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 Nov. 3, 2021.

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).12, 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 1 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. Randomized controlled trials 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 transoral incisionless fundoplication (TIF) (e.g., EsophyX; MUSE) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with gastroesophageal reflux disease (GERD) and hiatal hernias of 2 cm or less not controlled by proton pump inhibitors (PPIs).

The question addressed in this evidence review is: Does TIF using the EsophyX 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 (e.g., EsophyX ).

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.¹³ 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.¹⁴ 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.

Testoni et al. (2021) published a systematic review and meta-analysis focusing on long-term (≥ 3 years) outcomes of patients with GERD undergoing TIF (using either EsophyX or MUSE).¹⁵ Outcomes of interest included patient satisfaction, QOL, and PPI use. The mean follow-up time across studies was 5.3 years (range: 3 to 10 years). Daily PPI use was 100% in 5 studies, 97% in 1 study, and was not provided in the other 2 studies. Overall, the pooled proportion of patient-reported satisfaction before and after TIF was 12.3% and 70.6%, respectively. Additionally, the pooled rates of patients completely off, or on occasional, PPIs post-TIF was 53.8% and 75.8%. The analysis was limited by various factors including the nature of included studies, which involved only 1 open-label RCT among the 8 studies included, and the high heterogeneity across studies for patient reported overall satisfaction after the TIF procedure.

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)13	2008 – 2016	32	Patients met standard criteria for the TIF procedurea	1475 (10 to 124)	5 RCTs, 21 prospective and 6 retrospective studies	NR
Richter et al. (2018)14	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. PPI)	TIF: 6 to 12 mo LNF vs. PPI: 1 to 5 y
Testoni et al. (2021)15	Inception to May 2020	8	Patients had refractory GERD and underwent a TIF procedure	418 (15 to 86)	1 RCT, 3 muticenter, prospective studies, and 4 single-center prospective studies	Median follow-up: 5.3 years (range: 3 to 10 years)

GERD: gastroesophageal reflux disease; LNF: laparoscopic Nissen fundoplication; NR: not reported; PPI: proton pump inhibitor; RCT: randomized controlled trial; TIF: transoral incisionless fundoplication.
^a Body mass index < 35 kg/m2; 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)13
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	<.001	< .001	< .001	< .001	< .001
I2 (p)	93.6 (.00)	94 (< .001)	98 (< .001)	95 (< .001)	86 (< .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		< .001			< .001
Richter et al. (2018)14
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
Testoni et al. (2021)15
	Patient Satisfaction With TIF (median %)	PPI Use (pooled % off/occasional use)		Normalized Heartburn Scores (median pooled %)	Normalized Regurgitation Scores (median pooled %)
After 3 years	74	53.5/73.8		68.6	79
After 4 to 5 years	86.2	57.5/76.4		86.2	87.1
After 8 years	78	34.4/91.7
			GERD-HRQL (pooled estimated mean [95% CI])
Before TIF (off PPI)			26.1 (21.5 to 30.7)
After TIF (mean follow-up 5.3 years)			5.9 (0.35 to 11.4)
p value			< .001

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 EsophyX2 in patients with troublesome symptoms despite daily PPI therapy (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.16, 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.¹⁷ The primary outcome in both trials was the elimination of symptoms, measured in slightly different ways (Table 3).

In both trials, the primary outcome was achieved by a higher percentage of patients treated with TIF than with PPIs (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 = .023). In TEMPO, the relative risk of achieving the primary outcome was 12.9 (95% confidence interval [CI], 1.9 to 88.9; p < .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)16; 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)17;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.
^a Troublesome regurgitation was defined as mild symptoms for ≥ 2 days a week or moderate-to-severe symptoms > 1 day a week.
^b 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)16
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	.023	.072	.936	.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)17
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 to 88.9)
p	.001	NR	NR	NR	.914
TIF	62% to 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.
a Primary outcome measure.
^b 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 (Table 5).¹⁸ 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 (Table 5).¹⁹ 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).^18,19
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.
^a 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 with 5.3% as the threshold for normality.

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)16			2. Not compared to fundoplication 3. Measurement off PPI group
Trad et al. (2015)17			2. Not compared to fundoplication 3. No sham surgery
Hakansson et al. (2015)20			2. Sham only (no active treatment)
Witteman et al. (2015)21			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)16
Trad et al. (2015)17		1, 2. No blinding				1. Within-group analysis only
Hakansson et al. (2015)20				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)21		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.^22,23

A nonrandomized study by Toomey et al. (2014) compared 20 patients undergoing TIF, 20 patients undergoing Nissen fundoplication, and 20 patients undergoing Toupet fundoplication.²² 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.²³ 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 0 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)22	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)23	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)23
TIF, %	70	50	20	40	10	0
Fundoplication, %	0	100	90	100	20	20
p	.003	.03	.005	.011	NR	NR

