Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Procedures for the Treatment of Gastroesophageal Reflux Disease (GERD)

Policy #:11.03.11n

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

SURGICAL FUNDOPLICATION

Surgical fundoplication of the lower esophageal sphincter (LES) is considered medically necessary and, therefore, covered for the treatment of gastroesophageal reflux disease (GERD) when an individual has either of the following:
  • Fails medical management with a conservative treatment approach that follows current standards of practice (e.g., lifestyle modifications, histamine2-receptor blockers, proton pump inhibitors, or promotility agents), as documented by a professional provider after a reasonable period
  • Develops comorbidities

TRANSESOPHAGEAL ENDOSCOPIC PROCEDURES

The following transesophageal endoscopic procedures for the treatment of GERD are considered experimental/investigational and, therefore, not covered because the safety and effectiveness of these procedures cannot be established by review of the available published peer-reviewed literature:
  • Transesophageal radiofrequency ablation, including, but not limited to:
    • Stretta® Therapy
  • Transesophageal endoscopic fundoplication, including, but not limited to:
    • transoral incisionless fundoplication (TIF) using EsophyX®, EsophyX®2, EsophyX®2 HD, EsophyX® Z, StomaphyX™, MUSE™ System, and Medigus SRS™ Endoscopic Stapling System
  • Transesophageal endoscopic suturing and plication, including, but not limited to:
    • Bard® EndoCinch™ Suturing System, Bard® Endoscopic Suturing System
    • NDO Surgical Endoscopic Plication System, NDO Plicator™
    • Syntheon ARD Plicator
  • Endoscopic submucosal implantation or injection of a bulking agent, including, but not limited to:
    • ethylene-vinyl alcohol (e.g., Enteryx™)
    • zirconium oxide spheres (e.g., Durasphere® GR)
    • Gatekeeper™ Reflux Repair System
    • polymethylmethacrylate (PMMA) beads

MAGNETIC ESOPHAGEAL RING IMPLANTATION

An implanted sphincter augmentation device to treat gastroesophageal reflux disease (GERD) (e.g., the LINX Reflux Management System) is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

ANTI-ESOPHAGEAL REFLUX DEVICE IMPLANTATION

Surgical implantation of an anti-gastroesophageal reflux device (e.g., the Angelchik Anti-Reflux Prosthesis, the EndoStim LES Stimulation System) is considered experimental/investigational and, therefore, not covered because the safety and effectiveness of this procedure cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.
Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, surgical fundoplication is covered under the medical benefits of the Company's products when medical necessity criteria in the medical policy are met.

Subject to the terms and conditions of the applicable benefit contract, antigastroesophageal reflux device implantation is not eligible for payment under the medical benefits of the Company’s commercial products (non-Medicare) because the service is considered experimental/investigational and, therefore, not covered.

Subject to the terms and conditions of the applicable benefit contract, transesophageal endoscopic procedures are not eligible for payment under the medical benefits of the Company's products because these services are considered experimental/investigational and, therefore, not covered. Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.

Subject to the terms and conditions of the applicable benefit contract, an implanted sphincter augmentation device to treat gastroesophageal reflux disease (GERD) is not eligible for payment under the medical benefits of the Company’s commercial products (non-Medicare) because the service is considered experimental/investigational and, therefore, not covered.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

The transesophageal endoscopic treatment of gastroesophageal reflux disease (GERD) is not regulated by the FDA; however, any device used in related procedures requires FDA approval.

The FDA has approved numerous devices for the treatment of symptomatic chronic gastroesophageal reflux disease.

The Syntheon ARD Plicator (Syntheon, Miami, FL) is not FDA approved for the treatment of symptomatic chronic gastroesophageal reflux disease.

The EndoStim LES Stimulation System (EndoStim, Dallas, TX) is not FDA approved for the treatment of symptomatic chronic gastroesophageal reflux disease.

The Gatekeeper Reflux Repair System (Medtronic, Shoreview, MN) is not FDA approved for the treatment of symptomatic chronic gastroesophageal reflux disease.

The ethylene vinyl alcohol (Enteryx™) device has FDA approval for injection into the lower esophageal wall. However, the manufacturer has issued a recall for all ethylene vinyl alcohol (Enteryx™) procedure kits, as the FDA instructed physicians to stop injecting ethylene vinyl alcohol because of serious, adverse events.

BILLING GUIDELINES

When reporting transesophageal endoscopic gastroplication, use a procedure code for an unlisted laparoscopy procedure, esophagus, or for an unlisted laparoscopy procedure, stomach.

When reporting transesophageal radiofrequency ablation, use a procedure code for an endoscopy of the upper gastrointestinal structures that includes the esophagus, stomach, and duodenum and/or jejunum, with application of thermal energy to the lower esophageal sphincter muscle and/or the gastric cardia, to treat GERD.

When reporting endoscopic implantation of polymethylmethacrylate beads and ethylene-vinyl-alcohol injections, use a procedure code for an unlisted laparoscopy procedure, esophagus, or for an unlisted laparoscopy procedure, stomach.

Description

Gastroesophageal reflux disease (GERD) is a condition in which gastric content refluxes into the esophagus, causing symptoms such as chronic heartburn and/or regurgitation and mucosal damage of the esophagus, i.e., esophagitis. Some individuals may also present with extraesophageal symptoms such as asthma, hoarseness, cough, chest pain, or aspiration.

Gastric reflux can result from a number of conditions, including gastric emptying disorder, failed esophageal peristalsis, or improper closure of the lower esophageal sphincter (LES). Symptoms are caused when refluxed stomach acid comes into contact with the lining of the esophagus.

The diagnosis of GERD is made when at least one of the following is demonstrated:
  • Chronic symptoms, including persistent heartburn, acid regurgitation, and/or dysphagia
  • The presence of esophageal mucosal injury determined by photographic or histological investigation
  • Excessive acid reflux evidenced through 24-hour intraesophageal pH monitoring

The goal of treatment is to relieve and control symptoms, heal and prevent the relapse of esophagitis, and prevent long-term complications. Treatment is typically individualized based on symptoms and their severity and can include lifestyle modifications or medical interventions such as antacid or proton-pump inhibitor (PPI) medication, or corrective antireflux surgery.

MEDICAL THERAPIES FOR GERD

The first line of treatment should include lifestyle modification, antacids, and over-the-counter acid suppressants for individuals who have uncomplicated GERD, i.e., heartburn and/or regurgitation).

Diagnostic work-up and/or gastroenterology evaluation is recommended for individuals whose symptoms persist while taking over-the-counter medications or who develop warning signs of dysphagia, bleeding, unplanned weight loss, chest pain, coughing, shortness of breath, or hoarseness.

Surgical or endoscopic intervention may be another option for treating GERD in either of the following instances:
  • Medical treatment fails after a reasonable period of medical management following current standards of practice (e.g., histamine receptor blockers, proton pump inhibitors, and promotility agents).
  • An individual develops comorbidities.

SURGICAL TREATMENTS FOR GERD

Surgical therapy may be considered for individuals who experience any of the following: failed medical management; complications of GERD, such as non-healing ulcer, Barrett’s esophagus, or grade 3 or 4 erosive esophagitis; complications attributable to a large hiatal hernia, such as bleeding or dysphagia; extraesophageal symptoms, such as asthma, hoarseness, cough, chest pain, or aspiration; and documented reflux on 24-hour ambulatory intraesophageal pH monitoring.

SURGICAL FUNDOPLICATION
Surgical fundoplication is considered the gold standard surgical intervention for individuals with refractory GERD. In this procedure, a portion or all of the stomach fundus is wrapped around the lower esophagus, consequently strengthening, lengthening, and raising the pressure of the LES. Fundoplication can be performed as an open or laparoscopic procedure.

TRANSESOPHAGEAL ENDOSCOPIC TREATMENTS FOR GERD

Several minimally invasive transesophageal endoscopic treatments for GERD have been investigated. Currently, the clinical effectiveness of these treatments has not been established by review of the available published literature. These treatments include, but are not limited to, the following technologies.

TRANSESOPHAGEAL RADIOFREQUENCY ABLATION
Stretta® System

The Stretta System (Mederi Therapeutics, Greenwich, CT) uses a monopolar electrosurgical catheter along with a radiofrequency (RF) generator to treat individuals whose GERD has not responded adequately to previous medical therapy with PPIs. The catheter consists of a flexible balloon-basket assembly with 4 electrode needle sheaths. RF is delivered at different levels starting 1 cm above the squamo-columnar junction. Each application lasts 60 seconds for a total of 22 sets of needle deployments with 4 antegrade levels at the junction and two rings of cardia lesions made in pull back. The procedure is easily carried out either under conscious sedation or general anesthesia on an outpatient basis.

Systematic Reviews and Meta-Analyses

In 2016, ECRI Institute published a Product Brief evaluating the Stretta System for treating gastroesophageal reflux disease. In their report, ECRI Institute stated that the results from studies on the Stretta procedure's effectiveness are mixed. However, the authors stated that the procedure does appear to be relatively safe. The authors further stated that "large, longer-term RCTs are needed to determine the efficacy of Stretta compared to other GERD procedures and PPI therapy".

In 2015, Lipka et al published a systematic review and meta-analysis evaluating the efficacy of Stretta for the management of GERD. Four RCTs [Corley et al (2003), Coron et al (2008), Aziz et al (2010), and Arts et al (2012)] with a total of 165 individuals were included in the meta-analysis (153 individuals were analyzed). Three of the trials compared Stretta to sham treatment, and one trial compared Stretta to PPI therapy. The authors reported that the overall quality of evidence was very low with a high risk of bias. The pooled results showed no significant difference between Stretta and sham or PPI management for the outcomes of mean (%) time the pH was less than 4 over a 24-hour time course, lower esophageal sphincter pressure (LESP), ability to stop proton pump inhibitors (PPIs), or health-related quality of life (HRQOL). The mean difference (control minus Stretta) in the percent time that pH was less than 4 was 1.56 (95% CI, -2.56 to 5.69). The mean difference for LESP was -0.32 mm Hg (95% CI, -2.66 to 2.02). The mean difference in HRQOL from 2 studies was -5.24 (95% CI, -12.95 to 2.46). The relative risk for the ability to discontinue PPIs was 0.87 (95% CI, 0.75 to 1.00). The authors concluded that "Stretta for patients with GERD does not produce significant changes, compared with sham therapy, in physiologic parameters, including time spent at a pH less than 4, LESP, ability to stop PPIs, or HRQOL". This meta-analysis is limited by heterogeneity in the included studies, which may be due to small sample sizes, differences in measures, and differences in follow-up time.

In a 2015 clinical review, Lo and Mashimo stated the following regarding Stretta radiofrequency treatment: "A wealth of research has demonstrated the safety, efficacy, durability, and repeatability of Stretta radiofrequency treatment. Most important, it does not preclude alternative treatments including medical, surgical, or repeat radiofrequency treatments, and may also provide potential treatment for patients who have failed fundoplication. Stretta is likely the least expensive alternative to medical therapy. This technique should be considered a viable complement or alternative to medical and surgical treatment of GERD symptoms."

