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Original article Clinical endoscopy: Editorial| Volume 92, ISSUE 6, P1202-1203, December 2020

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Endotherapy for gastroesophageal reflux disease: Another chance of success?

      Abbreviations:

      AET (acid exposure time), ARAT (antireflux ablation therapy), ARMS (antireflux mucosectomy), PPI (proton pump inhibitor)
      Endotherapy for GERD has been a topic of interest over the past 25 years, with successive waves of enthusiasm and disappointment. However, until now, it has not really entered routine clinical practice. The first techniques to be investigated included injection of bulking agents (Enteryx, Boston Scientific, Marlborouth, Mass, USA), submucosal implants (Gatekeeper, Medtronic, Minneapolis, Minn, USA), suturing techniques (Endocinch, Bard and Plicator, NDO), injection of collagen, and radiofrequency of the muscle layer around the lower esophageal sphincter. These techniques all demonstrated encouraging results in open clinical studies, and some were investigated in randomized controlled trials, but none of them were adopted as routine. This was due to several factors, including adverse events, the most severe being reported with injection and radiofrequency techniques, lack of persistent efficacy, or costs for development and clinical assessment. The only surviving technique from this period is Stretta (radiofrequency ablation), acquired by Mederi Therapeutics (Greenwich, Conn, USA), for which the main mechanism of action is a decrease of esophageal sensitivity and of lower esophageal sphincter distensibility.
      • Arts J.
      • Bisschops R.
      • Blondeau K.
      • et al.
      A double-blind sham-controlled study of the effect of radiofrequency energy on symptoms and distensibility of the gastroesophageal junction in GERD.
      This is potentially indicated in a small niche of patients with nonerosive reflux disease. As stated by Hogan,
      • Hogan W.J.
      Clinical trials evaluating endoscopic GERD treatments: is it time for a moratorium on the clinical use of these procedures?.
      “similar to the holiday turkey, the esophagus was stuffed, stitched, and baked by enthusiastic endoscopist’s intent,” and the moratorium on the clinical use of these techniques he suggested came for a short period.
      Later, stapling techniques performed with sophisticated dedicated devices were developed (Esophyx, Endogastric Solutions, Redmond, Wash, USA; MUSE, Medigus Ltd, Omer, Israel; GERDX [an improved version of the plicator], G-Surg GMBH, Seeon-Seebruck, Germany) of which EsophyX was the most thoroughly investigated, including a randomized controlled trial that demonstrated good midterm efficacy, particularly for patients with prominent regurgitations.
      • Hunter J.G.
      • Kahrilas P.J.
      • Bell R.C.
      • et al.
      Efficacy of transoral fundoplication versus omeprazole for treatment of regurgitation in a randomized controlled trial (with video).
      The cost of these devices and the fact that, in most countries, they never reached the level of being reimbursed by social security or health insurance drastically limited their applicability in routine practice.
      Remodeling the cardia with a simple, safe, and inexpensive technique is an attractive approach and might be achieved through resection and/or ablation of the mucosa below the Z line. This may decrease the distensibility of the cardia and reduce its opening. The first description of such an approach was reported by the group from Indianapolis, using 4 band ligations placed 5 mm below the cardia. They observed good clinical results in a pilot study of 10 patients.
      • Kessler W.R.
      • McNulty G.
      • Lehman G.A.
      A prospective randomized study on the effect of band ligation with or without mucosectomy as a treatment for GERD: pilot study, 12 month [abstract].
       Inoue et al
      • Inoue H.
      • Ito H.
      • Ikeda H.
      • et al.
      Anti-reflux mucosectomy for gastroesophageal reflux disease in the absence of hiatus hernia: a pilot study.
      introduced the technique of antireflux mucosectomy (ARMS) and also reported excellent results in uncomplicated GERD without hiatal hernia refractory to proton pump inhibitors (PPIs). This technique generated new enthusiasm, being simple and inexpensive.
      • Inoue H.
      • Ito H.
      • Ikeda H.
      • et al.
      Anti-reflux mucosectomy for gastroesophageal reflux disease in the absence of hiatus hernia: a pilot study.
      The rate of adverse events with ARMS, mainly strictures requiring balloon dilation, is below 10%, provided that the resection does not involve the squamous esophageal mucosa and preserves a segment of normal mucosa at the greater curve or, even better, on both sides of the lesser and greater curve, the so-called “butterfly” resection.
      • Shimamura Y.
      • Inoue H.
