

• The individual is aged 18 years or older; and
• The individual has been diagnosed with achalasia; and
• The diagnosis of achalasia has been confirmed by a positive esophageal manometry, esophagogastroduodenoscopy (EGD), and barium swallow.

POEM not meeting the criteria as indicated in this policy is investigational/unproven therefore considered NOT MEDICALLY NECESSARY, non-covered because the safety and/or effectiveness of this service cannot be established by the available published peer reviewed literature. 

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, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use 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. Randomized controlled trials 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 peroral endoscopic myotomy (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.

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 to 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.

Laparoscopic Heller 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, and 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). Gastroesophageal reflux disease 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.

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. These reviews are heterogeneous in whether they assessed data on POEM alone or compared POEM to other interventions, which outcomes they assessed, which studies they included, and in the statistical methods used. The majority addressed the comparison of POEM to LHM.

Results of systematic reviews that primarily relied on data from noncomparative case series studies are not comprehensively summarized herein.^7,8,9,10,11 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 The authors calculated pooled success rates for POEM, LHM, and pneumatic dilation (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 or Pneumatic Dilation
Below are summarized the most recent systematic reviews (published on or after 2017) that address the comparison of POEM to LHM or PD using data from comparative observational studies and RCTs. Table 1 provides a crosswalk of the comparative studies included in these systematic reviews.

Table 1. Comparison of Studies of POEM Versus LHM or PD Included in SR and M-A

Study	Dirks et al. (2021)12	Facciorusso et al. (2021)13	Martins et al. (2020)14	Aiolfi et al. (2020)15	Schlottmann et al. (2018)16	Awaiz et al. (2017)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	⚫			⚫
Caldaro et al. (2015)36	⚫
Fumagalli et al. (2016)37	⚫
Greenleaf et al. (2018)38	⚫
Kim et al. (2019)39	⚫
Meng et al. (2017)40	⚫
Miller et al. (2017)41	⚫
Ponds et al. (2019)42	⚫	⚫
Sanaka et al. (2019)43	⚫
Wang et al. (2016)44	⚫
Werner et al. (2019)45	⚫	⚫
Wirsching et al. (2019)46	⚫
Zheng et al. (2019)47	⚫
Podboy et al. (2020)48	⚫
Tan et al. (2016)49	⚫
Boeckxstaens et al. (2011)50		⚫
Borges et al. (2014)51		⚫
Kostic et al. (2007)52		⚫
Hamdy et al. (2015)53		⚫

LHM: laparoscopic Heller myotomy; M-A: meta-analysis; PD: pneumatic dilation; POEM: peroral endoscopic myotomy; SR: systematic review.

Tables 2 and 3 summarize characteristics and results of the included systematic reviews published on or after 2017 that address the comparison of POEM to LHM or PD using data from comparative studies. The included comparative studies are heterogenous in their patient populations, proportions of patients with any previous treatments , and proportions of each achalasia subtype I – III, follow-up duration, and definition of treatment success. These differences limit interpretation of their findings.

Dirks et al. (2021) conducted a systematic review and meta-analysis that evaluated the efficacy and safety of POEM in comparison to LHM and PD.¹² The review included 28 studies (2 RCTs [Ponds et al. (2019)⁴² and Werner et al. (2019)⁴⁵]; 26 observational studies). Most comparative studies on POEM included LHM (n = 21), with a minority involving POEM versus PD (n = 8). One study included all 3 interventions. Since POEM is a relatively new intervention, studies evaluating POEM often had shorter follow-up. Two studies included children, with 1 each comparing POEM to PD and LHM. The majority of included studies had a baseline achalasia subtype that was either predominantly type 2 and/or type 1; only 1 study had predominantly type 3 achalasia. The vast majority of included studies had < 100 total patients. Results revealed POEM to have similar efficacy to LHM. However, POEM treated dysphagia better than PD in a RCT and observational studies and POEM needed reintervention less than PD in a RCT (risk ratio [RR] 0.19; 95% CI, 0.08 to 0.47) and LHM in an observational study (RR 0.33; 95% CI, 0.16 to 0.68). POEM had similar safety outcomes to LHM and PD. The authors concluded that POEM has similar outcomes to LHM and greater efficacy than PD.

