Gastroesophageal Reflux Disease (GERD): Treatments
Number: 0213
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses treatments for gastroesophageal reflux disease (GERD).
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Experimental and Investigational
The following interventions are considered experimental and investigational for the management of persons with gastroesophageal relux disease (GERD) and other indications because the effectiveness of these approaches has not been established:
- Angelchik anti-reflux prosthesis;
- Anti-reflux mucosal interventions (e.g., anti-reflux band ligation/anti-reflux mucosectomy/anti-reflux mucosal ablation);
- Bard EndoCinch Suturing System (C.R. Bard Inc., Murray Hill, NJ) and the Apollo OverStitch endoscopic suturing system;
- C-BLART (clip band ligation anti-reflux therapy;
- Durasphere (Carbon Medical Technologies, St Paul, MN), the Gatekeeper Reflux Repair System (Medtronic, Inc., Minneapolis, MN), an endoscopically-implanted injectable esophageal prosthesis, and the Plexiglas polymethylmethacrylate (PMMA) microspheres (Arkema Inc., Bristol, PA);
- Electrical stimulation of the lower esophageal sphincter (e.g., the EndoStim);
- Enteryx;
- Endoscopic Plicator System (NDO Surgical, Inc., Mansfield, MA) and the Syntheon ARD Plicator (Syntheon, Miami, FL);
- Gastric bypass procedures for the treatment of GERD in nonobese persons;
- Laparoscopic gastrojejunostomy for the treatment of GERD;
- Laparoscopic magnetic sphincter augmentation for individuals with medically-refractory GERD after sleeve gastrectomy;
- LINX Reflux Management System (a sphincter augmentation device) (Ethicon, Bridgewater, NJ);
- Nasal continuous positive airway pressure for the treatment of nocturnal GERD;
- Osteopathic visceral treatment for the treatment of GERD;
- Partial gastrectomy for the treatment of GERD;
- StomaphyX or EsophyX (EndoGastric Solutions, Inc., Redmond, WA);
- Stretta System (Curon Medical, Sunnyvale, CA).
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Related Policies
Background
Gastroesophageal reflux disease (GERD), also known as reflux esophagitis, is probably the most prevalent clinical condition that arises from the gastrointestinal (GI) tract. There are 2 principal factors involved in esophageal reflux:
- the GI contents and
- the anti-reflux mechanism, which is comprised of the lower esophageal sphincter (LES) and the anatomic configuration of the gastroesophageal junction.
Reflux occurs when the gradient between the LES pressure and the intra-gastric pressure is compromised as a result of a transient or sustained reduction in the former, or an elevation in the latter. Most patients with GERD have decreased LES pressures. However, some patients have normal LES pressures, but their sphincters relax inappropriately, thus resulting in refluxes. Treatments for gastroesophageal reflux disease (GERD) are designed to improve the function of the lower esophageal sphincter (LES). The objectives are to eliminate symptoms, heal esophagitis, prevent recurrence of symptoms or progression of disease. The initial treatment of GERD is geared toward reducing esophageal refluxes. Antacids, H2-receptor antagonists, as well as dietary and lifestyle modifications have been used for such purposes. For patients who fail initial treatment, proton pump inhibitors (e.g., lansoprazole and omeprazole) should be tried. When these standard medical therapies fail, surgery may be considered.
Anti-reflux surgery is required in only 1 to 2% of all patients with GERD. These procedures are designed to raise the pressure within the LES by wrapping a portion or all of the cardia stomach around the esophagus. With the advent of laparoscopic anti-reflux surgery, the 2 most common procedures are the Nissen fundoplication and the Toupet partial fundoplication. The most commonly used surgical procedure, Nissen fundoplication (open or laparoscopic), is the mobilization of the lower end of the esophagus and plication of the fundus of the stomach around it. Dependent on the skill and experience of the operating surgeon, anti-reflux surgery has been reported to have an efficacy rate of 90%. These operations are usually performed on the day of hospital admission and take about 90 mins. In general, patients are discharged from the hospital on the second post-operative day and can return to work in 7 to 10 days. Other surgical options include Belsey partial fundoplication as well as Collis gastroplasty combined with Belsey partial fundoplication. However, anti-reflux surgery can be associated with complications. The most common complications are dysphagia and an inability to belch or vomit, occurring in 4 to 11% of patients.
A number of minimally invasive devices are marketed to provide a treatment option to patients who have failed standard medical therapies, or individuals who decide against or could not afford drug therapy. However, there is insufficient scientific data to support the effectiveness of these devices. Well-designed studies are needed to show that these procedures reduce or eliminate the use of anti-GERD medications. Comparative studies with standard drug therapy and traditional surgical procedures may shed some light on the role these devices play in the treatment of GERD. Some of the issues that have to be addressed are:- what are the long-term outcomes of these procedures, and
- do patients need retreatment, and if so, how often?
In a review on endoscopic and laparoscopic treatment of GERD, Watson and Immanuel (2010) staetd that for selected patients, there is an established role for the surgical treatment of reflux, and possibly an emerging role for endoscopic anti-reflux procedures. Randomized trials have compared medical versus surgical management, laparoscopic versus open surgery and partial versus total fundoplications. However, the evidence base for endoscopic procedures is limited to some small sham-controlled studies, and uncontrolled cohort studies. Laparoscopic fundoplication has been shown to be an effective anti-reflux operation. It facilitates quicker convalescence and is associated with fewer complications, but has a similar longer term outcome compared with open anti-reflux surgery. In most randomized trials, anti-reflux surgery achieves at least as good control of reflux as medical therapy, and these studies support a wider application of surgery for the treatment of moderate-to-severe reflux. Laparoscopic partial fundoplication is an effective surgical procedure with fewer side effects, and it may achieve high rates of patient satisfaction at late follow-up. Many of the early endoscopic anti-reflux procedures have failed to achieve effective reflux control, and they have been withdrawn from the market. Newer procedures have the potential to fashion a surgical fundoplication. However, at present there is insufficient evidence to establish the safety and efficacy of endoscopic procedures for the treatment of GERD, and no endoscopic procedure has achieved equivalent reflux control to that achieved by surgical fundoplication.
Bredenoord (2010) stated that it is estimated that approximately 30% of the GERD patients is not satisfied about the effect of proton pump inhibitor (PPI) on their symptoms. Esophageal hyper-sensitivity, persistent non-acid reflux and incomplete acid suppression all can play a role in the pathogenesis of persistent GERD symptoms. More powerful PPIs are now being developed, resulting in a more prolonged and profound acid suppression. New prokinetics and inhibitors of transient lower esophageal sphincter relaxations (TLESRs) can potentially reduce both acid and non-acid reflux and drugs that reduce hyper-sensitivity are possibly helpful for the treatment of non-erosive reflux disease. Whether these drugs will make it to the markets will mainly depend on their side effect profile and their ability to have an additional beneficial effect over the current gold standard therapy as it likely that a new anti-reflux drug will be used in combination with PPIs. Over the last decade various endoscopic anti-reflux techniques have been introduced, most of them have been withdrawn soon after introduction due to lack of effect or after the occurrence of severe side-effects. Several endoluminal plication techniques and endoluminal RF ablation therapy are still available and being evaluated in research centers; but more data on safety and efficacy is needed before a more widespread use can be advised.
A systematic evidence review prepared for the Australian Safety and Efficacy Register of New Interventional Procedures - Surgical (ASERNIP-S) (McLoughlin et al, 2006) reached the following conclusions about endoscopic treatments of GERD: "The scope, applicability, efficacy and cost effectiveness of endoscopic anti-reflux therapies for the treatment of GORD have not been established. These procedures may provide an alternative treatment for selected patients with mild to moderate GORD who are dependent on medication and are reluctant or unable to undergo surgery. However, a substantial placebo effect has been demonstrated in sham controlled trials, and endoscopic results were generally inferior when compared with laparoscopic fundoplication. Doubts about the durability of the therapeutic effect remain since the follow-up period in most studies was short."A systematic evidence review prepared for the Agency for Healthcare Research and Quality (Ip et al, 2005) reached similar conclusions about the need for reliable evidence about endoscopic treatments for GERD. The assessment found that data on comparative endoscopic treatments with continued (or intensified) use of PPIs are needed to better understand their efficacy compared to an established standard. The report also noted the need for more efficacy and safety data on new endoscopic approaches tested against a sham procedure with adequate follow-up.
Other reviews of the evidence have reached similar conclusions about the unproven status of endoscopic treatments for GERD, Schwarz and Smout (2007) reported that endotherapy has shown the potential to treat (uncomplicated) GERD, but that some procedures have failed or proven unsafe. The authors concluded: "Further developments and studies are necessary to determine what modifications to these techniques are required to produce optimal efficacy and durability. Until then, widespread clinical use of endotherapy for GORD should probably be avoided." Triadafilopoulos (2007) noted that future comparative studies with pre-determined clinically significant end points, validated outcome measures, prolonged follow-up, and complete complication registries will eventually determine the precise role of endoscopic therapies for patients with GERD.
In a review on endoscopic anti-reflux procedures, Pace et al (2008) concluded that none of the proposed anti-reflux therapies has fulfilled the criteria of efficacy, safety, cost, durability and, possibly, of reversibility. There is at present no definite indication for endoscopic therapy of GERD.
Endocinch
EndoCinch Suturing System is suggested for endoscopic placement of sutures in the soft tissue of the esophagus and stomach and for approximation of tissue.
The Food and Drug Adminsitration (FDA) cleared for marketing via a 510 (k) application minimally invasive devices for the treatment of refractory GERD including:- the Bard EndoCinch Suturing System (BESS), and
- the Stretta System.
The BESS entails insertion of a thin, flexible endoscopic tube into the patient's esophagus. The end of the scope holds a tiny device, much like a miniature sewing machine, which places stitches in 2 different locations near the LES. The suturing material is then tied to effectively tighten the valve and prevent reflux. The procedure requires no incisions and usually no general anesthesia. It is performed on an outpatient basis, and patients usually can return to work the next day.
Jafri and colleagues (2009) analyzed existing endoscopy-based interventions for GERD. The focus is on the effectiveness of available procedures and to delineate goals for future research. These investigators noted that recent evaluations of the EndoCinch system reveal poor long-term results and no significant improvement over sham therapy due to poor apposition of mucosa with stitches. Recent studies with transoral incisionless fundoplication demonstrate improvement in GERD symptoms, quality of life, esophageal acid exposure, esophagitis, resting LES pressure and medication use. The SRS endoscopic stapling system creates a partial fundoplication wrap, and a preliminary study demonstrated improved symptoms and acid exposure. The Stretta system delivers RF energy to the gastro-esophageal junction. A large prospective series demonstrates sustained improvement in GERD symptoms, quality of life and PPI therapy elimination after RF ablation at the gastro-esophageal junction. A sham-controlled study showed improvement in symptoms at 6 months. The authors concluded that EndoCinch plication requires further study and modification of technique before it can be recommended for general clinical use. Transoral incisionless fundoplication is a very promising procedure in its early stages of development. They stated that further evaluation of procedure safety and durability is needed. Radiofrequency ablation therapy has been re-introduced and may have potential in patients with refractory GERD.