In a meta-analysis, Perry et al. (2012) performed a comprehensive search for studies evaluating the effectiveness of the Stretta procedure in controlling symptoms in individuals with GERD. Twenty studies (2 RCTs, 18 case series), published between 2000 and 2010, representing 1441 individuals, were included in the meta-analysis. The outcomes of interest were subjective indices [assessed as heartburn and individual satisfaction scores, disease specific quality-of-life scores (GERD-HRQL and QOLRAD), and global quality-of-life scores] and objective indices [assessed as DeMeester scores (composite pH scores of global esophageal acid exposure), esophageal acid exposure (EAE) time, and mean lower esophageal sphincter (LES) pressure.] In pooled analysis, the review found statistically significant improvements in the subjective indices of individuals who had undergone the Stretta procedure: GERD-HRQL score (lower scores indicate better outcome): 26.11 (baseline) versus 9.25 (Post-Stretta); mean follow-up of 19.8 months; p = 0.0001]; [QOLRAD Score (higher scores indicate better outcome): 3.30 (baseline) versus 4.97 (post-Stretta); mean follow-up of 25.2 months; p = 0.001], and Heartburn score (lower score indicates better outcome): 3.55 (baseline) versus 1.19 (Post-Stretta); mean follow-up of 24.1 months; p = 0.0001). The authors also found statistically significant improvements in some objective indices: LES pressure (higher pressure indicates better outcome): 16.54 (baseline) versus 20.24 (post-Stretta); mean follow-up of 8.7 months; p = 0.03], and [esophageal acid exposure (lower better): 10.29 (baseline) versus 6.51 (Post-Stretta); mean follow-up of 11.9 months; p = 0.0003]. Average composite esophageal PH scores also improved but did not normalize (DeMeester score < 14.72): DeMeester score (lower scores indicate better outcome: 44.37 (baseline) versus 28.53 (Post-Stretta); mean follow-up of 13.1 months; p = 0.007. Across all studies, gastroparesis and ulcerative esophagitis were the most commonly reported complications resulting from the Stretta procedure. The authors concluded that Stretta significantly improves reflux symptoms in the short and intermediate term and may be used as an alternative to other GERD interventions in well-selected individuals. This meta-analysis is limited by significant variation in the included studies specifically, heterogeneity in study populations and differences in inclusion criteria and variable classification among studies. The risk of publication bias may also be a concern.

In 2011, the Agency for Healthcare Research and Quality (AHRQ) published a report which concluded that for the 3 available endoscopic procedures (EndoCinch, Stretta, EsophyX), effectiveness remains substantially uncertain for the long-term management of GERD. The study noted that while some clinical benefits were observed in individuals who had undergone these procedures, these studies had been generally small, of variable quality, and of short duration. In addition, all of these procedures had been associated with complications, including dysphagia, infection/fever, and bloating. They concluded that higher quality studies are needed to determine the role and value of endoscopic procedures in the treatment of individuals with GERD. This was an update of a systematic review on management strategies for gastroesophageal reflux disease published in 2005. The 2005 review included EndoCinch and Stretta, as well as Enteryx and the NDO Plicator. Enteryx and the NDO Plicator were excluded from the 2011 update because they were no longer available in the United States, and EsophyX was added.

Randomized Controlled Trials Comparing Transesophageal Radiofrequency to a Sham Procedure

In 2003, Corley et al reported the results of a randomized, sham-controlled trial evaluating radiofrequency energy delivered to the gastroesophageal junction to a sham procedure. A total of 64 individuals were randomized, with 35 individuals treated with radiofrequency energy and 29 individuals treated with a sham procedure. Partial or complete 6-month follow-up data were available on 56 individuals. The results of this trial were inconsistent. Although improvement in heartburn symptoms, quality of life, and general physical quality of life was observed in the radiofrequency energy group compared with the sham group, there were no differences in medication usage and esophageal acid exposure. Thus in terms of the objective measures of GERD, the findings are equivocal. In addition, a large proportion of sham-treated individuals successfully reduced their use of medication, which indicates a possible placebo effect of the procedure.

In a randomized, double-blind, sham-controlled trial, Aziz et al. (2010) investigated the impact of single-dose and double-dose Stretta on outcomes in individuals with GERD. Thirty-six individuals were randomized to three groups: the first (n = 12) underwent a single treatment of Stretta; the second (n =12) underwent a sham procedure; and in a third group (n =12), individuals underwent single Stretta treatment followed by repeat Stretta if an individual’s GERD-HRQL score had not improved by 75% in 4 months. The study’s primary outcome was improvement in GERD-HRQL scores, while secondary outcomes were changes in PPI usage, LES basal pressure, endoscopic grade of esophagitis, and EAE measured by pH probe. At 12- month follow-up, mean GERD-HRQL scores were significantly better in both Stretta groups [single treatment (51.3%) and double treatment group (65.5%)] compared with the Sham group (18.2%). Additionally, 17% of individuals in the single-session group, 50% in the double-session group, and 0% of the sham-treated indiviudals had discontinued PPIs, and EAE had normalized in 50% of individuals in the treatment group compared to 0% of those in the control group. There were no serious complications, and only two individuals experienced significant delayed gastric emptying after undergoing a second Stretta treatment. The authors concluded that Stretta significantly improves both objective and subjective outcomes in individuals with GERD. They also stated that improvement with double therapy is superior to that with single therapy but cautioned that higher doses of RF energy increase risk of thermal injury to the vagus nerve, which in turn could lead to gastroparesis. This study is limited by a small sample size.

In 2012, Arts et al reported the results from a double-blind randomized crossover study of Stretta and sham treatment in 22 individuals (11 in each treatment group) with GERD. Individuals underwent two upper gastrointestinal endoscopies with a 3 month interval, during which active or sham Stretta treatment was performed in a randomized double-blind manner. Symptom assessment, endoscopy, manometry, 24-h esophageal pH monitoring, and a distensibility test of the gastro-esophageal junction (GEJ) were performed before the start of the study and after 3 months. The initial sham treatment in 11 individuals did not affect any of the outcome measures. Three months after the Stretta procedure, the symptom score was significantly improved (14.7 to 8.3), and gastroesophageal junction compliance was significantly decreased (17.8 vs 7.4 mL/mm Hg). The quality-of-life score for bodily pain improved from 49.5 to 24.0. No changes were observed in PPI use, esophageal acid exposure, or lower esophageal sphincter pressure after the Stretta procedure. The decrease in compliance of the gastroesophageal junction was reversed by a smooth muscle relaxant, suggesting that the effect of the Stretta procedure on gastroesophageal junction compliance was not due to fibrosis.

In 2008, Coron et al reported the results of an unblinded, prospective randomized trial of 43 PPI-dependent individuals with GERD who either continued the effective dose of their PPI or received the Stretta procedure. At 6 months, significantly more individuals in the Stretta group compared to the control group were able to discontinue or decrease their PPI use by at least 50%. In the Stretta group, 18/20 individuals stopped (n=3) or decreased (n=15) PPI use as compared to eight of 16 in the PPI group (p=0.01). None of the PPI individuals could stop PPI. This difference was not maintained at 12 months. The number of individuals able to discontinue PPI medication did not differ significantly between groups. Health-related quality of life scores were not different between groups. No significant change in oesophageal acid exposure (OAE) was noted between baseline and 6-months after Stretta. No severe complication was reported.

Controlled Trials Comparing Transesophageal Radiofrequency to Laparoscopic Fundoplication

In 2015, Liang et al reported the results from a prospective observational study assessing the short-term and mid-term outcomes associated with laparoscopic Toupet fundoplication (LTF) and the Stretta procedure in the treatment of GERD. Eighty individuals were treated with LTF, and 85 individuals were treated using the Stretta procedure. Of the 165 patients treated, 65 LTF individuals and 60 Stretta individuals completed the 3-year follow-up and were included in the analysis. At the end of the 3-year follow-up, the symptom scores were all significantly decreased compared with the corresponding values before the two procedures in both groups (p<0.05). After LTF and the Stretta procedure, 47/65 (72.3%) and 41/60 (68.3%) individuals, respectively, achieved complete PPI therapy independence (72.3% versus 68.3%, p=0.627). The Stretta procedure was less effective than LTF in improving symptoms of heartburn (mean improvement, 2.53 vs 4.05; p=0.01), regurgitation (mean improvement, 2.41 vs 4.03; p=0.004), and chest pain (mean improvement, 2.96 vs 5.50; p=0.005). Significantly more individuals in the Stretta group underwent reoperation (11.8% vs 0%; p=0.006), while more individuals in the LTF group complained of bloating (6.2% vs 0%, p=0.120), but these differences were not statistically significant. This study lacked randomization and had high loss to follow-up. While symptom scores were comparable at baseline, the study may have been subject to selection bias related to treatment choice, which may have affected baseline differences for other variables.

Case Series Trials

In a prospective case series, Noar et al. (2014) used an intent-to-treat analysis to assess outcomes of 99 consecutive individuals with symptomatic GERD who had undergone the Stretta procedure at their facility. Of a total of 217 patients treated, 149 had reached 10-year follow-up. Of those, 50 were lost to follow-up (11 were deceased), resulting in 99 patients in the cohort. The primary endpoint was defined as normalization of GERD-HRQL scores in 70% or more of study participants by 10-year follow-up. Secondary endpoints were 50% or greater reduction or cessation of PPI usage at 10-year follow-up, and 60% or greater improvement in satisfaction scores compared to baseline. At 10-year follow-up, GERD-HRQL scores had normalized in 72% of participants (n=71) and overall, 64% of participants had a 50% or greater reduction in PPI use, and 41% eliminated PPIs completely. Additionally, satisfaction scores increased greater than 60% in 55% of participants. Two episodes of minor proximal gastric bleeding were reported. Comparison of results out to 4 years in the total cohort (n=217) and completers only (n=99) showed no evidence of bias associated with non-completers. The authors concluded that their findings establish Stretta as a safe and viable option for individuals with GERD. This study is limited by significant attrition and lack of an appropriate control. The risk of publication bias may also be a concern.

Liang et al (2014) reported the results from a prospective observational study that evaluated outcomes of individuals with refractory GERD five years after the Stretta procedure. A total of 152 individuals underwent the Stretta procedure. They were followed up for 5 years, during which the primary outcome measures including symptom scores of heartburn, regurgitation, chest pain, cough and asthma and the secondary outcome measures including proton pump inhibitor (PPI) use and patients' satisfaction were analyzed at 6, 12, 24, 36, 48 and 60 months respectively. Of the 152 patients, 138 completed the designated 5-year follow-up and were included in the final analysis. At the end of the 5-year follow-up, the symptom scores of heartburn (2.47 ± 1.22 vs. 5.86 ± 1.52), regurgitation (2.23 ± 1.30 vs. 5.56 ± 1.65), chest pain (2.31 ± 0.76 vs. 4.79 ± 1.59), cough (3.14 ± 1.43 vs. 6.62 ± 1.73) and asthma (3.26 ± 1.53 vs. 6.83 ± 1.46) were all significantly decreased as compared with the corresponding values before the procedure (p<0.001). After the Stretta procedure, 59 (42.8%) individuals achieved complete PPI therapy independence and 104 (75.4%) individuals were completely or partially satisfied with the GERD symptom control. No severe complications were observed except for complaint of abdominal distention in 12 (8.7%) individuals after the Stretta procedure. No reoperations were reported.

In 2011, Dughera et al reported the 4-year results from 56 individuals with GERD who were treated with the Stretta procedure. Stretta treatment significantly improved heartburn scores, GERD-specific quality of life scores, and general quality of life scores at 24 and 48 months in 52 out of 56 individuals (92,8%). At each control time both mean heartburn and GERD-HRQL scores decreased (p=0.001 and p=0.003, respectively) and both mental SF-36 and physical SF-36 ameliorated (p=0.001 and p=0.05, respectively). At 48 months, 41 out of 56 patients (72,3%) were completely off PPIs. Morbidity was minimal, with only one relevant but transient complication.

