CAM 20138

Transesophageal Endoscopic Therapies for Gastroesophageal Reflux Disease

Category:Medicine   Last Reviewed:September 2021
Department(s):Medical Affairs   Next Review:September 2022
Original Date:December 2000    

Description
Transesophageal endoscopic therapies are being developed for the treatment of gastroesophageal reflux disease (GERD). A variety of procedures are being evaluated, including transesophageal (or transoral) incisionless fundoplication (TIF), application of radiofrequency energy, and injection/implantation of prosthetic devices or bulking agents.

For individuals who have GERD and a hiatal hernia of 2 cm or less that is not controlled by proton pump inhibitors (PPIs) who receive TIF (e.g., EsophyX), the evidence includes 2 randomized controlled trials (RCTs) comparing TIF with PPI therapy, nonrandomized studies comparing TIF with fundoplication, and case series with longer-term follow-up. Relevant outcomes are symptoms, change in disease status, quality of life (QOL), medication use, and treatment-related morbidity. The highest quality RCT (RESPECT) was sham-controlled that compared TIF with PPI therapy while the other RCT (TEMPO) compared TIF with maximum PPI therapy. Both trials found a significant benefit of TIF on the primary outcome measure in about 65% of patients. The sham-controlled trial reported improvement in 45% of the sham-controlled group and no benefit on secondary subjective outcome measures. The nonblinded RCT found significant improvements in subjective measures but no difference in objective outcome measures compared with PPI therapy. Together, these trial results would suggest a strong placebo effect of the surgery and a modest benefit of TIF in patients whose symptoms were not controlled by PPIs. For these patients, the most appropriate comparator would be laparoscopic fundoplication. Studies comparing TIF with fundoplication have limitations that include earlier TIF procedures and unbalanced groups at baseline and are inadequate to determine relative efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have GERD and a hiatal hernia of 2 cm or less that is controlled by PPIs who receive TIF (e.g., EsophyX), the evidence includes 2 RCTs and observational studies with longer-term follow-up. Relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. A sham-controlled trial found that the time to resume PPI therapy was longer following TIF and the remission rate was higher, indicating that TIF is more effective than no therapy. The nonblinded RCT found a benefit of TIF compared with continued PPI therapy for subjective measures, but not for the objective measures of pH normalization and esophagitis. These results raise questions about a possible placebo effect for the procedure. Also, observational studies have indicated a loss of treatment effectiveness over time. Adverse events associated with the procedure (e.g., perforation) may be severe. At present, the available evidence does not support the use of this intervention in patients whose symptoms are adequately controlled by medical therapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have GERD who receive endoscopic radiofrequency energy (e.g., Stretta), the evidence includes 2 meta-analyses, 6 small RCTs, 2 nonrandomized comparative studies, and observational studies with longer-term follow-up. Relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. The RCTs reported some improvements in symptoms and QOL following treatment with radiofrequency energy compared with sham controls. However, objective measures of GERD and a meta-analysis of 4 RCTs s found no significant improvements in outcomes, raising questions about the mechanism of the symptom relief. Symptom relief and clinical success is reported to be lower than after fundoplication, and reoperations and other severe adverse events greater. Larger RCTs with longer follow-up, preferably compared with fundoplication, are needed to define the risks and benefits of this procedure better. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have GERD who receive esophageal bulking agents, the evidence includes an RCT and case series. Relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. The RCT for a single product was terminated early due to lack of efficacy, while other products have only case series to support use. High-quality data from large RCTs are needed to compare bulking procedures with both sham controls and with the currently accepted treatments for GERD (i.e., drug therapy, laparoscopic fundoplication). Well-designed trials should use standardized outcome measures to examine whether subjective improvement (e.g., discontinuation of medication therapy, Gastroesophageal Reflux Disease Health-Related Quality of Life scores) is supported by objective improvement (e.g., esophageal acid exposure). The evidence is insufficient to determine the effects of the technology on health outcomes.

Background
Gastroesophageal Reflux Disease
GERD is a common disorder characterized by heartburn and other symptoms related to reflux of stomach acid into the esophagus. Nearly all individuals experience such symptoms at some point in their lives; a smaller number have chronic symptoms and are at risk for complications of GERD. The prevalence of GERD has been estimated to be 10% to 20% in the Western world, with a lower prevalence in Asia.1,

Pathophysiology
The pathophysiology of GERD involves excessive exposure to stomach acid, which occurs for several reasons. There can be an incompetent barrier between the esophagus and stomach, either due to dysfunction of the lower esophageal sphincter or incompetence of the diaphragm. Another mechanism is an abnormally slow clearance of stomach acid. In this situation, delayed clearance leads to an increased reservoir of stomach acid and a greater tendency to reflux.

In addition to troubling symptoms, some patients will have a more serious disease, which results in complications such as erosive esophagitis, dysphagia, Barrett esophagus, and esophageal carcinoma. Pulmonary complications may result from aspiration of stomach acid into the lungs and can include asthma, pulmonary fibrosis, and bronchitis, or symptoms of chronic hoarseness, cough, and sore throat.

Treatment
Guidelines on the management of GERD emphasize initial medical management. Weight loss, smoking cessation, head of the bed elevation, and elimination of food triggers are all recommended in recent practice guidelines.1, Proton pump inhibitors have been shown to be the most effective medical treatment. In a Cochrane systematic review, van Pinxteren et al. (2010) reported that proton pump inhibitors demonstrated superiority to H2-receptor antagonists and prokinetics in both network meta-analyses and direct comparisons.2,

Surgical Treatment
The most common surgical procedure used for GERD is laparoscopic Nissen fundoplication. Fundoplication involves wrapping a portion of the gastric fundus around the distal esophagus to increase lower esophageal sphincter pressure. If a hiatal hernia is present, the procedure also restores the position of the lower esophageal sphincter to the correct location. Laparoscopic fundoplication was introduced in 1991 and has been rapidly adopted because it avoids complications associated with an open procedure.

Although fundoplication results in a high proportion of patients reporting symptom relief, complications can occur, and sometimes require conversion to an open procedure. Patients who have relief of symptoms of GERD after fundoplication may have dysphagia or gas-bloat syndrome (excessive gastrointestinal gas).

Other Treatment Options
Due in part to the high prevalence of GERD, there has been interest in creating a minimally invasive transesophageal therapeutic alternative to open or laparoscopic fundoplication or chronic medical therapy. This type of procedure may be considered natural orifice transluminal surgery. Three types of procedures have been investigated.

Transesophageal endoscopic gastroplasty (gastroplication, transoral incisionless fundoplication) can be performed as an outpatient procedure. During this procedure, the fundus of the stomach is folded and then held in place with staples or fasteners that are deployed by the device. The endoscopic procedure is designed to recreate a valve and barrier to reflux.

Radiofrequency energy has been used to produce submucosal thermal lesions at the gastroesophageal junction. (This technique has also been referred to as the Stretta procedure.) Specifically, radiofrequency energy is applied through 4 electrodes inserted into the esophageal wall at multiple sites both above and below the squamocolumnar junction. The mechanism of action of the thermal lesions is not precisely known but may be related to the ablation of the nerve pathways responsible for sphincter relaxation or may induce a tissue-tightening effect related to heat-induced collagen contraction and fibrosis.

Submucosal injection or implantation of a prosthetic or bulking agent to enhance the volume of the lower esophageal sphincter has also been investigated. One bulking agent, pyrolytic carbon-coated zirconium oxide spheres (Durasphere), is being evaluated. The Gatekeeper™ Reflux Repair System (Medtronic) 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. However, as the only identified RCT was terminated early due to lack of efficacy and no information is available on the ‘Digestive and Gastrointestinal’ Products section of Medtronic’s website, it is suspected that The Gatekeeper™ Reflux Repair System is not commercially available. U.S. Food and Drug Administration (FDA) product code: DQX. Endoscopic submucosal implantation of polymethylmethacrylate beads into the lower esophageal folds has also been investigated.

The Agency for Healthcare Research and Quality published a systematic review of management strategies for GERD in 2005, which was updated by Ip et al. (2011).3,4 The 2005 comparative effectiveness review evaluated studies on the EndoCinch Suturing System, Stretta, Enteryx, and the NDO Plicator.3 The 2011 update excluded Enteryx and the NDO Plicator, because they were no longer available in the US, and added the EsophyX procedure (endoscopic fundoplication), which was commercialized after the 2005 review.4, The 2011 report concluded that, for the 3 available endoscopic procedures (EndoCinch, Stretta, EsophyX), effectiveness remained substantially uncertain for the long-term management of GERD. All procedures have been associated with complications, including dysphagia, infection/fever, and bloating, although bloating and dysphagia are also adverse events of laparoscopic fundoplication.5 A review of endoscopic treatment of GERD by Hummel and Richards (2015) noted that EndoCinch is no longer manufactured.6,

Regulatory Status
The EsophyX® (EndoGastric Solutions) is a TIF device that was originally cleared for marketing by the FDA through the 510(k) process in 2007 and has subsequently undergone 2 evolutions: Generation 2=EsophyX2 iterations (E2-Plus, HD) and Generation 3=Z iterations (EZ/ZR, Z+).7 Some of the key Regulatory Status changes are summarized herein. In 2007, EsophyX® (EndoGastric Solutions) was cleared for marketing by the FDA through the 510(k) process for full-thickness plication. In 2016, EsophyX® Z Device with SerosaFuse Fasteners was cleared for marketing by the FDA through the 510(k) process (K160960) for use in transoral tissue approximation, full-thickness plication, ligation in the gastrointestinal tract, narrowing the gastroesophageal junction, and reduction of hiatal hernias of 2 cm or less in patients with symptomatic chronic GERD.8 In June 2017, EsophyX2 HD and the third-generation EsophyX Z Devices with SerosaFuse fasteners and accessories were cleared for marketing by the FDA through the 510(k) process (K171307) for expanded indications, including patients who require and respond to pharmacologic therapy and patients with hiatal hernias larger than 2 cm when a laparoscopic hiatal hernia repair reduces a hernia to 2 cm or less.9 The most recent FDA 510(k) clearance (K172811) occurred in October 2017 for new product specification iterations of EsophyX2 HD and EsophyX Z Devices. This clearance allows for "a moderate increase in the upper limit of the temporary Tissue Mold clamping pressure occurring during each fastener deployment."10 FDA product code: ODE.

