POEM Versus Laparoscopic Heller Myotomy With Dor Fundoplication for Esophageal Achalasia

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.