      Anti-reflux mucosectomy: can we do better?.
      They also proposed to simplify the technique by replacing ARMS with antireflux mucosal ablation using spray coagulation.
      Hernandez Mondragon et al
      • Hernandez Mondragon O.V.
      • Zamarripa Mottu R.A.
      • Garcia Contreras L.F.
      • et al.
      Clinical feasibility of a new antireflux ablation therapy on gastroesophageal reflux disease.
      report, in this issue, the largest single-center prospective series of patients treated with antireflux ablation therapy (ARAT), in which they treated 108 patients (84 of whom completed the protocol) with a hybrid argon plasma coagulation system (Erbe Jet, ERBE, Tübingen, Germany). This system uses the same catheter to perform high-pressure submucosal injection, followed by selective mucosal ablation, in the hope of reducing deep thermal injury and muscular damage and thereby the risk of stricture. Although it was not reported as a severe adverse event, the rate of strictures requiring up to 4 dilations that they observed (12.9%) cannot be overlooked, and identifying factors associated with these adverse events (eg, extent of circumference ablation or involvement of the squamous mucosa) would be useful before the technique could be widely promoted. However, the results they report, particularly at 36 months of follow-up, are quite impressive, with 72% of patients having an acid exposure time at pHmetry <4%, 79% were no longer using PPI, and most had a restored anatomy (Hill type I), even taking into account that 12 patients underwent a second treatment at 3 months.
      One major factor associated with favorable outcome at 36 months was a pre-ARAT favorable (Hill type II) anatomy, the fact being emphasized that this treatment should be offered not only after a careful clinical assessment but also on the basis of anatomic aspect, with any patient with hiatal hernia being excluded. This, of course, will further reduce the niche of applicability. Interestingly, 3-month assessment by endoscopy (restoration of Hill type I normal anatomy) and pHmetry (acid exposure time [AET] <4%) may predict midterm positive outcomes and allows clinicians to select a minority of patients who may benefit from a second treatment. Although not described in the article, this type of additional treatment could be associated with technical problems because lifting a mucosa that was ablated 3 months before may not be feasible.
      As acknowledged by the authors, a limitation of the study is that there is no comparison group, and the real efficacy of this type of treatment may require a sham-controlled trial to be formally established, particularly when symptom changes are considered. Indeed, the placebo effect may be impressive in this indication. In a randomized trial we conducted in 2005 on GERD endotherapy, focused on PPI-dependent patients,
      • Devière J.
      • Costamagna G.
      • Neuhaus H.
      • et al.
      Nonresorbable copolymer implantation for gastroesophageal reflux disease: a randomized controlled multicenter trial.
      we observed that 41% of patients were no longer using PPIs and experienced a median reduction of 25% in symptom score 3 months after a sham procedure. With the technique presented here, mild and transient dysphagia may induce some weight loss, another potential factor favoring symptomatic improvement.
      Another matter for attention is the apparent simplicity of the treatment. This may be true only in the hands of experienced physicians. As with any new technique, its adoption may need dedicated training even if most therapeutic endoscopists believe that they can do a submucosal injection and an argon plasma coagulation ablation. Severe adverse events in the management of such a benign disease should not happen, and the history of GERD endotherapy has shown that they can happen with the apparently simplest techniques.
      • Hogan W.J.
      Clinical trials evaluating endoscopic GERD treatments: is it time for a moratorium on the clinical use of these procedures?.
      The strength of this study is that it was prospective and was associated with objective evaluations such as pHmetry and anatomic evaluation. The affordable cost of ARAT may allow for its introduction into the repertoire for GERD if strict criteria for treatment are defined. For example, patients with only proven GERD nonresponsive to PPIs or intolerance to PPIs and with moderately altered anatomy of the cardia (Hill type II) could be offered such treatment. This indication niche, if confirmed in multicentric trials, may have the potential to become accepted for health insurance reimbursement, and these strict indications could avoid potential overuse of this treatment only in cash payers.

      Disclosure

      Dr Devière is the recipient of grants from Olympus and Boston Scientific and a shareholder in Endotools Therapeutics.

      References

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