Feasibility and safety of peroral endoscopic myotomy with fundoplication in patients with achalasia: a systematic review and meta-analysis

Introduction

Achalasia is a neurodegenerative disorder that can cause disabling symptoms, such as dysphagia, regurgitation and chest pain, and may increase the risk of developing squamous cell cancer of the esophagus [1]. It is a rare disorder, with an estimated prevalence of 1.8-12.6 per 100,000 persons per year [2]. Mechanical interruption of the lower esophageal sphincter using pneumatic dilation (PD) or Heller myotomy (HM) are the most commonly used treatments. HM has better long-term outcomes compared to PD [3,4]. High relapse rates warrant additional treatment after PD, limiting its usefulness.

Since its introduction in 2009, peroral endoscopic myotomy (POEM) has shown promising results in the management of achalasia and has become the first-line treatment at many centers. One side-effect of a successful POEM procedure is iatrogenic gastroesophageal reflux disease (GERD) which can occur in up to 28% of patients [5]. HM is often performed with a simultaneous fundoplication, which decreases the risk of GERD. The incidence of GERD is much higher after POEM compared to HM with fundoplication [6]. Reduction in GERD is one potential area for improvement in the current technique of POEM. POEM with fundoplication (POEM+F) has been introduced, which can potentially lower the risk of post-POEM GERD. Inoue et al published a case series of 21 patients who underwent POEM+F and found that it was technically feasible in all patients, while no immediate or delayed complications were reported [7]. Since then, several other studies have evaluated the feasibility of POEM+F and have reported promising results [8-10]. In this meta-analysis we have evaluated the feasibility and safety of POEM+F.

Materials and methods

Data sources and search strategy

We followed the guidelines of Preferred Reporting items for Systematic Review and Meta-Analysis (PRISMA) to conduct this systematic review and meta-analysis. An experienced medical librarian (WL-S) conducted a comprehensive search of Embase (Embase.com, Elsevier), MEDLINE (PubMed platform, National Center for Biotechnology Information, National Library of Medicine), Cochrane Central Register of Controlled Trials (CochraneLibrary.com, Wiley, and the Web of Science Core Collection (Web of Science platform, Clarivate) from inception to July 28, 2022. There was no limitation of language in conducting the search. The search included keywords and database-specific controlled subject terms for the concepts peroral endoscopic myotomy, fundoplication, and achalasia. Full search strategies for all databases are provided in Supplementary Table 1. Two authors (FK and SS) independently reviewed the titles and abstracts of the articles retrieved and excluded those that did not address our question of interest. Full texts of the remaining articles, including references were reviewed. The screening results are illustrated in the form of a PRISMA flowchart in Fig. 1.

Figure 1 PRISMA flowchart

Results

The search strategy yielded 124 articles; from these, 33 duplicates were removed (Fig. 1). Of the remaining 91 articles, 78 were removed after title and abstract review. One additional article was identified by reviewing the bibliographies of articles and by manual search. We reviewed the full texts of 14 articles. Three case reports and 1 case series with fewer than 5 patients were excluded. Five studies had overlapping data and hence were excluded. We ultimately included 4 studies with 90 patients in the final analysis [7,9,10,14]. Three were full publications and 1 was an abstract. The characteristics of the included studies are summarized in Table 1.

Table 1 Characteristics of studies

Technical success

Four studies with 90 patients were included in this analysis. The pooled rate (95%CI) of technical success was 92% (83-96%), I²=0% (Fig. 2).

Figure 2 Technical success of peroral endoscopic myotomy with fundoplication

CI, confidence interval

Adverse events

Four studies with 109 patients were included in this analysis. The pooled rate (95%CI) of adverse events was 5% (2-11%), I²=0% (Fig. 3).

Figure 3 Adverse events of peroral endoscopic myotomy with fundoplication

CI, confidence interval

Esophagitis and wrap integrity on follow-up upper endoscopy

Two studies with 63 patients reported data on esophagitis on follow-up upper endoscopy. The pooled rate (95%CI) of esophagitis on follow-up upper endoscopy was 18% (11-30%), I²=0% (Fig. 4). Two studies with 41 patients reported data on wrap integrity. The pooled rate of wrap integrity on follow-up upper endoscopy was 85% (43-98%), I²=70% (Fig. 5).

Figure 4 Esophagitis on upper endoscopy after peroral endoscopic myotomy with fundoplication

CI, confidence interval

Figure 5 Wrap integrity on upper endoscopy after peroral endoscopic myotomy with fundoplication

CI, confidence interval

Discussion

This meta-analysis found that POEM+F is a feasible and safe option in patients with achalasia. POEM is the preferred treatment for achalasia at many centers, given its proven advantages over HM and PD. One meta-analysis comparing POEM with HM showed that the short-term efficacy of POEM was superior to that of HM [15]. However erosive esophagitis was more common in the POEM group compared to HM [15]. In a recent network meta-analysis comparing POEM, HM and PD, POEM was ranked first in terms of treatment efficacy, followed by HM [16].