The Medigus SRS Endoscopic Stapling System (MUSE, Medigus) was cleared for marketing by the FDA through the 510(k) process in 2012 (K120299) and 2014 (K132151). MUSE is intended for endoscopic placement of surgical staples in the soft tissue of the esophagus and stomach to create anterior partial fundoplication for the treatment of symptomatic chronic GERD in patients who require and respond to pharmacologic therapy. FDA product code: ODE.

In 2000, the CSM Stretta® System was cleared for marketing by the FDA through the 510(k) process for general use in the electrosurgical coagulation of tissue and was specifically intended for use in the treatment of GERD. Stretta® is currently manufactured by Mederi Therapeutics. FDA product code: GEI.

Durasphere® is a bulking agent approved for the treatment of urinary and fecal incontinence (see evidence review 7.01.19). Use of this product for esophageal reflux would be considered off-label use. The website of Carbon Medical Technologies states that the Durasphere® GR product is “intended to treat problems associated with GERD” but is considered an investigational device in the U.S.  

Related Policies
20180 Endoscopic Radiofrequency Ablation or Cryoablation for Barrett’s Esophagus
70119 Injectable Bulking Agents for the Treatment of Urinary and Fecal Incontinence
701137 Magnetic Esophageal Ring to Treat Gastroesophageal Reflux Disease (GERD)

Policy
Magnetic esophageal sphincter augmentation to treat gastroesophageal reflux disease is considered MEDICALLY NECESSARY when the following criteria are met:1

  • Patient has a history of severe GERD for ≥1 year with daily symptoms, AND
  • Patient has tried and failed optimal non-surgical management of symptoms, including lifestyle modification, weight loss (if indicated), and daily proton pump inhibitor use for ≥ 6 months, AND
  • Patient has proven gastroesophageal reflux by either endoscopy or ambulatory pH monitoring, AND
  • Patient has evidence of adequate peristalsis by manometry or barium esophagram, AND
  • None of the following contraindications are present:
    • Morbid obesity (BMI >35)
    • Suspected or known allergies to metals such as iron, nickel, titanium, or stainless steel
    • Grade C or D (LA classification) esophagitis
    • Scleroderma
    • Esophageal stricture or gross esophageal anatomic abnormalities
    • Suspected or confirmed esophageal or gastric cancer
    • Prior esophageal or gastric surgery or endoscopic intervention.

Transoral incisionless fundoplication (TIF) (i.e., EsophyX®) is considered MEDICALLY NECESSARY as a treatment of gastroesophageal reflux disease when the following criteria are met:1 

  • Patient has a history of severe GERD for ≥1 year with daily symptoms, AND
  • Patient has tried and failed optimal non-surgical management of symptoms, including lifestyle modification, weight loss (if indicated), and daily proton pump inhibitor use for ≥ 6 months, AND
  • Patient has proven gastroesophageal reflux by either endoscopy, ambulatory pH monitoring, or barium esophagram, AND
  • None of the following contraindications are present:
    • Hiatal hernia >2cm in axial height and >2cm in greatest transverse dimension
    • Morbid obesity (BMI >35)
    • Esophagitis grade C or D
    • Barrett's esophagus > 2 cm
    • Non-healing esophageal ulcer
    • Fixed esophageal stricture or narrowing
    • Portal hypertension and/or varices
    • Active gastro-duodenal ulcer disease
    • Gastric outlet obstruction or stenosis
    • Gastroparesis
    • Prior esophageal surgery
    • Scleroderma
    • Suspected or confirmed esophageal or gastric cancer.

Transesophageal radiofrequency to create submucosal thermal lesions of the gastroesophageal junction (i.e., the Stretta® procedure) is considered investigational and/ or unproven and therefore considered NOT MEDICALLY NECESSARY as a treatment of gastroesophageal reflux disease.

Endoscopic submucosal implantation of a prosthesis or injection of a bulking agent (e.g., polymethylmethacrylate beads, zirconium oxide spheres) is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY as a treatment of gastroesophageal reflux disease.

Policy Guidelines
There are specific CPT codes for transoral incisionless fundoplication and the radiofrequency procedure:

43210 Esophagogastroduodenoscopy, flexible, transoral; with esophagogastric fundoplasty, partial or complete, includes duodenoscopy when performed

43257: Esophagogastroduodenoscopy, flexible, transoral; with delivery of thermal energy to the muscle of lower esophageal sphincter and/or gastric cardia, for treatment of gastroesophageal reflux disease.

Endoscopic submucosal injection of a bulking agent would most likely be coded using 43201 (Esophagoscopy, flexible, transoral; with directed submucosal injection[s], any substance) or code 43236 (Esophagogastroduodenoscopy, flexible, transoral; with directed submucosal injection[s], any substance).

Endoscopic implantation of a prosthesis would most likely be coded using code 43212 (Esophagoscopy, flexible, transoral; with placement of endoscopic stent [includes pre- and postdilation and guide wire passage, when performed]), code 43266 (Esophagogastroduodenoscopy, flexible, transoral; with placement of endoscopic stent [includes pre- and postdilation and guide wire passage, when performed]), or code 43499 (unlisted procedure, esophagus).

Benefit Application
BlueCard/National Account Issues
Some state or federal mandates (e.g., FEP) prohibit Plans from denying FDA-approved technologies as investigational. In these instances, Plans may have to consider the coverage eligibility of U.S. Food and Drug Administration (FDA)-approved technologies on the basis of medical necessity alone.

Rationale 
This evidence review was created in December 2000 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through October 20, 2020. 

This evidence review was informed, in part, by a TEC Assessment (2003) of transesophageal endoscopic treatments for gastroesophageal reflux disease (GERD) and an Evidence Street Assessment (2016) on transoral incisionless fundoplication (TIF).11 This review addresses procedures currently available for use in the U.S. 

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms. 

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Transoral Incisionless Fundoplication for Symptoms Uncontrolled by Proton Pump Inhibitors 
Clinical Context and Therapy Purpose 
The purpose of TIF (e.g., EsophyX) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with GERD and hiatal hernias of 2 cm or less not controlled by PPIs. 

The question addressed in this evidence review is: Does TIF using the EsophyX2 System improve the net health outcomes in individuals with GERD? 

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with GERD and a hiatal hernia of 2 cm or less uncontrolled by PPIs.

Interventions 
The therapy being considered is TIF2.0 (eg, EsophyX2).

Comparators 
The following practice is currently being used to treat GERD: laparoscopic fundoplication. 

Outcomes 
The general outcomes of interest are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. Follow-up at 3 years is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs; 
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies. 
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought. 
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews 
McCarty et al. (2018) published a systematic review of RCTs and nonrandomized studies that showed significant improvement in a number of clinical outcomes for patients treated with TIF.12 For example, 89% of TIF patients discontinued PPI therapy after the procedure, and the Gastroesophageal Reflux Disease Health-Related Quality of Life (GERD-HRQL) questionnaire, Gastroesophageal Reflux Symptom Score, and Reflux Symptom Index measures showed significant improvement. The review had several limitations, including the risk of heterogeneity bias, due to the inclusion of studies of first- and second-generation TIF devices and protocols. 

Richter et al. (2018) published a network meta-analysis of RCTs comparing TIF or laparoscopic Nissen fundoplication (LNF) with sham or PPIs.13, The meta-analysis was limited by low-quality studies (1 did not report the randomization method, others lacked data on allocation concealment, blinding of outcome assessors, or other aspects of study protocol). It should be noted that a reason behind the scarcity of direct comparisons between TIF and LNF is the discrepancy in populations requiring the respective treatments: consequently, TIF studies included patients with mild esophagitis and small hiatal hernias (<2 cm), while LNF studies included patients with Los Angeles grade A, B, C, or D esophagitis and all sizes of hiatal hernias. 

Tables 1 and 2 summarize the characteristics and results of selected systematic reviews. 