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

Case Series
Bell et al. (2021) evaluated the durability of TIF with the EsophyX2 in 151 patients via a single institution prospective registry between November 2008 and July 2015.²⁴ Of these patients, the average duration of GERD symptoms was 11.3 years and 78% reported moderate to severe ongoing symptoms preoperatively despite PPI therapy. Eighty-six percent (n = 131) were available for follow-up at a median of 4.92 years (0.7 to 9.7 years). Results revealed a reduction in the median GERD-HRQL scores from 21 (off PPI) and 14 (on PPI) at baseline to 4 (at 4.92 years) and 5 (at 5 to 9 years post-TIF). A successful (> 50%) reduction in GERD-HRQL score at 4.92 years was seen in 64% of evaluable patients and 68% of patients followed for ≥5 years. Thirty-three (22%) of TIP patients underwent laparoscopic revisional surgery at a median of 14.7 months after surgery. Approximately 70% of patients remained free of daily PPI use throughout follow-up. The authors concluded that TIF provides durable relief of GERD symptoms for up to 9 years with a significant portion of patients having a successful outcome by symptom response and PPI use.

Section Summary: Transoral Incisionless Fundoplication for Symptoms Uncontrolled by Proton Pump Inhibitors
Studies Comparing Transoral Incisionless Fundoplication With Continued Proton Pump Inhibitors
The evidence on TIF in patients whose symptoms are not controlled by PPIs includes 2 RCTs, 1 of which followed TIF patients for up to 5 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; elimination of regurgitation was achieved in 67% of patients treated with TIF. 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 Transoral Incisionless Fundoplication 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., EsophyX; MUSE) 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 EsophyX 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., EsophyX ).

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 (Table 10). Hakansson et al. (2015) compared TIF (n = 22) with sham only (n=22).²⁰ 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 (Table 10).²¹ 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 < .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 = .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 (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)20	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)21	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)20
TIF	197	13 (59%)	4	1.5		3.6%
Sham only	107	4 (18%)	1.4	0.4		9.8%
p	.001	.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)21
TIF			55%	-14.1	-19%	50%
Continued PPI			5%	-3.1	-20%	63%
p			< .001	< .001	> .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 < .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 not 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 (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.²⁵

In a prospective cohort by Testoni et al. (2015, 2019), 72% of patients were completely responsive to PPIs at baseline, and 24% were partially responsive.^26,27 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)25	Greece	PPI-controlled, hiatal hernia ≤ 2 cm	EsophyX2	59
Testoni et al. (2015, 2019)26,27	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 13. Long-Term Durability of TIF in Patients Whose Symptoms Were Controlled by PPIs

Outcomes	Mean Baseline	6 Months	1 Year	2 Years	3 Years	6 to 7 Years	10 Years
Stefanidis et al. (2017)25
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)26,27
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.
^b 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.²⁸ The authors 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 Proton Pump Inhibitors
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 (N = 165 patients) was published by Lipka et al. (2015) (Table 14).²⁹ Three trials compared Stretta with sham, and 1 compared Stretta with PPI therapy (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.³⁰ Aziz et al. (2010) found statistically significant improvements in GERD-HRQL scores in all treatment groups.³¹ 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.³² 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 (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.³³ 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.

Xie et al. (2021) published a systematic review and network meta-analysis of 10 RCTs that evaluated the comparative effects of Stretta, TIF, and PPIs in patients with GERD.³⁴ Table 14 summarizes its overall characteristics. Of the included RCTs, 5 compared Stretta to control (PPI or sham + PPI) and 5 compared TIF to control (PPI or sham + PPI). Results of the network meta-analysis revealed that improvements in the health-related quality of lifes core induced by Stretta were not significantly different than the improvements seen with TIF (mean difference [MD], 2.45; 95% CI, -2.37 to 7.26); however, both Stretta and TIF were significantly superior to PPIs. Additionally, both Stretta and TIF were significantly better than PPIs at improving heartburn scores. With regard to reduction in PPI use and esophagitis incidence, no significant differences between TIF and Stretta were observed. This network meta-analysis had several limitations including a lack of assessment of long-term efficacy, the inclusion of only 10 studies with even fewer studies evaluated for each individual outcome, and lack of RCTs directly comparing Stretta and TIF. Additionally, some of the comparisons were significantly affected by heterogeneity and the evidence quality of each outcome (as assessed by GRADE) ranged from moderate to very low.

Table 14. Meta-Analytic Characteristics

Study	Dates	Trials	Participants	N (Range)	Design	Duration, mo
Fass et al. (2017)33	Inception to May 2016	28	Patients with GERD undergoing endoscopic radiofrequency (Stretta)	2468 (9 to 558)	Meta-analysis of 4 RCTs, 23 cohort studies, and 1 registry	3 to 20
Lipka et al. (2015)29	Inception to Feb 2014	4	Patients with physiologic evidence of GERD who were on PPI therapy	165 (22 to 64)	Meta-analysis of RCTs	6 to 12
Xie et al. (2021)34	Inception to Dec 2019	10	Patients with GERD diagnosed by typical symptoms, abnormal esophageal acid exposure, or esophagitis	516 (20 to 129)	Network meta-analysis of RCTs	3 to 60

