| Coverage Policy Manual | |
| Policy #: | 2018001 |
| Category: | Surgery |
| Initiated: | January 2018 |
| Last Review: | January 2024 |
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| Transesophageal Endoscopic Therapies for Gastroesophageal Reflux Disease | |
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| Description: |
GASTROESOPHAGEAL REFLUX DISEASE
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 (Katz, 2013).
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 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 the 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 (Katz, 2013). Proton pump inhibitors have been shown to be the most effective medical treatment. In a 2010 Cochrane systematic review, Proton pump inhibitors demonstrated superiority to H2-receptor agonists and prokinetics in both network meta-analyses and direct comparisons (van Pinxteren, 2010).
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.
1. 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.
2. 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 ablation of the nerve pathways responsible for sphincter relaxation or may induce a tissue-tightening effect related to heat-induced collagen contraction and fibrosis.
3. 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, Shoreview, MN) uses a soft, pliable, expandable prosthesis made of a polyacrylonitrile-based hydrogel. The prosthesis is implanted into the esophageal submucosa, and with time, the prosthesis absorbs water and expands, creating bulk in the region of implantation. 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.
REGULATORY STATUS
In 2007, EsophyX® (EndoGastric Solutions, Redmond, WA) was cleared for marketing by FDA through the 510(k) process for full-thickness plication. In 2016, EsophyX® Z Device with SerosaFuse Fasteners was cleared for marketing by 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 hernia of 2 cm or less in patients with symptomatic chronic GERD (FDA, 2016). In June 2017, EsophyX2 HD and the third-generation EsophyX Z Devices with SerosaFuse fasteners and accessories were cleared for marketing by FDA through the 510(k) process (K171307) for expanded indications, including patients who require and respond to pharmacologic therapy and in patients with hiatal hernias larger than 2 cm when a laparoscopic hiatal hernia repair reduces a hernia to 2 cm or less (FDA, 2017). FDA product code: ODE.
The Medigus SRS Endoscopic Stapling System (MUSE, Medigus) was cleared for marketing by 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 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 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 (Greenwich, CT). FDA product code: GEI.
Durasphere® is a bulking agent approved for 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 United States.
Coding
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.
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Policy/ Coverage: |
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Transoral incisionless fundoplication does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness as a treatment of gastroesophageal reflux disease.
For members with contracts without primary coverage criteria, transoral incisionless fundoplication is considered investigational as a treatment of gastroesophageal reflux disease. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Transesophageal radiofrequency to create submucosal thermal lesions of the gastroesophageal junction does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness as a treatment of gastroesophageal reflux disease.
For members with contracts without primary coverage criteria, transesophageal radiofrequency to create submucosal thermal lesions of the gastroesophageal junction is considered investigational as a treatment of gastroesophageal reflux disease. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Endoscopic submucosal implantation of a prosthesis or injection of a bulking agent (e.g., polymethylmethacrylate beads, zirconium oxide spheres) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness as a treatment of gastroesophageal reflux disease.
For members with contracts without primary coverage criteria, endoscopic submucosal implantation of a prosthesis or injection of a bulking agent (e.g., polymethylmethacrylate beads, zirconium oxide spheres) is considered investigational as a treatment of gastroesophageal reflux disease. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
This evidence review was created in December 2000 and has been updated regularly with searches of the MEDLINE database.
The most recent literature update was performed through October 31, 2017.
This evidence review was informed, in part, on a 2003 TEC Assessment of transesophageal endoscopic treatments for gastroesophageal reflux disease (GERD) and a 2016 Evidence Street Assessment on transoral incisionless fundoplication (TIF). This review addresses procedures currently available for use in the United States.
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to 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 balance of benefits and harms.
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.