Facciorusso et al. (2021) completed a systematic review and network meta-analysis of first-line therapeutic interventions for achalasia.¹³ The review included 6 RCTs in adults with achalasia that compared the efficacy of PD (n = 260), LHM (n = 309) and POEM (n = 176). Four trials compared LHM with PD, 1 compared POEM to PD, and 1 compared POEM with LHM. Overall, low-quality evidence, based primarily on direct evidence, supported the use of POEM over PD for treatment success at 1 year while there was no significant difference observed between LHM and POEM. Severe esophagitis occurred at an incidence of 5.3%, 3.7% and 1.5% for POEM, LHM and PD, respectively. Procedure-related serious adverse events after POEM, LHM, and PD were 1.4%, 6.7% and 4.2%, respectively. The authors concluded that POEM and LHM have comparable efficacy and may increase treatment success as compared to PD, with low confidence in estimates.

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).¹⁴ 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 PD.¹⁵ 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 PD. POEM was associated with improved dysphasia remission and Eckardt scores, but higher risk of GERD compared to LHM. Results of the comparison to PD 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.16, Data were 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 a 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.¹⁷ 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). Laparoscopic Heller myotomy 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.

Table 2. SR and M-A Characteristics

Systematic Review	Dates	Included Comparative Studies	Participants	N (Range)	Design	Duration
Dirks et al. (2021)12	2010 – 2019	28	Adult and pediatric patients with achalasia	2339 (15 to 241)	26 observational; 2 RCTs	Follow-up: ≥ 2 months to 5.4 years; most studies had < 2 year follow-up
Facciorusso et al. (2021)13	Through Dec 2019	6	Adults with achalasia	745 (50 to 221)	RCTs	Minimum follow-up of 1 year; range: 1 to 5 years
Martins et al. (2020)14	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 to 178)	Observational	9 to 260 weeks
Aiolfi et al. (2020)15	2012 – 2018	10	Esophageal achalasia	645 (23 to 101)	Observational	NR
Schlottmann et al. (2018)16	2015 – 2016	3a	Esophageal achalasia	116 (25 to 49)a	Observational	9 to 12 months
Awaiz et al. (2017)17	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

^aOverall number of studies was 21 and overall N = 1958, including noncomparative studies.
M-A: meta-analysis; NR: not reported; RCT: randomized controlled trial; SR: systematic review.

Table 3. SR & M-A Results

Systematic Review	Dysphasia	Eckardt Score/Treatment Success	GERD	Length of Hospital Stay	Overall Major/Severe Adverse Events
Dirks et al. (2021)12
POEM vs. LHM; Pooled effect (95% CI)		RCT (success by Eckhardt score): 83% vs. 82%; RR, 1.02 (0.9 to 1.15)	RCT (severe reflux esophagitis): 4.6% vs. 6.4%; RR, 0.73 (0.20 to 2.58)	RCT (mean): 2.9 vs.3.2; MD, -0.3 (-0.67 to 0.07)	RCT (treatment-related serious adverse events): 3% vs. 7%; RR, 0.32 (0.9 to 1.17)
POEM vs. PD Pooled effect (95% CI)		RCT (success by Eckhardt score): 92% vs. 54%; RR, 1.71 (1.34 to 2.17)	RCT (severe reflux esophagitis): 6% vs. 0%; RR, 3.82 (0.20 to 71.48)		RCT (treatment-related serious adverse events): 0% vs. 1.6%; RR, 0.19 (0.08 to 0.47)
Facciorusso et al. (2021)13
POEM vs. LHM RR (95% CI)		Treatment success at 1 year: no significant difference observed Treatment success at 2 years: RR, 1.02 (0.90 to 1.15)
POEM vs. PD RR (95% CI)		Treatment success at 1 year: RR, 1.29 (0.99 to 1.69) Treatment success at 2 years: RR, 1.76 (1.37 to 2.25)
Martins et al. (2020)14
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)15
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)16
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 = .04)	NR
Awaiz et al. (2017)17
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

CD: Clavien-Dindo; CI: confidence interval; GERD: gastroesophageal reflux disease; LHM: laparoscopic Heller myotomy; MD: mean difference; N/A: not applicable; NR: not reported; OR: odds ratio; PD: pneumatic dilation; 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 PD (n = 321).⁵⁴ 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, 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 (mean difference [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 PD (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 PD.¹⁵ Overall, 19 studies of 4,407 patients were included. Of those, none directly compared POEM and PD. Therefore, data from the POEM and PD arms of studies that compared them each, respectively, to LHM, were indirectly compared in the network meta-analysis. Compared to PD, 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 a 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.