In a systematic review, Chen et al (2009) evaluated the safety and effectiveness of endoscopic procedures for GERD. Randomized controlled trials and non-randomized comparative studies with at least 10 patients in each study arm, and case series studies of at least 10 patients, were included. A total of 33 studies examining 7 endoscopic procedures (Stretta procedure, Bard EndoCinch, Wilson-Cook Endoscopic Suturing Device, NDO Plicator, Enteryx, Gatekeeper Reflux Repair System and Plexiglas) were included in the review. Of the 3 procedures that were tested against sham controls (Stretta procedure, Bard EndoCinch and Enteryx), patient outcomes in the treatment group were either as good as, or significantly better than, those of control patients in terms of heartburn symptoms, quality of life and medication usage. However, for the 2 procedures that were tested against laparoscopic fundoplication (Stretta procedure and Bard EndoCinch), outcomes for patients in the endoscopic group were either as good as, or inferior to, those for the laparoscopic group. The authors concluded that currently there is insufficient evidence to determine the safety and effectiveness of endoscopic procedures for GERD, especially in the long-term.
In a systematic review and meta-analysis, Testoni et al (2021) stated that few reports exist regarding the long-term outcomes of transoral incisionless fundoplication (TIF) for the treatment of refractory gastro-esophageal reflux disease (GERD). These researchers carried out a literature search of 4 major scientific databases up to May 2020 for studies reporting on more than 3-year outcomes of TIF. Data on patient satisfaction, proton pump inhibitor (PPI) daily consumption, PPI use reduction, GERD health-related quality-of-life (GERD-HRQL) score, and normalization of heartburn and regurgitation scores were pooled and summarized with forest plots. Publication bias and heterogeneity were explored. A total of 8 studies (418 patients, 232 men; 55.5 %) with a mean follow-up of 5.3 years (range of 3 to 10 years) were included. The pooled proportion of patient-reported satisfaction before and after TIF was 12.3 % (95 % CI: 12.3 to 35.1 %, I2 = 87.4 %) and 70.6 % (95 % CI: 51.2 to 84.6, I2 = 80 %), respectively, corresponding to an odds ratio (OR) of 21.4 (95 % CI: 3.27 to 140.5). Pooled rates of patients completely off PPIs and on occasional PPIs were 53.8 % (95 % CI: 42.0 % to 65.1 %) and 75.8 % (95 % CI: 67.6 to 82.6 %), respectively. The pooled estimated mean GERD-HRQL scores off PPI before and after TIF were 26.1 (95 % CI: 21.5 to 30.7; range of 20.0 to 35.5) and 5.9, respectively (95 % CI: 0.35.1 to 11.4; range of 5.3 to 9.8; p < 0.001). The overall pooled rates of heartburn and regurgitation scores normalization were 73.0 % (95 % CI: 0.62 to 0.82 %) and 86 %, respectively (95 % CI: 75.0 to 91.0 %). The authors concluded that the findings of this study showed that TIF appeared to offer a safe, long-term therapeutic option for selected patients with GERD who refused life-long medical therapy or surgery, were intolerant to PPIs, or were at increased surgical risk.
The authors stated that this analysis had several drawbacks, partly due to the nature of included studies. First, the long-term follow-up in most included studies (3 to 10 years) was rarely performed with a complete clinical assessment (i. e., endoscopic and/or functional evaluations) in a small number of patients; however, studies evaluating long-term outcomes (5 to 10 years) after surgical fundoplication also harbored the same drawbacks (usually assessing only clinical outcomes) permitting nonetheless a trustworthy comparison. Furthermore, the symptomatic curve over a such long period suggested that the results would not change much even with a larger number of fully-assessed patients. Second, a high heterogeneity across studies for patient reported overall satisfaction after TIF was found. However, this result must be analyzed next to the substantial reduction in overall PPI use, which yielded a much lower heterogeneity, as well as the solid reduction in GERD-HRQL scores that was maintained over time, which were both more objective parameters for evaluating procedure outcomes.
Xie et al (2021) noted that both TIF and radiofrequency ablation (Stretta) are representative endoscopic treatments for the treatment of GERD; however, they have not been directly compared. This systematic review and network meta-analysis (NMA) examined the comparative effects of Stretta, TIF, and PPIs. PubMed, Cochrane Central Register of Controlled Trials, Web of Science, and Embase were searched for randomized controlled trials (RCTs) that compared the effectiveness of either the Stretta, TIF, or PPIs/sham procedure for the treatment of GERD; the NMA was conducted using frequentist methods. A total of 516 participants from 10 RCTs were included in this NMA. Both Stretta (mean difference [MD] - 9.77, 95 % CI: - 12.85 to - 6.70) and TIF (MD - 12.22, 95 % CI - 15.93 to - 8.52) were significantly superior to PPIs at improving HRQL scores and heartburn scores (Stretta: MD - 1.53, 95 % CI: - 2.98 to - 0.08; TIF: MD - 9.60, 95 % CI: - 17.79 to - 1.41). Stretta (MD - 3.77, 95 % CI: - 6.88 to - 0.65) was less effective at increasing lower esophageal sphincter (LES) pressure than TIF. Stretta was significantly superior to TIF (MD - 3.25, 95 % CI: - 5.95 to - 0.56) at improving esophageal acid exposure. Regarding the decrease in PPIs use and esophagitis incidence, no significant differences were observed between TIF and Stretta. The authors concluded that in terms of short-term reduction of the HRQL score and heartburn score in patients with GERD, TIF and Stretta may be comparable to each other, and both may be more effective than PPIs. TIF may increase the LES pressure in comparison with Stretta and PPIs. PPIs may reduce the percentage of time pH < 4.0 when compared with TIF. Moreover, these researchers stated that this evidence should be interpreted with caution given the small number of included studies and inherent heterogeneity.
In a systematic review and meta-analysis, Chandan et al (2021) stated that PPI are effective therapeutic options for GERD; however, 20 to 40 % of patients report symptoms despite taking daily PPI. Magnetic sphincter augmentation (MSA) and TIF are less invasive options for the treatment of refractory GERD and are increasingly gaining popularity. These researchers carried out a comprehensive search of several databases to identify relevant studies. The primary objective was to compare the effectiveness of both interventions reported as improvement in GERD-HRQL score, overall patient satisfaction, improvement in post-procedure regurgitation, and fraction of patients completely off PPI therapy at follow-up. A total of 24 studies with 1,942 patients were included in the final analysis. Both MSA and TIF had comparable technical success and clinical success based on improvement in GERD-HRQL scores (i.e., 98.8 % (CI: 95.6 to 99.7 %) versus 98.5 % (CI: 95.7 to 99.5 %) and 80.4 % (CI: 66 to 89.6 %) versus 77.7 % (CI: 64.1 to 87.2 %), respectively. A significantly greater proportion of patients reported improvement in regurgitation (i.e., 91.1 % (CI: 83.8 to 95.3 %) versus 73.1 % (CI: 62.5 to 81.7 %) and were able to completely discontinue PPI therapy with MSA compared to TIF (i.e., 91.3 % (CI: 81.5 to 96.2 %) versus 63.8 % (CI: 51.6 to 74.4 %). Patients’ BMI and presence of a hiatal hernia did not have any effect on procedural outcomes. The authors concluded that both procedures performed at par when comparing clinical success in terms of improvement in GERD-HRQL scores. In terms of overall patient satisfaction, post-procedure regurgitation and cumulative number of patients off PPI therapy, MSA outperformed TIF. Moreover, these researchers stated that future well-conducted trials with adequate follow-up time are needed to establish or refute these findings.
The authors stated that there were limitations to this study; most of which were inherent to any meta-analysis. This analysis had studies that were retrospective in nature contributing to selection bias. These investigators compared outcomes based on improvement in GERD-HRQL score and used greater than or equal to 50 % improvement in score as a measure of clinical success. While this was the most consistently reported outcome in the included studies, it was possible that studies reporting less than 50 % improvement in GERD-HRQL score for either MSA or TIF2 were missed. While these researchers were able to quantify the proportion of patients who discontinued PPI therapy at follow-up, they were unable to objectively study these data in terms of post-procedural pH testing data.
de Santiago et al (2021) stated that GERD has an increasing incidence and prevalence worldwide. A significant proportion of patients have a suboptimal response to PPIs or are unwilling to take lifelong medication due to concerns regarding long-term AEs. Endoscopic anti-reflux therapies offer a minimally invasive option for patients unwilling to undergo surgical treatment or take lifelong medication. The best candidates are those with a good response to PPIs and without a significant sliding hiatal hernia. Non-ablative radiofrequency and TIF are the techniques with the largest body of evidence and that have been tested in several randomized clinical trials. Band-assisted ligation techniques, anti-reflux mucosectomy, anti-reflux mucosal ablation, and new plication devices have yielded promising results in recent non-controlled studies. The authors concluded that the role of endoscopic procedures remains controversial due to limited long-term and comparative data, and no consensus exists in current clinical guidelines. Moreover, these researchers stated that careful patient selection, ongoing technical refinements, and RCTs with long-term data are the roadmap to unveil the potential of minimally invasive anti-reflux endoscopic techniques.
Ramai et al (2022) examined the complications associated with TIF using a national database. These researchers analyzed post-marketing surveillance data from the FDA Manufacturer and User Facility Device Experience (MAUDE) database from January 2011 through January 2021. During the study period, approximately 95 event cases reported to the FDA; approximately 131 patient complications were identified. The number of AEs declined from 2011 to 2016 (R2 = 0.96) but increased from 2016 to 2020 (R2 = 0.99). The most common AE was perforation (19.8 %), followed by laceration 17.6 %, bleeding (9.2 %), and pleural effusion (9.2 %). The most common patient complications were treated using endoscopic clips (12.3 %), chest tube or drain insertion (12.3 %), use of endoscopic retriever device (11.1 %), esophageal stent (8.6 %), and emergent or open surgery (11.1 %). The authors concluded that AEs from TIF range from mild to severe; these investigators stated that further research is needed to develop approaches aimed at reducing patient risks.
An UpToDate review on “Approach to refractory gastroesophageal reflux disease in adults” (Fass, 2021) states that “Endoscopic procedures -- The two main endoscopic approaches for treating GERD include application of controlled radiofrequency energy to the lower esophageal sphincter region (Stretta procedure) and transoral incisionless fundoplication. Both techniques have demonstrated a decrease in PPI requirement in patients with GERD. However, their long-term efficacy has not been established”.
Furthermore, the Austrian Institute for Health (AIH)’s technology assessment on “Endoscopic plication therapy in patients with gastroesophageal reflux disease (GERD” (Grossmann et al, 2021) stated that no conclusion can be made whether endoscopic plication would result in better outcomes than the investigated comparators since HRQoL results were contradicting. In general, endoscopic plication therapy appeared to improve HRQoL and symptom scores over time; however, considering the 4 available study group differences only an improvement compared to PPI medication could be identified, but comparisons to laparoscopic surgery showed either no difference or were favoring the control arm. Altogether, no differences in the safety profile of endoscopic plication therapy and respective comparators could be identified. Moreover, current safety data is lacking quality as well as degree of detail. Furthermore, the included studies showed an overall very low quality of evidence; therefore, in combination with the afore-mentioned contradicting results and poor data quality, no reliable conclusions regarding the safety and effectiveness for endoscopic plication compared to laparoscopic surgery, or PPI therapy and/or a sham intervention in chronic GERD patients can be drawn. Further RCTs and/or non-RCTs with a higher quality of evidence are needed, examining currently available generations of devices. Thus, comparative studies with larger sample sizes (n greater than 100) and longer follow-up times of at least 3 years are crucial to clarify the currently uncertain available evidence on endoscopic plication and to add knowledge to the current scarce evidence on the safety profile. The authors concluded that the current evidence is insufficient to prove that endoscopic plication is more effective and equally safe or equally effective and safer than laparoscopic surgery, PPI therapy and/or sham treatment in chronic GERD patients. Due to the methodological shortcomings of the available evidence no solid conclusions can be drawn neither for clinical effectiveness nor for the safety of endoscopic plication therapy. Hence, there is a need for high-quality studies showing consistent long-term effectiveness results as well as properly reported and detailed safety data. The report stated that new results based on a relevant ongoing RCT (NCT03322553), may potentially influence the effect estimates, since the newest available device generation (GERDxTM) is applied. However, it will not fill the current evidence gap on controlled trials with large sample sizes and long-term follow-up; thus, a re-evaluation is recommended in 2023 at the earliest after the results of the ongoing RCT are published and adequate additional trials have potentially become accessible. The inclusion of this technology in the catalog of benefits is currently not recommended.