In a prospective single-center case series, Reymunde and Santiago (2007) evaluated the efficacy of the Stretta procedure for individuals with GERD based on symptom control, quality of life (QOL), and medication use. The primary assessment was a validated health-related QOL score for heartburn and regurgitation and GERD symptoms index performed at baseline, 12, 36, and 48 months after treatment. A secondary outcome measure was the dose and the frequency of antisecretory pharmaceutical use. The Stretta procedure was performed in 83 consecutive individuals with persistent GERD symptoms. The mean GERD QOL score was 2.4 (baseline), 4.6 (36 months), and 4.3 (48 months, p<0.001). The mean GERD symptom score was 2.7 (baseline), 0.3 (36 months), and 0.6 (48 months, p<0.001). Daily medication usage was 100% (baseline) and 13.6% (48 months, p<0.001). Limitations of this study include: nonrandomized study design, lack of control arm, and lack of 24-hour pH.

Practice Guidelines and Position Statements

In 2013, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) provided evidence-based guidelines on endoluminal treatments for GERD. In their guidelines, SAGES gave a strong recommendation based on high-quality evidence that Stretta is considered appropriate therapy for patients being treated for GERD who are 18 years of age or older, who have had symptoms of heartburn, regurgitation, or both for 6 months or more, who have been partially or completely responsive to antisecretory pharmacologic therapy, and who have declined laparoscopic fundoplication.

In 2013, the National Institute for Health and Care Excellence (NICE) updated their interventional procedure guidance on endoscopic radiofrequency treatment for GERD, stating that although the evidence on the safety of this intervention is adequate in the short and medium term, there is uncertainty about longer-term outcomes. They also noted that with regard to efficacy, there is evidence of symptomatic relief but objective evidence on reduction of reflux is inconclusive. They concluded that this procedure should only be used with special arrangements for clinical governance, consent and audit or research. They also noted that their reviewing committee expressed concern about the possibility that symptoms in individuals undergoing RF ablation may improve as a result of denervation caused by the procedure; if this were the case, then failure to recognize and treat reflux might lead to complications in the long term.

Summary

The evidence base evaluating the use of radiofrequency energy (e.g., the Stretta procedure) to treat GERD included four small randomized controlled trials which reported improvements in symptoms and quality of life following treatment, however, a meta-analysis of these same trials found no significant improvement in outcomes. Nonrandomized studies show maintenance of efficacy at 3 to 10 years, however symptom relief with radiofrequency energy may be lower than with fundoplication and reoperations greater. Larger randomized controlled trials with longer follow-up are needed to better define the risks and benefits of this procedure.

ENDOSCOPIC SUTURING OR PLICATION
EsophyX® System / EsophyX®2 System / EsophyX®2 HD Device / EsophyX® Z Device / StomaphyX™

The EsophyX System (EndoGastric Solutions, Inc., Redmond WA) creates a transoral incisionless fundoplication (TIF). The EsophyX device is a cylindrical tool that enables transoral modeling of the gastric cardia and fundus to the esophagus, with the placement of multiple transmural H-shaped polypropylene fasteners to fix the molded tissues in place. The device is introduced transorally over a flexible endoscope with the individual under general anesthesia. A specially designed helical retractor and tissue mold enable the surgeon to elongate the gastric cardia (TIF1 technique) or to fold the gastric fundus around the esophagus (TIF2). With tissues held in place by the tissue mold and helical retractor, stylets are deployed from the device chassis and traverse the molded tissue. H-shaped fasteners are deployed over these stylets in a circumferential fashion to create a plication that resembles a surgical fundoplication.

Several different versions of the EsophyX System have been cleared for marketing by the FDA through the 510(k) process. All versions of the EsophyX System are indicated for use in endoluminal, transoral tissue approximation, full thickness plication and ligation in the GI tract and are indicated for the treatment of symptomatic chronic GERD in individuals who require and respond to pharmacological therapy. They are also indicated to narrow the gastroesophageal junction and reduce hiatal hernia less than 2cm in size in individuals with symptomatic chronic GERD. The predicate device to the EsophyX System is the StomaphyX (EndoGastric Solutions, Inc., Redmond WA), which is indicated for use in endoluminal transoral tissue approximation and ligation in the GI tract.

Systematic Reviews and Meta-Analyses

In 2017, Huang et al. conducted a systematic review with meta-analysis of TIF for the treatment of GERD. They included 5 RCTs and 13 prospective observational studies, of which 14 were performed with the TIF 2 procedure. Efficacy results from the RCTs were combined for individuals whose symptoms were controlled by PPIs and for those whose symptoms were not controlled by PPIs. Follow-up to six years in prospective observational studies indicated a decrease in efficacy over time.

In 2016, ECRI Institute published a Product Brief evaluating EsophyX for treating gastroesophageal reflux disease. In their report, ECRI Institute stated that "[o]verall, the comparative results for EsophyX are mixed. Some analyses favor EsophyX; others favor laparoscopic fundoplication."

In a systematic review, Wendling et al (2013) performed a comprehensive search for studies evaluating the impact of TIF performed with the EsophyX device in individuals with GERD. The review included 15 studies published between January 2006 and March 2012 representing 550 procedures. Both subjective data (e.g., GERD-HRQL) and objective data (e.g., DeMeester scores (composite pH scores)) were extracted from the included studies. In a pooled analysis, statistically significant improvements were reported in the subjective indices of individuals who had undergone TIF: GERD-HRQL (lower score representing better outcome): 21.9 vs. 5.9, p<0.0001; mean follow-up 9.8 months, and Reflux Symptom Index—RSI (lower score representing better outcome): 24.5 vs 5.4, p<0.0001; mean-follow-up 7.6 months. In terms of objective outcomes, the review found that PPI discontinuation was 67% across all studies with a mean follow-up of 8.3 months. DeMeester scores had also decreased in 3 of the 4 studies reporting pH measurements (data not included) but did not normalize (DeMeester score<14.72). The major complication rate was 3.2% across all studies and reported complications included: hemorrhage (n=6), mediastinal abscess (n =1) and esophageal perforations (n =4). Commonly reported side effects were de novo dysphagia (n=3), and bloating (n = 7). The authors concluded that TIF appears to provide symptomatic relief with reasonable levels of individual satisfaction at short-term, but that a well-designed prospective clinical trial is needed to assess long-term outcomes and to identify the individual population likely to benefit from this procedure. This study is limited by the heterogeneity of included studies: studies differed in study population characteristics, variable classification, surgical procedure protocol, etc.

Randomized Controlled Trials Comparing TIF with EsophyX to Medical Therapy

In 2015, Hunter et al reported the results from a prospective, sham-controlled trial that sought to determine whether or not TIF using the EsophyX2 device was better than PPI treatment of troublesome GERD symptoms, particularly regurgitation, in a population of chronic PPI-dependent GERD individuals. Individuals with GERD and hiatal hernias ≤2 cm were randomly assigned to groups that underwent TIF using the EsophyX2 device and then received 6 months of placebo (n=87), or sham TIF and 6 months of once- or twice-daily omeprazole (controls, n=42). Individuals were blinded to therapy during follow-up period and reassessed at 2, 12, and 26 weeks. At 6 months, individuals underwent 48-hour esophageal pH monitoring and esophagogastroduodenoscopy. The primary outcome was elimination of troublesome regurgitation at 6 months. Secondary outcomes included percent early failure (continued troublesome regurgitation at 3 months after increased medication), symptom scores, acid exposure, healing of esophagitis, and common side effects of treatment. The intention-to-treat analysis of the primary outcome (elimination of troublesome regurgitation) showed that the TIF group had a success rate of 67% (58 out of 87 individuals) whereas the control group had a success rate of 45% (19 out of 42 individuals) (p=0.023). A larger proportion of controls had no response at 3 months (36%) than individuals that received TIF (11%; p=0.004). Other secondary outcomes (e.g., RDQ regurgitation score, RDQ heartburn score) showed no significant differences between treatments. Physiologic measurements such as number of reflux episodes, percent total time pH less than 4, and DeMeester score (a composite score of acid exposure based on esophageal monitoring) showed differences that were statistically significant.

In a randomized double-blind sham-controled trial, Hakansson et al (2015) compared TIF using EsophyX (n=22) to sham only (n=22) in individuals who were well controlled by chronic PPI treatment. Although individuals were controlled by chronic PPI treatment, trial eligibility required a run-in phase that required persistent GERD symptoms off PPI therapy and abnormal laboratory or endoscopic findings consistent with recurrence of GERD. Thus the expected outcome in the sham group was that, without PPI, GERD symptoms would eventually recur. The primary outcome was the proportion of individuals in clinical remission after 6-month follow-up. Secondary outcomes were: PPI usage, oesophageal acid exposure, reduction in Quality of Life in Reflux and Dyspepsia and Gastrointestinal Symptom Rating Scale scores and healing of reflux esophagitis. Kaplan-Meier curves of treatment failure showed a higher rate of treatment failure in the sham group than in the TIF group (p<0.001, time to treatment failure). The average time in remission in the TIF group was 197 days versus 107 days in the sham group (p<0.001). After 6 months, 59% (13 out of 22) of the individuals in the TIF group were in remission compared to 18% (4 out of 22) of the individuals in the sham group (p=0.01). Secondary outcome measures were all in favor of the TIF procedure.

In a randomized controlled trial, Witteman et al (2015) evaluated the effectiveness of TIF using EsophyX (n=40) to continuing PPI therapy (n=20) without sham surgery in individuals with GERD that was well-controlled with PPIs. The study was described as an equivalence trial, whose objective was to demonstrate that outcomes with TIF were not significantly worse than those with continued PPI therapy. The declared equivalence delta was 2 points measured on the GERD-HQRL. The primary outcome was treatment success, defined by an improvement of 50% or more on the GERD-HQRL. Secondary outcome measures included adverse events, esophageal acid exposure, number of reflux episodes, PPI usage, appearance of gastroesophageal valve, and healing of esophagitis. The trial was originally designed as a two center study, but this analysis was reported as an interim before the second center enrolled patients. Based on these results, the trial was terminated. Another critical aspect of the study is that baseline measurements of GERD symptoms were assessed after a 14-day cessation period of PPI therapy, thus allowing GERD symptoms to recur in many individuals. Thus baseline GERD symptom levels do not represent individuals’ steady-state levels of controlled symptoms. In the PPI therapy group, PPI therapy was stepped up or down as necessary during follow-up. In the TIF group, although individuals did not initially start PPI therapy, they were allowed to use PPI in a similar step-up or step-down protocol as controls. At 6 months, 55% of the TIF group had more than 50% improvement in GERD symptoms versus 5% of the PPI group (p<0.001). Mean change in GERD symptoms from baseline was consistent with this result (TIF group, -14.1; control group, -3.1; p<0.001). For this primary outcome, the noninferiority aspect of the trial is irrelevant, because the superiority result means that the noninferiority criterion was also met. Twenty-six percent of TIF group resumed at least occasional PPI use by 6 months, and 100% of control group remained on PPI therapy. With the exception of LES resting pressure, secondary physiologic and endoscopic outcome measures did not differ significantly between groups.

