POEM Versus Laparoscopic Heller Myotomy With Dor Fundoplication for Esophageal Achalasia

Overview

Achalasia is a disorder of the esophagus in which the muscular valve between the esophagus and the stomach fails to relax, and the body of the esophagus loses its normal coordinated squeezing movement. People with achalasia have difficulty swallowing both solids and liquids, bring up undigested food, may have chest pain, and often lose weight. None of the available treatments cures the disease; all of them work by reducing the resistance at the junction between the esophagus and the stomach so that food and liquid can pass more easily. Two established treatments do this by cutting the muscle of the valve (a myotomy). Laparoscopic Heller myotomy with a Dor anterior partial fundoplication (LHM + Dor) is performed through small abdominal incisions and includes a wrap of the stomach designed to limit acid reflux afterwards. Peroral endoscopic myotomy (POEM) achieves the same muscle division from inside the esophagus through a tunnel created under the lining, with no skin incisions and no anti-reflux wrap. POEM allows a longer, tailored myotomy, which may be an advantage in the spastic (type III) form of the disease, but reflux after the procedure is more common because no wrap is performed. This trial will randomly assign 220 adults with newly diagnosed, previously untreated achalasia, in equal numbers, to receive either POEM or LHM + Dor. Randomization will be stratified by achalasia subtype (Chicago Classification type I or II versus type III). The main question is whether POEM controls symptoms about as well as LHM + Dor, so the trial is designed as a non-inferiority study with a pre-specified margin of 12.5 percentage points. The primary outcome is clinical success at 12 months, defined as an Eckardt symptom score of 3 or less without any further treatment for achalasia. Participants will be assessed before treatment and again at 30 days and at 3, 6 and 12 months. Assessments include the Eckardt symptom score, reflux symptoms and quality of life, upper endoscopy, high-resolution manometry, timed barium esophagram and, at 3 months, 24-hour pH-impedance testing to measure acid reflux objectively. Complications will be graded using the Clavien-Dindo classification for surgical events and the AGREE classification for endoscopic events. Because one treatment is endoscopic and the other is laparoscopic, neither the participants nor the operators can be masked. To protect against biased outcome assessment, the investigators reporting manometry, endoscopy, barium studies and pH-impedance, the trial statistician and the endpoint adjudication committee will all be masked to treatment allocation. The trial will be conducted at Minia University Hospital, Faculty of Medicine, Minia University, Minia, Egypt, with provision for expansion to additional tertiary centers under a common standard-operating-procedure manual.