StomaphyX
In March 2007, the FDA granted 510(k) premarketing clearance to the StomaphyX (EndoGastric Solutions, Inc.), an endoluminal fastener and delivery system used to tighten esophageal tissue. The FDA clearance indicated that the StomaphyX is substantially equivalent to EndoCinch. In September 2007, the FDA granted 510(k) premarketing clearance to the EsophyX System with SerosaFuse Fastenter (Endogastric Solutions, Inc.) as being substantially equivalent to the StomaphyX and EndoCinch devices. The EsophyX System is designed to perform a transoral incisionless fundoplication procedure using to reconstruct a valve at the gastro-esophageal junction through transoral delivery of multiple fasteners. Cadiere et al (2008) reported on the outcome of a short-term, uncontrolled study of the EsophyX system for treating GERD. A total of 86 patients with chronic GERD treated with proton pump inhibitors (PPIs) were enrolled. Exclusion criteria included an irreducible hiatal hernia greater than 2 cm. At 12 months, 73% of study subjects had 50% or greater improvement in GERD health-related quality of life scores, and 81% of study subjects discontinued PPI use. However, less than half (37%) of study subjects had normalization of esophageal acid exposure. Serious adverse events consisted of 2 esophageal perforations upon device insertion and 1 case of post-operative intraluminal bleeding. The investigators reported that other adverse events were mild and transient.
Transoral Incisionless Fundoplication and EsophyX
Transoral Incisionless Fundoplication (TIF) with EsophyX is inserted through the patient's mouth under visual guidance of an endoscope, the EsophyX device is purportedly used to construct a durable antireflux valve with SerosaFuse Fasteners and tighten the LES, supposedly reestablishing a barrier to reflux and restoring the competency of the gastroesophageal junction.
In a retrospective study, Bergman and co-workers (2008) examined the safety and effectiveness of the first generation EsophyX system in patients with GERD who had undergone endolumenal fundoplication with the device. At follow-up, PPI usage was elicited and 2 validated questionnaires were administered measuring GERD health-related quality of life (range of 0 to 50) and symptom severity (range of 0 to 72). In limited preliminary evaluation, the initial North American experience with endolumenal fundoplication using the EsophyX device is that it appears to be safe and provides moderate effectiveness in treating the symptoms of GERD. Moreover, the authors stated that further studies comparing this technique with conventional medical and surgical therapies are necessary.
In a retrospective study, Barnes et al (2011) evaluated the clinical outcomes in 124 consecutive gastro-esophageal reflux disease (GERD) patients who underwent transoral incisionless fundoplication (TIF) using the second generation Esophyx device (Esophyx2) at 2 community hospitals. Out of 123 patients treated successfully, 110 gave consent (74% females, median age 60 [range of 21 to 87] years, body mass index (BMI) 27.5 [19.0 to 47.9]). At a median 7-month follow-up (range of 5 to 17), typical and atypical symptom scores were normalized in 75% to 80% of patients, PPIs were completely discontinued by 93%, and 83% were satisfied with their current health condition. Endoscopy in 53 patients revealed Hill grade I tight valves in 89% of the cases, reduced hiatal hernia in 33/34 (97%), and healed reflux esophagitis in 25/30 (83%). Based on global analysis, 72% of the patients were in remission, 20% improved symptomatically, and only 8% had ongoing GERD. These results supported the safety and efficacy of TIF as well as encouraged its application as an alternative treatment of GERD refractory to PPIs. The drawbacks of this study were its retrospective nature (symptom data at baseline were based on retrospective recall) and short-term follow-up. Furthermore, the lack of pH measuring systems at the authors' institutions prevented these researchers from measuring esophageal acid exposure before and after TIF.
Bell and Freeman (2011) retrospectively evaluated the safety and effectiveness of a rotational/longitudinal esophagogastric TIF with the second generation Esophyx device using subjective and objective outcomes. A total of 37 consecutive patients on anti-secretory medication and with proven GERD and limited hiatal hernia underwent TIF for persistent GERD symptoms. Five patients were re-operated for failed laparoscopic fundoplication. Of the 37 treated patients, 57% were female. The median age was 58 (range of 20 to 81) years and BMI was 25.5 (range of 15.9 to 36.1) kg/m(2). Sixty-eight percent indicated GERD-associated cough, asthma, or aspiration as a primary complaint and 32% complained of heartburn or regurgitation. The TIF procedures created tight wraps of 230° to 330° extending 3-4 cm above the Z-line. Two complications occurred: 1 mediastinal abscess treated laparoscopically and 1 post-operative bleeding requiring transfusion. At 6 (range of 3 to 14) months median follow-up, TIF resulted in a significant improvement of both atypical and typical symptoms in 64% and 70 to 80% of patients, respectively, as indicated by the corresponding GERD health-related quality of life (HRQL) and reflux symptom index (RSI) score reduction by 50% or more compared to baseline on proton pump inhibitors (PPIs). No patient reported problems with dysphagia, bloating, or excess flatulence, and 82% were not taking any PPIs. Reflux characteristics were significantly improved and normalized in 61, 89, and 56% of patients in terms of acid exposure, number of refluxates, and DeMeester scores, respectively. TIF was effective in treating GERD in 75% of patients among whom 54% were in a complete "remission" and 21% were "improved". The remaining 25% were considered failures, and 5 (13.5%) patients underwent revision. The authors concluded that rotational/longitudinal esophagogastric fundoplication using the EsophyX device significantly improved symptomatic and objective outcomes in over 70% of patients at median 6-month follow-up. Post-fundoplication side effects were not reported after TIF. This was a small, retrospective study with short-term follow-up; its findings need to be validated by well-designed studies.
Testoni et al (2012) assessed the long-term effect of TIF using the second generation Esophyx device in patients with symptomatic GERD. TIF 2.0 fundoplication was done in 42 consecutive patients. All were studied with GERD-HRQL and GERD-QUAL questionnaires, upper gastrointestinal (GI) endoscopy, esophageal manometry, and 24-hr pH impedance before and at 6, 12, and 24 months after TIF. In all, 35 patients completed 6-month follow-up; 21 (60.0%) completely stopped proton pump inhibitor (PPI) therapy, 6 (17.1%) more than halved it, and 8 (22.9%) continued with the same dose as before the procedure. There were 26 patients with complete 24-month follow-up; 11 (42.3%) completely stopped PPI therapy, 7 (26.9%) more than halved it, and 8 (30.8%) were taking the same dose as before the procedure. Hiatal hernia and ineffective esophageal motility seemed to raise the risk of recurrence of symptoms (p = 0.02 and p < 0.001, respectively). The number of fasteners deployed during TIF was the only factor predictive of successful outcome (p = 0.018). The authors concluded that TIF using the EsophyX device allowed withdrawal or reduction of PPI in about 77% of patients at 6-month follow-up and about 69% at 24 months. Larger number of fasteners deployed during TIF was predictive of positive outcome; pre-TIF ineffective esophageal motility and hiatal hernia raised the risk of recurrence of GERD symptoms, but were not significant from a prospective point of view. The major drawback of this small study was its uncontrolled design. Also, while 77% of patients stopped or at least halved PPI use at 6-month follow-up; this proportion dropped to about 69% at 24-month evaluation, raising concerns regarding how long fundoplication lasts with the current technique. The authors stated that "[i]n light of these results and awaiting randomized controlled studies on larger series, the TIF procedure can at present be offered as a complement to medical therapy or an alternative to surgery only in selected patients with small or no hiatal hernia, who refuse surgery or do not want long-term PPI therapy, or are intolerant or partial responders to PPI".
In a retrospective study, Trad et al (2012) evaluated safety, symptom resolution, patient satisfaction, and medication use 1 to 2 years after TIF using the second generation Esophyx device in patients with GERD and/or laryngopharyngeal reflux (LPR) symptoms. A total of 34 patients with a confirmed diagnosis of GERD symptoms that were inadequately controlled by anti-secretory medications, and who where either dissatisfied with their current therapy or not willing to continue taking medication, underwent TIF using EsophyX at the authors' community-based hospital. Follow-up assessments were completed in 28 patients. Median age of the study group was 57 years (range of 23 to 77), BMI was 25.7 (18.3 to 36.4) kg/m(2), and 50% were female. All patients had documented chronic GERD for a median 5 years (1 to 20) and refractory symptoms to PPIs. Hiatal hernia was present in 75% (21/28) of patients, and 21% (6/28) had erosive esophagitis (LA grade A or B). Transoral incisionless fundoplication was performed following a standardized TIF-2 protocol and resulted in reducing hiatal hernia and restoring the natural anatomy of the gastroesophageal (GE) junction (Hill grade I). There were no post-operative complications. At a median 14-months follow-up, 82% (23/28) of patients were off daily PPIs (64% completely off PPIs), and 68% (19/28) were satisfied with their current health condition compared to 4% before TIF. Median GERD-HRQL scores were significantly reduced to 4 (0 to 25) from 26 (0 to 45) before TIF (p < 0.001). Heartburn was eliminated in 65% (17/26) and improved by greater than 50% in 86% (24/28) of patients. Regurgitation was eliminated in 80% (16/20) of patients. Atypical LPR symptoms such as hoarseness, coughing, and throat clearing were eliminated in 63% (17/27) of patients as measured by Reflux Symptom Index scores. The authors concluded that these findings in 28 patients confirmed the safety and effectiveness of TIF, documenting symptomatic improvement of GERD and LPR symptoms and clinically significant discontinuation of daily PPIs in 82% of patients. Limitations of this study included its retrospective, single-center design, small sample size and a lack of follow-up comparative pH/impedance monitoring data. The authors are currently enrolling patients in a prospective, multi-center TIF Registry.
Svoboda et al (2011) stated that natural orifice transluminal surgery (NOTES) has been introduced in endoscopic surgery as a new system offering the advantage of a less invasive procedure. Gastro-esophageal reflux disease appears to be the most promising application of NOTES treatment. The aims of our study were to evaluate the safety and efficacy of this procedure and length of hospital stay. Patients indicated for surgery of GERD were randomly assigned (ratio 2:1) to TIF (n = 34) using the first generation Esophyx device and control group, where gold standard Nissen laparoscopic fundoplication was performed (NLF group, n = 18). For TIF, the Plicator method was initially used for 18 patients, but the company terminated production in 2008 without a follower. During the last 2 years the EsophyX method was used for 16 patients. After the evaluation of 34 TIF patients and 18 NLF patients we observed similar efficacy of TIF procedures compared with NLF after 3 and 12 months. The hospital stay was significantly shorter (p < 0.0001) in TIF group (average of 2.9 +/- 0.8 days) than in NLF group (6.4 +/ - 0.7). The TIF procedure was safe; 1 serious adverse event in the TIF group and 3 in the NLF group were observed. The authors concluded that both NOTES TIF procedures were, after the initial learning curve, safe and effective methods for treatment of GERD, allowing substantial shortening of hospital stay. The effect of both procedures was sustained over 12 months. Moreover, they noted that longer follow-up is necessary to verify efficacy for more years.