Individuals in the TIF group were followed beyond 6 months as a nonrandomized case series, with additional individuals from the control group who crossed over to have TIF. A total of 60 individuals eventually underwent TIF, but there were losses to follow-up at 6 (7 individuals) and 12 months (an additional 8 individuals). Although GERD symptoms remained improved over baseline (p<0.05), esophageal acid exposure did not differ significantly from baseline. At least occasional use of PPI increased between 6 months and 12 months, from 34% to 61%. Three TIF individuals underwent fundoplication during this follow-up period. Endoscopy findings at 6 months and 12 months showed several findings indicating possible worsening of GERD in terms of esophagitis rating, Hill grade rating of the gastroesophageal valve, and size of hiatal hernia, but no formal statistical analysis of these changes was reported. Although this RCT met its principal end point at 6 months, and improvements in GERD symptoms appeared to be maintained to 12 months, due to findings observed between 6 months and 12 months in TIF individuals, the authors concluded that “TIF is no[t an] equivalent alternative for PPIs in GERD treatment, even in this highly selected population.”

In a multi-center, randomized clinical trial, Trad et al (2015) compared the safety and effectiveness of TIF to PPIs in controlling symptoms in individuals with GERD. Sixty-three individuals met the study’s eligibility criteria and were randomized to 2 arms: a control group (n=23) placed on the Maximum Standard Dose (MSD) of current PPI therapy, and an experimental group (n=40) undergoing the TIF procedure performed with the EsophyX device. At 6-month follow-up, 3 individuals had been lost to attrition, leaving 39 TIF and 21 MSD-PPI individuals. The study’s primary outcome was the elimination of troublesome regurgitation or extraesophageal symptoms, while the secondary outcomes were normalization of esophageal acid exposure, PPI usage, and healing of esophagitis. At 6-month follow-up, the study found that subjective indices were significantly better in the TIF group compared with the PPI group: troublesome regurgitation was eliminated in 97% of TIF individuals versus 50% of PPI individuals (RR=1.9; p=0.006), and, overall, 62% of TIF individuals experienced elimination of regurgitation and extraesophageal symptoms versus 5% of PPI individuals (RR=12.9; p=0.009). In terms of objective indices, they found that 90% of individuals in the TIF group had ceased taking PPIs, and endoscopic assessment revealed that more individuals in the TIF group achieved complete healing or reduction in reflux esophagitis compared with those in the PPI group (90% versus 38%, respectively; p=0.018). However, the study found no statistically significant difference in EAE normalization between the two groups: 54% of individuals in the TIF group had normalized versus 52% of individuals in the PPI group (RR=1.0; p=0.914). There were no reports of serious adverse events or hospital readmissions associated with the TIF procedure. The authors concluded that at 6-month follow-up, TIF was more effective than MSD PPI therapy in eliminating troublesome regurgitation and extraesophageal symptoms of GERD. The study is limited by the lack of an appropriate control (i.e., a sham procedure), short follow-up time and risk of potential publication bias. At three year follow-up, about twice as many individuals reported symptom improvement compared with improvement in the objective measure. It is not clear whether the discrepancy is due to a general lack of correlation between pH and symptoms, or to a placebo effect on the subjective assessment. Together, these data suggest that the most appropriate comparator for individuals whose symptoms are not controlled on PPIs is laparoscopic fundoplication.

Trials Comparing TIF with EsophyX to Laparoscopic Fundoplication

In 2011, Svoboda et al published the results from a RCT that compared TIF using either the Plicator method (n=18) or EsophyX (n=16) to Nissen laparoscopic fundoplication (NLF; n=18). Individuals were enrolled if they had chronic GERD symptoms, abnormal esophageal acid exposure test results, partial response to PPI therapy, hiatal hernia < 2 cm, and no findings associated with severe esophagitis and/or complications. At 12-months follow-up, 76% (26/34) of the individuals in the TIF group and 78% (14/18) of the individuals in the NLF group were available. GERD-HRQL scores improved in both groups to a similar extent at 3 months and 12 months (12-month scores, 6.6 for TIF vs 6.7 for NLF; p=0.7). In terms of the percentage of individuals with 50% or more improvement in GERD-HRQL scores at 12 months, results were similar (68% for TIF vs 71% for NLF; p=0.397). Fifty percent of the TIF group were off PPIs at 12 months versus 71% of the NLF group (p=0.2). The hospital stay was significantly shorter (p<0.0001) in TIF group (average, 2.9±0.8 days) than in NLF group (average, 6.4±0.7). Four serious adverse events occurred: 1 in the TIF group and 3 in the NLF group. The adverse event in the TIF group did not occur in an EsophyX subject. The adverse events in the NLF group were unrelated to surgery. Using U.S. Preventive Services Task Force criteria, this RCT was rated poor for the following reasons: TIF was performed using a different device in some individuals and the reporting lacked details on other aspects of the trial. Furthermore, more than half of the individuals who had TIF did so using a discontinued device. Therefore, the trial results may not generalize specifically to EsophyX. In addition, there was no separate analysis of individuals undergoing TIF with the EsophyX device.

In 2011, Frazzoni et al reported the results from a nonrandomized study that compared 10 individuals who chose to undergo TIF using EsophyX to 10 individuals who chose to undergo laparoscopic fundoplication (LF). Eligible individuals had persisting symptoms despite at least four weeks of high-dose PPI therapy. Individuals with signs of severe esophagitis and extra-esophageal manifestations of GERD were excluded. At baseline, patients had similar levels of acid exposure and reflux as assessed by preprocedure endoscopy and manometry. With regards to clinical outcomes assessed at 3 months, 7 individuals in the TIF group reported only partial/no symptom remission versus 0 individuals in the LF group (p=0.003). Mild dysphagia was reported by 2 individuals after LF and 1 individual after TIF. Two individuals reported epigastric bloating after LF. Several measures of GERD as assessed by manometry and impedance pH monitoring showed greater improvement in the LF group than in the TIF group. This study reported that TIF is less effective than LF in improving symptoms of GERD.

In a nonrandomized, case-controlled study published by Toomey et al (2014) compared three cohorts of individuals undergoing TIF using EsophyX (n=20), laparoscopic Nissen fundoplication (LNF; n=20), or Toupet fundoplication (TF; n=20). The authors stated that age, body mass index, and preoperative DeMeester score were controlled, but it is not clear how this matching or control was achieved. The indications for each procedure resulted in an imbalance in important individual characteristics. For example, individuals with abnormal esophageal motility underwent TF, and only individuals who had a hiatal hernia of 2 cm or less were offered TIF. Due to these selection criteria, at baseline, 15% of the TIF group had a hiatal hernia versus 65% and 55% of the 2 fundoplication groups. Another incidental difference in baseline characteristics was the proportion of individuals undergoing a reoperation for GERD: 25% in the TIF group versus 5% and 5% in the 2 fundoplication groups. It is unclear from the article at what time postsurgery the outcomes were evaluated. An analysis plan was not provided, and it is unclear how statistical testing was performed. Results are displayed in the published article as preoperative and postoperative median values of various symptoms’ severity or frequency for each procedure. It appears as if, qualitatively, most measures of symptoms decreased to low levels (median ranges, 0-2) after all procedures. The authors stated that “… there was significant amelioration of symptom frequency and severity and with no significant difference among patients who underwent TIF or … Nissen or Toupet fundoplications.” At follow-up, 83% of the individuals in the TIF group, 80% of the individuals in the LNF group, and 92% of the individuals in the TF group had symptoms less than once per month (p= 0.12). Patient-rated satisfaction was 67% for TIF, 86% for LNF, and 92% for TF (p value not reported), but described as “similar.” Adverse events were not reported for any of the procedures.

Practice Guidelines and Position Statements

In 2013, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) provided evidence-based guidelines on endoluminal treatments for GERD. In their guidelines, SAGES gave a weak recommendation based on low-quality evidence for the EsophyX procedure, stating that long-term data are not yet available and that further studies are required to define optimal techniques and most appropriate patient selection criteria, and to further evaluate device and technique safety.

In 2011, the National Institute for Health and Care Excellence (NICE) issued guidance on endoluminal gastroplication for gastro-oesophageal reflux disease, stating that “The evidence on endoluminal gastroplication for gastro-oesophageal reflux disease (GORD) raises no major safety concerns. Evidence from a number of randomised controlled trials (RCTs) shows a degree of efficacy in terms of reduced medication requirement in the short term, but changes in other efficacy outcomes are inconsistent and there is no good evidence of sustained improvement in oesophageal pH measurements. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.”

Summary

The evidence base comparing the use of TIF (using EsophyX) to medical therapy for the treatment of GERD included four randomized controlled trials. Although the trials have shown that GERD symptoms improve with TIF compared to medical therapy, analysis of outcomes was limited to 6 months post-procedure. Differences between trials in patient selection criteria, intervention comparators, and outcome measures make it difficult to determine the magnitude of treatment benefit. Longer term follow up studies are needed to assess the clinical significance and durability of the results.

The evidence base comparing the use of TIF (using EsophyX) to fundoplication for the treatment of GERD included three nonrandomized trials. The evidence is not sufficient to demonstrate that TIF improves the net health outcome compared to fundoplication. Studies comparing TIF to fundoplication are small and have numerous methodological weaknesses. Therefore, studies comparing TIF and fundoplication are inadequate to determine relative efficacy.

Medigus Ultrasonic Surgical Endostapler or MUSE™ System (formerly the SRS™ Endoscopic Stapling System)

The MUSE System (MediGus Ltd., Omer, Israel) creates a transoral incisionless fundoplication (TIF). According to the FDA the system enables the operator to staple the fundus of the stomach to the esophagus, in two or more locations around the esophageal circumference, entirely through the mouth, without incisions. The system consists of three main parts: the endoscopic stapler, the control console and several accessories.

In 2014, the Medigus Ultrasonic Surgical Endostapler (MUSE) was cleared for marketing by the FDA through the 510(k) process. The system is intended for endoscopic placement of surgical staples in soft tissue of the esophagus and stomach in order to create anterior partial fundoplication for treatment of symptomatic chronic GERD in individuals who require and respond to pharmacological therapy. The predicate device to the MUSE System is the Medigus SRS Endoscopic Stapling System (MediGus Ltd., Omer, Israel), which has the same indication as the MUSE System.

Systematic Reviews and Meta-Analyses

In a 2015 clinical review, Lo and Mashimo stated the following regarding the MUSE System: "Initial 6-month follow-up data for MUSE are promising, although the presence of 2 early severe adverse events including esophageal leak and postprocedural upper gastrointestinal bleeding necessitated changes to the procedure protocol and to the device. Questions about safety and long-term durability of symptom relief remain."

Clinical Trials

In 2014, Danalioglu et al compared the safety and efficacy of the SRS Endoscopic Stapling System (SRS) to laparoscopic anti-reflux surgery (LARS). Twenty-seven individuals enrolled in the study. Eleven underwent SRS and 16 underwent LARS. Symptoms were assessed using Velanovich GERD-health-related quality of life (GERD-HRQL) scores. The groups were compared in reference to operation time, improvement in GERD-HRQL scores, and postoperative course. Chi-squared and Mann-Whitney-U-tests were used for statistical analysis. Both groups were statistically similar. An esophageal perforation observed in the SRS group completely recovered after over-the-scope clipping. Procedure times for SRS and LARS were 89 and 47 minutes, respectively (p < 0.05). Mean discharge time was longer for SRS than LARS (3 days vs 1.2 days, p< 0.05). However, this difference disappeared with the exclusion of a complicated patient with long hospitalization in the SRS group. During 6 months mean follow up, PPI use was higher in the SRS group compared to the LARS group, but the difference was not significant. Mean GERD-HRQL scores dropped in 87% and in 64% of individuals (p>0.05) from 29.3 to 4.1 and from 24.8 to 8.9 (p=0.016) in LARS and SRS groups, respectively.