The Agency for Healthcare Research and Quality published a systematic review on management strategies for GERD in 2005, which was updated in 2011 (Ip, 2005; Ip 2011). The 2005 comparative effectiveness review evaluated studies on the EndoCinch Suturing System, Stretta, Enteryx, and the NDO Plicator (Ip, 2005). The 2011update of the Agency for Healthcare Research and Quality report7 excluded Enteryx and the NDO Plicator, because they were no longer available in the United States, and added the EsophyX procedure (endoscopic fundoplication), which was commercialized after the 2005 review. 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 dsyphagia are also adverse events of laparoscopic fundoplication (Humphries, 2013). A 2015 review of endoscopic treatment of GERD noted that EndoCinch is no longer manufactured (Hummel, 2015).
TRANSORAL INCISIONLESS FUNDOPLICATION (ESOPHYX)
The following discussion examines separately studies for patients whose symptoms are not controlled by proton pump inhibitors and those whose symptoms are controlled by PPIs. For patients whose symptoms are not controlled by PPIs, the optimal comparator would be fundoplication, while the optimal comparator in patients whose symptoms are controlled by PPIs would be continued PPI therapy.
TIF in Patients Whose Symptoms Are Not Controlled by PPIs
Randomized Trials
Two RCTs have evaluated TIF using ExophyX2 in patients with troublesome symptoms despite daily PPI therapy. (Hunter et al (2015) compared treatment using TIF plus placebo pills (n=87) with treatment using sham TIF plus PPIs (n=42) in the RESPECT trial (Hunter, 2015). 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 TIF (n=40) with maximum PPI therapy (n=23) without a sham procedure in the TEMPO trial (Trad, 2015). The primary outcome in both trials was the elimination of symptoms, measured in slightly different ways.
In both trials, the primary outcome was achieved by a higher percentage of patients treated with TIF than with PPIs. 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. In TEMPO, the relative risk of achieving the primary outcome was 12.9 (95% confidence interval [CI], 1.9 to 88.9; p<0.001).
Secondary outcomes for the RESPECT trial showed no significant differences between treatments. Physiologic measurements such as number of reflux episodes, percent total time pH less than 4, and DeMeester score (a composite score of acid exposure based on esophageal monitoring) showed 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.
Studies Comparing TIF with Laparoscopic Fundoplication
Svoboda et al (2011) compared TIF with laparoscopic fundoplication, but more than half of the patients who had TIF did so with a discontinued device, so that the trial results may not generalize to EsophyX (Svoboda, 2011). There was no separate analysis of patients undergoing TIF with the EsophyX device, and the results of this trial are not discussed further.
Nonrandomized Studies
Two nonrandomized comparative studies have compared TIF with laparoscopic fundoplication in patients whose symptoms were not controlled on PPIs (Frazzoni, 2011; Toomey, 2014).
Frazzoni et al (2011) compared 10 patients undergoing TIF with 10 patients undergoing laparoscopic fundoplication with the first-generation EsophyX procedure (Frazzoni, 2011). 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 vs 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.
A nonrandomized study by Toomey et al (2014) compared 20 patients undergoing TIF, 20 patients undergoing Nissen fundoplication, and 20 patients undergoing Toupet fundoplication (Toomey, 2014). 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 vs 65% and 55% of the 2 fundoplication groups, limiting comparison of both treatments. Adverse events were not reported.
Section Summary: Patients Whose Symptoms Are Not Controlled by PPIs
Studies Comparing TIF with Continued PPIs
The evidence on TIF in patients whose symptoms are not controlled by PPIs includes 2 RCTs, one of which followed TIF patients out to 3 years. The highest quality study is the sham-controlled RESPECT trial by Hunter et al (2015). RESPECT found a significantly greater proportion of patients who reported elimination of troublesome regurgitation compared with sham plus PPIs; however, elimination of regurgitation was achieved in only 67% of patients treated with TIF. Also, other symptom measures were no different between the TIF and sham-PPI group. 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 a significant improvement in subjective measures with TIF compared to 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 suggest that the most appropriate comparator for patients whose symptoms are not controlled on PPIs is laparoscopic fundoplication.