Randomized Controlled Trials
Although included in the 2 most recent meta-analyses, the RCTs by Ponds et al. (2019)⁴² and Werner et al. (2019)⁴⁵ remain the landmark studies involving POEM. These are described below.

Ponds et al. (2019) published a RCT comparing POEM and PD for treatment-naïve patients with achalasia.⁴² Between 2012 and 2015, patients from 6 sites in 5 countries were randomized to receive either POEM or PD (Tables 4 and 5). The primary outcome was overall 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 PD. Two serious adverse events (including 1 perforation) occurred after PD; no serious adverse events occurred after POEM. The study was limited by lack of blinding, lack of an 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.⁴⁵ 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%) 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 PD, 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)42	Netherlands, Germany, Italy, Hong Kong	6	2012 – 2015	Treatment naïve adults with newly diagnosed achalasia and Eckardt score ≥ 3	POEM (n = 64)	PD Initial with 30 mm balloon Subsequent with 35 mm balloon if Eckardt score ≥ 3 at 3 weeks (n = 66)
Werner et al. (2019)45	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; PD: pneumatic dilation; 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)42,	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
PD	34 (54%)	34 Median (IQR) SD 7(21) 7	29 n (%) SD 2(7) 4.7	63 n (%) SD 26 (41) 10.5	63 n (%) SD 1(1.6) 1.7
Comparative treatment effect (95% CI)	RR, 1.71 (1.34 to 2.17)a	AD, 20 (1 to 38)a	AD, 34 (12 to 49)a	AD, 33 (17 to 47)a	AD, 1.6 (-5 to 10)a
Werner et al. (2019)45,	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 effect (95% CI)	RR, 1.4 (-8.7 to 11.4)a	NR	OR, 2.00 (1.03 to 3.85)	NR	RR, 4.6 (-1.1 to 10.4)a

^a Unadjusted 

AD: absolute difference; CI: confidence interval; IQR: interquartile range; LHM: laparoscopic Heller's myotomy; NR: not reported; OR: odds ratio; PD: pneumatic dilation; POEM: peroral endoscopic myotomy; PPI: proton pump inhibitor; RCT: randomized controlled trial; RR: risk ratio; 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)42			2. PD protocol limited to 1 to 2 dilations as compared to clinical practice 2. Optimal comparator would be LHM	4. Eckardt score not validated symptom assessment
Werner et al. (2019)45	4. Non-US		2. LHM 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.
LHM: laparoscopic Heller's myotomy; PD: pneumatic dilation.

Table 7. Study Design and Conduct Limitations

Study	Allocationa	Blindingb	Selective Reportingc	Follow-Upd	Powere	Statisticalf
Ponds et al. (2019)42		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)45		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.

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 (ie, 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.55, 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 = .472) or at time of discharge (1.6 ± 2.420 vs. 2.09 ± 2.157, p = .0657). The POEM group required significantly fewer narcotics while hospitalized than the LHM group (35.8 mg vs. 101.8 mg, p < .001), and fewer POEM patients needed a prescription for a narcotic analgesic at discharge (6.81% vs. 92.4%, p < .001). Also, the average length of stay was 31.2 hours for POEM and 55.79 for LHM (p < .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 PD (n = 10) in patients ages 65 years and older.⁴⁴ All were treated successfully, with decreases in Eckardt scores. At a mean follow-up of 21.8 months for POEM and 35 months for PD patients, 1 POEM case failed, and 2 PD 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 group 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 = .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 = .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 = .01). However, an important limitation of this study is that LHM patients had 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: Peroral Endoscopic Myotomy for Adult Patients With Achalasia
Studies on POEM for adults with achalasia included systematic reviews, nonrandomized studies, 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 RCTs demonstrated that POEM had a similar or greater treatment success rate based on the Eckardt score and similar or fewer adverse events compared with PD 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, PD), potential confounding and selection bias makes outcome comparisons uncertain. The comparative studies did not report long-term outcomes.

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 is 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.