Zagol and Mikami (2011) evaluated transoral fundoplication devices for GERD that have been commercially available within the last 5 years. Literature databases including Medline and PubMed were searched from January 2005 to November 2010. Both blinded and unblinded randomized studies were evaluated. These investigators reviewed the literature for evaluations of primary transoral endoluminal fundoplication devices which included EndoCinch, NDO Plicator, Esophyx, and Stretta. Reviews of all studies with greater than 20 patients were evaluated to assess the efficacy and safety of transoral fundoplication devices. These endoluminal devices were primary matched against sham procedures. The EndoCinch and Stretta procedures were the only devices compared to laparoscopic fundoplication, the current standard for surgical management of GERD. The authors concluded that the field of endoluminal treatment of GERD has gained popularity over the last several years. Endoluminal treatment of GERD has been shown to be safe and effective in recent studies. The authors still believe more randomized prospective studies need to be carried out to determine if endoluminal therapies will be a durable option for patients with GERD. Continuing research will further the advancement of endoluminal GERD procedures in the future. Also, Frazzoni et al (2011) concluded that in patients with refractory GERD, EsophyX fundoplication is significantly less effective than laparoscopic fundoplication in improving reflux parameters and accordingly, in inducing symptom remission.
The Agency for Healthcare Research and Quality's updated evidence report on "Treatment options for GERD or acid reflux disease" (AHRQ, 2011) compared the risks and benefits of treatments for GERD. The report stated that "[t]hree types of endoscopic treatments are EndoCinch™, Stretta®, and EsophyX™. These treatments are very new and are not as common as medicines or surgery to treat GERD. People receiving one of these treatments may be in a study to see how well it works. There are not enough studies to say how well endoscopic treatments (EndoCinch™, Stretta®, and EsophyX™) work to control the symptoms of GERD". Regarding the EndoCinch procedure, the AHRQ assessment (Ip, et al., 2011) concluded that the quality of evidence was "low", consisting of two sham-controlled studies and 6 noncomparative cohort studies. The AHRQ report found that no consistent differences between EndoCinch and sham were reported, and that significant improvements in heartburn, qualtiy of life, and esophagitis healing were found in some but not all cohort studies. The AHRQ assessment (Ip, et al., 2011) found the strength of evidence for the EsophyX procedure was "insufficient," consisting of five small cohort studies. The reported proportion of patients who were off PPIs at the end of the followup period ranged from 47 to 71%. Significant improvement of quality as measured by the GERD-HRQL scale was reported by 2 of 5 studies. The AHRQ assessment (Ip, et al., 2011) found "insufficient" evidence for the.Stretta procedure, consisting of one sham-controlled study and 7 noncomparative cohort studies. In the randomized controlled trial, the proportion of patients who stopped or decreased PPI use was significantly greater in the Stretta group than the control group at 6 months (but it was not significant at 1 year). No significant differences in heartburn symptoms, quality of life, acid exposure, and esophagitis outcomes were found. The majority of cohort studies found significant improvements in GERD symptoms, quality of life, and medication use.
In a prospective, open-label, multi-center, single-arm study, Bell et al (2012) attempted to validate previously reported safety and symptomatic outcomes of TIF:- evaluate the relative benefit of TIF within different GERD subgroups, and
- determine predictors of success in community settings.
Between January 2010 and February 2011, a total of 100 consecutive patients who underwent TIF procedures using the second generation Esophyx device at 10 centers were enrolled in this study. Symptom improvement and objective outcomes of TIF were analyzed at 6-month follow-up. One hundred TIF procedures were performed. No complications were reported. Median GERD symptom duration was 9 years (range of 1 to 35 years) and median duration of PPI use was 7 years (1 to 20 years). Maximal medical therapy resulted in incomplete symptom control for 92% of patients; GERD-HRQL total score was normalized in 73%. Median heartburn and regurgitation scores improved significantly, from 18 (range of 0 to 30) and 15 (range of 0 to 30) on PPIs before TIF to 3 (range of 0 to 25) and 0 (range of 0 to 25), respectively; p < 0.001. Median Reflux Symptom Index scores were reduced after TIF from 24 (range of 14 to 41) to 7 (range of 0 to 44); p < 0.001. Eighty percent of patients were completely off PPIs after TIF versus 92% of patients on PPIs before TIF. Pre-operative factors associated with clinical outcomes were less severe heartburn (total GERD-HRQL less than or equal to 30, p = 0.02) and the presence of esophagitis (p < 0.02). The authors concluded that TIF is safe and effective in multiple community-based settings in the treatment of medically refractory GERD, as demonstrated by an absence of complications, excellent symptom relief, and complete cessation of PPIs at 6-month follow-up. The main drawbacks of this study were its non-randomized nature and short-term follow-up. Furthermore, TIF is not as effective in primary symptom response as traditional laparoscopic fundoplication.
Muls et al (2013) prospectively evaluated the long-term safety and durability of TIF using the first generation Esophyx device in a multi-center setting. A longitudinal per protocol (PP) and a modified intention-to-treat (mITT) analysis at 1 and 3 years consisted of symptom evaluation using the GERD-HRQL questionnaire, medication use, upper GI endoscopy, and pH-metry. Of 79 patients previously reported at 1 year, 12 were lost to follow-up, and 1 died from an unrelated cause. The remaining 66 patients were followed-up and analyzed (mITT). Of 66 patients, 12 underwent revisional procedures, leaving 54 patients for PP analysis at a median of 3.1 years (range of 2.9 to 3.6). No adverse events related to TIF were reported at 2- or 3-year follow-up. On PP analysis, median GERD-HRQL score off PPIs improved significantly to 4 (range of 0 to 32) from both off (25 [13 to 38], p < 0.0001) and on (9 [0 to 22], p < 0.0001) PPIs. Discontinuation of daily PPIs was sustained in 61% (mITT) and 74% (PP) of patients. Of 11 patients with pH data at 3 years (PP), 9 (82%) remained normal. Based on mITT analysis, 9/23 (39%) remained normal at 3 years. The authors concluded that the clinical outcomes at 3 years following TIF, patient satisfaction, healing of erosive esophagitis, and cessation of PPI medication support long-term safety and durability of the TIF procedure for those with initial treatment success. Moreover, they noted that although complete normalization of pH studies occurred in a minority of patients, successful cases showed long-term durability. Furthermore, they stated that “the steep learning curve with the EsophyX device may negatively influence the results of this study. Perhaps, multi-center studies with surgeons who are through their learning curve with a focus primarily on physiological outcomes may further define the role of TIF in the management of chronic GERD in the future”.
The Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (2013) identified the Stretta, Esophyx, Linx, and EndoStim as procedures that are under research and offered at specialist centers performing suitable registered research projects.
Yew and Chuah (2013) discussed the past and present status of anti-reflux endoluminal therapy. Currently, there are 3 commonly employed anti-reflux endoluminal procedures:- fundoplication or suturing techniques (EndoCinch, NDO, and EsophyX),
- intramural injection or implant techniques enhancing LES volume and/or strengthening compliance of the LES-Enteryx and Gatekeeper), and
- RF ablation of LES and cardia.
EndoCinch plication requires further study and modification of technique before it can be recommended because of durability issues.Esophyx, the TIF, may reduce hiatal hernias and increase LES length. Preliminary studies have shown promising reduction in symptoms and medication use but evidence concerning safety and long-term durability is still pending. The safety issue with injection technique is the main concern as evident from the incidences of implant withdrawals after reported major adverse events. Future research with cautious monitoring is required before any new implant material can be recommended for commercial application. Radiofrequency ablation therapy is regaining popularity in treating refractory symptoms despite PPI use due to improved efficacy, durability, and safety after years of refinement of protocol.
Toomey et al (2014) undertook a case-controlled registry study of three cohorts of 20 patients undergoing TIF or laparoscopic Nissen or Toupet fundoplications from 2010 to 2013 controlling for age, body mass index, and preoperative DeMeester scores. All patients were prospectively followed. Median data are reported. The investigators reported that patients undergoing TIF had significantly shorter operative times (in minutes: 71 vs 119 and 85, respectively, P < 0.001) and length of stay (in days: 1, 2, and 1, respectively, P < 0.001). The authors stated that, no matter the approach, patients reported dramatic and similar reduction in symptom frequency and severity (e.g., heartburn 8 to 0, P < 0.05). At follow-up, 83 per cent of patients after TIF, 80 per cent after Nissen, or 92 per cent after Toupet fundoplications had symptoms less than once per month (P = 0.12).
Kim and colleagues (2013) noted that while acid suppression with PPIs remains the mainstay of treatment of GERD, some patients showed refractory response to PPIs, necessitating further intervention. After increasing dosage of PPIs and other kinds of pharmacological intervention adopting prokinetics or others, variable endoscopic treatments were introduced for the treatment of these refractory cases. Implantation of reabsorbable or synthetic materials in the distal esophagus was tried in vain and is expelled from the market due to limited efficacy and serious complication. The authors stated that RF energy delivery (Stretta) and TIF (EsophyX) are actively tried currently.
Hakansson et al (2015) reported on a double-blind sham-controlled study of TIF in GERD patients who were chronic PPI users. The investigators studied patients with objectively confirmed GERD and persistent moderate to severe GERD symptoms without PPI therapy. Of 121 patients screened, the investigators randomised 44 patients with 22 patients in each group. Those allocated to TIF had the TIF2 procedure completed during general anaesthesia by the EsophyX device with SerosaFuse fasteners. The sham procedure consisted of upper GI endoscopy under general anaesthesia. Neither the patient nor the assessor was aware of the patients' group affiliation. The primary effectiveness end-point was the proportion of patients in clinical remission after 6-month follow-up. Secondary outcomes were: PPI consumption, oesophageal acid exposure, reduction in Quality of Life in Reflux and Dyspepsia and Gastrointestinal Symptom Rating Scale scores and healing of reflux esophagitis. The time (average days) in remission offered by the TIF2 procedure (197) was significantly longer compared to those submitted to the sham intervention (107), p < 0.001. After 6 months 13/22 (59%) of the chronic GERD patients remained in clinical remission after the active intervention. Likewise, the secondary outcome measures were all in favour of the TIF2 procedure. The authors stated that no safety issues were raised. Limitations of this study included its small size and limited duration of follow-up.
Testoni et al (2015) assessed the long-term effect of TIF 2.0 on pathological reflux and symptoms in GERD patients with daily dependence on PPI. Fifty patients underwent TIF. All underwent GERD-HRQL and GERD-QUAL questionnaires, upper GI endoscopy, esophageal manometry, and 24-h pH-impedance before and 6, 12, and 24 months after TIF, and subsequent yearly clinical re-evaluation. Patients were followed for up to 6 years (mean of 52.7 ± 19.7 months). In all, 83.7, 79.6, 87.8, and 84.4% of patients stopped or halved the PPI therapy 6, 12, 24, and 36 months after TIF. Three-year figure remained stable up to 6 years. Symptom scores off PPI were significantly lower at 6, 12, 24, and 36 months. At 6 months, Hill's grade I of the newly created valve persisted in all pre-procedure Hill's grade I patients, in 66.7% of grade II and 58.3% of grade III. This figure remained substantially unchanged at 12 and 24 months, too. Impedance monitoring indicated significantly fewer total and acid refluxes after treatment (p = 0.01). Factors predicting good outcomes were pre-procedure Hill's grade I-II, no hiatal hernia or hernia less than or equal to 2 cm (p = 0.03), absence of ineffective esophageal motility (p < 0.0001), and number of fasteners deployed (p = 0.01). This small, single-center study needs to be replicated in larger multi-center studies.