Table 1. Characteristics of Systematic Reviews 

Study Dates Trials Participants N (Range) Design Duration
McCarty et al. (2018)12 2008-2016 32 Patients met standard criteria for the TIF procedurea 1475 (10-124) 5 RCTs, 21 prospective and 6 retrospective studies NR
Richter et al. (2018)13 NR 7 Patients had GERD, established by endoscopic results indicating erosive esophagitis and/or abnormal ambulatory esophageal pH monitoringb   2 RCTs (TIF vs PPI); 2 RCTs (TIF vs sham); 3 RCTs (LNF vs PPIs)
  • TIF: 6-12 mo
  • LNF vs PPI: 1-5 y

GERD: gastroesophageal reflux disease; LNF: laparoscopic Nissen fundoplication; NR: not reported; PPI: proton pump inhibitor; RCT: randomized controlled trial; TIF: transoral incisionless fundoplication.
Body mass index <35 kg/m; hiatal hernia size ≤2 cm; grade A, B, or C esophagitis using the Los Angeles classification; no underlying esophageal motility disorder.
b  DeMeester score >14.7 and/or percentage total time at a pH <4 of ≥4.0%. 

Table 2. Results of Systematic Reviews 

Study Complete PPI Cessation GERD-HRQL Score GERSS RSI Score Other Objective Measures
          Esophageal Acid Exposure (% time with pH <4)
McCarty et al. (2018)12,          
N 1407 (28 studies) 1236 (25 studies) NR (6 studies) NR (8 studies) 722 (15 studies)
% (95% CI) 89 (82 to 95)        
MD (95% CI)   17.72
(17.31 to 18.14)
23.78
(22.96 to 24.60)
14.28
(13.56 to 15.01)
3.43
(2.98 to 3.88)
p <0.001 <0.001 <0.001 <0.001 <0.001
I2 (p) 93.6 (0.00) 94 (<0.001) 98 (<0.001) 95 (<0.001) 86 (<0.001)
Mean follow-up (SD), mo 15.5 (14.6)        
    TIF-2 Subgroup     TIF-2 Subgroup
N   997 (15 studies)      
MD (95% CI)   17.62
(17.19 to 18.05)
    53.18
(49.49 to 56.87)
p   <0.001     <0.001
Richter et al. (2018)13,          
N  
  • TIF=293 (4 studies)
  • LNF=875 (3 studies)
     
OR (95% CrI)   TIF vs LNF: 2.08
(0.71 to 6.09)
    LNF vs TIF: 0.08
(0.02 to 0.36)
Ranking probability (SUCRA)  
  • TIF=0.96
  • LNF=0.66
  • Sham=0.35
  • PPI=0.042
   
  • LNF=0.99
  • PPI=0.64
  • TIF=0.32
  • Sham=0.05

CI: confidence interval; CrI: credible interval; GERD-HRQL: Gastroesophageal Reflux Disease Health-Related Quality of Life questionnaire; GERSS: Gastroesophageal Reflux Symptom Score; LNF: laparoscopic Nissen fundoplication; MD: mean difference; NR: not reported; OR: odds ratio; PPI: proton pump inhibitor; RSI: Reflux Symptom Index; SD: standard deviation; TIF: transoral incisionless fundoplication.

Randomized Controlled Trials 
Two RCTs have evaluated TIF using ExophyX2 in patients with troublesome symptoms despite daily PPI therapy (see Table 3). Hunter et al. (2015) compared treatment using TIF2.0 plus placebo pills (n=87) with treatment using sham TIF plus PPIs (n=42) in the RESPECT trial.14 Increases in medication (placebo or PPI depending on treatment group) were allowed at 2 weeks. At 3 months, patients with continued troublesome symptoms were declared early treatment failures and failed TIF patients were given PPI and failed sham patients were offered TIF. Trad et al. (2015) compared TIF2.0 (n=40) with maximum PPI therapy (n=23) without a sham procedure in the TEMPO trial.15 The primary outcome in both trials was the elimination of symptoms, measured in slightly different ways (see Table 3). 

In both trials, the primary outcome was achieved by a higher percentage of patients treated with TIF than with PPIs (see Table 4). Elimination of symptoms was reported by 62% to 67% of patients treated by TIF compared with 5% of patients treated with maximum PPIs and 45% of patients who had a sham procedure plus PPIs (p=0.023). In TEMPO, the relative risk of achieving the primary outcome was 12.9 (95% confidence interval, 1.9 to 88.9; p<0.001). 

Secondary outcomes for the RESPECT trial showed no significant differences between treatments, except for Reflux Disease Questionnaire scores, which showed significant improvement in the TIF group compared with baseline. Physiologic measurements such as the number of reflux episodes, percentage of total time pH less than 4, and DeMeester score (a composite score of acid exposure based on esophageal monitoring) showed statistically significant differences between groups, but these measurements were performed when off PPIs for 7 days and the difference in pH between TIF and continued PPI therapy cannot be determined from this trial. 

In TEMPO, self-reported troublesome regurgitation was eliminated in 97% (29/30) of TIF patients who were off PPIs. However, the objective measure of esophageal acid exposure did not differ significantly between groups.

Table 3. Characteristics of Randomized Controlled Trials Comparing TIF With Medical Management in Patients Whose Symptoms Were Not Controlled on PPIs 

Study; Trial TIF/CTL, n Patient Symptoms or Other Characteristics Comparator FU, mo Principal Clinical Outcome
Hunter et al. (2015)14; RESPECT 87/42
  • Hiatal hernia≤2 cm
  • Troublesome regurgitationa not controlled on PPI
Sham + PPI 6 Relief of regurgitation without PPI in TIF group vs PPI escalation in control group
Trad et al. (2015)15;TEMPO 40/23
  • Hiatal hernia≤2 cm
  • Troublesome symptoms not controlled on PPIb
Maximum-dose PPI 6 Elimination of daily symptoms other than heartburn

CTL: control; FU: follow-up; PPI: proton pump inhibitor; TIF: transoral incisionless fundoplication.
Troublesome regurgitation was defined as mild symptoms for ≥2 days a week or moderate-to-severe symptoms >1 day a week.
Gastroesophageal reflux disease for >1 year and a history of daily PPI use for >6 months.

Table 4. Results for RCTs Comparing TIF With Medical Management in Patients Whose Symptoms Were Not Controlled on PPIs 

Trial Symptomsa Regurgitation Heartburn Reflux Esophageal pH
  Elimination of Troublesome Regurgitation Change in RDQ Regurgitation Score Change in RDQ Heartburn Score Change in RDQ Heartburn Plus Regurgitation Score  
RESPECT (2015)14          
TIF + placebo, % (n/N) 67% (58/87) -3 -2.1 -2.5  
Sham + PPI, % (n/N) 45% (19/42) -3 -2.2 -2.4  
p 0.023 0.072 0.936 0.313  
  Elimination of Symptoms Other Than Heartburnb Change in GERD-HRQL Score Change in GERD-HRQL Heartburn Score RSI Score Percent Time With pH >4
TEMPO (2015)15,          
TIF 62% -21.1 -14 -17.4 54%
Maximum-dose PPI 5% -7.6 -5.2 -3.0 52%
RR (95% CI) -12.9 (1.9-88.9)        
p 0.001 NR NR NR 0.914
TIF 62%-67%        

CI: confidence interval; GERD-HRQL: Gastroesophageal Reflux Disease Health-Related Quality of Life; NR: not reported; PPI: proton pump inhibitor; RCT: randomized controlled trial; RDQ: Reflux Disease Questionnaire; RR: relative risk; RSI: Reflux Symptom Index; TIF: transoral incisionless fundoplication.
Primary outcome measure.
Primary outcome measure a composite of 3 GERD symptom scales: the GERD-HRQL, RSI, and RDQ. 

Trad et al. (2017) reported a 3-year follow-up for patients treated with TIF in the TEMPO trial (see Table 5).16 All patients in the control group (maximum PPIs) had crossed over to TIF and were included in the follow-up. Symptom scores, esophagogastroduodenoscopy , and 48-hour pH monitoring were conducted off PPIs, and the 2 TIF failures who had undergone fundoplication were assigned the worst scores. Of 63 patients treated with TIF, data on PPI use was available for 52 (83%), with 71% of patients reporting a cessation of PPI use. However, completion of the Reflux Disease Questionnaire and assessment of pH normalization were available for 77% of patients. pH normalization was available for 40% of available patients following TIF, whereas 90% reported the elimination of troublesome regurgitation. 

Trad et al. (2018) also reported a 5-year follow-up for the TEMPO trial (see Table 5).17, Data were available for 44 patients, of whom 37 (86%) showed elimination of troublesome regurgitation at 5 years. Twenty (43%) patients were completely off PPIs at the 5-year follow-up, and 31 (70%) patients expressed satisfaction with the procedure, as assessed by the GERD-HRQL scores. While data on pH normalization were available for 24 patients at the 3-year follow-up, at 5 years, 22% (n=5) of these patients could not be assessed for pH normalization. 

Table 5. Follow-Up of Patients Treated With EsophyX2 in the TEMPO Trial 

Outcome Measure Baseline 1 Year 2 Years 3 Years 5 Years
Sample size (% of 63)   60 (95%) 55 (87%) 52 (83%) 44 (70%)
Elimination of troublesome regurgitation (RDQ)a   88% (42/48) 90% (41/44) 90% (37/41) 86% (37/43)
Elimination of atypical symptoms (RSI ≤13)a   82% (45/55) 84% (43/51) 88% (42/48) 80% (31/39)
GERD-HRQL score 32.8 (/60) 7.1 (/58) 7.3 (/52) 5.0 (/43) 6.8 (/31)
Esophagitis 55% (33/60) 5% (3/59) 10% (5/50) 12% (5/41)  
Cessation of PPI use   78% (47/60) 76% (42/55) 71% (37/52) 46% (20/44)
pH normalizationb   41% (24/59) 37% (18/49) 40% (16/40)  

Adapted from Trad et al. (2017) and Trad et al. (2018).16,17
Values are % (n/N) unless otherwise noted.
GERD-HRQL: Gastroesophageal Reflux Disease Health-Related Quality of Life; PPI: proton pump inhibitor; RDQ: Reflux Disease Questionnaire; RSI: Reflux Symptom Index.
Primary outcome: elimination of daily troublesome regurgitation and atypical symptoms as measured with the RDQ and RSI. Troublesome symptoms are defined as mild symptoms, occurring ≥2 days a week, or moderate-to-severe symptoms, occurring >1 day a week.
b  Normality was defined as percent of total recorded time pH <4 of ≥5.3%. 