In 2015, Zacherl et al reported the results from a multi-center, prospective study that evaluated the clinical experiences of 69 individuals who received the Medigus Ultrasonic Surgical Endostapler (MUSE). Individuals with well-categorized GERD were enrolled at six international sites. Efficacy data was compared at baseline and at 6 months post-procedure. The primary endpoint was a ≥ 50% improvement in GERD health-related quality of life (HRQL) score. Secondary endpoints were elimination or ≥ 50% reduction in dose of PPI medication and reduction of total acid exposure on esophageal pH probe monitoring. A safety evaluation was performed at time 0 and weeks 1, 4, 12, and 6 months. Sixty-six individuals completed follow-up. Six months after the procedure, the GERD-HRQL score improved by >50% off PPI in 73% (48/66) of individuals (95% CI 60-83%). Forty-two individuals (64.6%) were no longer using daily PPI medication. Of the 23 individuals who continued to take PPI following the procedure, 13 (56.5%) reported a ≥ 50% reduction in dose. The mean percent of total time with esophageal pH <4.0 decreased from baseline to 6 months (p<0.001). Common adverse events were peri-operative chest discomfort and sore throat. Two severe adverse events requiring intervention occurred in the first 24 subjects, no further esophageal injury or leaks were reported in the remaining 48 enrolled subjects. From their results, the authors concluded that "[t]he initial 6-month data reported in this study demonstrate safety and efficacy of this endoscopic plication device. Early experience with the device necessitated procedure and device changes to improve safety, with improved results in the later portion of the study. Continued assessment of durability and safety are ongoing in a three-year follow-up study of this patient group."

Bard® EndoCinch™ Suturing System / Bard® Endoscopic Suturing System

In this procedure, a metal guidewire with a spring tip is passed through the endoscope into the pylorus and the endoscope is removed. A polyvinyl dilator and overtube are passed over the guidewire. The dilator and guidewire are removed and the overtube serves as a conduit for subsequent instrument passage. Another gastroscope with the mounted sewing capsule is advanced to the level of the z line. A minimum of two plications are placed for each procedure. One or two of these plications is placed along the lesser and the other below the Z line. Stitches to form the plication are placed in a circumferential pattern.

In 2001, the Bard EndoCinch Suturing System (Bard Endoscopic Technologies, Billerica, MA) was cleared for marketing by the FDA through the 510(k) process. The system is intended for endoscopic placement of sutures in the soft tissue of the esophagus and stomach and for approximation of tissue for the treatment of symptomatic GERD. The predicate device to the Bard EndoCinch Suturing System is the Bard Endoscopic Suturing System, which has the same indication as the Bard EndoCinch Suturing System.

Clinical Trials

In 2005, Chen et al published the results from a prospective, multicenter trial evaluating 85 individuals with GERD that were treated with endoluminal gastroplication (EndoCinch). Individuals underwent manometry, 24-hour pH monitoring, and symptom severity scoring before and after the procedure. Patient diaries were used to assess medication use and to estimate annual medication cost. At 1- and 2-year follow-up, individuals had significant reductions in median heartburn symptom scores (72 at baseline vs. 4 at 12 months and 16 at 24 months; p<0.0001 vs. baseline) and median regurgitation symptoms (2 at baseline vs. 0 at 12 months and 1 at 24 months; p<0.0001 vs. baseline). Fifty-nine percent and 52% of the individuals showed heartburn symptom resolution at 12 and 24 months, respectively (p<0.0001 vs. baseline). Also, 83% and 77% had regurgitation symptom resolution at 12 and 24 months, respectively (p<0.0001 vs. baseline). Proton pump inhibitor use also was significantly reduced at 12 and 24 months after the procedure. Endoluminal gastroplication significantly reduced the duration and the number of episodes of esophageal acid exposure (p<0.0001 vs. baseline). Seven individuals experienced adverse events.

In a prospective study of 38 individuals with GERD, Abou-Rebyeh et al (2005) performed a total of 43 endoscopic gastroplications (EndoCinch). Two or three EndoCinch gastroplications were constructed at the level of the gastric cardia in each individual; five individuals were treated twice within 6-12 months. Post-procedure data after two months and after one year were compared with preoperative data, focusing on symptoms, medication requirements, endoscopic findings, and pH-metry results. In contrast to the findings at two months (which showed that 72% of the sutures were present and that there was a reduction in the percentage of time when the esophageal pH was < 4 from 15.4 % to 8.7%), the results one year after EndoCinch were considered to indicate failure of the treatment in all 38 individuals because none of them still had all of the initially placed gastroplications in situ (90% of gastroplications were lost). The percentage of individuals who did not require PPI medication decreased from 52% at two months to only 20% at one year and even more individuals had evidence of reflux esophagitis at one year (56%) than had initially demonstrated signs of this (41%). The authors concluded that endoscopic gastroplications (EndoCinch) "has some short-term beneficial effects on clinical symptoms and pH-metry. However, mainly due to the loss of the endoscopically placed sutures, these effects were not maintained at the 1-year follow-up. EGP cannot therefore be recommended for routine clinical use. Better endoscopic methods need to be developed, and they should be adequately tested before being marketed."

In a prospective case series, Schiefke et al (2005) evaluated the long term (18 months) outcomes of 70 individuals treated with EndoCinch. All individuals were interviewed using a standardized questionnaire regarding their symptoms and medication prior to and 18 months after EndoCinch. In addition, follow up included endoscopy, 24 hour pH monitoring, and oesophageal manometry. At 18 months follow-up, 80% of the individuals were considered treatment failures as their heartburn symptoms did not improve or PPI medication exceeded 50% of the initial dose. Endoscopy showed all sutures in situ in 17% of the individuals, while no remaining sutures could be detected in 26% of the individuals. In 54 and 50 individuals examined, respectively, no significant changes in 24 hour pH monitoring or lower oesophageal sphincter (LOS) pressure were observed while median LOS length slightly increased. The author concluded that "[e]ndoscopic gastroplication (EndoCinch) is a safe and minimally invasive endoscopic treatment for GORD with reasonable short term results. In contrast, long term outcome is disappointing, probably due to suture loss in the majority of patients. Therefore, technical improvements to ensure suture durability are mandatory before endoscopic suturing can evolve as a therapeutic option for GORD treatment."

In a non-randomized comparative study, Mahmood et al. (2006) reported on outcomes in 27 individuals undergoing endoscopic plication with EndoCinch and 24 individuals undergoing laparoscopic Nissen fundoplication. Many of those receiving endoscopic procedures were referred to a gastroenterologist, while those undergoing LNF were often referred directly to a surgeon. At follow-up, symptom control had improved in both groups but was better for the LNF group. In terms of objective indices, 91% of individuals in the LNF group achieved normal esophageal pH compared to 48% in the endoscopic group. The study is limited by a small sample size and short follow-up time.

In a single-centre, double-blind, randomized, sham-controlled trial, Schwartz et al (2007) reported the findings of 60 individuals with GERD. In this study, 20 individuals were randomly assigned to EndoCinch, 20 underwent a sham procedure, and 20 received no intervention (observation group). At 3-month follow-up, the proportion of individuals who had reduced their PPI use by at least greater than 50% was significantly higher in the treatment group (65%) than in either the sham (25%) or observation groups (0%) (p<0.02). However, there was no significant difference between the two groups in terms of acid exposure time: acid exposure times normalized in 29% of actively treated patients and in 22% of sham patients (p=0.71). During the 12-month follow-up, 29% of individuals in the treatment group required a revision procedure. The authors concluded that endoscopic gastroplication using Endocinch reduces PPI use and improves general GERD symptoms and quality of life. However, the reduction in oesophageal acid exposure was not greater after endoscopic treatment than after a sham procedure. The study is limited by a small sample size and limited follow-up time.

In 2013, Schwartz et al reported the results obtained from 50 individuals who were recruited from an initial randomized, placebo-controlled, single-center study (Schwartz et al. 2007) and followed for four years. Three individuals were lost to follow-up. At 4-years, symptom scores and 4 out of 6 QOL subscales were improved (all p<0.01 compared to baseline). However, 80% of the individuals required PPIs for their GERD symptoms. Ultimately, 64% of the individuals were classified as treatment failures. In 60% a post-procedural endoscopy was carried out, in which 16% were diagnosed with reflux esophagitis. The authors concluded that during the 4-year follow-up period the number of individuals that benefited from endoscopic gastroplication (EndoCinch) gradually declined, and nearly half of the individuals chose retreatment and 80% eventually required PPIs.

Summary

Comparative studies evaluating EndoCinch have failed to show improvement in acid exposure time when compared to sham controls. Prospective, case series studies report that at follow-up there is a high rate of suture loss. Therefore, large, well designed, RCTs are needed to show long-term safety and efficacy of EndoCinch.

NDO Surgical Endoscopic Plication System / NDO Plicator™

In this procedure, the Plicator and gastroscope assembly are passed into the stomach and the stomach is distended with air. The Plicator is retroflexed to within 1cm below the GE junction, and the helical tissue retractor is advanced deeply into the gastric wall. The gastric wall is retracted into the Plicator instrument arms. The arms are then closed, and the suture-implant is deployed to secure the full-thickness plication. The tissue retractor is then disengaged and the suture-implant released from the instrument. Additional sutures are placed in the same manner described above, with each additional implant placed incrementally closer to the GE junction in a linear configuration along the anterior gastric cardia. A search of online site www.ClinicalTrials.gov in December 2016 found several studies with the NDO Plicator listed as terminated, since the sponsoring company (NDO Surgical Inc.) was acquired by Johnson & Johnson and has ceased business operations.

The NDO Surgical Endoscopic Plication System and the NDO Plicator (NDO Surgical, Inc., Mansfield, MA) were cleared for marketing by the FDA through the 510(k) process in 2003 and 2007, respectively. Both systems are indicated for the treatment of the symptoms of chronic GERD in individuals who require and respond to pharmacological therapy.

Clinical Trials

The safety and efficacy of the Plicator procedure was evaluated in a prospective multicenter study, and the 6, 12, 36, and 60 months follow-up results were reported in Pleskow et al (2004), Pleskow et al (2005), Pleskow et al (2007), and Pleskow et al (2008). Sixty-four individuals initially underwent plication to assess the safety and efficacy of endoscopic full-thickness plication. At 6 months after plication, PPI therapy had been eliminated in 74% of previously medication-dependent individuals. Twenty-nine patients completed the 12-month and 36-month follow-up. At 36 months, 57% of baseline PPI-dependent individuals remained off daily PPI therapy. Treatment effect remained stable from 12–36 months, with 21 out of 29 individuals off daily PPI at 12 months compared to 17 out of 29 individuals at 36 months. Median GERD–HRQL scores remained significantly improved at 36 months versus baseline off meds scores. Furthermore, the proportion of individuals achieving ≥50% improvement in GERD-HRQL score was consistent from 12 months (59%) to 36 months (55%). No long-term procedural adverse effects were reported. The results of the prospective, uncontrolled studies suggest that endoscopic full-thickness plication is effective, reduces symptoms and medication use associated with GERD. The treatment effect was stable for at least five years post-procedure. The limitations of the studies include: small sample size, lack of a control group, only a subset of the individuals who had originally undergone the Plicator procedure were enrolled in the 60 month follow-up study, and the studies exclusion criteria.