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 to 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 and 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. Gastroesophageal reflux disease 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
Zhong et al. (2021) published an updated systematic review and meta-analysis evaluating clinical outcomes of POEM for the treatment of achalasia in children.⁵⁶ The review included 11 studies published between January 2009 to June 2020 (N = 389; 222 boys). The mean age of the patients ranged from 5.5 to 15.2 years with symptom duration ranging from 1.7 to 26.4 months. The pooled technical success (completion of the POEM procedure successfully) was achieved in 385 children (97.4%; 95% CI, 94.7% to 98.7%) and the pooled clinical success (decrease in Eckhardt score to ≤ 3 during follow-up) was achieved in 343 children (92.4%; 95% CI, 89% to 94.8%). The Eckhardt score was significantly reduced by 6.76 points following POEM (95% CI, 6.18 to 7.34; p < .00001). Regarding adverse events, the pooled major adverse event rate was 12.8% (95% CI, 4.5% to 31.5%) with a pooled gastoesophageal reflux rate of 17.8% (95% CI, 14.2% to 22%). The authors concluded that POEM was effective and safe for treating children with achalasia; however, all included studies in the analysis were observational in nature.

Lee et al. (2019) published a systematic review and meta-analysis evaluating POEM for the treatment of pediatric achalasia.⁵⁷ 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 ( 95% CI 6.28 to 7.48, p < .001) and a reduction in LES pressure of 20.73 mmHg (95% CI 15.76 to 25.70, p < .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 included 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.⁵⁸ 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 adverse events, including retroperitoneal CO2 (n = 7), capnoperitoneum (n = 3), and mucosal injury (n = 1). Clinical success at 1, 2, 3 and 4 years of 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.⁵⁹ Twenty-one children (aged 11 months to 18 years) diagnosed with achalasia and treated between 2014 and 2016 were included. Mean follow-up time was 13.2 months. No severe adverse events 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 < .001). At 6 months, an average weight gain of 2.7 kg 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
Two systematic reviews and meta-analyses evaluating POEM for the treatment of pediatric achalasia were 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 the majority of 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 primarily observational studies, 2 RCTs, and nonrandomized comparative studies. Relevant outcomes are symptoms, functional outcomes, health status measures, resource utilization, and treatment-related morbidity. Compared with PD or 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. 

For pediatric patients who have achalasia who receive POEM, the evidence includes several nonrandomized studies and 2 systematic reviews. 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 LES pressure. No RCTs have been reported. 

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Gastroenterology
In 2020, the American College of Gastroenterology (ACG) issued evidence-based clinical guidelines on the diagnosis and management of achalasia.⁶⁰ The quality of the evidence and the strength of recommendations were rated based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. The evidence review includes the 2 RCTs of POEM compared to LHM or pneumatic dilation (PD). 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 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 2020, ASGE issued an evidence-based guideline on the management of achalasia.⁶² 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 GRADE framework. ASGE rated the strength of individual recommendations 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 PD 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 PD 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).

American Society of Gastrointestinal and Endoscopic Surgeons
In 2020, ASGE issued an evidence-based guideline on the management of achalasia.⁶² 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 GRADE framework. ASGE rated the strength of individual recommendations 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 PD 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 PD 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.⁶³ 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 PD.	Conditional	Low
Pretreatment information on GERD, nonsurgical options (PD), and surgical options with lower GERD risk (Heller myotomy) should be provided to the 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; PD: pneumatic dilation; POEM: peroral endoscopic myotomy.

Society of American Gastrointestinal and Endoscopic Surgeons
In 2020, SAGES endorsed the guideline on the management of achalasia issued by ASGE (2020) as described above.⁶²

In 2021, SAGES issued its own evidence-based guidelines for the use of POEM for the treatment of achalasia.⁶⁴ The expert panel agreed on 4 recommendations for adults and children with achalasia. These include:

• The panel suggests that adult and pediatric patients with type I and II achalasia may be treated with either POEM or LHM based on surgeon and patient's shared decision making (conditional recommendation; very low certainty evidence).
• The panel suggests POEM over LHM for type III adult or pediatric achalasia. (expert opinion)
• The panel recommends POEM over PD in patients with achalasia. (strong recommendation, moderate certainty evidence)
• For the subgroup of patients who are particularly concerned about the continued use of proton pump inhibitors post-operatively, the panel suggests that either POEM or PD can be used based on joint patient and surgeon decision-making. (conditional recommendation, very low certainty evidence)

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
NCT01601678	Endoscopic Versus Laparoscopic Myotomy for Treatment of Idiopathic Achalasia: A Randomized, Controlled Trial	240	Apr 2022
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
NCT02518542	Per Oral Endoscopic Myotomy (POEM) and Prolonged Dilatation (PRD) as Additional Endoscopic Treatment Options for Achalasia and Other Esophageal Motility Disorders	400	Jun 2027
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.