Tables 6 and 7 summarize the important limitations of the RCTs discussed above. 

Table 6. Study Relevance Limitations 

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Hunter et al. (2015)14     2. Not compared to fundoplication
3. Measurement off PPIs group
   
Trad et al. (2015)15     2. Not compared to fundoplication
3. No sham surgery
   
Hakansson et al. (2015)18     2. Sham only (no active treatment)    
Witteman et al. (2015)19     3. Continued PPI only (no sham surgery)    

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
PPI: proton pump inhibitor
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms

Table 7. Study Design and Conduct Limitations 

Study

Allocationa

Blindingb

Selective Reportingc

Data Completenessd

Powere

Statisticalf

Hunter et al. (2015)14

 

 

 

 

 

 

Trad et al. (2015)15

 

1, 2. No blinding

 

 

 

1. Within-group analysis only

Hakansson et al. (2015)18

 

 

 

1. Unequal dropout rates in both treatment groups

1. Power calculations not reported

2. Adjusted for baseline values but not for repeated measures

Witteman et al. (2015)19

 

1, 2. No blinding

 

1. Study stopped following unplanned interim analysis

1. Power calculations not reported

 

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a  Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b  Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c  Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d  Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e  Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f  Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Nonrandomized Studies 
Two nonrandomized comparative studies have compared TIF with laparoscopic fundoplication in patients whose symptoms were not controlled on PPIs.20, 21 

A nonrandomized study by Toomey et al. (2014) compared 20 patients undergoing TIF, 20 patients undergoing Nissen fundoplication, and 20 patients undergoing Toupet fundoplication.20, Age, body mass index and preoperative DeMeester score were controlled, however, the indications for each procedure differed. Patients with abnormal esophageal motility underwent Toupet fundoplication, and only patients who had a hiatal hernia of 2 cm or less were offered TIF. As a result, only 15% of the TIF group had a hiatal hernia versus 65% and 55% of the 2 fundoplication groups, limiting comparison of both treatments. Adverse events were not reported. 

Frazzoni et al. (2011) compared 10 patients undergoing TIF with 10 patients undergoing laparoscopic fundoplication with the first-generation EsophyX procedure.21, The patients selected which treatment they wanted, but the groups were comparable to a baseline. Regarding clinical outcomes assessed at 3 months, 7 patients undergoing TIF reported only partial/no symptom remission versus zero patients undergoing fundoplication. Mild dysphagia was reported by 2 patients after fundoplication and 1 patient after TIF. Two patients reported epigastric bloating after fundoplication. Several measures of GERD assessed by manometry and impedance-pH monitoring showed greater improvement in the fundoplication group than in the TIF group. This study reported that TIF with the first-generation EsophyX device is less effective than fundoplication in improving symptoms of GERD. 

Tables 8 and 9 summarize the characteristics and results of selected nonrandomized studies. 

Table 8. Nonrandomized Study Characteristics

Study Study Type Country Dates Participants Treatment Comparator Follow-Up
Toomey et al. (2014)20 Case-control U.S. 2010-2013 Patients with GERD undergoing TIF, LNF, or LTF 20 patients underwent TIF 20 patients each had LTF or LNF NR
Frazzoni et al. (2011)21 Prospective open-label Italy 2000-2008 Patients had heartburn and/or regurgitation despite high-dose PPIs 10 patients chose first-generation EsophyX fundoplication 10 patients chose laparoscopic fundoplication 3 mo

GERD: gastroesophageal reflux disease; LNF: laparoscopic Nissen fundoplication; LTF: laparoscopic Toupet fundoplication; NR: not reported; PPI: proton pump inhibitor; TIF: transoral incisionless fundoplication. 

Table 9. Nonrandomized Study Results in Patients Whose Symptoms Were Not Controlled by PPIs 

Study Percent Partial or No Symptom Remission Normalization Esophageal Acid Exposure Time Normalization of Distal Refluxes Normalization of Proximal Refluxes Mild Dysphagia Bloating
Frazzoni et al. (2011)21            
TIF, % 70 50 20 40 10 0
Fundoplication, % 0 100 90 100 20 20
p 0.003 0.03 0.005 0.011 NR NR

NR: not reported; PPI: proton pump inhibitor; TIF: transoral incisionless fundoplication.

Section Summary: TIF for Symptoms Uncontrolled by PPIs 
Studies Comparing Transoral Incisionless Fundoplication With Continued PPIs
The evidence on TIF in patients whose symptoms are not controlled by PPIs includes 2 RCTs, 1 of which followed TIF patients for 3 years. The highest quality study is the sham-controlled RESPECT trial by Hunter et al (2015). RESPECT found a significantly greater proportion of patients who reported the elimination of troublesome regurgitation compared with sham plus PPIs, however, elimination of regurgitation was achieved in only 67% of patients treated with TIF. Also, other symptom measures did not differ between the TIF and sham-PPI groups. A strong placebo effect of the procedure is suggested by the subjective outcome measures in the sham group, in which 45% of patients whose symptoms were not previously controlled on PPIs reported elimination of troublesome regurgitation. The strong placebo effect suggested by the RESPECT trial raises questions about the validity of the nonblinded TEMPO trial. TEMPO reported significant improvements in subjective measures with TIF compared with maximum PPI treatment, but there was no significant difference in the objective measure of esophageal acid exposure. At a 3-year follow-up, about twice as many patients 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 would suggest the most appropriate comparator for patients whose symptoms are not controlled on PPIs is laparoscopic fundoplication. However, a 5-year follow-up of the TEMPO trial found sustained cessation of PPI therapy in most patients with data available, as well as the resolution of several types of trouble symptoms. These results may suggest long-term safety and durability of TIF 2.0 as an alternative to LNF.

Studies Comparing TIF With Laparoscopic Fundoplication
Each study comparing TIF with laparoscopic fundoplication has methodologic problems that do not permit conclusions on the comparative efficacy of the 2 procedures. The Frazzoni et al. (2011) nonrandomized study showed that TIF is less effective than a fundoplication. However, this study was conducted with an earlier device. In the Toomey et al. (2014) study, patients were assigned to different procedures based on specific baseline characteristics. Two of the studies concluded that TIF and fundoplication were similarly effective based on a lack of statistically significant differences across symptom outcomes. However, because of the small sizes of these samples, the lack of a statistically significant difference in outcomes cannot be interpreted as equivalent outcomes. For these studies, several outcomes favored fundoplication over TIF. The studies did not report adverse events or rates of postoperative symptoms associated with fundoplication (e.g., dysphagia, bloating). Thus, it is not possible to evaluate whether a difference in effectiveness between procedures might be accompanied by a difference in adverse events. Limited data suggest that the first-generation TIF is considerably inferior to laparoscopic fundoplication in patients who have failed PPI therapy, and this treatment is no longer available. Current data are insufficient to determine the risks and benefits of the second-generation TIF procedure compared with laparoscopic fundoplication in patients whose symptoms are not controlled by PPIs.

Transoral Incisionless Fundoplication for Symptoms Controlled by Proton Pump Inhibitors 
Clinical Context and Therapy Purpose
The purpose of TIF (e.g., EsophyX2) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with GERD and hiatal hernias of 2 cm or less controlled by PPIs.

The question addressed in this evidence review is: Does TIF using the EsophyX2 System improve the net health outcomes in individuals with GERD?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with GERD and hiatal hernias of 2 cm or less controlled by PPIs.

Interventions
The therapy being considered is TIF (e.g., EsophyX2).

Comparators
The following therapy is currently being used to treat GERD: PPI therapy.

Outcomes
The general outcomes of interest are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. Follow-up at 2, 3, and 6 years is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Trials
Two published RCTs have evaluated the efficacy of TIF in patients whose symptoms were adequately controlled on PPIs, but who were considering an intervention over lifelong drug dependence (see Table 10). Hakansson et al. (2015) compared TIF (n=22) with sham only (n=22).18 The expected outcome in the sham group was that, without PPIs, GERD symptoms would eventually recur. Witteman et al. (2015) compared TIF (n=40) with continued PPI therapy (n=20) without a sham procedure (see Table 10).19 The objective was to demonstrate that outcomes with TIF were not significantly worse than those with continued PPI therapy.

The primary outcome of the Hakansson et al. (2015) trial was treatment failure, defined as the need to resume PPIs. The primary outcome of the Witteman et al. (2015) trial was treatment success, defined by an improvement of 50% or more on the GERD-HQRL score.