Studies Comparing TIF with Laparoscopic Fundoplication
Each study comparing TIF with laparoscopic fundoplication has methodologic problems that do not permit conclusions on the comparative efficacy of the 2 procedures. The Frazzoni nonrandomized study showed that TIF is less effective than fundoplication. However, this study was conducted with an earlier device. The Svoboda RCT included patients who underwent the TIF procedure using a different device. In the Toomey 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 lack of statistically significant differences across symptom outcomes. However, because of the small sizes of these samples, 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 (eg, 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.
TIF in Patients Whose Symptoms Are Controlled by PPIs
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. Hakansson et al (2015) compared TIF (n=22) with sham only (n=22) (Hakansson, 2015). 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 (Witteman, 2015). 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 trial was treatment failure, defined as the need for resumption of PPIs. The primary outcome of the Witteman trial was treatment success, defined by an improvement of 50% or more on the Gastroesophageal Reflux Disease Health-Related Quality of Life (GERD-HQRL) score.
In Hakansson et al, Kaplan-Meier curves showed a higher rate of treatment failure in the sham group than in the TIF group (p<0.001, time to treatment failure), with significantly more patients in the TIF group in remission at 6 months (59%) compared with the sham without PPI group (18%, p=0.01). In Witteman et al, PPI therapy was stepped up or down as necessary during follow-up. At 6 months, 55% of TIF patients had more than 50% improvement in subjective GERD symptoms vs 5% of patients on continued PPI therapy. 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 Hakansson et al 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 was reported in twice as many patients undergoing TIF (four, four, and two, respectively) compared with sham (two, two, and one, respectively). These results were reported as not statistically different. However, it is unlikely that the trial was powered to detect differences in these outcomes.
In Witteman et al, 26% of TIF patients resumed at least occasional PPI use by 6 months, and 100% of control patients remained on PPI therapy. With the exception of lower esophageal sphincter resting pressure, physiologic and endoscopic outcome measures did not differ significantly between groups. No adverse events related to fundoplication were identified on the Symptom Rating Scale.
TIF patients were followed beyond 6 months, with additional control patients who crossed over to have TIF. Sixty patients eventually underwent TIF. Although GERD symptoms remained improved over baseline (p<0.05), esophageal acid exposure did not differ significantly from baseline. At least occasional use of PPI increased between 6 months and 12 months, from 34% to 61%. Endoscopy findings at 6 months and 12 months showed several findings indicating possible worsening of GERD in terms of esophagitis rating, Hill grade rating of the gastroesophageal valve, and size of hiatal hernia. Although this RCT met its principal end point at 6 months, and improvements in GERD symptoms appeared to be maintained for 12 months, long-term reflux control was not achieved, and the authors concluded that “TIF is no[t an] equivalent alternative for PPIs in GERD treatment, even in this highly selected population.” The trial was originally designed as a dual-center study, but it was terminated following interim analysis showing loss of reflux control.
Observational Studies
Observational case series and prospective cohort studies can provide information on the durability of the TIF procedure. Studies are included if they provide additional information on treatment durability or address treatment safety.
A case series and a cohort study have evaluated outcomes to 6 years after TIF 2. Both of these 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. In a prospective cohort by Testoni et al (2015), 72% of the patients were completely responsive to PPIs at baseline, and 24% were partially responsive (Testoni, 2015). 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 TIF procedures were considered unsuccessful. Eight 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, presence of esophagitis at baseline, and use of fewer fasteners. About half the patients with a complete response initially had gone back to PPI use, although this finding is limited by the low number of patients followed to 6 years. The number of fasteners used in this study might also be lower than current procedures.
Stefanidis et al (2017) reported in a retrospective series that about 75% of patients had elimination of esophagitis and had discontinued PPI use at 6 years, while 62% of the 13 patients with a hiatal hernia had a reduction in hernia size at follow-up (Stefanidis, 2017).