Hunter et al (2015) performed a prospective, sham-controlled trial to determine if TF reduced troublesome regurgitation to a greater extent than PPIs in patients with GERD. The investigators screened 696 patients with troublesome regurgitation despite daily PPI use with 3 validated GERD-specific symptom scales, on and off PPIs. Those with at least troublesome regurgitation (based on the Montreal definition) on PPIs underwent barium swallow, esophagogastroduodenoscopy, 48-hour esophageal pH monitoring (off PPIs), and high-resolution esophageal manometry analyses. Patients with GERD and hiatal hernias less than or equal to 2 cm were randomly assigned to groups that underwent TF and then received 6 months of placebo (n = 87), or sham surgery and 6 months of once- or twice-daily omeprazole (controls, n = 42). Patients were blinded to therapy during follow-up period and reassessed at 2, 12, and 26 weeks. At 6 months, patients underwent 48-hour esophageal pH monitoring and esophagogastroduodenoscopy. By intention-to-treat analysis, TF eliminated troublesome regurgitation in a larger proportion of patients (67%) than PPIs (45%) (P = .023). A larger proportion of controls had no response at 3 months (36%) than subjects that received TF (11%; P = .004). Control of esophageal pH improved after TF (mean 9.3% before and 6.3% after; p < 0.001), but not after sham surgery (mean 8.6% before and 8.9% after). Subjects from both groups who completed the protocol had similar reductions in GERD symptom scores. Severe complications were rare (3 subjects receiving TF and 1 receiving the sham surgery).
Trad et al (2015) reported on a short-term multicenter randomized study compared the efficacy of TIF against PPIs in controlling these symptoms in patients with small hiatal hernias. Between June and August 2012, 63 patients were randomized at 7 US community hospitals. Patients in the PPI group were placed on maximum standard dose (MSD). Patients in the TIF group underwent esophagogastric fundoplication using the EsophyX device. Primary outcome was elimination of daily troublesome regurgitation or extraesophageal symptoms. Secondary outcomes were normalization of esophageal acid exposure (EAE), PPI usage and healing of esophagitis. Of 63 randomized patients (40 TIF and 23 PPI), 3 were lost to follow-up leaving 39 TIF and 21 PPI patients for analysis. At 6-month follow-up, troublesome regurgitation was eliminated in 97% of TIF patients versus 50% of PPI patients, relative risk (RR) = 1.9, 95% confidence interval (CI): 1.2 to 3.11 (p = 0.006). Globally, 62% of TIF patients experienced elimination of regurgitation and extraesophageal symptoms versus 5% of PPI patients, RR = 12.9, 95% CI = 1.9-88.9 (P = .009). EAE was normalized in 54% of TIF patients (off PPIs) versus 52% of PPI patients (on MSD), RR = 1.0, 95% CI: 0.6 to 1.7 (p = 0.914); 90% of TIF patients were off PPIs.
A review by Lo and Mashimo (2015) noted that, "although these results seem promising, additional research raises the issue of poor efficacy and early treatment failure after TIF". The authors noted that results of TIF have been "mixed" with a few cases requiring surgical intervention. The authors noted that there is also concern over damage to adjacent structures such as the vagal nerves during relatively blind endoscopic suturing. The authors stated that further study is needed to identify the most appropriate subjects for these devices.
Witteman et al (2015) evaluated effectiveness of TIF compared with proton pump inhibition in a population consisting of GERD patients controlled with PPIs who opted for an endoscopic intervention over lifelong drug dependence. Patients with chronic GERD were randomized (2:1) for TIF or continuation of PPI therapy. American Society of Anesthesiologists greater than 2, body mass index (BMI) greater than 35 kg/m(2), hiatal hernia greater than 2 cm, and esophageal motility disorders were exclusion criteria. Primary outcome measure was GERD-related quality of life. Secondary outcome measures were esophageal acid exposure, number of reflux episodes, PPI usage, appearance of the gastro-esophageal valve, and healing of reflux esophagitis. Cross-over for the PPI group was allowed after 6 months. A total of 60 patients (TIF: n = 40; PPI: n = 20, mean BMI of 26 kg/m(2), 37 males) were included. At 6 months, GERD symptoms were more improved in the TIF group compared with the PPI group (p < 0.001), with a similar improvement of distal esophageal acid exposure (P=0.228) compared with baseline. The pH normalization for TIF group and PPI group was 50% and 63%, respectively. All patients allocated for PPI treatment opted for crossover. At 12 months, quality of life remained improved after TIF compared with baseline (p < 0.05), but no improvement in esophageal acid exposure compared with baseline was found (p = 0.171) and normalization of pH was accomplished in only 29% in conjunction with deteriorated valve appearances at endoscopy and resumption of PPIs in 61%. The authors concluded that although TIF resulted in an improved GERD-related quality of life and produced a short-term improvement of the anti-reflux barrier in a selected group of GERD patients, no long-term objective reflux control was achieved.
Trad et al (2017) reported on the TF EsophyX versus Medical PPI Open Label (TEMPO) trial, which was conducted in seven US sites. Between June and August 2012, the investigators enrolled patients with small ( less than 2 cm) or absent hiatal hernias who suffered from troublesome GERD symptoms while on PPI therapy for at least 6 months and had abnormal esophageal acid exposure (EAE). Randomization was to TF group (n = 40) or to PPI group (n = 23). Following evaluation at 6 months, all remaining PPI patients (n = 21) elected to undergo cross-over to TF; 52 patients were assessed at 3 years for- GERD symptom resolution using three GERD-specific quality of life questionnaires,
- healing of esophagitis using endoscopy,
- EAE using 48-h Bravo testing, and
- discontinuation of PPI use.
Two patients who underwent revisional procedures by year 3 were included in the final analysis. At 3-year follow-up, elimination of troublesome regurgitation and all atypical symptoms was reported by 90 % (37/41) and 88 % (42/48) of patients, respectively. The mean Reflux Symptom Index score improved from 22.2 (9.2) on PPIs at screening to 4 (7.1) off PPIs 3 years post-TF, p < 0.0001. The mean total% time pH <4 improved from 10.5 (3.5) to 7.8 (5.7), p = 0.0283. Esophagitis was healed in 86 % (19/22) of patients. At the end of study, 71 % (37/52) of patients had discontinued PPI therapy. All outcome measures remained stable between 1-, 2-, and 3-year follow-ups.
Sami Trad (2016) noted TIF performed with the EsophyX device is a totally endoscopic procedure with the objectives to mechanically repair a defective gastro-esophageal valve and to reduce small hiatal hernias. The recent publication of randomized controlled trials (RCTs) and long-term follow-up data offers the opportunity to re-evaluate this treatment modality and its role in the management of patients with chronic gastro-esophageal reflux disease (GERD). Randomized controlled trials have confirmed the ability of TIF to eliminate troublesome GERD symptoms, heal esophagitis, and improve distal esophageal acid exposure in appropriately selected patient populations. These studies establish TIF's superiority to conventional medical therapy, especially in clinical scenarios where proton-pump inhibitors (PPIs) fail to provide complete symptom relief across the spectrum of classic and atypical GERD manifestations, including regurgitation and laryngopharyngeal reflux. Long-term data indicated sustained positive outcomes and durability up to 6 years after procedure. These results were achieved with a low rate of serious adverse events and usually without introducing troublesome dysphagia, gas bloat, or flatulence. The authors concluded that based on the most recent data, TIF appeared to be a valuable treatment alternative for the management of appropriately selected patients with moderate-to-severe chronic GERD symptoms.
Huang et al (2017) stated that the effectiveness of TIF performed with the EsophyX device and its long-term outcomes in GERD are debated. These investigators performed a systematic review with meta-analysis of studies evaluating the role of TIF in GERD. A systematic search of Embase, Scopus, PubMed, and the Cochrane Library Central was performed. All original studies reporting outcomes in GERD patients who underwent TIF were identified. Only RCTs evaluating the effectiveness of TIF, and prospective observational studies reporting outcomes after TIF were included. A total of 18 studies (963 patients) published between 2007 and 2015 were identified, including 5 RCTs and 13 prospective observational studies. The pooled relative risk of response rate to TIF versus PPIs/sham was 2.44 (95% confidence interval [CI]: 1.25 to 4.79, p = 0.0009) in RCTs in the intention-to-treat analysis. The total number of refluxes was reduced after TIF compared with the PPIs/sham group. The esophageal acid exposure time and acid reflux episodes after TIF were not significantly improved; PPIs usage increased with time and most of the patients resumed PPIs treatment at reduced dosage during the long-term follow-up. The total satisfaction rate after TIF was about 69.15% in 6 months. The incidence of severe adverse events consisting of gastro-intestinal (GI) perforation and bleeding was 2.4%. The authors concluded that TIF is an alternative intervention in controlling GERD-related symptoms with comparable short-term patient satisfaction. Moreover, they stated that long-term results showed decreased effectiveness with time; patients often resume PPIs at reduced doses in the near future.
Stefanidis and colleagues (2017) stated that TIF using the EsophyX device has been shown to be effective and safe in patients with gastro-esophageal reflux disease (GERD); however, the subset of patients that would mostly benefit from this technique remains unknown. These researchers evaluated the long-term efficacy and safety of the TIF procedure in patients with a history of esophagitis or proven chronic GERD who have achieved symptom control with the administration of proton pump inhibitors (PPIs), but did not wish to continue receiving medications for life. A total of 45 patients with typical GERD symptoms (heartburn, regurgitation, chest pain) and a history of esophagitis grade A and B or proven GERD by esophageal pH monitoring underwent TIF using EsophyX. Patients with eosphagitis C and D or those with large hiatal hernias (greater than 2 cm in length) were excluded. The primary clinical effectiveness measure was GERD symptom elimination at follow-up based on normalization of the GERD health related quality of life (GERD-HRQL) questionnaire. After a median follow-up period of 59 months (36 to 75) the median GERD-HRQL scores improved significantly from 27 (2 to 45) at baseline to 4 (0 to 26) (p < 0.001) in the 44 patients completing the study. Heartburn was eliminated in 12 out of the 21 patients included (57.1%), regurgitation was eliminated in 15 out of the 17 patients included (88.2%) and finally chest pain was eliminated in 5 patients out of the 6 patients included (83.3%). Overall, 32 patients out of the 44 patients (72.7%) that completed the study follow-up reported elimination of their main symptom, without the need for PPI administration (none PPI usage). Furthermore, 6 more patients (13.6%), 5 with heartburn, and 1 with regurgitation reported half PPI dose taken for less than 50% of the preceding follow-up period (occasional PPI usage), while 6 more patients (4 with heartburn, 1 with regurgitation, and 1 with chest pain) reported full or half PPI dose taken for more than 50% of the preceding follow-up period (daily PPI usage). The authors concluded that creation of an esophagogastric fundoplication using the EsophyX device abolished reflux symptoms in 72.7% of PPI-responsive GERD patients at a median 59 month follow-up.
Kethman and Hawn (2017) noted that GERD is the most common gastro-intestinal (GI) disorder of the esophagus. It is a chronic, progressive disorder that presents most typically with heartburn and regurgitation and atypically with chest pain, dysphagia, chronic cough, globus, or sore throat. The mainstay for diagnosis and characterization of the disorder is esophagoduodenoscopy (EGD), high-resolution esophageal manometry, and symptom-associated ambulatory esophageal pH impedance monitoring. Additional studies that can be useful in certain clinical presentations include gastric scintigraphy and oral contrast upper GI radiographic series. Refractory GERD can be surgically managed with various techniques. In obese individuals, laparoscopic Roux-en-Y gastric bypass should be considered due to significant symptom improvement and lower incidence of recurrent symptoms with weight loss. Otherwise, laparoscopic Nissen fundoplication is the preferred surgical technique for treatment of this disease with concomitant hiatal hernia repair when present for either procedure. The short-term risks associated with these procedures include esophageal or gastric injury, pneumothorax, wound infection, and dysphagia. Emerging techniques for treatment of this disease include the Linx Reflux Management System, EndoStim LES Stimulation System, EsophyX and MUSE endoscopic fundoplication devices, and the Stretta endoscopic ablation system. Outcomes after surgical management of refractory GERD are highly dependent on adherence to strict surgical indications and appropriate patient-specific procedure selection.