In Hakansson et al. (2015), Kaplan-Meier curves showed a higher rate of treatment failure in the sham group than in the TIF group (p<0.001, time to treatment failure), with significantly more patients in the TIF group in remission at 6 months (59%) compared with the sham without PPI group (18%, p=0.01). In Witteman et al. (2015), PPI therapy was stepped up or down as necessary during follow-up. At 6 months, 55% of TIF patients had more than a 50% improvement in subjective GERD symptoms versus 5% of patients on continued PPI therapy (see Table 11). Mean change in GERD symptoms from baseline was consistent with this result (TIF, -14.1; control, -3.1), however, it is uncertain whether the difference between groups was due to a combination of TIF plus PPI, or if the PPI therapy in the control group was at maximum following the step-up protocol.

Secondary outcomes measuring GERD symptoms in the Hakansson et al. (2015) trial showed results consistent with more favorable outcomes in the TIF group. However, no statistical between-group analysis was reported for these outcomes. Dysphagia, bloating, and flatulence were reported in twice as many patients undergoing TIF (4, 4 and 2, respectively) compared with sham (2, 2 and 1, respectively). These results were reported as not statistically different. However, it is unlikely that the trial was powered to detect differences in these outcomes.

Table 10. Characteristics of Randomized Trials Assessing TIF in Patients Whose Symptoms Were Controlled by PPIs

Study TIF/CTL, n Patient Symptoms or Other Characteristics Comparator FU, mo Principal Clinical Outcome
Hakansson et al. (2015)18 22/22 Controlled on PPI, run-in to confirm PPI dependence Sham only > 6 Time to resumption of PPI, percent needing PPI at 6 mo
Witteman et al. (2015)19 40/20 Controlled on PPI; those who received TIF had GERD with hiatal hernias 2 cm Continued PPI only 6 Mean GERD symptoms, percent with >50% improvement

CTL: control; FU: follow-up; GERD: gastroesophageal reflux disease; PPI: proton pump inhibitor; TIF: transoral incisionless fundoplication.

Table 11. Results of RCTs Comparing TIF With Nonsurgical Treatment in Patients Whose Symptoms Were Controlled on PPIs

Study Days to PPI Resumption Change in PPI Therapy Change in Symptoms Change in QOL Change in Esophagitis Esophageal pH
    Remission at 6 Months Median GSRS Score Median QOLRAD Score   Percent Time pH <4
Hakansson et al. (2015)18            
TIF 197 13 (59%) 4 1.5   3.6%
Sham only 107 4 (18%) 1.4 0.4   9.8%
p 0.001 0.01 NR NR   NR
      Percent >50% Improvement in GERD-HRQL Score Mean GERD-HRQL Score Percentage With Esophagitis Percent Patients With Normalized pHa
Witteman et al. (2015)19            
TIF     55% -14.1 -19% 50%
Continued PPI     5% -3.1 -20% 63%
p     <0.001 <0.001 >0.05 NR

GERD-HRQL: Gastroesophageal Reflux Disease Health-Related Quality of Life; GSRS: Gastrointestinal Symptom Rating Scale; NR: not reported; PPI: proton pump inhibitor; QOL: quality of life; QOLRAD: Quality of Life in Reflux and Dyspepsia; RCT: randomized controlled trial; TIF: transoral incisionless fundoplication.
a  Defined as <4% for ≤4.2% of recording time. 

In the trial by Witteman et al. (2015), 26% of TIF patients resumed at least occasional PPI use by 6 months, and 100% of control patients remained on PPI therapy. With the exception of lower esophageal sphincter resting pressure, physiologic and endoscopic outcome measures did not differ significantly between groups. No adverse events related to fundoplication were identified on the Symptom Rating Scale.

TIF patients were followed beyond 6 months, with additional control patients who crossed over to have TIF. Sixty patients eventually underwent TIF. 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%. 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 a hiatal hernia. Although this RCT met its principal endpoint at 6 months and improvements in GERD symptoms appeared to be maintained for 12 months, long-term reflux control was not achieved, and the trialists concluded that “TIF is no[t an] equivalent alternative for PPIs in GERD treatment, even in this highly selected population.” The trial was originally designed as a dual-center study, but it was terminated following interim analysis showing loss of reflux control.

Observational Studies 
Observational case series and prospective cohort studies can provide information on the durability of the TIF procedure. Studies were included if they provided additional information on treatment durability or addressed treatment safety. 

A case series and a cohort study have evaluated outcomes to 6 years after TIF2.0 (see Tables 12 and 13). Both studies were performed in patients with hiatal hernias of 2 cm or less in size whose symptoms were adequately controlled on PPIs but did not want to take medication indefinitely. Stefanidis et al. (2017) reported on a retrospective series that about 75% of patients had the elimination of esophagitis and had discontinued PPI use at 5 years, while 62% of the 13 patients with hiatal hernias had a reduction in hernia size at follow-up.22, 

In a prospective cohort by Testoni et al. (2015, 2019), 72% of the patients were completely responsive to PPIs at baseline, and 24% were partially responsive.23,24 Hiatal hernias had recurred by 12 months in 46% of the patients who had hernias at baseline, and at the 24-month follow-up, 20% of TIF2.0 procedures were considered unsuccessful. Nine percent of patients had additional surgery for poor response by 2 years. The Johnson-DeMeester score was not significantly improved. A poor response to treatment was associated with a hiatal hernia of 2 cm, higher Hill grade, the presence of esophagitis at baseline, and the use of fewer fasteners. About half the patients with a complete response initially resumed PPI use by 6 years and 20% had undergone additional surgery for a poor response, although these findings are limited by the low number of patients at follow-up. The number of fasteners used in this study might also be lower than current procedures. 

Table 12. Characteristics of Observational Studies With Long-Term Outcomes in Patients Whose Symptoms Were Controlled by PPIs

Study Country Participants Treatment Delivery Mean FU, mo
Stefanidis et al. (2017)22 Greece PPI-controlled, hiatal hernia ≤2 cm EsophyX2 59
Testoni et al. (2015, 2019)23, 24 Prospective study from 1 center in Italy Daily PPI, esophagitis or abnormal pH, hiatal hernias ≤2 cm ExophyX2 53

FU: follow-up; PPI: proton pump inhibitor.

Table 13Long-Term Durability of TIF in Patients Whose Symptoms Were Controlled by PPIs

Outcomes Mean Baseline 6 Months 1 Year 2 Years 3 Years 6-7 Years 10 Years
Stefanidis et al. (2017)22              
Sample size 45         44  
GERD-HRQL score off PPI 27         4  
PPI discontinuation           72.7%  
Elimination of esophagitis n=33   81.8%     72.7%  
Reduction in hiatal hernia n=13         61.5%  
Testoni et al. (2015, 2019)23, 24              
Sample size 50 49a 49 45b 45 30 14
GERD-HRQL score off PPI (SD) 46 (19)     18 (13) 19 (14) 10 (7.7) 9.5 (6.1)
GERD-QUAL score off PPI (SD) 114 (20)     71 (24) 80 (21)    
Johnson-DeMeester score (SD) 22 (12) 18 (15)   19 (20)      
PPI discontinuation n(%)   61.2% 51.0% 25/45 (55.6) 24/45 (53.3) 11/30 (36.7) 5/14 (35.7)
Additional surgery for poor response n (%)       4/45 (8.8) 4/45 (8.8) 6/30 (20.0) 2/14 (14.1)

GERD-HRQL: Gastroesophageal Reflux Disease Health-Related Quality of Life; GERD-QUAL: Gastroesophageal Reflux Disease Quality of Life; PPI: proton pump inhibitor; SD: standard deviation; TIF: transoral incisionless fundoplication.
a  Excluding 1 failed procedure due to pneumothorax
Excluding 4 patients who underwent Nissen fundoplication for failed procedure.

Adverse Events
Huang et al. (2017) conducted a systematic review with a meta-analysis of TIF for the treatment of GERD.25, They included 5 RCTs and 13 prospective observational studies, of which 14 were performed with the TIF2.0 procedure. Efficacy results from the RCTs were combined for patients whose symptoms were controlled by PPIs and for those whose symptoms were not controlled by PPIs, and are not further discussed here. The follow-up to 6 years in prospective observational studies indicated a decrease in efficacy over time. The reported incidence of severe adverse events, consisting of gastrointestinal perforation and bleeding, was 19 (2.4%) of 781 patients. This included 7 perforations, 5 cases of post-TIF bleeding, 4 cases of pneumothorax, 1 case requiring intravenous antibiotics, and 1 case of severe epigastric pain.

Section Summary: Transoral Incisionless Fundoplication for Symptoms Controlled by PPIs 
The evidence on TIF in patients whose symptoms are controlled by PPIs includes 2 RCTs and observational studies with long-term follow-up. The sham-controlled trial by Hakansson et al. (2015) found the time to resume PPI therapy was longer following TIF and the remission rate was higher, indicating that TIF is more effective than no therapy. The nonblinded trial by Witteman et al. (2015) found a benefit of TIF compared with continued PPI therapy for subjective measures, but not for the objective measures of pH normalization and esophagitis, raising questions about a possible placebo effect. Extended follow-up of the TIF patients in the Witteman trial found the use of PPI increased over time, while endoscopy showed several findings indicating possible worsening of GERD. The limited evidence beyond 2 years is consistent with some loss of treatment effectiveness. Increased use of PPIs beyond 2 years occurred in Testoni et al. (2015). Adverse events associated with the procedure may be severe. Current evidence is insufficient to determine the effect of this intervention on the net health outcome in patients whose symptoms are adequately controlled by PPIs.

Transesophageal Radiofrequency 
Clinical Context and Therapy Purpose 
The purpose of endoscopic radiofrequency energy (e.g., Stretta) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with GERD. 