Adverse Events
In 2017, Huang et al conducted a systematic review with meta-analysis of TIF for the treatment of GERD (Huang, 2017). They included 5 RCTs and 13 prospective observational studies, of which 14 were performed with the TIF 2 procedure. Efficacy results from the RCTs were combined for patients whose symptoms were controlled by PPIs and for those whose symptoms were not controlled by PPIs, and are not further discussed here. 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: TIF in Patients Whose Symptoms Are Controlled by PPIs
The evidence on TIF in patients whose symptoms are controlled by PPIs includes 2 RCTs and observational studies with long-term follow-up. The sham-controlled trial by Hakansson et al (2015) found 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. Statistical analysis was not reported for other subjective and objective outcome measures, and it is unclear whether the trial was adequately powered for these outcomes. The nonblinded trial by Witteman et al 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) (Testoni, 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 (STRETTA PROCEDURE)
The available evidence on the use of transesophageal radiofrequency (TERF) consists of meta-analyses and 4 small RCTs, three of which included a sham control, along with numerous uncontrolled case series.
Systematic Reviews
A meta-analysis of 4 RCTs (total N=165 patients) was published by Lipka et al in 2015 (Lipka, 2015). Three trials compared Stretta with sham, and one compared Stretta with PPI therapy. 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 improvement in heartburn symptoms, quality of life, and general physical quality of life in the active treatment group compared with the sham group, but there were no significant differences in medication use and esophageal acid exposure (Corley, 2003). Aziz et al (2010) found statistically significant improvements in GERD-HRQL score in all treatment groups (Aziz, 2010). 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 RF (Arts, 2012). Pooled results of the meta-analysis showed no significant difference between Stretta and either sham treatment or PPI management for the measured outcomes, including the ability to stop PPI therapy. 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 time.
A 2012 meta-analysis by Perry et al included 20 studies (Perry, 2012). This review analyzed the within-subjects results following treatment only. The control groups of available clinical trials were not included for comparison. Significant improvements were reported for subjective heartburn scores, GERD-HRQL scores, and 36-Item Short-Form Health Survey Physical Component Summary scores. For the studies that measured esophageal pH, significant improvements were found in the Johnson-DeMeester score, the esophageal acid exposure time, and lower esophageal sphincter pressure. This meta-analysis was limited by the inclusion of lower quality studies and by its analysis of within-subject differences and not between-subject differences, as reported in the RCTs.
Controlled Trials Comparing TERF with Laparoscopic Fundoplication
In 2015, Liang et al reported on a prospective comparison of laparoscopic Toupet fundoplication with the Stretta procedure (Liang, 2015). 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 improving symptoms of heartburn, regurgitation, and chest pain. Significantly more patients in the Stretta group underwent reoperation, while more patients in the fundoplication group complained of bloating, but this difference was not statistically significant. This study lacked randomization and, along with not reporting the TERF failures, had a high loss to follow-up. Also, while symptom scores were comparable at baseline, the study may have been subject to selection bias related to treatment choice, which affected baseline differences for other variables.
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-up after TERF were reported in 2014(Liang, 2014; Noar, 2014). Elimination of PPI use was similar for both studies at around 42%. Liang et al reported that symptoms of heartburn, regurgitation, chest pain, cough, and asthma were all decreased compared with baseline. Noar et al 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.
Section Summary: Transesophageal Radiofrequency (Stretta Procedure)
Four RCTs (N range, 22-64 patients), three 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 these same studies found no significant improvements in outcomes. The findings of improvements in symptoms but not esophageal acid exposure have led to questions 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, interpretation depends on the efficacy of the procedure in the short term. A nonrandomized comparative study has suggested that symptom relief with TERF is lower than with fundoplication and there is a greater incidence of reoperations. Larger RCTs with longer follow-up are needed to define the risks and benefits of this procedure better.