In a randomized sham-controlled study, Rothstein et al. (2008) reported the outcomes of 159 individuals with GERD undergoing full-thickness plication (Plicator™). At 3-month follow-up, complete cessation of PPI therapy was higher among those in the treatment group than in the sham group (50% vs. 24%, respectively). Quality-of-life scores also improved more in the active group. The percent reduction in median percent time the pH was less than 4 was improved more in the active group (7% vs. 10%, respectively) but did not change in the sham group (10% vs. 9%, respectively). The authors noted that the single full-thickness plication normalized the distal esophageal acid contact for less than one-third of the patients and was not effective in healing esophagitis. Also, radiating shoulder pain and abdominal pain were more frequent adverse events in the active treatment group (12% vs. 0% and 9% vs. 0%, respectively).

In an open-label, prospective multicenter postmarket registry study, Birk et al (2009) evaluated the safety and efficacy of the Plicator procedure in individuals with GERD. The study included 131 individuals who were evaluated at 12 months after plication. At 12 months, 81 individuals (62%) were available for assessment. The mean GERD Health-Related Quality-of-Life score had improved significantly compared with the baseline score, with 66% of the individuals showing an GERD-HRQL score improved 50% or more. Statistically significant improvements also were observed in median heartburn and regurgitation symptom scores. The need for daily PPI therapy was eliminated for 58% of the individuals. At baseline, 18% of the individuals had been satisfied with their GERD symptom control while on antisecretory therapy. At 12 months, 75% of the individuals were satisfied with their GERD symptom control after undergoing the Plicator procedure, and 86% would recommend the procedure to family or friends. Limitations of the study include a lack of a control or comparison group.

In a randomized comparative study, Antoniou et al (2012) evaluated the effectiveness of endoscopic plication and laparoscopic fundoplication in terms of quality of life and symptom control. A total of 60 individuals with GERD were randomly assigned to undergo either endoscopic plication or laparoscopic fundoplication. Quality-of-life scores and symptom grading were recorded before treatment and at 3- and 12-month follow-up. Twenty-nine individuals from the endoscopic group and 27 individuals from the operative group were available at follow-up. Quality-of-life scores showed a substantial and similar increase for both groups after treatment. Symptoms of heartburn, regurgitation, and asthma were significantly improved in the endoscopic group, whereas laparoscopic fundoplication was more effective in controlling symptoms of heartburn and regurgitation compared to the endoscopic procedure. Limitations of this study include small sample size and lack of long-term follow-up.

ANTI-GASTROESOPHAGEAL REFLUX DEVICE IMPLANTATION
LINX™ Reflux Management System

The LINX™ Reflux Management System (Torax Medical, Shoreview, MN) consists of a small flexible band of 10 to 18 interlinked titanium beads with magnetic cores that is laparoscopically inserted around the esophagus at the gastroesophageal junction. The magnetic attraction between the beads is intended to help the LES resist opening due to gastric pressure, and preventing the backflow of refluxate into the esophagus. The magnetic attraction of the device also closes the LES immediately after swallowing, restoring the body’s natural barrier to stomach content reflux. The system is intended for individuals who have GERD despite maximum medical therapy (e.g., PPIs), but who do not want to risk the adverse effects of a surgical procedure like Nissen fundoplication. Adverse events of the system include dysphagia or odynophagia. The FDA required a 5-year follow-up of the 100 individuals from the investigational device exemption pivotal study to evaluate safety and efficacy of the device, which was completed in March 2016. In addition, the FDA has required a 5-year new enrollment study. This new prospective, multicenter, single-arm observational study will enroll a minimum of 200 individuals, and will monitor the safety and effectiveness of the LINX™ Reflux Management System in a post-approval environment to supplement existing safety and effectiveness data.

No randomized controlled trials (RCTs) evaluating the LINX™ Reflux Management System were identified in the literature. Some nonrandomized comparative studies and case series were identified.

Nonrandomized Comparative Trials

In a retrospective case-controlled study, Louie et al (2014) reported on 66 individuals with GERD who had undergone either magnetic sphincter augmentation (MSA) using the LINX™ Reflux Management System (n=34) or laparoscopic Nissen fundoplication (LNF) (n=32). The outcomes of interest were subjective and objective indices of GERD and follow-up data was collected between 6 and 10 months post-procedure. At follow-up, the study found a statistically significant improvement in GERD-Health-Related Quality of Life (HRQL) scores in both groups: 20.6 to 5.0 in the MSA group and 22.8 to 5.1 in the LNF group. DeMeester scores were also significantly normalized post-operatively in both groups, with greater improvements occurring in the LNF group: 14.2 in the MSA group versus 5.1 in the LNF group (p=0.0001). They also found that the MSA procedure resulted in improved gassy and bloated feelings (1.32 vs 2.36; p=0.59) and enabled belching in 67% of individuals compared to none of the LNF individuals.

In another retrospective, case-controlled study, Sheu et al (2015) compared outcomes from 12 MSA (LINX™ Reflux Management System) individuals with a contemporaneous case-matched cohort of individuals who underwent LNF. Over half of the MSA patients were self-referred, compared with none who underwent LNF (p<0.001). Both procedures were effective for reflux (MSA=75%, LNF=83%). Severe dysphagia requiring endoscopic dilation was more frequent after MSA (MSA=50%, LNF=0%; p=0.01), while there was a trend for a reduction in bloating, flatulence, and diarrhea after MSA compared to LNF.

In 2015, Riegler et al reported the results of a prospective, multicenter registry that compared magnetic sphincter augmentation (MSA; n=202) to laparoscopic fundiplication (LF; n=47). Outcomes were evaluated 1-year after surgery. The LF group had a greater frequency of large hiatal hernias (>3 cm, 45.7% vs 1.6%), and was older and had a greater frequency of Barrett esophagus (19.1% vs 1.0%, p<0.001) compared to the MSA group. Improvements in GERD-HRQL scores were similar for the 2 groups (MSA, 20.0 to 3.0; LF, 23.0 to 3.5). Individuals who underwent LF had greater regurgitation (13% vs 3.1%; p=0.014) and fewer individuals who discontinued PPIs after treatment (63% vs 81.8%; p=0.009). Excessive gas and abdominal bloating (31.9% vs 10%; p<0.001) and inability to vomit (55.6% vs 8.7%; p<0.001) were significantly higher after LF than MSA. Reoperation rate was 4.0% following MSA compared to 6.4% following LF.

Reynolds et al (2015) reported their findings from a retrospective analysis of 1-year outcomes of 50 individuals who underwent magnetic sphincter augmentation (MSA) using the LINX™ Reflux Management System and 50 individuals who underwent laparoscopic Nissen fundoplication (LNF). At 1 year after surgery, both groups had similar GERD-HRQL (Health-Related Quality-of-Life) scores (MSA=4.2, LNF=4.3; p=0.897) and PPI use (MSA=17%, LNF=8.5%; p=0.355). There was no difference in the number of individuals reporting mild gas and bloating (MSA=27.6%, LNF=27.6%; p=1.000), but more LNF individuals reported severe gas and bloating compared to the MSA individuals (10.6% vs 0%; p=0.022). Furthermore, more LNF individuals were unable to belch (MSA=8.5%, LNF=25.5%; p=0.028) or vomit when needed (MSA=4.3%, LNF=21.3%; p=0.004). The incidence of postoperative dysphagia was similar between the groups (MSA=46.8%, LNF=44.7%; p=0.766).

Asti et al (2016) reported 1-year data from an observational cohort study comparing magnetic sphincter augmentation (MSA, n=135) using the LINX™ Reflux Management System and laparoscopic Toupet fundoplication (LTF, n=103). Eligible individuals had GERD symptoms despite PPI for at least 6 months, and normal esophageal motility. In a generalized estimating equations (GEE) model for GERD-HRQL, there was no significant difference at 1 year in GERD-HRQL between MSA and LTF groups (odds ratio: 1.04, 95% CI 0.89 to 1.27, p=0.578). Similarly, there was no significant difference between the MSA and LTF groups at 1 year in PPI use (odds ratio: 1.18, 95% CI 0.81 to 1.70, p=0.3888), gas-related symptoms (odds ratio: 0.69, 95% CI 0.21 to 2.28; p= 0.542), dysphagia (odds ratio: 0.62, 95% CI 0.26-1.30; p = 0.241), and reoperation-free probability (stratified log-rank test = 0.556).

In 2016, Warren et al reported the 1-year results of a multi-institutional retrospective cohort study of individuals with GERD undergoing either magnetic sphincter augmentation (MSA; n=201) or Nissen fundoplication (NF; n=214). The groups were similar in age, gender, and GERD-HRQL scores but significantly different in preoperative obesity (32% vs 40%), dysphagia (27% vs 39%), DeMeester scores (34 vs 39), presence of microscopic Barrett's (18% vs 31%), and hiatal hernia (55% vs 69%). Given the differences in baseline groups, the authors used propensity score matching to generate 114 matched pairs based on preoperative esophagitis, presence of Barret esophagus, hiatal hernia, and body mass index (BMI). Mean follow up differed for matched pair MSA and NF groups (11 months vs 16 months, respectively, P<0.001). At a minimum of 1-year follow-up, 354 individuals (169 MSA and 185 NF) had significant improvement in GERD-HRQL scores (pre to post: 21-3 and 19-4). MSA individuals had greater ability to belch (96% vs 69%) and vomit (95% vs 43%) with less gas bloat (47% vs 59%). Propensity-matched cases showed similar GERD-HRQL scores and the differences in ability to belch or vomit, and gas bloat persisted in favor of MSA. Mild dysphagia was higher for MSA (44% vs 32%). Resumption of daily PPIs was higher for MSA (24 vs 12, p=0.02) with similar patient-reported satisfaction rates.

Single-Arm Trials (Case Series)

Data submitted to the FDA for the LINX™ Reflux Management System included two single-arm FDA-regulated investigational device exemption (IDE) trials with a total of 144 individuals and follow-up data between two and five years. The feasibility IDE study enrolled 44 individuals at four clinical sites (2 United States, 2 Europe) and has published data out to five years. Published results from the feasibility IDE study are reported below.

In 2010, Bonavina and colleagues reported the 1- and 2-year results from a multicenter, prospective, single-arm feasibility study evaluating the safety and efficacy of the LINX™ Reflux Management System. The LINX™ device was laparoscopically implanted at the gastroesophageal junction in 44 individuals. Individuals served as their own controls. At baseline, all individuals had abnormal esophageal acid exposure on 24-hour pH monitoring and improved, but persistent, typical GERD symptoms while on acid suppression therapy with proton pump inhibitors (PPIs). Individuals were evaluated after surgery by GERD Health-Related Quality of Life symptom score, PPI usage, endoscopy, esophageal manometry, and 24-hour esophageal pH monitoring. The total mean GERD Health-Related Quality of Life symptom scores improved from a mean baseline value of 25.7 to 3.8 and 2.4 at 1- and 2-year follow-up, representing an 85% and 90% reduction, respectively (p<0.0001). Complete cessation of PPI use was reported by 90% of individuals at 1 year and by 86% of individuals at 2 years. Early dysphagia occurred in 43% of the individuals and self-resolved by 90 days. One device was laparoscopically explanted for persistent dysphagia without disruption of the anatomy or function of the cardia. There were no device migrations, erosions, or induced mucosal injuries. At 1 and 2 years, 77% and 90% of individuals had a normal esophageal acid exposure. The mean percentage time pH was less than 4 decreased from a baseline of 11.9% to 3.1% (p<0.0001) at 1 year and to 2.4% (p<0.0001) at 2 years. Patient satisfaction was 87% at 1 year and 86% at 2 years.