The question addressed in this evidence review is: Does the use of endoscopic radiofrequency energy improve the net health outcomes in individuals with GERD? 

The following PICO was used to select literature to inform this review.

Populations 
The relevant population of interest is individuals with GERD.

Interventions 
The therapy being considered is endoscopic radiofrequency energy (e.g., Stretta).

Comparators 
The following therapies and practices are currently being used to treat GERD: PPI therapy and laparoscopic fundoplication.

Outcomes 
The general outcomes of interest are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A meta-analysis of 4 RCTs (total n=165 patients) was published by Lipka et al. (2015) (see Table 14).26 Three trials compared Stretta with sham, and 1 compared Stretta with PPI therapy (see Table 15). Results of the individual sham-controlled trials were inconsistent, generally supporting some improvement in symptoms, but not in objective measures of esophageal acid exposure. For example, Corley et al. (2003) reported improvements in heartburn symptoms, QOL, and general physical QOL in the active treatment group compared with the sham group, but there were no significant differences in medication use or esophageal acid exposure.27, Aziz et al. (2010) found statistically significant improvements in GERD-HRQL scores in all treatment groups.28 Arts et al. (2012) reported that the symptom score and quality-of-life score for bodily pain improved, but no changes were observed in PPI use, esophageal acid exposure, or lower esophageal sphincter pressure after radiofrequency.29, Pooled results of the meta-analysis showed no significant differences between Stretta and either sham treatment or PPI management for the measured outcomes, including the ability to stop PPI therapy (see Table 16). The overall quality of evidence was considered to be very low with a high-risk of bias, and the meta-analysis was limited by heterogeneity in the included studies, which might have been due to small sample sizes, differences in measures, and differences in follow-up times.

Fass et al. (2017) published a meta-analysis of the same 4 RCTs plus 23 prospective cohort studies and 1 registry that evaluated the Stretta procedure for patients with GERD.30 Pooled results showed clinically significant improvements in subjective outcome measures and a reduction in PPI use from a baseline of 97% of patients to 49% of patients after treatment, but there was a smaller difference from the sham group in the RCTs and high heterogeneity in the cohort studies. For objective outcome measures, erosive esophagitis was not significantly improved using a random-effects model, and there was high heterogeneity in the cohort studies. The time that esophageal acid exposure was less than 4 was significantly improved in the cohort studies but was not significantly different from sham in the RCTs. The authors are business advisors to Mederi Therapeutics.

Table 14. Meta-Analytic Characteristics of RCTs Assessing TERF

Study Dates Trials Participants N (Range) Design Duration, mo
Fass et al. (2017)30 Inception to May 2016 28 Patients with GERD undergoing endoscopic radiofrequency (Stretta) 2468 (9-558) Meta-analysis of 4 RCTs, 23 cohort studies, and 1 registry 3-120
Lipka et al. (2015)26 Inception to Feb 2014 4 Patients with physiologic evidence of GERD who were on PPI therapy 165 (22-64) Meta-analysis of RCTs 6-12

GERD: gastroesophageal reflux disease; PPI: proton pump inhibitor; RCT: randomized controlled trial; TERF: transesophageal radiofrequency.

Table 15. Characteristics of RCTs Assessing TERF

Study TERF/CTL, n Patient Symptoms or Other Characteristics Comparator FU, mo Principal Clinical Outcome
Arts et al. (2012)29 11/11 GERD at least partially controlled by PPIs and abnormal pH, hiatal hernia ≤3 cm Sham with crossover at 3 mo 3 Composite reflux symptom score, esophageal pH, motility, and distensibility
Aziz et al. (2010)28 12/12 GERD controlled by PPIs; patients randomized to single or double TERF or sham Sham 12 GERD-HRQL score
Coron et al. (2008)31 20/16 GERD symptoms controlled by PPIs and abnormal EAE Continued PPI 6 Stopping or decreasing PPI use
Corley et al. (2003)27 35/29 Abnormal EAE, symptoms at least partially controlled by PPIs, hiatal hernia ≤2 cm Sham 6 Heartburn, QOL, PPI use, pH

CTL: control; EAE: esophageal acid exposure; FU: follow-up; GERD: gastroesophageal reflux disease; GERD-HRQL: Gastroesophageal Reflux Disease Health-related Quality of Life; PPI: proton pump inhibitor; QOL: quality of life; RCT: randomized controlled trial; TERF: transesophageal radiofrequency.

Table 16. Meta-Analytic Results

Study Heartburn GERD-HRQL Score Use of PPI Therapy Acid Exposure Time (pH <4) Other Objective Outcome Measures
  Heartburn Score       DeMeester score
Fass et al. (2017)30          
Patients (studies), n 637 (12) 507 (11) 1795 (23) 364 (11) 407 (8)
Change (95% CI) -1.53
(-1.97 to -1.09)
RCT: -14.56
(-16.63 to -12.48)
Cohort: -14.69
(-16.90 to -12.47)
Baseline: 1743 (97.1%)
Post-treatment: 850 (49%)
RR: 0.49 (0.40 to 0.60)
-3.01
(-3.72 to -2.30)
-13.79
(-20.01 to -7.58)
p <0.001 <0.001 <0.001 <0.001 <0.001
I2 (p) Significant in all subgroups (p<0.001) RCTs: NS
Cohort: 85% (<0.001)
RCTs: NS
Cohort: 95% (<0.001)
Not significant in any subgroup 77%
  Ability to Stop PPI Therapy       Mean LES Pressure
Lipka et al. (2015)26          
Patients (studies), n 118 (3) 88 (2)   153 (4) 110 (3)
MD (95% CI) RR=0.87
(0.75 to 1.00)
-5.24
(-12.95 to 2.46)
  1.56%
(-2.56% to 5.69%)
0.32 mm Hg
(-2.66 to 2.02 mm Hg)
p 0.06 0.18   0.46 0.79
I2 (p) 0% 96% (<0.001)   99% (<0.001) 96% (<0.001)
Range of N 24-51 22-64   22-64  

CI: confidence interval; GERD-HRQL: Gastroesophageal Reflux Disease Health-related Quality of Life; LES: lower esophageal sphincter; MD: mean difference; PCS: Physical Component Summary; PPI: proton pump inhibitor; RCT: randomized controlled trial; RR; relative risk.

Randomized Controlled Trials
Additional randomized controlled trials have been published since the meta-analyses summarized in Table 14.

Kalapala et al. (2017) published interim results from a small RCT of 20 patients randomized to PPI plus Stretta or PPI alone, with 3 months of follow-up.32 While short-term outcomes such as GERD symptoms and cessation of PPIs appeared improved for the Stretta group, the study sample was small and power calculations were not conducted.

Zerbib et al. (2020) published a double-blind RCT that compared Stretta plus PPI therapy (n=29) to sham plus PPI therapy (n=33) in individuals with PPI-refractory heartburn from 8 French centers.33 The primary endpoint was clinical success at week 24, defined as an intake of fewer than 7 PPI doses over the previous 2 weeks and adequate subjective patient-reported symptom control. Fewer patients achieved the primary endpoint in the Stretta group, but the difference was not statistically significant (3.4% vs 15.1%; odds ratio (OR)=0.20; 95% CI, 0.02 to 1.88). Severe adverse events were more frequent in the Stretta group (7 vs 2) and included epigastric pain (n = 3), delayed gastric emptying, vomiting, headache, and 1 leiomyoma. Limitations of this RCT include that pH-impedance monitoring was not performed either at enrollment or during follow-up. Thus, baseline status of GERD diagnosis is unclear and the physiologic effects of Stretta are unknown.

Controlled Trials Comparing Transesophageal Radiofrequency With Laparoscopic Fundoplication
Liang et al. (2015) reported on a prospective comparison of laparoscopic Toupet fundoplication with the Stretta procedure (see Table 17).34 Of 165 patients treated, 125 (76%) completed the 3-year follow-up (65 fundoplications, 60 Stretta) and were included in the analysis. Although the 2 groups were comparable in symptoms at baseline, 9 patients in the Stretta group had revised treatment and were not included in the final symptom scores. A similar percentage of remaining patients in the 2 groups achieved complete PPI independence and had similar improvements in belching, hiccup, cough, and asthma. The Stretta procedure was less effective than laparoscopic fundoplication in reducing symptoms of heartburn, regurgitation, and chest pain (see Table 18). Significantly more patients in the Stretta group underwent reoperation, while more patients in the fundoplication group complained of bloating, but this difference was not statistically significant. This study lacked randomization and, along with not reporting the TERF failures, had a high loss to follow-up. Also, while symptom scores were comparable at baseline, the study might have been subject to selection bias related to treatment choice, which affected baseline differences for other variables.

Ma et al. (2020) reported on a retrospective comparison of laparoscopic Toupet fundoplication with the Stretta procedure (see Table 17).35 GERD relapse was the primary endpoint. The 2 groups were comparable at baseline in demographic characteristics, body mass index, GERD family history, and comorbid hypertension, coronary disease, and diabetes. Two patients in each group were lost to follow-up and excluded from the final analyses. At 12 months, there were no statistically significant differences between the laparoscopic Toupet fundoplication and Stretta groups in GERD relapse (0 vs 1.4%; P=.744), reflux outcomes (e.g., reflux time [hours]: 1.7 vs 2.0; P=.390), dysphagia (2.3% vs 5.7%; P=.486), bloating (see Table 18), diarrhea (2.3% vs 4.3%; P=.792), or chronic stomach pain (2.3% vs 4.3%; P=.792). However, compared to laparoscopic Toupet fundoplication, the Stretta group had a high DeMeester score (8.8 vs 7.3; P<.05) and less lower esophageal sphincter pressure (11.6 vs 12.8 mmHg; P<.05). Important limitations of this study are its single-center design and short follow-up time.