ESOPHAGEAL BULKING AGENTS
Durasphere
The available evidence for Durasphere consists of a single case series. One open-label pilot study (2009) of 10 GERD patients injected Durasphere (Carbon Medical Technologies), a bulking agent approved for treatment of urinary and fecal incontinence, at the gastroesophageal junction (Ganz, 2009). At 12 months, 7 (70%) patients discontinued all antacid medication completely. No erosion, ulceration, or sloughing of material was noted at any injection site.
Gatekeeper Reflux Repair System
The available evidence for Gatekeeper Reflux Repair System consists of a single RCT from 2010. An industry-funded sham-controlled single-blind, multicenter study randomized 118 patients into Gatekeeper (n=75) or sham (n=43) treatment (Fockens, 2010). An additional 25 patients were treated as lead-ins during the initial training of investigators and included only in the safety analysis. The patients were implanted initially with 4 Gatekeeper prostheses. At 3 months, 44% of implanted patients received retreatment with up to 4 additional prostheses due to unsatisfactory symptom control. The primary safety end point was a reduction in serious device- and procedure-related adverse device events, compared with a surgical procedure composite complication rate of 15%. Four serious adverse events were reported (2 perforations, 1 pulmonary infiltrate related to a perforation, 1 severe chest pain). The primary efficacy endpoint was a reduction in heartburn symptoms using the GERD-HRQL questionnaire. Planned interim analysis after 143 patients were enrolled found that heartburn symptoms and esophageal acid exposure had improved significantly in both the Gatekeeper and sham groups at 6 months, but there was no significant difference between groups. The study was terminated early due to a lack of efficacy.
Polymethylmethacrylate Beads
The available evidence for polymethylmethacrylate beads consists of a single case series. A 2001 case series on transesophageal submucosal implantation of polymethylmethacrylate beads evaluated 10 patients with GERD who were either refractory to or dependent on PPIs (Feretis, 2001). 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 preclude scientific analysis. No additional studies have been identified evaluating this treatment option.
Section Summary: Esophageal Bulking Agents
The evidence on injection of bulking agents includes an RCT terminated early due to lack of efficacy and case series. High-quality data from large RCTs are needed to compare bulking procedures with both sham controls and with the currently accepted treatments for GERD (ie, drug therapy, laparoscopic fundoplication). Well-designed trials should use standardized outcome measures to examine both subjective (eg GERD-HRQL scores) and objective (eg, esophageal acid exposure) effects on health outcomes.
SUMMARY OF EVIDENCE
For individuals who have GERD and 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, quality of life, medication use, and treatment-related morbidity. The highest quality RCT (RESPECT) was a sham-controlled together 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, but the sham-controlled trial found 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 when compared with PPI therapy. Together, these trials suggest a strong placebo effect of the surgery and a modest benefit of TIF in patients whose symptoms are not controlled by PPIs. For these patients, the most appropriate comparator is laparoscopic fundoplication. Studies comparing TIF with fundoplication have limitations that include earlier TIF procedures and unequal 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 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, quality of life, 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 (eg, 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 (eg, Stretta), the evidence includes 4 small RCTs, a nonrandomized comparative study, and observational studies with longer term follow-up. Relevant outcomes are symptoms, change in disease status, quality of life, medication use, and treatment-related morbidity. The RCTs reported some improvements in symptoms and quality of life following treatment with radiofrequency energy compared with sham controls. However, objective measures of GERD and a meta-analysis of these studies found no significant improvements in outcomes, raising questions about the mechanism of the symptom relief. Symptom relief is reported to be lower than after fundoplication, and reoperations 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 or bulking agents, the evidence includes an RCT and case series. Relevant outcomes are symptoms, change in disease status, quality of life, medication use, and treatment-related morbidity. The RCT for a single product was terminated early due to lack of efficacy, while other products have only case series to support use. High-quality data from large RCTs are needed to compare bulking procedures with both sham controls and with the currently accepted treatments for GERD (ie, drug therapy, laparoscopic fundoplication). Well-designed trials should use standardized outcome measures to examine whether subjective improvement (eg, discontinuation of medication therapy, GERD–Health-Related Quality of Life scores) is supported by objective improvement (eg, esophageal acid exposure). The evidence is insufficient to determine the effects of the technology on health outcomes.