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)32	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)31	12/12	GERD controlled by PPIs; patients randomized to single or double TERF or sham	Sham	12	GERD-HRQL score
Coron et al. (2008)35	20/16	GERD symptoms controlled by PPIs and abnormal EAE	Continued PPI	6	Stopping or decreasing PPI use
Corley et al. (2003)30	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)33
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	< .001	< .001	< .001	<.001	< .001
I2 (p)	Significant in all subgroups (< .001)	RCTs: NS Cohort: 85% (< .001)	RCTs: NS Cohort: 95% (< .001)	NS in any subgroup	77%
	Ability to Stop PPI Therapy				Mean LES Pressure
Lipka et al. (2015)29
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 mmHg (-2.66 to 2.02 mmHg)
p	.06	.18		.46	.79
I2 (p)	0%	96% (< .001)		99% (< .001)	96% (< .001)
Range of N	24 to 51	22 to 64		22 to 64

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

Randomized Controlled Trials
Additional RCTs 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.³⁶ 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.³⁷ 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 (Table 17).³⁸ 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 (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 transesophageal radiofrequency (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 (Table 17).³⁹ 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 (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)38	Prospective cohort	China	2011	165	TERF	Laparoscopic fundoplication	3
Ma et al. (2020)39	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)38
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	.627	.01	.004	.005	.006	.120
Ma et al. (2020)39
TERF	NR	NR	NR	NR	NR	5.7%
LF	NR	NR	NR	NR	NR	4.7%
p	NR	NR	NR	NR	NR	.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 (Table 19).^40,41 Elimination of PPI use was similar for both studies at around 42% (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	FU, y	Loss to FU
Liang et al. (2014)40	China	152 who failed PPI therapy	5	9%
Noar et al. (2014)41	University of Pittsburgh	149 who failed PPI therapy	10	34% (7% deceased)

FU: follow-up; 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)40	42.8%	p < .001 vs. pretreatment		8.7%
Noar et al. (2014)41	41%	72%	85%

PPI: proton pump inhibitor.

Section Summary: Transesophageal Radiofrequency
Six RCTs (n range, 20 to 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
Durasphere
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.⁴² 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.

Polymethylmethacrylate Beads
The available evidence for polymethylmethacrylate beads consists of a single case series. A case series by Feretis et al. (2001) evaluated transesophageal submucosal implantation of polymethylmethacrylate beads in 10 patients with GERD who were either refractory to or dependent on PPIs.⁴³ 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 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 (i.e., drug therapy, laparoscopic fundoplication). Well-designed trials should use standardized outcome measures to examine both subjective (e.g., 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 (eg, 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 and 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, a network meta-analysis, 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 case series. Relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. 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, GERD-HRQL scores) is supported by objective improvement (e.g., esophageal acid exposure). 

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

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 (ie, 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
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society for Gastrointestinal Endoscopy
In 2015, the American Society for Gastrointestinal Endoscopy published guidelines on endoscopic procedures for GERD.44, 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, guidelines from the American College of Gastroenterology (currently undergoing an update) 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.⁴⁵ 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. The 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.”⁴⁶

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."⁴⁷ 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."⁴⁸

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
NCT03669874	Endoscopic Fundoplication With MUSE System	80	Sept 2026
Unpublished
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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42. Ganz RA, Fallon E, Wittchow T, et al. A new injectable agent for the treatment of GERD: results of the Durasphere pilot trial. Gastrointest Endosc. Feb 2009; 69(2): 318-23. PMID 19185691
43. Feretis C, Benakis P, Dimopoulos C, et al. Endoscopic implantation of Plexiglas (PMMA) microspheres for the treatment of GERD. Gastrointest Endosc. Apr 2001; 53(4): 423-6. PMID 11275880
44. Muthusamy VR, Lightdale JR, Acosta RD, et al. The role of endoscopy in the management of GERD. Gastrointest Endosc. 2015; 81(6): 1305-10. PMID 25863867
45. Society of American Gastrointestinal and Endoscopic Surgeons. Clinical Spotlight Review: Endoluminal Treatments for Gastroesophageal Reflux Disease (GERD). 2017; https://www.sages.org/publications/guidelines/endoluminal-treatments-for-gastroesophageal-reflux-disease-gerd/. Accessed November 3, 2021.
46. American Society of General Surgeons (ASGS). Coverage of Transoral fundoplication. 2011; https://theasgs.org/position-statements/coverage-of-transoral-fundoplication-2/. Accessed November 3, 2021.
47. National Institute for Health and Care Excellence (NICE). Endoscopic radiofrequency ablation for gastro-oesophageal reflux disease [IPG461]. 2013; https://www.nice.org.uk/guidance/ipg461. Accessed November 3, 2021.
48. National Institute for Health and Care Excellence (NICE). Endoluminal gastroplication for gastro-oesophageal reflux disease [IPG404]. 2011; https://www.nice.org.uk/guidance/ipg404. Accessed November 5, 2021.

Coding Section

Code	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 (i.e., 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 nonaffiliated 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     

09/01/2022	Annual review, no change to policy intent. Updating rationale and references.
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.