Furthermore, an UpToDate review on “Surgical management of gastroesophageal reflux in adults” (Schwaitzberg, 2020) states that “A number of methods for treating GERD endoscopically have been developed. Their efficacy (particularly long-term) is still being defined”.
Trad et al (2018) stated that questions remain regarding the therapeutic durability of transoral incisionless fundoplication (TIF). In this study, clinical outcomes were evaluated at 5 years post-TIF 2.0. A total of 63 chronic gastroesophageal reflux disease (GERD) sufferers with troublesome symptoms refractory to proton pump inhibitor (PPI) therapy, absent or less than or equal to 2 cm hiatal hernia, and abnormal esophageal acid exposure were randomized to the TIF group or PPI group. Following the 6-month evaluation, all patients in the PPI group elected for cross-over to TIF; thus, all 63 patients underwent TIF 2.0 with EsophyX2 device. Primary outcome was elimination of daily troublesome regurgitation and atypical symptoms at the 5-year follow-up. Secondary outcomes were improvement in symptom scores, PPI use, re-operations, and patient health satisfaction. The cost-effectiveness of TIF 2.0 was also estimated. Of 63 patients, 60 were available at 1 year, 52 at 3 years, and 44 at 5 years for evaluation. Troublesome regurgitation was eliminated in 88% of patients at 1 year, 90% at 3 years, and 86% at 5 years. Resolution of troublesome atypical symptoms was achieved in 82% of patients at 1 year, 88% at 3 years, and 80% at 5 years. No serious adverse events (AEs) occurred. There were 3 re-operations by the end of the 5-year follow-up. At the 5-year follow-up, 34% of patients were on daily PPI therapy as compared with 100% of patients at screening. The total GERD Health-related quality-of-life score improved by decreasing from 22.2 to 6.8 at 5 years (p < 0.001). The authors concluded that 5 years after undergoing TIF 2.0, the great majority of TEMPO trial patients experienced durable elimination of all types of troublesome GERD manifestations, including regurgitation and atypical symptoms. There were no SAEs or any safety concerns associated with the TIF 2.0 procedure. It appeared that in the appropriate patient population, the TIF 2.0 procedure could be a cost-effective alternative to laparoscopic Nissen fundoplication.
The authors stated that limitations of the study included the relatively small number of patients (44 at 5-year follow-up), which can be partially explained by the challenges involved in enrolling patients with such highly selective criteria. The study was, however, appropriately powered for statistical significance and had a respectable follow-up rate of 70% at 5-year assessment. These researchers could also be criticized for not performing functional tests and endoscopies at the 5-year mark, though they were performed and reported in the 3-year follow-up. They noted that a poor correlation between post-intervention GERD symptoms and physiological parameters has consistently been reported with all therapies, including traditional anti-reflux surgery, the TIF procedure and during PPI therapy (17% to 80% of patients demonstrated abnormal esophageal acid exposure while being asymptomatic on PPI therapy). An additional potential limitation of this study was that the results were reported regardless of PPI use at the time of post-procedure assessment (on or off PPI therapy). These investigators felt justified to use this methodology because all patients in the study experienced daily troublesome regurgitation and/or atypical symptoms on optimized PPI therapy before the TIF 2.0 procedure. Achieving control of troublesome symptoms and improving quality of life (QOL) with the use of PPIs after an endoscopic anti-reflux procedure in patients whose symptoms were refractory to high-dose PPIs before intervention should not necessarily be considered a treatment failure. In these cases, the TIF procedure may be viewed as a useful therapeutic adjunct to PPIs.
Richter et al (2018) noted that the effects of TIF and laparoscopic Nissen fundoplication (LNF) have been compared with those of PPIs or a sham procedure in patients with GERD, but there has been no direct comparison of TIF versus LNF. These researchers performed a systematic review and network meta-analysis of RCTs to compare the relative efficacies of TIF versus LNF in patients with GERD. They searched publication databases and conference abstracts through May 10, 2017 for RCTs that compared the efficacy of TIF or LNF with that of a sham procedure or PPIs in patients with GERD. These investigators carried out a network meta-analysis using Bayesian methods under random-effects multiple treatment comparisons. They assessed ranking probability by surface under the cumulative ranking curve. The search identified 7 trials comprising 1,128 patients. Surface under the cumulative ranking curve ranking indicated TIF had highest probability of increasing patients' health-related QOL (HR-QOL; 0.96), followed by LNF (0.66), a sham procedure (0.35), and PPIs (0.042). LNF had the highest probability of increasing percent time at pH of less than 4 (0.99), followed by PPIs (0.64), TIF (0.32), and the sham procedure (0.05). LNF also had the highest probability of increasing LES pressure (0.78), followed by TIF (0.72) and PPIs (0.01). Patients who underwent the sham procedure had the highest probability for persistent esophagitis (0.74), followed by those receiving TIF (0.69), LNF (0.38), and PPIs (0.19). Meta-regression showed a shorter follow-up time as a significant confounder for the outcome of HR-QOL in studies of TIF. The authors found LNF to have the greatest ability to improve physiologic parameters of GERD, including increased lower esophageal sphincter (LES) pressure and decreased percent time pH of less than 4. Although TIF produced the largest increase in HR-QOL, this could be due to the shorter follow-up time of patients treated with TIF versus LNF or PPIs. These researchers stated that TIF is a minimally invasive endoscopic procedure, yet based on evaluation of benefits versus risks, they do not recommend it as a long-term alternative to PPI or LNF treatment of GERD.
In a systematic review and meta-analysis, McCarty et al (2018) examined the feasibility, efficacy, and tolerability of TIF for the treatment of refractory GERD. Searches of PubMed, Embase, Web of Science, and Cochrane Library databases were performed to March 2017. Measured outcomes included immediate technical success rate and serious adverse events (AEs). Symptomatic improvement was measured using GERD-HRQOL, Gastroesophageal Reflux Symptom Score (GERSS), and Reflux Symptom Index (RSI). Objective success was determined by hiatal hernia reduction and pH monitoring. A total of 32 studies (1,475 patients; 48.2 % male) met inclusion criteria. TIF success rate was 99 % (95 % confidence interval [CI]: 97 to 100; p < 0.001), with an AE rate of 2 % (95 % CI: 1 to 3; p < 0.001). GERD-HRQOL, GERSS, and RSI improved significantly post-TIF (mean difference [MD] 17.72, 95 % CI: 17.31 to 18.14; MD 23.78, 95 % CI: 22.96 to 24.60; MD 14.28, 95 % CI: 13.56 to 15.01; all p < 0.001, respectively). Hernia reduction occurred in 91 % of patients (95 % CI: 83 to 98; p < 0.001). DeMeester scores improved significantly (mean difference [MD] 10.22, 95 % CI: 8.38 to 12.12; p < 0.001); PPI therapy was discontinued post-procedure in 89 % of patients (95 % CI: 82 to 95; p < 0.001). The authors concluded that TIF appeared to be a safe and effective endoscopic procedure for patients with refractory GERD. These researchers stated that future controlled trials are needed to directly compare efficacy, long-term durability, and safety between TIF and Nissen fundoplication.
Chimukangara et al (2019) stated that TIF offers an endoscopic approach to the treatment of GERD. Controlled trials have demonstrated the short-term efficacy of this procedure, but long-term follow-up studies are lacking. These researchers examined the long-term impact of TIF on disease-specific QOL and anti-secretory medication use. They carried out a retrospective cohort study of all patients undergoing TIF between 2007 and 2014 in a large academic medical center. Reflux symptoms and QOL were assessed using the GERD-HRQOL questionnaire at baseline, short-term, and long-term follow-up. A total of 57 patients with a median age of 46 (37 to 59) years and an average body mass index (BMI) of 28.8 ± 4.9 kg/m2 underwent TIF during the study period; 60% of the patients were women, and all were taking a PPI at least daily. At a median follow-up interval of 97 months, 12 patients had undergone subsequent laparoscopic anti-reflux surgery (LARS). Of those who had not, 23 had complete long-term follow-up data for analysis and were included in the study; 73% reported daily acid-reducing medication use, and the median GERD-HRQL score was 10 (6 to 14) compared to 24 (15 to 28) at baseline (p < 0.01); 78% of these patients expressed satisfaction or neutral feelings regarding their GERD management. There were no significant differences in the baseline characteristics of patients who underwent LARS during the study period and those who did not. The authors concluded that the findings of this study demonstrated that TIF could produce durable improvements in disease-specific QOL in some patients with symptomatic GERD. The majority of patients resumed daily PPI therapy during the study period, but with significantly improved GERD-HRQOL scores compared to baseline and increased satisfaction with their medical condition. These researchers believed that this study shed light to the unanswered question on what the natural history following TIF is. They stated that further studies are needed to identify the specific population who may benefit from TIF to avoid need for subsequent anti-reflux surgery.
The authors stated that this study was limited by its retrospective nature, small size, single institution cohort, and lack of a matched LARS cohort to compare data. The study was designed to provide long-term data on the natural history of patients undergoing TIF for reflux treatment, considering long-term outcome data are lacking. The study design of a telephone questionnaire also was a limitation, as the authors’ ability to study other variables such as diet, weight loss, etc. that may have affected outcomes was hampered. Another limitation of the study had to do with GERD recurrence confirmation. Other than in patients undergoing conversion to LARS for TIF failure, objective testing for disease recurrence was not routine; 73% of patients resumed PPI therapy post-TIF either by PMD prescription for GERD symptom recurrence or by self-medicating with over-the-counter PPI therapy for the same without objective retesting. Hence, using the PPI resumption rate as a marker for TIF failure may lead to unreliable and artificially elevated rates of TIF failures. These investigators did think as more institutions acquire long-term data, a meta-analysis of these data would certainly increase the weight of these findings.
Fass (2019) stated that durability assessment of all endoscopic procedures is still needed, especially for the TIF and Medigus Ultrasonic Surgical Endostapler (MUSE) techniques. The value of these procedures in patients with atypical and extra-esophageal manifestations of GERD or in unique clinical scenarios, such as post-peroral endoscopic myotomy (POEM) and post-sleeve gastrectomy, also requires further research.
Nabi and Reddy (2019) noted that GERD is one of the most commonly encountered GI diseases in out-patient clinics; PPIs are the cornerstone of the treatment of GERD. However, approximately 1/3 of patients have sub-optimal response to PPIs. The management options in such cases include anti-reflux surgery or endoscopic anti-reflux treatments. Anti-reflux surgery is not popular due to its invasive nature and potential for AEs. Thus, minimally invasive endoscopic anti-reflux therapies are gaining popularity for the management of PPI-dependent and PPI-refractory GERD. These endoscopic therapies include RF application, endoscopic fundoplication modalities, and mucosal resection techniques. In appropriately selected patients, the response to these endoscopic modalities is encouraging. Unlike surgical fundoplication, endoscopic anti-reflux therapies are less likely to be associated with complications such as dysphagia and gas-bloat syndrome. On the other hand, anti-reflux surgery remains the ideal treatment in patients with a large hiatal hernia (laparoscopic Nissen fundoplication), morbid obesity (gastric bypass), and severe reflux esophagitis. The authors concluded that endoscopic treatment modalities bear the potential to narrow the treatment gap between PPIs and anti-reflux surgery. Moreover, these researchers stated that long-term follow-up studies and randomized comparison with anti-reflux surgery are needed to provide a clear understanding of the current role of endoscopic modalities in patients with PPI-refractory and PPI-dependent GERD.