PRACTICE GUIDELINES AND POSITION STATEMENTS
American Society for Gastrointestinal Endoscopy
In 2015, the American Society for Gastrointestinal Endoscopy published guidelines on endoscopic procedures for gastroesophageal reflux disease (GERD) (ASGE, 2015). In their 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 end point could be useful in defining the clinical role of these procedures.
American College of Gastroenterology
Updated guidelines released by the American College of Gastroenterology in 2013 indicated that the use of current endoscopic therapy or transoral incisionless fundoplication (TIF) could not be recommended as an alternative to medical or traditional surgical therapy (conditional recommendation, moderate level of evidence) (Katz, 2013). The guidelines also cited limited data on small numbers of subjects and short duration of follow-up.
Society of American Gastrointestinal and Endoscopic Surgeons
In 2017, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) updated its evidence-based guidelines on endoluminal treatments for GERD (Sage, 2017). SAGES gave a strong recommendation based on moderate quality evidence that TIF with EsophyX can be performed with an acceptable safety risk in selected patients. 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 improvement in objective GERD measures compared with PPIs. TIF appears to lose effectiveness during longer term follow-up and is associated with moderate patient satisfaction scores. SAGES found no comparative, controlled trials between TIF and surgical fundoplication, but preliminary evidence suggested that the surgical fundoplication can be used safely after TIF failure.
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 more effective than PPI, but less so than fundoplication.
American Society of General Surgeons
The American Society of General Surgeons (ASGS) issued a position statement on transoral fundoplication in 2011 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” (ASGS, 2011).
American Gastroenterological Association
In 2016, the American Gastroenterological Association issued a technology coverage statement on minimally invasive surgical options for GERD (AGA, 2016). Based on a literature review of 4 randomized controlled trials, a multicenter registry, and case series with longer term follow-up, the Association stated:
“…evidence is sufficient to demonstrate sustainable improvement in health outcomes, symptom relief, decrease in PPI utilization and improvement in esophageal pH with transoral fundoplication. The selection criteria for transoral fundoplication includes GERD patients with BMI [body mass index] ≤ 35, hiatal hernia ≤ 2 cm, esophagitis LA [Los Angeles classification] grade A or B, Barrett’s esophagus ≤ 2 cm, and absence of achalasia and esophageal ulcer. This option should be considered in patients not responding to PPI therapy (symptoms of regurgitation) who have documented objective evidence of GERD (pathologic acid exposure on pH testing (both off and on medication)) or esophagitis.”
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. Therefore, this procedure should only be used with special arrangements …” (NICE, 2013). 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.”
NICE issued guidance in 2011 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. Therefore, this procedure should only be used with special arrangements ….” (NICE, 2011).
In 2017, NICE updated its guidance on bulking agents for GERD found that “Current evidence on the safety and efficacy of endoscopic injection of bulking agents for gastro-esophageal reflux disease does not appear adequate for this procedure to be used without special arrangements….” (Nice, 2017). In 2016, NICE removed guidance on endoscopic bulking agents/hydrogel implants from guidelines on treatment for “dyspepsia and gastro-esophageal reflux” because the product had been withdrawn by the manufacturer.
ONGOING CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed below:
Summary of Key Trials
Planned Enrollment: 500 Subjects Completion Date: Dec 2017
Planned Enrollment: 60 Subjects Completion Date: Dec 2018
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
TRANSORAL INCISIONLESS FUNDOPLICATION (ESOPHYX) FOR PATIENTS WHOSE SYMPTOMS ARE NOT CONTROLLED BY PROTON PUMP INHIBITORS
Clinical Context and Test Purpose
The purpose of transoral incisionless fundoplication (TIF; eg, EsophyX) 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 hernia of 2 cm or less that is not controlled by proton pump inhibitors (PPIs). The question addressed in this evidence review is: Does use of TIF using the EsophyX System improve the net health outcomes in individuals with GERD?