One of the major drawbacks of POEM is the greater risk of GERD and erosive esophagitis after the procedure. One meta-analysis comparing POEM and HM found that the risk of esophagitis after HM was lower compared to POEM [15]. The lower rate of GERD and esophagitis after HM is reasonable, because it is often accompanied by partial or complete fundoplication. The traditional POEM procedure is not accompanied by fundoplication. We found that the rate (95%CI) of esophagitis after POEM+F was 18% (11-30%), somewhat lower compared to the reported rate of esophagitis after traditional POEM without fundoplication [15]. There were a total of 11 cases of esophagitis: 8 patients had Los Angeles class A esophagitis, 2 patients had class B, and 1 patient had class C esophagitis. There were no cases of class D esophagitis.

We found that the pooled rate (95%CI) of wrap integrity on follow-up upper endoscopy was 85% (95%CI 43-98%). The rates of wrap integrity varied across the studies. In the study by Inoue et al, 95% of the patients were found to have intact wrap on follow-up endoscopy [7]. However, in the study by Patil et al, 59% of the patients had intact wrap on endoscopy 3 months after the procedure [9]. Wrap integrity is a crucial factor in the prevention of post-POEM GERD. The patients who were found to have loose wrap after the procedure developed GERD.

We found that the rate (95%CI) of technical success of POEM+F was 92% (83-96%). The procedure could not be completed in 5/90 patients, 3 in the study by Patil et al [9] and 2 in the study by Tyberg et al [10]. In the study by Patil et al [9], fundoplication was not successful in 3 patients: the peritoneal cavity could not be entered because of difficulty in localization, despite adequate dissection post myotomy.

An important question is: are the outcomes of POEM+F acceptable in the context of achalasia treatment? We found that POEM+F was not associated with a substantial increase in the risk of adverse events. In our meta-analysis, the pooled rate of adverse events of POEM+F was 5% (95%CI 2-11%). A previous meta-analysis [17], comparing POEM and PD, found that the pooled rates of adverse events of POEM were as follows: mucosal injury (4.5%), perforation (0.3%), significant bleeding (0.4%), subcutaneous emphysema (6.5%), pneumothorax (1.4%), and pneumomediastinum (1.8%). The overall technical success rate of POEM+F does seem to be slightly lower than the reported technical success rate of POEM alone. The rate of technical success of POEM+F was 92% (95%CI 83-96%) in our meta-analysis. A previous meta-analysis reported that the technical success rate of POEM was 97% [17]. Finally, we found that the rate of esophagitis after POEM+F was lower than the reported rates of esophagitis after POEM alone. In our meta-analysis, the rate of esophagitis after POEM+F was 18% (95%CI 11-30%). A previous meta-analysis [6] found that the rate of esophagitis after POEM alone was 29.4% (95%CI 18.5-43.3%). In light of these findings, we feel that the observed outcomes of POEM+F are acceptable in the context of achalasia treatment.

This is the first meta-analysis to evaluate the feasibility and safety of POEM+F. There was low heterogeneity in most of the analyses, apart from the analyses of wrap integrity and fundoplication time. However, this meta-analysis had several limitations. Only 4 studies with 90 patients met the inclusion criteria and the overall sample size of this meta-analysis was too small to allow firm conclusions. The small sample size may limit the generalizability of these findings. All the studies included were observational in nature, and were thus at risk of measured and unmeasured confounding [18]. The definitions of outcomes were not uniformly provided across the studies. There was substantial heterogeneity in the analysis of wrap integrity, and considerable heterogeneity in the analysis of procedure time and fundoplication time. As noted above, the rates of wrap integrity on follow-up endoscopy varied across studies, which may have contributed to heterogeneity. Differences in the number of operators, skills, experience and level of expertise may also have contributed to this heterogeneity. Slight variations in POEM+F technique could have contributed to heterogeneity and variations in rates of wrap integrity on follow-up endoscopy. All the studies included in this meta-analysis used endoloop and clips. However, in the study by Inoue et al [7], multiple simulations were carried out by grasping and pulling the anterior gastric wall towards the gastroesophageal junction at different sites in order to identify the ideal distal anchoring site on the gastric wall that would correspond to the starting point of the fundoplication. The site that created the most prominent identifiable wrap with closure of the gastroesophageal junction hiatus, as seen from the retroflexed scope, was selected for placement of the distal anchor with clip. Inoue et al [7] did not use the endoscopic hand suturing technique in the study that was included in our meta-analysis. However, they later refined this technique, using endoscopic hand-suturing instead of endoloop and clips in a published case report [19]. In view of the significant heterogeneity, the results for wrap integrity, procedure time and fundoplication times should be interpreted carefully. Future large-scale studies with a standardized fundoplication technique will be required before firm conclusions can be drawn.

Despite these limitations, this meta-analysis demonstrates the feasibility and safety of POEM+F in patients with achalasia and supports its use as a potential minimally invasive alternative to laparoscopic HM plus fundoplication. More studies with long-term follow-up are required to further validate these findings.