Lipham et al (2012) reported the 4-year results from 44 individuals enrolled in the multicenter, prospective, single-arm IDE feasibility study described in Bonavina et al (2010). Long-term efficacy measures included esophageal acid exposure, GERD quality-of-life measures, and use of PPIs. For esophageal acid exposure, the mean total % time pH < 4 was reduced from 11.9% at baseline to 3.8% at 3 years (p<0.001), with 80% (18/20) of individuals achieving pH normalization (≤ 5.3%). At ≥ 4 years, 100% (23/23) of the patients had improved quality-of-life measures for GERD, and 80% (20/25) had complete cessation of the use of PPIs. There were no reports of death or long-term device-related complications such as migration or erosion.

In 2015, Saino et al reported the 5-year results from 33 of the 44 individuals enrolled in the multicenter, prospective, single-arm IDE feasibility study described in Bonavina et al (2010). At 5 years, gastroesophageal reflux disease (GERD)-Health Related Quality of Life (HRQL) questionnaire score, esophageal pH, PPI use, and complications were evaluated. Mean total percentage of time with pH <4 was 11.9% at baseline and 4.6% at 5 years (p<0.001), with 85% of individuals achieving pH normalization or at least a 50% reduction. Mean total GERD-HRQL score improved significantly from 25.7 to 2.9 (p<0.001) when comparing baseline and 5 years, and 93.9% of individuals had at least a 50% reduction in total score compared with baseline. Complete discontinuation of PPIs was achieved by 87.8% of individuals. No complications occurred in the long term, including no device erosions or migrations at any point.

The pivotal IDE study included 100 individuals from 14 clinical sites (13 United States, 1 Europe) who had documented symptoms of GERD for more than 6 months (regurgitation or heartburn that responds to acid neutralization or suppression), required daily PPI or other antireflux drug therapy, had symptomatic improvement on PPI therapy, and had a total distal ambulatory esophageal pH less than 4 for 4.5% or more of the time when off GERD medications. The primary safety end point measured the rate of related device and procedure serious adverse events (SAEs). Efficacy end points were assessed off PPI therapy and measured esophageal acid exposure, total GERD-HRQL scores, and PPI usage. Individuals served as their own controls. Published results from the pivotal IDE study are reported below.

Three-year results of the pivotal IDE study were published by Ganz et al in 2013. In this study, 100 consecutive individuals received the LINX™ Reflux Management System. The primary outcome measure was normalization of or a 50% or greater reduction in esophageal acid exposure (EAE) at 1 year. The secondary outcome measures were 50% or greater improvement in quality of life (QOL) and a 50% or greater reduction in PPI use at 1 year. Successful treatment was pre-specified as achievement of the outcome in at least 60% of individuals. The primary outcome was achieved in 64% of study participants. Mean total acid exposure time was reduced from 11.6% at baseline to 5.1% at 12 months (56% reduction). For the secondary outcomes, a reduction of 50% or more in the use of PPIs occurred in 93% of individuals (79% and 83% of individuals were free from daily dependence at 12 and 24 months, respectively, vs 0% at baseline), and there was improvement of 50% or more in QOL scores in 92% of individuals (the mean QOL total score decreased from 28.4 at baseline to 5.9 and 5.5 at 12 and 24 months, respectively). The most frequent adverse event was dysphagia (in 68% of individuals postoperatively, 11% at 1 year, and in 4% at 3 years). Nineteen patients underwent esophageal dilation for dysphagia. There were 6 serious adverse effects, and the device had to be removed in 6 individuals. The authors concluded that the LINX™ Reflux Management System improves outcomes in individuals and is safe; however, they added that studies with larger sample size and longer-term follow-up are needed to confirm these findings.

In 2016, Ganz and colleagues reported the final 5-year results for the 100 individuals enrolled in the pivotal IDE study described in Ganz et al (2013). Eighty-five patients had follow up at 5 years. Of those 85, 83% achieved had a 50% reduction in the GERD-health-related quality of life (GERD-HRQL) score (95% CI 73% to 91%), and 89.4% had a reduction of 50% or more in average daily dose of PPI (95% CI 81 to 95%). Individuals with moderate or severe heartburn decreased from 89% to 11.9%, and moderate or severe regurgitation decreased from 57% to 1.2% without use of PPIs at baseline and 5 years. Daily use of PPIs decreased from 100% at baseline to 15.3% at 5 years. At 5 years, 75.3% of individuals reported complete cessation of PPIs, and 9.4% reported PPI use only as needed. Thus, 84.7% were either completely off PPIs or reported use as needed at 5 years. Over the follow-up period, there were no device erosions, migrations, or malfunctions. The device was removed in 7 individuals. The limitations of this study included the following: esophageal pH testing and manometry were not performed beyond 1 year, and there was no comparison group.

In 2013, Bonavina et al published longer follow-up from individuals in the pilot and multicenter registry studies. This study was a single-center, prospective case series of 100 individuals who received magnetic sphincter augmentation (MSA) for GERD. Median implant duration was 3 years (range, 378 days to 6 years). Thirty of the individuals had data beyond 5 years. Median total acid exposure time was reduced from 8% before implant to 3.2% post implant (p<0.001). The median GERD Health Related Quality Life (GERD-HRQL) score at baseline was 16 on PPIs and 24 off PPIs. The median GERD-HRQL score improved to a score of 2 (p<0.001). Freedom from daily dependence on PPIs was achieved in 85% of individuals. Three individuals had the device removed for persistent GERD, odynophagia, or dysphagia, however there were no occurrences of device migration or erosion.

In 2015, Lipham et al reported the results of a study that examined the safety profile of magnetic sphincter augmentation in the first 1048 implanted individuals (82 institutions). Median device implantation was 274 days. Of these, 144 were implanted as part of premarket clinical trials (previously described), 332 had been enrolled in the postmarket registry, and 572 were implanted outside of a postmarket registry. Published clinical literature along with the device’s Summary of Safety Effectiveness Data, the FDA database for device-related complications (MAUDE database), and information provided by the manufacturer were used to identify adverse events. Event rates were 0.1% intra- or perioperative complications, 1.3% hospital readmissions, 5.6% endoscopic dilations, and 3.4% reoperations for device removal. The primary reason for device removal was dysphagia. No device migrations or malfunctions were reported. Erosion of the device occurred in 1 (0.1%) individual. This study was limited by the short follow-up and the voluntary reporting of adverse events outside of the registry.

Additional Single-Arm Observational Trials (Case Series)

In 2008, Bonavina et al reported the results from a multi-center feasibility trial that was performed to evaluate the safety and efficacy of a magnetic sphincter augmentation device. Individuals enrolled in the study had typical heartburn (at least partially responding to proton-pump inhibitors), abnormal esophageal acid exposure, and normal esophageal peristalsis. Individuals with hiatal hernia >3 cm were excluded from the study. Over a 1-year period, 38 out of 41 enrolled individuals underwent this procedure in 3 hospitals. No operative complications were recorded. A free diet was allowed since post-operative day one, and 97% of the individuals were discharged within 48 hours. The mean follow-up was 209 days (range 12-434 days). The GERD-HRQL score decreased from 26.0 to 1.0 (p<0.005). At 3 months post-operatively, 89% of individuals were off anti-reflux medications, and 79% of individuals had a normal 24-h pH test. All individuals preserved the ability to belch. Mild dysphagia occurred in 45% of individuals. No migrations or erosions of the device occurred.

In 2014, Smith et al reported data from 66 individuals who underwent mechanical sphincter augmentation (MSA) using the LINX™ Reflux Management System. All individuals had objectively confirmed GERD with pH testing, acceptable esophageal motility, and no significant hiatal hernia (>3 cm). All individuals experienced clinical improvement on antisecretory medication, but incomplete symptom control or medication intolerance. There were no reported intra- or perioperative complications. Average length of hospital stay was 0.7 days. At an average follow-up of 5.8 months (range 1 to 18.6 months), 92% of individuals were satisfied or neutral with their GERD condition, and 83% were proton pump inhibitor free. The GERD-Health-Related Quality of Life (HRQL) scores were similar to those of individuals without GERD. There were no device ulcers or erosions and no devices explanted. Thirteen individuals underwent additional testing for dysphagia or persistent symptoms. Dysphagia and regurgitation were the most common concerns.

In a prospective observational study, Reynolds et al (2014) evaluated 67 individuals who were implanted with the LINX™ Reflux Management System at two institutions. There were no intraoperative complications and only four mild postoperative complications, which included three individuals with urinary retention and one readmission for dehydration. The mean operative time was 60 minutes (range, 31 to 159 minutes) and mean length of stay was 11 hours (range, 5 to 35 hours). Sixty-three individuals were at least three months postoperative and eligible for follow-up at the time of data analysis. Follow-up information was obtained for 83% of individuals with a median follow-up of five months (range, 3 to 14 months). The median GERD-HRQL score at follow-up was 4 (range, 0 to 26). A total of 76.9% of individuals were no longer taking PPIs. The most common postoperative complaint was dysphagia, which was seen in 82.7% of individuals, and was resolved in 79.1% of individuals with a median time to resolution of eight weeks. There were 8 individuals with persistent dysphagia that required balloon dilation with improvement in symptoms.

In a prospective case series, Schwameis et al. (2014) evaluated the safety and effectiveness of the LINX™ Reflux Management System in improving outcomes in 23 individuals with GERD. Primary outcome measures were overall feasibility of the procedure, short-term procedure safety, and effectiveness. Secondary outcomes were subjective individual indices assessed with the GERD health-related quality of life (GERD-HRQL) questionnaire. All laparoscopic procedures were performed within a median operative time of 23 minutes and there were no intraoperative complications. At four-week follow-up, PPI cessation was achieved in 71.4% of individuals and a significant number of individuals experienced reduction of primary GERD symptoms: [heartburn (96% to 22%; p<0.001); bloating (70% to 30%; P = 0.006); respiratory complaints (57% to 17%; p = 0.039); and sleep disturbance (56% to 4%; p<0.001)]. Median GERD-HRQL scores (lower scores better) also improved from 29 to 4 (p<0.001) after the Linx procedure and the proportion of individuals who were satisfied with their HRQL increased from 0% to 74%. Dysphagia was the only reported side effect and only 1 individual required endoscopic dilation.

Practice Guidelines and Position Statements

A 2017 report from the American Society for Gastrointestinal Endoscopy concluded that long-term data on the safety and efficacy of the LINX device were needed. The document indicated that the LINX band is currently being deployed laparoscopically; however, a natural orifice transluminal endoscopic surgery approach could be explored.

In 2015, ECRI Institute published an Emerging Technology Evidence Report evaluating magnetic sphincter augmentation (Linx Reflux Management System) for treating gastroesophageal reflux disease. In their report, ECRI Institute considered the quantity of evidence to be low "given the large number of patients affected by medically refractory GERD and the need for comparative data on procedures and patient-oriented outcomes". With regards to the quality of the evidence, ECRI Institute was unable to find any well-designed controlled trials. Regarding the available evidence, the authors stated that "[t]he case series lack many comparisons of interest, were sponsored by the manufacturer, and led by manufacturer consultants. These studies suffered from incomplete and vague results reporting: inconsistent results reporting (e.g., Ganz et al (2013) reported intent-to-treat [ITT] at one year, not at subsequent follow-ups, and did not report numbers lost to follow-up; Lipham et al (2012) reported findings on the basis of patients left at follow-up, not ITT). Both studies took baseline esophageal pH level measurements while patients were off PPI therapy, so no pre-post pH comparison data for PPI therapy and Linx are available. Results reported after one year were post hoc analyses with an unclear number of patients lost to follow-up—as many as half were unaccounted for in Lipham et al (2012) study. Results in the text of articles did not consistently correspond to results in tables."