The following PICOTS were used to select literature to inform this review.
Patients
The relevant population of interest are individuals with GERD and hiatal hernia of 2 cm or less that is not controlled by PPIs.
Interventions
The therapy being considered is TIF (eg, EsophyX).
Comparators
The following practice is currently being used to make treat GERD: laparoscopic fundoplication.
Outcomes
The general outcomes of interest are symptoms, change in disease status, quality of life, mediation use, and treatment-related morbidity.
Timing
Follow-up at 3 years is of interest to monitor outcomes.
Setting
Patients with GERD and hiatal hernia of 2 cm or less that is not controlled by PPIs are actively managed by gastroenterologists and primary care providers in an outpatient setting.
Study Selection Criteria
Methodologically credible studies were selected using the following principles:
Systematic Reviews
McCarty et al published a meta-analysis of RCTs and nonrandomized studies that showed significant improvement in a number of clinical outcomes for patients treated with TIF (McCarty, 2018). For example, 89% of TIF patients discontinued PPI therapy after the procedure, and Gastroesophageal Reflux Disease Health-Related Quality of Life (GERD HRQL), Gastroesophageal Reflux Symptom Score (GERSS), and Reflux Symptom Index (RSI) measures showed significant improvement. The study had several limitations, including risk of heterogeneity bias, due to the inclusion of studies of first- and second-generation TIF devices and protocols.
Richter et al published a network meta-analysis of RCTs comparing TIF and laparoscopic Nissen fundoplication (LNF) with sham or PPIs (Richter, 2018). The meta-analysis was limited by low-quality studies (one did not report randomization method, others lacked data regarding allocation concealment, blinding of outcome assessors, or other aspects of study protocol). It should be noted that one reason behind the scarcity of direct comparison 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 esophagitis grades A-D (LA) and all sizes of hiatal hernia.
Randomized Trials
Trad et al also reported 5-year follow-up for the TEMPO trial (Trad, 2018). 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 5-yar follow-up, and 31 (70%) patients expressed satisfaction with the procedure, as assessed by GERD-HRQOL. While data regarding pH normalization were available for 24 patients at 3-year follow-up, at 5 years, 22% (n=5) of these patients could not be assessed for pH normalization.
In summary, the evidence on TIF in patients whose symptoms are not controlled by PPIs includes 2 RCTs, one of which followed TIF patients out to 3 years. The highest quality study is the sham-controlled RESPECT trial by Hunter et al (Hunter, 2015). RESPECT found a significantly greater proportion of patients who reported elimination of troublesome regurgitation compared with sham plus PPIs, however, elimination of regurgitation was achieved in only 67% of patients treated with TIF. Also, other symptom measures were no different between the TIF and sham-PPI group. 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 a significant improvement in subjective measures with TIF compared to 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 suggest that the most appropriate comparator for patients whose symptoms are not controlled on PPIs is laparoscopic fundoplication. However, 5-year follow-up of the TEMPO trial found sustained cessation of PPI therapy in the majority of patients with data available, as well as 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.
TRANSESOPHAGEAL RADIOFREQUENCY (STRETTA PROCEDURE)
Fass et al published a meta-analysis of cohort studies and RCTs evaluating Stretta for patients with GERD (Fass, 2018). When RCT and cohort results were pooled, there were clinically significant treatment effects for several of the endpoints; however, the analysis was limited by the lack of control group in many of the studies. Also, only one of the end points was shared between the four included RCTs.
Randomized Controlled Trials
Although not included in the meta-analyses, Kalapala et al published interim results from a small RCT of 20 patients randomized to PPI plus Stretta or PPI alone, with 3 months of follow-up (Kalapala, 2017). 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.