Table 17. Characteristics of Studies Comparing TERF With Laparoscopic Fundoplication

Study Study Type Country Dates Participants Treatment 1 Treatment 2 FU, y
Liang et al. (2015)34 Prospective cohort China 2011 165 TERF Laparoscopic fundoplication 3
Ma et al. (2020)35 Retrospective cohort China 2014-2017 230 TERF Laparoscopic fundoplication 1

FU: follow-up; TERF: transesophageal radiofrequency.

Table 18. Results Comparing TERF With Laparoscopic Fundoplication

Study PPI Independence Improvement in Heartburn Score Improvement in Regurgitation Score Improvement in Chest Pain Score Reoperation Bloating
Liang et al. (2015)34            
TERF 68.3% 2.53 2.41 2.96 11.8% 0%
LF 72.3% 4.05 4.03 5.50 0% 6.2%
p 0.627 0.01 0.004 0.005 0.006 0.120
Ma et al. (2020)35            
TERF NR NR NR NR NR 5.7%
LF NR NR NR NR NR 4.7%
p NR NR NR NR NR 0.866

LF: laparoscopic fundoplication; NR: not reported; PPI: proton pump inhibitor; TERF: transesophageal radiofrequency.

Prospective Cohort Studies
Long-term follow-up from case series and cohort studies can inform the durability of TERF. For example, 5- and 10-year follow-ups after TERF were reported in 2014 (see Table 19).36, 37 Elimination of PPI use was similar for both studies at around 42% (see Table 20). Liang et al. (2014) reported that symptoms of heartburn, regurgitation, chest pain, cough, and asthma were all decreased compared with baseline. Noar et al. (2014) reported symptom improvement in 72% of patients and elimination of dysplasia in 85% of patients, but the interpretation of these findings is limited due to the 34% loss to follow-up in this study.

Table 19. Cohort Study and Case Series Characteristics

Study Country/Institution Participants Follow-Up, y Loss to Follow-Up
Liang et al. (2014)36 China 152 who failed PPI therapy 5 9%
Noar et al. (2014)37 University of Pittsburgh 149 who failed PPI therapy 10 34% (7% deceased)

PPI: proton pump inhibitor.

Table 20. Cohort Study and Case Series Results at Follow-Up

Study Elimination of PPI Use Symptom Improvement Elimination of Dysplasia Bloating
Liang et al. (2014)36 42.8% p<0.001 vs pretreatment   8.7%
Noar et al. (2014)37 41% 72% 85%  

PPI: proton pump inhibitor.

Section Summary: TERF (Stretta Procedure)
Six RCTs (n range, 20 -64 patients), 4 of which were sham-controlled, reported some improvements in symptoms following treatment with TERF. However, measures of esophageal acid exposure were typically not improved. Also, meta-analyses of 4 of these same studies found no significant improvements in outcomes. The findings of improvements in symptoms but not esophageal acid exposure have led to questions about whether TERF is acting by reducing sensation in the esophagus. Although single-arm studies have shown maintenance of symptom relief at 5 to 10 years, the interpretation depends on the efficacy of the procedure in the short term. Nonrandomized comparative studies have suggested that clinical success and symptom relief with TERF is lower than with fundoplication and there is a greater incidence of reoperations and severe adverse events. Larger RCTs with longer follow-up are needed to define the risks and benefits of this procedure with greater certainty.

Esophageal Bulking Agents
Clinical Context and Therapy Purpose
The purpose of esophageal bulking agents is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with GERD.

The question addressed in this evidence review is: Does the use of esophageal bulking agents improve the net health outcomes in individuals with GERD?

The following PICO was used to select literature to inform this review.

Populations 
The relevant population of interest is individuals with GERD.

Interventions 
The therapy being considered is esophageal bulking agents.

Comparators 
The following therapies and practices are currently being used to treat GERD: PPI therapy and laparoscopic fundoplication.

Outcomes 
The general outcomes of interest are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. Though not completely standardized, follow-up for GERD symptoms would typically occur in the months to years after starting treatment.

Study Selection Criteria 
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs; 
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies. 
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought. 
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence 
The available evidence for Durasphere consists of a single case series. One open-label pilot study by Ganz et al (2009) assessed 10 GERD patients injected with Durasphere (Carbon Medical Technologies), a bulking agent approved for the treatment of urinary and fecal incontinence, at the gastroesophageal junction.38, At 12 months, 7 (70%) patients discontinued all antacid medication completely. No erosion, ulceration, or sloughing of the material was noted at any injection site.

Gatekeeper Reflux Repair System 
The available evidence for Gatekeeper Reflux Repair System consists of a single RCT reported by Fockens et al. (2010).39 In this industry-funded sham-controlled single-blind, multicenter study randomized 118 patients into Gatekeeper (n=75) or sham (n=43) treatment. An additional 25 patients were treated as lead-ins during the initial training of investigators and included only in the safety analysis. The patients were implanted initially with 4 Gatekeeper prostheses. At 3 months, 44% of implanted patients received retreatment with up to 4 additional prostheses due to unsatisfactory symptom control. The primary safety endpoint was a reduction in a serious device- and procedure-related adverse events, compared with a surgical procedure composite complication rate of 15%. Four serious adverse events were reported (2 perforations, 1 pulmonary infiltrate related to a perforation, 1 severe chest pain). The primary efficacy endpoint was a reduction in heartburn symptoms using the GERD-HRQL questionnaire. Planned interim analysis after 143 patients were enrolled found that heartburn symptoms and esophageal acid exposure had improved significantly in both the Gatekeeper and sham groups at 6 months, but there was no significant difference between groups. The trial was terminated early due to a lack of efficacy.

Polymethylmethacrylate Beads 
The available evidence for polymethylmethacrylate beads consists of a single case series. A case series by Feretis et al. (2001) evaluated on transesophageal submucosal implantation of polymethylmethacrylate beads in 10 patients with GERD who were either refractory to or dependent on PPIs.40 While a significant decrease in symptom scores was noted at posttreatment follow-up (time not specified), the small number of patients and lack of long-term follow-up precluded scientific analysis. No additional studies have been identified evaluating this treatment option.

Section Summary: Esophageal Bulking Agents 
The evidence on the injection of bulking agents includes an RCT terminated early due to a lack of efficacy and case series. High-quality data from large RCTs are needed to compare bulking procedures with both sham controls and with the currently accepted treatments for GERD (ie, drug therapy, laparoscopic fundoplication). Well-designed trials should use standardized outcome measures to examine both subjective (eg, GERD-HRQL scores) and objective (e.g., esophageal acid exposure) effects on health outcomes.

Summary of Evidence 
For individuals who have GERD and a hiatal hernia of 2 cm or less that is not controlled by PPIs who receive TIF (e.g., EsophyX), the evidence includes 2 RCTs comparing TIF with PPI therapy, nonrandomized studies comparing TIF with fundoplication, and case series with longer-term follow-up. Relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. The highest quality RCT (RESPECT) was sham-controlled that compared TIF with PPI therapy while the other RCT (TEMPO) compared TIF with maximum PPI therapy. Both trials found a significant benefit of TIF on the primary outcome measure in about 65% of patients. The sham-controlled trial reported improvement in 45% of the sham-controlled group and no benefit on secondary subjective outcome measures. The nonblinded RCT found significant improvements in subjective measures but no difference in objective outcome measures compared with PPI therapy. Together, these trial results would suggest a strong placebo effect of the surgery and a modest benefit of TIF in patients whose symptoms were not controlled by PPIs. For these patients, the most appropriate comparator would be laparoscopic fundoplication. Studies comparing TIF with fundoplication have limitations that include earlier TIF procedures and unbalanced groups at baseline and are inadequate to determine relative efficacy.  

For individuals who have GERD and a hiatal hernia of 2 cm or less that is controlled by PPIs who receive TIF (eg, EsophyX), the evidence includes 2 RCTs and observational studies with longer-term follow-up. Relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. A sham-controlled trial found that the time to resume PPI therapy was longer following TIF and the remission rate was higher, indicating that TIF is more effective than no therapy. The nonblinded RCT found a benefit of TIF compared with continued PPI therapy for subjective measures, but not for the objective measures of pH normalization and esophagitis. These results raise questions about a possible placebo effect for the procedure. Also, observational studies have indicated a loss of treatment effectiveness over time. Adverse events associated with the procedure (e.g., perforation) may be severe. At present, the available evidence does not support the use of this intervention in patients whose symptoms are adequately controlled by medical therapy.  

For individuals who have GERD who receive endoscopic radiofrequency energy (e.g., Stretta), the evidence includes 2 meta-analyses, 6 small RCTs, 2 nonrandomized comparative studies, and observational studies with longer-term follow-up. Relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. The RCTs reported some improvements in symptoms and QOL following treatment with radiofrequency energy compared with sham controls. However, objective measures of GERD and a meta-analysis of 4 RCTs found no significant improvements in outcomes, raising questions about the mechanism of the symptom relief. Symptom relief and clinical success is reported to be lower than after fundoplication, and reoperations and other severe adverse events greater. Larger RCTs with longer follow-up, preferably compared with fundoplication, are needed to define the risks and benefits of this procedure better.  