The American Society for Gastrointestinal Endoscopy (ASGE, 2015) state that "Endoluminal antireflux techniques represent potentially new therapeutic indications for GI endoscopy. Prospective trials comparing these therapies with existing medical and surgical options by using objective measures of GERD as the primary endpoint could be useful in further defining the clinical role of these procedures." Specifically, regarding transoral incisionless fundoplication, the ASGE commented that most studies involving TIF have been small with short-term follow-up. The results have been variable, with poorer results observed with earlier versions of the device/technique.
Guidelines from the European Society for Gastrointestinal Endoscopy (ESGE) (Weusten et al, 2020) recommend against the widespread clinical use of transoral incisionless fundoplication (TIF) as an alternative to proton pump inhibitor therapy or antireflux surgery in the treatment of gastroesophageal reflux disease (GERD), because of the lack of data on the long-term outcomes, the inferiority of TIF to fundoplication, and its modest efficacy in only highly selected patients. ESGE said that TIF may have a role for patients with mild GERD who are not willing to take PPIs or undergo antireflux surgery. This was a strong recommendation, with moderate quality of evidence, level of agreement 92.8 %.
Snow et al (2022) stated that patients with laryngopharyngeal reflux (LPR) symptoms may not respond to PPI if they have an alternative laryngeal diagnosis or high-volume reflux. Transoral incisionless fundoplication (TIF) or TIF with concomitant hiatal hernia repair (cTIF) are effective in decreasing symptoms of GERD but are not well studied in patients with LPR symptoms. In a prospective, multi-center study, these investigators examined the patient-reported and clinical outcomes following TIF/cTIF in patients with LPR symptoms and proven GERD. Patients with refractory LPR symptoms (RSI greater than 13) and with erosive esophagitis, Barrett's esophagus (BE), and/or pathologic acid reflux by distal esophageal pH testing were examined before and after a minimum of 6 months following TIF/cTIF. The primary outcome was normalization of RSI. Secondary outcomes were greater than 50 % improvement in GERD-HRQL, normalization of esophageal acid exposure time, discontinuation of PPI, and patient satisfaction. A total of 49 patients had TIF (n = 26) or cTIF (n = 23) with at least 6 months follow-up. Mean pre- and post TIF/cTIF RSI were 23.6 and 5.9 (MD: 17.7, p < 0.001). Post TIF/cTIF, 90 % of patients had improved GERD-HQRL score, 85 % normalized RSI, 75 % normalized esophageal acid exposure time, and 80 % discontinued PPI. No serious procedure-related AEs occurred. Patient satisfaction was 4 % before TIF/cTIF and 73 % following TIF/cTIF (p < 0.001). The authors concluded that in patients with objective evidence of GERD, TIF, or cTIF was safe and effective in controlling LPR symptoms as measured by normalization of RSI and improvement in patient satisfaction following TIF/cTIF. Level of Evidence = IV.
The authors stated that this study had several drawbacks. First, there was a relatively short duration of follow-up (median of 10.5 months, maximum of 12 months). Data from the TEMPO Trial reported a sustained normalization of RSI at 5 years post-TIF; thus, these researchers would anticipate a sustained benefit in their patient population as well. Larger ongoing prospective studies will report long-term outcomes. Second, the RSI does not include some symptoms that could be attributed to LPR, such as throat pain, odynophagia, and halitosis, so these symptoms were not fully captured in this study. Nevertheless, RSI was chosen as it is a validated and widely used patient-reported outcome measure (PROM). This study included patients with LPR symptoms with objective evidence of GERD, and the results may not be generalizable to patients with LPR symptoms and/or evidence of LPR on pharyngeal pH testing who do not have an objective diagnosis of GERD. Third, there was not a formalized protocol for pre-operative laryngoscopy or stroboscopy examination by otolaryngologists. However, patients were evaluated by otolaryngologists before referral for TIF/cTIF or were referred for otolaryngology evaluation by their treating physician as deemed necessary. Fourth, these investigators reported outcomes of TIF and cTIF together because there was no significant difference in this trial’s primary endpoint of normalization of RSI. Ongoing larger long-term studies of TIF/cTIF may highlight the key advantages of surgical hiatal hernia repair in patients with specific LPR symptoms.
Stretta
Stretta System is an endoscopic radiofrequency (RF) energy delivery system that uses a special single-use catheter to deliver constant tissue temperature for collagen contraction, purportedly resulting in tissue shrinkage and tightening of the gastroesophageal junction.
The Stretta System uses radiofrequency (RF) energy to treat GERD. The procedure involves insertion of a flexible catheter with needle electrodes for energy delivery down the patient’s esophagus (patient is conscious but sedated). Precisely controlled RF energy is delivered to create lesions in the muscle of the LES and gastric cardia. The resorption of these lesions over the following weeks creates a tighter LES and a less compliant cardia. The tighter valve is thought to provide significantly increased resistance to gastric reflux. The procedure takes approximately 1 hour or less. Patients undergoing the procedure can get back to normal activities the next day.
Triadafilopoulos and Utley (2001) reported that temperature-controlled endoluminal radiofrequency energy delivery (the Stretta procedure) has been demonstrated in several studies to be safe and effective for the treatment of GERD and is a promising new technology for this chronic disorder. In a recent review, Katz (2002) noted that 2 endoscopic procedures were recently approved by the FDA for treatment of GERD: radiofrequency energy delivery to the gastro-esophageal junction, and transoral flexible endoscopic suturing. The author concluded that these techniques should be used selectively until more data are available and until results are compared to the safe and highly effective medical therapies. This is in agreement with Koop (2002) who stated that a number of new endoscopic techniques for the treatment of GERD have been developed, but the future for these is unclear.
Galmiche and des Varannes (2003) reviewed the literature on endoluminal therapies for GERD, and reached the following conclusions about the Stretta procedure:
- Although some surgeons propose use of the Stretta procedure for patients with severe, refractory, or complicated GERD, clinical studies of the Stretta procedure have excluded these patients. "Virtually all trials of these new therapeutic approaches have enrolled PPI-dependent patients without severe esophagitis. Patients refractory to PPIs, those with hiatus hernia larger than 2 cm, those with severe esophagitis, as well as obese individuals, have usually been excluded from these trials".
- No studies have involved direct comparisons with other established medical or surgical therapies.
- Some concern has also been expressed about the potential impact of these procedures on definitive management of GERD. For instance, it is possible that previous endoscopic therapy might complicate or reduce the effectiveness of subsequent procedures.
- Some severe, although very rare, complications (including perforations) have been observed, especially during early experience with the Stretta procedure.
- Studies have been short-term; the long-term effectiveness of the procedure is unknown.
- Studies of radiofrequency catheterization (Stretta) have largely been uncontrolled.
- The only controlled study (Corley, 2002) of the Stretta procedure has been published in abstract form only, and has failed to confirm that the results of uncontrolled studies regarding significant reductions in acid exposure and symptom relief.
Gamiche and des Varannes (2003) concluded: "In our opinion, endoscopic treatment for GERD needs to be done in reference centers with highly skilled staff, and not outside the framework of well-designed prospective, and appropriately controlled studies. Comparative studies of the cost-effectiveness of endoscopic therapy should include medical strategies such as intermittent or on-demand PPI therapy. Assessment of relevant outcome measures, including economic endpoints and long-term efficacy, are required before these novel approaches are used in routine practice."
Another published evidence review (Hochberger et al, 2003) reached similar conclusions about the Stretta procedure: "While many of these techniques have shown good results in preliminary studies, long-term results are not yet available and therefore all such procedures have to be considered experimental. Their effectiveness will need to be compared with that of established treatment forms."
A technology assessment of the Stretta procedure (Kahrilas, 2003), reached a similar conclusion: "Thus, within the framework of GERD subgroups discussed earlier, this author concludes that the current role of Stretta in clinical practice (circa January 2003) is as follows. Clear indications for Stretta treatment are nil because of the paucity of controlled data available, the limited follow-up currently available on treated patients, and the confusing nature of the data that are available. This opinion is in sharp disagreement with the FDA 510(k) summary statement on Stretta concluding that, "the risk-benefit profile (of Stretta) is substantially equivalent to that of fundoplication surgery." Because there are no clear indications for the procedure, it is the opinion of this author that all Stretta treatments rendered at this time should be done in the setting of clinical trials."
In a prospective, randomized trial, Coron et al (2008) compared RF (Stretta procedure) and a PPI strategy in PPI-dependent patients. Patients with PPI-dependent typical reflux symptoms were randomly allocated to either RF or PPI regimen alone. The primary endpoint, evaluated at 6-month, was defined as the possibility for the patient to stop or to decrease PPI use to less than 50% of the effective dose required at baseline. In the RF group, 18/20 patients stopped (n = 3) or decreased (n = 15) PPI use as compared to 8/16 in the PPI group (p = 0.01). None of the control patients could stop PPI. Health-related quality of life scores were not different between groups. No significant change in oesophageal acid exposure (OAE) was noted between baseline and 6-months after RF. No severe complication was reported. The authors concluded that RF energy delivery is a safe and effective therapeutic option, allowing reduction in or discontinuation of PPI therapy in patients with PPI-dependent symptoms, without loss of quality of life. However, in a majority of patients, PPI therapy can not be completely stopped. The effectiveness of RF does not seem to be related to a decrease in OAE. This was a small study with short-term follow-up. These findings need to be validated by well-designed studies with larger number of subjects and longer follow-up.
Aziz et al (2010) noted that GERD is a prevalent disorder that often requires long-term medical therapy or surgery. Radiofrequency energy delivery has been shown in several studies to improve GERD symptoms and quality of life for approximately 2/3 of patients. The authors proposed that increasing the dose of Stretta would further improve the response to this therapy. For this study, 36 patients were randomized into 3 groups:- group A; 12 patients underwent a single session Stretta procedure,
- group B; 12 patients under went a sham Stretta procedure (mirror of the active procedure in all aspects except there was no deployment of the electrodes), and
- group C; 12 patients underwent a single Stretta treatment followed by repeat Stretta if GERD health-related quality of life (HRQL) was not 75% improved after 4 months.
For each patient, 56 RF lesions were created per session. The principal outcome was GERD HRQL improvement. The secondary outcomes were medication use, LES basal pressure, endoscopic grade of esophagitis, and OAE by pH probe. The Stretta procedure was completed successfully for all the patients in both active treatment groups. At 12 months, the mean HRQL scores of those off medications, the LES basal pressure, the 24-hr pH scores, and the PPI daily dose consumption were significantly improved from baseline in both Stretta groups (p < 0.01). The double Stretta was numerically but not significantly better than the single Stretta for mean HRQL, mean 24-hr pH, mean LES pressure, and PPI use. Seven patients in the double Stretta treatment group had normalized their HRQL at 12 months compared with 2 patients in the single-treatment group (p = 0.035). The sham patients had a small but statistically significant decrease in their daily PPI dosages (p < 0.05) and mean HRQL scores (p < 0.05). No serious complications (bleeding, perforation, or death) occurred. However, 2 patients experienced significant delayed gastric emptying after the second Stretta treatment. The authors concluded that the Stretta procedure significantly reduced GERD HRQL, use of PPI drugs, OAE, LES pressure, and grade of esophagitis compared with the sham procedure. The double Stretta therapy had numerically superior outcomes for most parameters and a significantly more frequent normalization of HRQL scores compared with the single Stretta. These findings need to be validated by well-designed studies with larger number of subjects and longer follow-up.