PRACTICE GUIDELINES AND POSITION STATEMENTS
Agency for Healthcare Research and Quality
The Agency for Healthcare Research and Quality published a systematic review on management strategies for GERD in 2005, which was updated in 2011 (Ip, 2005; Ip, 2011). The 2005 comparative effectiveness review evaluated studies on the EndoCinch Suturing System, Stretta, Enteryx, and the NDO Plicator (Ip, 2005). The 2011 update of the Agency for Healthcare Research and Quality report7 excluded Enteryx and the NDO Plicator, because they were no longer available in the United States, and added the EsophyX procedure (endoscopic fundoplication), which was commercialized after the 2005 review. 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 dsyphagia are also adverse events of laparoscopic fundoplication (Humphries, 2013). A 2015 review of endoscopic treatment of GERD noted that EndoCinch is no longer manufactured (Hummel, 2015).
2020 Update
A literature search was conducted through December 2019. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
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+) (Ihde, 2020).
Zerbib et al 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 (Zerbib, 2020). 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.
Ma et al reported on a retrospective comparison of laparoscopic Toupet fundoplication with the Stretta procedure (Ma, 2020). 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, 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.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Testoni et al 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) (Testoni, 2021). 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.
Bell et al evaluated the durability of TIF with the EsophyX2 in 151 patients via a single institution prospective registry between November 2008 and July 2015 (Bell, 2021). 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.
Xie et al 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 (Xie, 2021). 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.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
An additional prospective cohort study of the MUSE by Testoni et al included 46 individuals with full or partial response to PPIs at baseline (Testoni, 2022). Recurrent hiatal hernia <2.5 cm occurred in 6.5% of patients at 6 months and 4.4% at 1 year follow-up. There was no significant change in Johnson-DeMeester score at 6-month and 1 year follow-up. Two individuals (4.3%) had perforations requiring surgical repair.
In 2022, the American Gastroenterological Association issued a clinical practice update on the personalized approach to the evaluation and management of GERD (Yadlapati, 2022). The guideline stated that "transoral incisionless fundoplication is an effective endoscopic option in carefully selected patients" with proven GERD. The guideline further stated that TIF has "demonstrable value in patients with regurgitation-predominant GERD" and that "further research into risks/benefits, durability, effectiveness, and treatment outcomes will enhance optimal utilization" as part of a personalized approach to treatment.
The American College of Gastroenterology (2022) guidelines on the diagnosis and management of GERD include the following statements regarding TIF and Stretta (Katz, 2022):
According to the guideline methods, a conditional recommendation equates to a suggestion, and low level of evidence signifies "very little confidence in the effect estimate to support a particular recommendation, based on the risk of bias of the studies, evidence of publication bias, heterogeneity among studies, directness of the evidence, and precision of the estimate of effect." The guideline additionally noted that if TIF or Stretta is used, such use should be limited to patients with milder forms of GERD.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Rausa et al published a network meta-analysis of RCTs comparing TIF (n=188) to anterior partial fundoplication (n=322), laparoscopic Toupet fundoplication (n=1120), laparoscopic Nissen fundoplication (n=1740), and PPI therapy (N=80) in patients with recalcitrant GERD (Rausa, 2023). The outcomes of interest were differences in the rate of heartburn, regurgitation, dysphagia, bloating, and PPI discontinuation. TIF did not differ significantly from the other treatments in the pooled network analysis for any outcome. Treatment failure was not included in the quantitative analysis due to the considerable heterogeneity across studies.
In 2023, consensus guidance was issued by the Society of American Gastrointestinal and Endoscopic Surgery, American Society for Gastrointestinal Endoscopy, American Society for Metabolic and Bariatric Surgery, European Association for Endoscopic Surgery, Society for Surgery of the Alimentary Tract, and The Society of Thoracic Surgeons on the diagnosis and treatment of GERD (Slater, 2023). The relevant questions and recommendations for TIF and Stretta are as follows:
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