BACKGROUND AND RATIONALE Achalasia is a primary esophageal motility disorder characterized by failure of the lower esophageal sphincter to relax appropriately and by absent or abnormal esophageal body peristalsis. Diagnosis is established by high-resolution manometry (HRM) and classified by the Chicago Classification version 4.0 into type I (no contractility), type II (panesophageal pressurization in at least 20% of swallows) and type III (spastic), with an elevated integrated relaxation pressure (IRP) supporting the diagnosis after exclusion of mechanical obstruction. All available treatments are palliative and aim to reduce esophagogastric junction (EGJ) resistance; none restores peristalsis. Laparoscopic Heller myotomy (LHM) with a partial fundoplication has been a durable surgical standard for two decades. Peroral endoscopic myotomy (POEM), introduced in 2010, achieves myotomy through a submucosal tunnel, avoids cutaneous incisions and permits a tailored longer myotomy, but includes no anti-reflux procedure and is associated with more frequent post-procedural gastroesophageal reflux disease (GERD). Randomized evidence indicates that POEM is non-inferior to LHM with partial fundoplication for clinical success at short- and medium-term follow-up, at the cost of more reflux. Questions persist about comparative durability, the burden and management of post-treatment reflux, the influence of achalasia subtype and resource use outside high-volume Western referral centers. TRIAL DESIGN This is a prospective, single-center (with provision for multicenter expansion), two-arm, parallel-group, randomized, assessor-blinded, non-inferiority trial with 1:1 allocation. Randomization uses a computer-generated sequence with random permuted blocks of varying size prepared by an independent statistician, stratified by achalasia subtype (Chicago type I/II versus type III) and by center if more than one site participates. Allocation is concealed using a secure central web-based system, or sequentially numbered opaque sealed envelopes, accessed only after eligibility confirmation and written informed consent. Enrollment, sequence generation and assignment are performed by separate individuals. INTERVENTIONS Both interventions are performed under general anesthesia with endotracheal intubation. Each surgical operator must have performed at least 20 prior LHM procedures and each endoscopist at least 20 prior POEM procedures. Procedures are video-recorded where feasible for quality assurance and adjudication. POEM: after a clear-liquid diet for 48 hours and an overnight fast, with on-table esophageal lavage and CO2 insufflation throughout, a longitudinal mucosal incision is made approximately 10 to 12 cm proximal to the EGJ after submucosal lift. A submucosal tunnel is dissected distally across the EGJ and 2 to 3 cm onto the gastric cardia, confirmed by landmarks and a retroflexion check. A selective circular-muscle or full-thickness myotomy (operator discretion, recorded) is performed from approximately 7 to 10 cm above the EGJ to 2 to 3 cm below it, giving a total myotomy length of approximately 8 to 12 cm, which may be lengthened for type III disease. The mucosal entry is closed with endoscopic clips or an equivalent device. No anti-reflux procedure is performed. LHM + Dor: a standard laparoscopic approach with 4 to 5 ports is used, with retraction of the left lobe of the liver and limited hiatal dissection preserving the posterior attachments. An anterior longitudinal myotomy of the circular and longitudinal muscle layers extends approximately 6 cm onto the distal esophagus and 2 to 3 cm onto the gastric cardia. Mucosal integrity is confirmed by intraoperative endoscopy and/or an air-leak submersion test. A Dor anterior (180 to 200 degrees) partial fundoplication is constructed over the exposed mucosa. Conversion to open surgery, if required for safety, is recorded as a protocol deviation, and the participant remains in the assigned arm for the intention-to-treat analysis. Common peri-operative care is standardized across arms: a contrast study or endoscopic check before resuming oral intake where clinically indicated, a stepwise diet advanced by tolerance, and a shared enhanced-recovery pathway for analgesia, thromboprophylaxis and discharge criteria. Routine proton-pump inhibitor therapy at standard once-daily dose is offered to all participants for the first 8 weeks and continued thereafter on the basis of symptoms and objective reflux testing, applying identical decision rules in both arms. Calcium-channel blockers and nitrates are discouraged during follow-up. MASKING Masking of participants and operators is not feasible. Outcome assessors performing and reporting HRM, upper endoscopy (esophagitis grading), timed barium esophagram and pH-impedance, the trial statistician and the endpoint adjudication committee are masked to allocation. Participant-reported instruments are collected by masked coordinators using standardized scripts. Any unmasking is documented with justification. SAMPLE SIZE Assuming clinical success of 90% in both arms, a non-inferiority margin of 12.5 percentage points, one-sided alpha of 0.025 and 80% power, approximately 90 evaluable participants per arm are required. Inflating for 15% attrition or non-evaluability gives an enrollment target of 110 per arm, or 220 in total. A blinded review of the pooled clinical-success rate and attrition will be undertaken at the midpoint to confirm that design assumptions remain plausible; the margin and target will not be altered on the basis of unblinded effect estimates. STATISTICAL ANALYSIS The primary estimand is the difference in clinical-success proportions (POEM minus LHM + Dor) at 12 months. The difference and its two-sided 95% confidence interval are estimated using the Miettinen-Nurminen method or a Wald interval with continuity adjustment. Non-inferiority is concluded if the lower bound of the 95% confidence interval lies above -12.5 percentage points. Non-inferiority must be supported in both the intention-to-treat and per-protocol populations. If non-inferiority is established, a pre-specified hierarchical test for superiority is performed at the two-sided 0.05 level. The primary analysis is adjusted for the stratification factor(s) using a generalized linear model with a binomial family. Binary secondary outcomes are compared by risk difference and relative risk with 95% confidence intervals and logistic regression adjusted for stratification factors. Repeated continuous outcomes are analyzed with mixed-effects models for repeated measures including fixed effects for arm, time, arm-by-time interaction, baseline value and stratification factors, with a random participant effect. Procedure duration, length of stay and time to oral intake are compared with t-tests or Mann-Whitney tests as appropriate. Retreatment-free survival is summarized by Kaplan-Meier curves and compared by log-rank test and Cox proportional-hazards regression. Adverse events are summarized descriptively by arm, severity grade and timing. A pre-specified exploratory subgroup analysis examines effect modification of the primary outcome by achalasia subtype through an arm-by-subtype interaction term and is interpreted as hypothesis-generating. Sensitivity analyses include a tipping-point/best-worst-case analysis and multiple imputation under a missing-at-random assumption. A detailed statistical analysis plan is finalized and signed before database lock and unmasking.