In 2014, the American Society of General Surgeons (ASGS) issued a position statement supporting the use of the LINX™ Reflux Management System. In their position statement, the ASGS stated that "[b]ased on currently available information and the experience of our members with the procedure we do support the LINX procedure as mechanism for controlling GERD when it is placed by properly trained laparoscopic surgeons with experience in foregut surgery and the management of GERD patients".

A 2013 report on emerging technology from the American Society for Gastrointestinal Endoscopy (ASGE) concluded that long-term data on the safety and efficacy of the LINX™ device are needed. The document indicated that the LINX™ band is currently being deployed laparoscopically; however, a natural orifice transluminal endoscopic surgery approach could be explored.

In 2012, the National Institute for Health and Excellence (NICE) published a guidance report regarding laparoscopic insertion of a magnetic-bead band for gastro-oesophageal reflux disease. In their report, NICE stated that "[t]he evidence on the safety and efficacy of laparoscopic insertion of a magnetic bead band for gastro-oesophageal reflux disease (GORD) is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research".

Summary

The evidence base evaluating magnetic sphincter augmentation (i.e., the Linx Reflux Management System) for treating gastroesophageal reflux disease includes prospective and retrospective observational comparative studies, 2 single-arm interventional trials, and a number of single-arm observational studies. Outcomes of interest include symptoms, change in disease status, medication use, and treatment-related morbidity. Two single arm uncontrolled studies were submitted to the FDA for device approval. In these two studies, improvements in GERD-HRQL and reduced proton pump inhibitor (PPI) use were reported. Observational comparative studies, which compared magnetic sphincter augmentation with laparoscopic fundoplication, reported that GERD-HRQL did not differ significantly between fundoplication and magnetic sphincter augmentation, and individuals were able to reduce PPI use after magnetic sphincter augmentation. However, the comparative studies were retrospective and nonrandomized, and therefore may be affected by selection bias, and the subjective outcome measures used in these studies (e.g., the GERD-HRQL scores) may be biased.

Because of the potential biases in nonrandomized trials, randomized controlled trials (RCTs) are necessary to establish the efficacy of treatments for GERD. GERD has a variable natural history, with exacerbations and remissions, and, as a result, a control group is required to differentiate improvements in symptoms from the natural history of the disorder. A placebo control is optimal due to the subjective nature of the patient reported outcome measures, which are prone to bias if the patient is not blinded to treatment assignment. Random assignment is important because of the multiple potential confounders of GERD outcomes, such as diet, smoking, and obesity. Randomization minimizes the chance that these confounders will be distributed unequally among treatment groups. It is also important to determine comparative efficacy of treatments for GERD, because numerous medical and surgical treatments are effective.

Angelchik Antireflux Prosthesis

In this procedure, a C-shaped silicon ring (i.e., Angelchik prosthesis) is surgically implanted around the esophagus at the gastroesophageal junction. It is secured in place by a circumferential tie strap. This is designed to reduce and prevent further sliding of hiatal hernias and to prevent reflux of gastric contents into the esophagus. The Angelchik Antireflux Prosthesis (Allergan, Inc., Santa Barbara, CA) weas cleared for marketing by the FDA through the PMA process in 1979.

Because follow-up assessment of individuals with the antigastroesophageal reflux device implantation revealed poor long-term results and complications, including dysphagia, erosion, perforation, obstruction, and migration of the prosthesis, use of the device has been largely abandoned. In addition, the American Medical Association’s (AMA) Diagnostic and Therapeutic Technology Assessment (DATTA) evaluation of the Angelchik prosthesis has determined that the safety and effectiveness of this device have not been established; therefore, its routine use is discouraged.

EndoStim LES Stimulation System

The EndoStim LES Stimulation System (EndoStim, Dallas, TX) is a minimally invasive implantable device designed to provide long-term reflux control by restoring normal esophageal function through neurostimulation. The therapy directly targets an individual's weak or dysfunctional lower esophageal sphincter (LES) muscle between the stomach and the esophagus, often the underlying cause of reflux. The EndoStim LES Stimulation System is not FDA approved for the treatment of symptomatic chronic gastroesophageal reflux disease.

INJECTION OR IMPLANTATION OF BULKING AGENTS
In these procedures, a biomaterial is injected/implanted in the submucosa of the LES augmenting the sphincter and reducing gastric reflux into the esophagus. Commonly used products include Enteryx™, Durasphere® GR, Gatekeeper Reflux Repair System, and plexiglas polymethylmethacrylate (PMMA) microbeads.

In 2004 and again in 2017, the National Institute for Health and Care Excellence (NICE) issued guidance on endoscopic injection of bulking agents for gastro-oesophageal reflux disease, stating that “Current evidence on the safety and efficacy of endoscopic injection of bulking agents for gastro-oesophageal reflux disease does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research.”

Enteryx™

In this procedure, a nonresorbable biocompatible polymer is endoscopically implanted in the distal esophagus and proximal gastric cardia. In a single-blind RCT, Deviere et al. (2005) reported on 64 patients with GERD who were randomly assigned to either Enteryx implantation or a sham procedure. At 3 and 6 months’ follow-up, patients in the Enteryx group had greater reductions in PPI use and more improvement in GERD-HRQL heartburn scores. The small sample size and short follow-up time of the study limit interpretation of findings.

The US Food and Drug Administration (FDA) issued a preliminary health notification on October 14, 2005, regarding the recall of the ethylene vinyl alcohol (Enteryx) Procedure Kits and ethylene vinyl alcohol (Enteryx) Injector Single Packs by the manufacturer (Boston Scientific Corp., Natick, MA) on September 23, 2005, due to the occurrence of adverse events, including death. The FDA instructed physicians to stop injecting ethylene vinyl alcohol (Enteryx) and to follow the manufacturer's procedures for returning unused products. In September 2005, Enteryx was voluntarily removed from the market due to serious adverse effects.

Durasphere® GR

Durasphere GR (Carbon Medical Technologies, Inc., St. Paul, MN) is a bulking agent approved by the FDA for use in the treatment of adult women with stress urinary incontinence (SUI) due to intrinsic sphincter deficiency (ISD). Use of this product for the treatment of GERD would be considered an off-label use. Carbon Medical Technologies' website states that Durasphere GR is an investigational device in the United States, and is “intended to treat problems associated with Gastroesophageal Reflux Disease (GERD).”

The available evidence for this device consists of a single case series (Ganz et al. 2009) in which 10 individuals with GERD were injected with Durasphere. At 12 months, 7 individuals (70%) discontinued all antacid medication completely. No erosion, ulceration, or sloughing of material was noted at any injection site.

Gatekeeper™ Reflux Repair System

The Gatekeeper™ Reflux Repair System (Medtronic, Shoreview, MN) uses a soft, pliable, expandable prosthesis made of a polyacrylonitrile-based hydrogel. The prosthesis is implanted into the esophageal submucosa, and with time, the prosthesis absorbs water and expands, creating bulk in the region of implantation. The Gatekeeper Reflux Repair System is not FDA approved for the treatment of symptomatic chronic gastroesophageal reflux disease.

The available evidence base for this device consists of a single RCT (Fockens et al. 2010). In a sham-controlled single-blind multicenter study, 118 individuals were randomized to receive Gatekeeper (n=75) or sham (n=43) treatment. An additional 25 individuals were treated as lead-ins during the initial training of investigators and included only in the safety analysis. The individuals were implanted initially with four Gatekeeper prostheses. At 3 months, 44% of implanted individuals received retreatment with up to four additional prostheses due to unsatisfactory symptom control. Four serious adverse events were reported (two perforations, one pulmonary infiltrate related to a perforation, one severe chest pain). The primary efficacy end point was reduction in heartburn symptoms using the GERD-HRQL questionnaire. Planned interim analysis after 143 individuals were enrolled found that heartburn symptoms and esophageal acid exposure had improved significantly in both the Gatekeeper and sham groups at six months, but there was no significant difference between the two groups. The study was terminated early due to a lack of efficacy.

Plexiglas Polymethylmethacrylate (PMMA) Microbeads

In this procedure, PMMA microspheres are submucosally injected in the LES. This process augments the LES and helps to reduce gastric reflux in to the esophagus.

In a case series, Feretis et al (2001) reported on 10 patients with GERD who underwent transesophageal submucosal implantation of polymethylmethacrylate (PMMA) beads. While a significant decrease in symptom scores was noted at post-treatment follow-up (time not specified), the small number of patients and lack of long-term follow-up preclude scientific analysis. No additional studies have been identified evaluating this treatment option.
References


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US Food and Drug Administration (FDA). Center for Devices and Radiological Health. Durasphere™ Injectable Bulking Agent (P980053). Approval order, summary of safety and effectiveness, labeling. [FDA Web site]. 09/13/1999. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=p980053. Accessed June 21, 2018.

US Food and Drug Administration (FDA). Center for Devices and Radiological Health. EndoGastric Solutions (EGS) EsophyX™ System with SerosaFuse™ Fastener and accessories. 510(k) Summary. [FDA Web site]. 09/14/2007. Available at:http://www.accessdata.fda.gov/cdrh_docs/pdf7/K071651.pdf. Accessed June 21, 2018.

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Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

MEDICALLY NECESSARY
43280, 43285, 43325, 43327, 43328


EXPERIMENTAL/INVESTIGATIONAL

THE FOLLOWING CODE IS USED TO REPRESENT TRANSESOPHAGEAL RADIOFREQUENCY ABLATION:
43257

THE FOLLOWING CODE IS USED TO REPRESENT TRANSORAL INCISIONLESS FUNDOPLICATION (TIF):
43210

THE FOLLOWING CODE IS USED TO REPRESENT TRANSORAL INCISIONLESS FUNDOPLICATION (TIF) DONE WITH ANY LAPAROSCOPIC REPAIR OF A LARGER HIATAL HERNIA:
43659

THE FOLLOWING CODES ARE USED TO REPRESENT TRANSESOPHAGEAL ENDOSCOPIC SUTURING AND PLICATION:
43499, 43999

THE FOLLOWING CODES ARE USED TO REPRESENT ENDOSCOPIC SUBMUCOSAL IMPLANTATION OR INJECTION OF A BULKING AGENT:
43192, 43201

THE FOLLOWING CODE IS USED TO REPRESENT MAGNETIC ESOPHAGEAL RING IMPLANTATION:
43284

THE FOLLOWING CODES ARE USED TO REPRESENT IMPLANTATION OF ANTI-ESOPHAGEAL REFLUX DEVICE:
43289, 43499


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

K21.0 Gastro-esophageal reflux disease with esophagitis

K21.9 Gastro-esophageal reflux disease without esophagitis



HCPCS Level II Code Number(s)

N/A


Revenue Code Number(s)

N/A

Coding and Billing Requirements



Policy History

Revisions from 11.03.11n:
08/01/2018As of 8/01/2018, this policy has been reviewed and reissued to communicate the Company’s continuing position on Procedures for the Treatment of Gastroesophageal Reflux Disease (GERD).


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 01/01/2017
Version Issued Date: 12/30/2016
Version Reissued Date: 08/01/2018

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