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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. Caldaro T, Familiari P, Romeo EF, et al. Treatment of esophageal achalasia in children: Today and tomorrow. J Pediatr Surg. May 2015; 50(5): 726-30. PMID 25783358
37. Fumagalli U, Rosati R, De Pascale S, et al. Repeated Surgical or Endoscopic Myotomy for Recurrent Dysphagia in Patients After Previous Myotomy for Achalasia. J Gastrointest Surg. Mar 2016; 20(3): 494-9. PMID 26589525
38. Greenleaf EK, Winder JS, Hollenbeak CS, et al. Cost-effectiveness of per oral endoscopic myotomy relative to laparoscopic Heller myotomy for the treatment of achalasia. Surg Endosc. Jan 2018; 32(1): 39-45. PMID 29218664
39. Kim GH, Jung KW, Jung HY, et al. Superior clinical outcomes of peroral endoscopic myotomy compared with balloon dilation in all achalasia subtypes. J Gastroenterol Hepatol. Apr 2019; 34(4): 659-665. PMID 30695124
40. Meng F, Li P, Wang Y, et al. Peroral endoscopic myotomy compared with pneumatic dilation for newly diagnosed achalasia. Surg Endosc. Nov 2017; 31(11): 4665-4672. PMID 28411346
41. Miller HJ, Neupane R, Fayezizadeh M, et al. POEM is a cost-effective procedure: cost-utility analysis of endoscopic and surgical treatment options in the management of achalasia. Surg Endosc. Apr 2017; 31(4): 1636-1642. PMID 27534662
42. 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
43. Sanaka MR, Thota PN, Parikh MP, et al. Peroral endoscopic myotomy leads to higher rates of abnormal esophageal acid exposure than laparoscopic Heller myotomy in achalasia. Surg Endosc. Jul 2019; 33(7): 2284-2292. PMID 30341655
44. 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
45. 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
46. Wirsching A, Boshier PR, Klevebro F, et al. Comparison of costs and short-term clinical outcomes of per-oral endoscopic myotomy and laparoscopic Heller myotomy. Am J Surg. Oct 2019; 218(4): 706-711. PMID 31353034
47. Zheng Z, Zhao C, Su S, et al. Peroral endoscopic myotomy versus pneumatic dilation - result from a retrospective study with 1-year follow-up. Z Gastroenterol. Mar 2019; 57(3): 304-311. PMID 30861554
48. Podboy AJ, Hwang JH, Rivas H, et al. Long-term outcomes of per-oral endoscopic myotomy compared to laparoscopic Heller myotomy for achalasia: a single-center experience. Surg Endosc. Feb 2021; 35(2): 792-801. PMID 32157405
49. Tan Y, Zhu H, Li C, et al. Comparison of peroral endoscopic myotomy and endoscopic balloon dilation for primary treatment of pediatric achalasia. J Pediatr Surg. Oct 2016; 51(10): 1613-8. PMID 27339081
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51. Borges AA, Lemme EM, Abrahao LJ, et al. Pneumatic dilation versus laparoscopic Heller myotomy for the treatment of achalasia: variables related to a good response. Dis Esophagus. Jan 2014; 27(1): 18-23. PMID 23551592
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53. Hamdy E, El Nakeeb A, El Hanfy E, et al. Comparative Study Between Laparoscopic Heller Myotomy Versus Pneumatic Dilatation for Treatment of Early Achalasia: A Prospective Randomized Study. J Laparoendosc Adv Surg Tech A. Jun 2015; 25(6): 460-4. PMID 25951417
54. 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
55. 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
56. Zhong C, Tan S, Huang S, et al. Clinical outcomes of peroral endoscopic myotomy for achalasia in children: a systematic review and meta-analysis. Dis Esophagus. Apr 07 2021; 34(4). PMID 33316041
57. 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
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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 Blue Shield Association technology assessment program (TEC) and other nonaffiliated 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     

11/15/2022	Interim review to expand coverage criteria not to be specific to achalasia type. No other changes.
10/11/2022	Annual review, no change to policy intent. Updating rationale and references.
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