For individuals who have GERD who receive esophageal bulking agents, the evidence includes an RCT and case series. Relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. The RCT for a single product was terminated early due to lack of efficacy, while other products have only case series to support use. High-quality data from large RCTs are needed to compare bulking procedures with both sham controls and with the currently accepted treatments for GERD (ie, drug therapy, laparoscopic fundoplication). Well-designed trials should use standardized outcome measures to examine whether subjective improvement (eg, discontinuation of medication therapy, GERD-HRQL scores) is supported by objective improvement (eg, esophageal acid exposure). 

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2015 Input
In response to requests for clinical input on transesophageal radiofrequency (Stretta) as a treatment of gastroesophageal reflux disease (GERD), input was received from 1 physician specialty society (2 reviewers) and 3 academic medical centers while this policy was under review in 2015. Input was mixed on the treatment of GERD with transesophageal radiofrequency to create submucosal thermal lesions of the gastroesophageal junction (i.e., Stretta). Potential conflicts of interest were noted by 2 reviewers.

2011 Input
In response to requests for clinical input on transoral incisionless fundoplication (TIF) using EsophyX, input was received from 2 physician specialty societies and 4 academic medical centers while this policy was under review in 2011. Reviewers agreed that TIF differed sufficiently from laparoscopic Nissen fundoplication to warrant evaluation as a separate procedure. Reviewers considered TIF (i.e., EsophyX) to be investigational for the treatment of GERD.

Practice Guidelines and Position Statements
American Society for Gastrointestinal Endoscopy
In 2015, the American Society for Gastrointestinal Endoscopy published guidelines on endoscopic procedures for GERD.41, In its review of the EsophyX and Stretta procedures, the Society noted some positive findings but discrepancies between subjective and objective outcome measures or a lack of objective outcome measures in reported trials, concluding that these techniques represent “potentially new therapeutic indications for GI endoscopy”, but that prospective trials using objective measures of GERD as the primary endpoint could be useful in defining the clinical role of these procedures.

American College of Gastroenterology
In 2013, updated guidelines from the American College of Gastroenterology indicated the use of current endoscopic therapy or TIF could not be recommended as an alternative to medical or traditional surgical therapy (conditional recommendation, moderate level of evidence). The guidelines also cited limited data on small numbers of subjects and short duration of follow-up.1

Society of American Gastrointestinal and Endoscopic Surgeons
In 2017, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) provided a clinical spotlight review on endoluminal treatments for GERD.42 The SAGES gave a strong recommendation based on moderate-quality evidence that TIF using EsophyX can be performed with an acceptable safety risk in selected patients. The SAGES concluded that EsophyX results in better control of GERD symptoms than proton pump inhibitor (PPI) treatment in the short term (6 months), and leads to similar improvements in objective GERD measures compared with PPIs. TIF appears to lose effectiveness during longer-term follow-up and is associated with moderate patient satisfaction scores. SAGES found no comparative, controlled trials between TIF and surgical fundoplication, but preliminary evidence suggested that surgical fundoplication can be used safely after TIF failure.

The SAGES gave a strong recommendation based on moderate-quality evidence that Stretta is safe for adults and significantly improves health-related quality of life score, heartburn scores, the incidence of esophagitis, and esophageal acid exposure in patients with GERD. Stretta was found to decrease PPI use by about 50%, and be more effective than PPIs, but less effective compared to fundoplication. The effectiveness of the procedure decreases over time.

American Society of General Surgeons
In 2011, the American Society of General Surgeons issued a position statement on transoral fundoplication stating that “ASGS supports the use of transoral fundoplication by trained General Surgeons for the treatment of symptomatic chronic gastroesophageal reflux disease (GERD) in patients who fail to achieve satisfactory response to a standard dose of Proton Pump Inhibitor (PPI) therapy or for those who wish to avoid the need for a lifetime of medication dependence.”43,

National Institute for Health and Care Excellence
In 2013, the National Institute for Health and Care Excellence (NICE) updated its guidance on endoscopic radiofrequency treatment for GERD, concluding: "The evidence on the safety of endoscopic radiofrequency ablation for gastro-esophageal reflux disease is adequate in the short and medium term, but there is uncertainty about longer‑term outcomes. With regard to efficacy, there is evidence of symptomatic relief, but objective evidence on reduction of reflux is inconclusive ... ."44 The NICE noted "concern on the part of some specialists about the possibility that symptoms may improve as a result of denervation caused by the procedure; if that were the case then failure to recognize and treat reflux might lead to complications in the long term."

In 2011, the NICE issued guidance on endoluminal gastroplication for GERD, concluding that "The evidence on endoluminal gastroplication for gastroesophageal reflux disease raises no major safety concerns. Evidence from a number of RCTs [randomized controlled trials] 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 esophageal pH measurements...."45,

In 2004, the NICE issued guidance on bulking agents for GERD, concluding that "Current evidence on the safety and efficacy of endoscopic injection of bulking agents for gastro-esophageal reflux disease does not appear adequate for this procedure to be used without special arrangements....."46 The NICE (2016) removed guidance on endoscopic bulking agents/hydrogel implants from guidelines on treatment for "dyspepsia and gastro-esophageal reflux" because the product had been withdrawn by the manufacturer.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 21.

Table 21. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date (status)
Ongoing      
NCT04306380 Transoral Incisionless Fundoplication Database Repository (TIF) 500 Dec 2030
Unpublished      
NCT01110811a A Randomized Controlled Trial Comparing Transoral Incisionless Fundoplication (TIF) Using EsophyX With Sham Procedure for the Treatment of PPI Dependent GERD: the TIF vs Sham Study 60 Dec 2018 (completed)
NCT01118585a Prospective Outcome Evaluation of Transoral Incisionless Fundoplication (TIF) for the Treatment of Gastroesophageal Reflux Disease (GERD): The TIF Registry Study 278 Dec 2018 (completed)
NCT02366169a A Worldwide Post-Market Surveillance Registry to Assess the Medigus Ultrasonic Surgical Endostapler (MUSE™) System for the Treatment of GERD 200 Dec 2019 (unknown)

NCT: national clinical trial.
a  Denotes industry-sponsored or cosponsored trial.

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Coding Section

Codes

Number

Description

CPT  43201 

Esophagoscopy, flexible, transoral; with directed submucosal injection(s), any substance 

  43210 

Esophagogastroduodenoscopy, flexible, transoral; with esophagogastric fundoplasty, partial or complete, includes duodenoscopy when performed (new code 01/01/16) 

  43212

Esophagoscopy, flexible, transoral; with placement of endoscopic stent (includes pre- and dilation and guide wire passage, when performed) 

  43236 

Esophagogastroduodenoscopy, flexible, transoral; with directed submucosal injection(s), any substance 

  43257 

Esophagogastroduodenoscopy, flexible, transoral; with delivery of thermal energy to the muscle of lower esophageal sphincter and/or gastric cardia, for treatment of gastroesophageal reflux disease 

  43266 

Esophagogastroduodenoscopy, flexible, transoral; with placement of endoscopic stent (includes pre- and dilation and guide wire passage, when performed)

  43284 

Laparoscopy, surgical, esophageal sphincter augmentation procedure, placement of sphincter augmentation device (ie, magnetic band), including cruroplasty when performed

  43499

Unlisted procedure, esophagus 

HCPCS  C9724 

Endoscopic full-thickness plication of the stomach using endoscopic plication system (EPS); includes endoscopy

ICD-9 Procedure  44.66  Other procedure for creation of esophagogastric sphincteric competence (used for endoscopic suturing of the esophagogastric junction)  
ICD-9 Diagnosis  530.10-530.19  Esophagitis, code range 
ICD-10-CM (effective 10/1/15)    Investigational for all diagnoses 
  K21.0, K21.9  Gastro-esophageal reflux disease code list 
ICD-10-PCS (effective 10/1/15)  0DQ48ZZ  Repair, gastrointestinal system, esophagogastric junction, via natural or artificial opening, endoscopic  
  0DU48JZ  Supplement, gastrointestinal system, esophagogastric junction, via natural or artificial opening, endoscopic, synthetic substitute  
  0DV48DZ  Restriction, gastrointestinal system, esophagogastric junction, via natural or artificial opening, endoscopic, intraluminal device  
Type of Service  Medicine   
Place of Service     

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

09/01/2021 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

09/01/2020 

Annual review, no change to policy intent. 

12/06/2019 

Interim review with updated policy statements including medical necessity criteria for magnetic esophageal sphincter augmentation and transoral incisionless fundoplication. Updating description, rationale and references. 

09/03/2019 

Annual review, no change to policy intent. Updating background, guidelines, rationale and references. 

09/04/2018 

Annual review, no change to policy intent. Updating description, rationale and references. 

09/12/2017

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references.

09/01/2016 

Annual review, no change to policy intent. Updating background, description, regulatory status, guidelines, rationale, coding and references. 

09/14/2015 

Annual review, no change to policy intent. Updated background, description, rationale, references and coding. Added guidelines and regulatory status.

09/18/2014

Annual review. Updated background/description, rationale & references. Added benefit application & ICD 9 & 10. No change to policy intent.

 


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