An appraisal by the National Institute for Health and Clinical Excellence (NICE, 2009) concluded: "The evidence on safety and efficacy of endoscopic radiofrequency (RF) ablation for gastro-oesophageal reflux disease (GORD) is inadequate and there are inconsistencies in the evidence on efficacy." The Committee noted that improvements in subjective outcomes in the published series were not supported by objective outcomes (pH and pressure measurements). They also noted that symptomatic improvement may result from denervation caused by the procedure, making the lower esophagus insensitive to potentially harmful acid reflux, as opposed to true reflux control. More recently, updated NICE guidance (2013) concluded: “The evidence on the safety of endoscopic radiofrequency ablation for gastroesophageal reflux disease (GORD) 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 for clinical governance, consent and audit or research.”
Franciosa et al (2013) noted that GERD is one of the leading gastro-intestinal (GI) disorders. Current treatments include lifestyle modifications, pharmacological therapies, surgical fundoplications, and, more recently, endoscopic procedures. The rising concern of long-term side effects of the popular proton-pump inhibitors (PPIs) and the more recent evidence raising doubts about the durability of fundoplication have spurred re-interest in endoscopic procedures to treat GERD. In the aftermath of several innovative anti-reflux procedures that were introduced and failed clinically or financially over the past 10 years, there is lingering confusion regarding the merits of the presently available interventions. These investigators focused on one endoscopic procedure, Stretta, which now enjoys the longest experience, a recent meta-analysis, and robust data supporting its safety, efficacy, and durability. The authors concluded that Stretta reduces esophageal acid exposure, decreases the frequency of transient lower esophageal relaxation, increases patient satisfaction, decreases medication use, and improves quality of life (QOL). As such, this procedure remains a valuable non-surgical therapeutic option in the management of GERD.
The authors stated that one of the drawbacks of Stretta is that it has not proven to be cost-effective. In a study by Comay et al, which followed a cohort of patients for 5 years after being randomized to either once-daily PPIs therapy, fundoplication, or Stretta, this cohort was evaluated for quality-adjusted life years, symptom-free months, and cost-effectiveness. Their results showed that the PPIs procedure was the most cost-effective strategy depending on the price of omeprazole per pill. If the price of omeprazole was over $2.00 per pill, then Stretta was deemed the most cost-effective of the 3 strategies. The costs in this study were reported in Canadian dollars and based on costs in the Canadian health system. The estimated cost in this study of 5 years of PPIs use was $2,394.10, the cost of Stretta was $3,239.30, and the cost of fundoplication was $7,394.70. There is great variability in the cost of PPIs in the United States. At the time of this publication, the average retail price per pill in 1 major pharmacy chain was for $2.63 per pill omeprazole, for $4 per pill pantoprazole, and for $8.30 per pill esomeprazole. The hidden cost the patient must also take into consideration is the increasing number of side effects of PPIs that are being reported and the increasing appreciation of treatment failures. Although Stretta has been associated with 29 complications in over 15,000 cases, including 5 esophageal perforations early in its launch, no serious adverse events (SAEs) have been experienced since the modified generator and catheter in 2011 under Mederi Therapeutics were used. Gastroparesis is a side effect of Stretta. Dughera and colleagues found that only 1 out of 56 patients treated with Stretta developed gastroparesis, and this resolved in 8 weeks. Noar and colleagues showed that Stretta improved gastroparesis in a study where they followed a cohort of 31 patients with gastroparesis 6 months after Stretta and found that 74% of patients have normalization of gastric emptying. There have been more frequent cases of post-surgical gastroparesis that develops after surgical fundoplication for GERD. It is estimated that 4% to 40% of patients who undergo laparoscopic fundoplication develop intra-operative vagal damage to some degree. These investigators stated that Stretta is not for every patient with GERD. Stretta is ideal for patients with heartburn or regurgitation, patients who have adequate esophageal peristalsis, who have unsatisfactory GERD control with PPIs therapy, patients who have 24-hour pH monitoring demonstrating pathologic acid reflux, and patients who have non-erosive reflux disease or grade A or B esophagitis. Patients who are not considered good candidates for the Stretta procedure include those patients with a greater than 2 cm long hiatal hernia, patients who have significant dysphagia, patients who have grade C or D esophagitis, and patients who have inadequate esophageal peristalsis and incomplete LES relaxation with swallowing. Thus, careful patient selection is important to assure benefit from this as well as other comparable procedures.
Dughera et al (2014) stated that from June 2002 to March 2013, a total of 26 patients who underwent Stretta procedure (16 females, 10 males) reached an 8-year follow-up. Primary end-point of the study was to verify the durability of the procedure at this time. All patients underwent clinical evaluation by upper endoscopy, esophageal pressure, and pH studies. For each patient 8-year data were compared to those recorded at baseline and at 4 years. There was a significant decrease in both heartburn and GERD HRQL scores at 4 years (p = 0.001) and at 8 years (p = 0.003) as well as a significant increase of QoL scores at each control time (mental SF-36 and physical SF-36, p = 0.001). After 4 and 8 years, 21 patients (80.7%, p = 0.0001) and 20 patients (76.9%, p = 0.0001) were completely off PPIs. Median LES pressure did not show significant amelioration at 4 and 8 years and mean esophageal acid exposure significantly improved at 4 years (p = 0.001;) but returned to baseline values after 8 years. The authors concluded that this further follow-up study of from 4 to 8 years confirmed that RF energy delivery for GERD provided durable improvement in symptoms and in quality of life and reduced anti-reflux drugs consumption. Moreover, these researchers stated that these results clearly need to be confirmed in larger cohorts of patients, but, if so, it will be reasonable to recommend Stretta to the younger GERD sufferers as a “bridge therapy” between the continuous medical treatment and the optimal timing for laparoscopic fundoplication. (This was an uncontrolled, small study with 21 patients available for 4-yr follow-up and 20 patients for 8-yr follow-up).
Noar and colleagues (2014) stated that patients with GERD often seek alternative therapy for inadequate symptom control, with over 40% not responding to medical treatment. These researchers evaluated the long-term safety, efficacy, and durability of response to RF treatment (Stretta) of the lower esophageal sphincter. Using an intent-to-treat analysis, these researchers prospectively assessed 217 patients with medically refractory GERD before and after Stretta. There was no concurrent control group in the study. Primary outcome measure was normalization of GERD health-related quality of life (HRQOL) in 70% or greater of patients at 10 years. Secondary outcomes were 50% reduction or elimination of PPIs and 60% or greater improvement in satisfaction at 10 years. Successful treatment was defined as achievement of secondary outcomes in a minimum of 50% of patients. Complications and effect on existing co-morbidities were evaluated. The results of a 10-year study were reported. The primary outcome was achieved in 72% of patients (95% CI: 65 to 79). For secondary outcomes, a 50% or greater reduction in PPI use occurred in 64% of patients, (41% eliminating PPIs entirely), and a 60% or greater increase in satisfaction occurred in 54% of patients. Both secondary end-points were achieved. The most common side effect was short-term chest pain (50%). Pre-existing Barrett's metaplasia regressed in 85% of biopsied patients. No cases of esophageal cancer occurred. The authors concluded that in this single-group evaluation of 217 patients before and after Stretta, GERD HRQOL scores, satisfaction, and PPI use significantly improved and results were immediate and durable at 10 years. The major drawbacks of this study include the following:
- this was a non-randomized, single-center, open-label prospective trial;
- there was no inclusion of long-term pH and motility data, and no Nissen fundoplication (NF) comparison arm;
- due to the long study period, patient migration and associated difficulty in assessing GERD via validated questionnaires, it was difficult to collect complete 10-year data;
- the data presented were only 10-year data and perhaps 15- and 20-year data may be needed to show continued durability of response;
- not all 10-year patients had undergone final endoscopic screening, which limited the ability to definitively conclude that the procedure may influence the rate of esophageal cancer or course of Barrett’s esophagus; and
- the study did not directly address the potential cost benefits, which may merit further study.
Lipka et al (2015) noted that a RF ablation technique known as Stretta was recommended by the Society of American Gastrointestinal and Endoscopic Surgeons as an alternative treatment for GERD. However, RCTs of the effectiveness of Stretta have produced conflicting findings, and those from previous systematic reviews were compromised as a result of deficiencies in study conduct and reporting of findings. These investigators performed a systematic review and meta-analysis to evaluate all evidence on the effectiveness of Stretta for the management of GERD. They searched MEDLINE and the Cochrane Central Register of Controlled Trials (The Cochrane Library) from inception until February 28, 2014, along with other databases, for RCTs of Stretta in patients with GERD. Primary outcomes were physiologic parameters of GERD, including normalization of esophageal pH values and augmentation of lower esophageal sphincter pressure (LESP). Secondary outcomes were health-related quality of life (HRQOL) and ability to stop the use of proton pump inhibitors (PPIs). For quality assurance purposes, 2 investigators were involved throughout the study. Data were pooled under a random-effects model. The systematic review was performed as per the standards of the Cochrane collaboration. These researchers collected data from 4 trials and a total of 165 patients (153 patients were analyzed). Three trials compared Stretta vs sham, and 1 trial compared Stretta with PPI therapy. The overall quality of evidence was very low. The pooled results showed no difference between Stretta and sham or management with PPI in patients with GERD for the outcomes of mean (%) time the pH was less than 4 over a 24-hour time course, LESP, ability to stop PPIs, or HRQOL. The authors concluded that in a meta-analysis of trials, they found that Stretta for patients with GERD did not produce significant changes, compared with sham therapy, in physiologic parameters, including time spent at a pH less than 4, LESP, ability to stop PPIs, or HRQOL.
Hopkins et al (2015) commented that "published reviews of the literature are conflicted in their recommendations of Stretta in the management of GERD. The literature suggests that the Stretta procedure has an acceptable safety profile and may be effective in reducing symptom burden and quality of life scores up to 8 years post-intervention. However, there does not appear to be any sustained improvement in objective outcomes and there is no evidence that Stretta results in improved outcomes as compared to surgical intervention."
A clinical trial on “Stretta In Reflux Uncontrolled by IPP (SIRUP)” that is currently recruiting participants. This trial is designed to compare the Stretta procedure and the sham procedure efficiency 6 months post-procedure in reflux uncontrolled by intake of inhibitors of protons pump (IPP) patients. (Last verified 4/2014).
Kalapala et al (2017) noted that GERD is the most common chronic GI disorder, affecting 1/3 of the population worldwide. Recently, there has been a renewed interest in Stretta therapy in view of potential long-term side effects of PPIs and the durability of relief with fundoplication. In a prospective, randomized study, these researchers compared the Stretta treatment with controls receiving PPIs. Patient (greater than 18 years, n = 20) with symptoms of heartburn, regurgitation, abnormal esophageal acid exposure (greater than or equal to 4 %), and endoscopically confirmed esophagitis were included into the study. The primary measure was improvement in QOL and decrease in the frequency and severity of GERD symptoms. The mean age of the patients was 39 (± 15) years and controls were 34 (± 11) years. Three months after Stretta, 80 % reported improvement in QOL compared to 40 % in the control group. At the end of 3 months, significant (p < 0.05) improvement in GERD symptom score for heartburn, regurgitation, chest pain, and cough compared with the control group was observed. After Stretta treatment, 60 % of the patients were free of PPIs whereas there was no change in the control group. Almost 80 % of the patients on Stretta treatment were satisfied with the treatment compared to 30 % of the patients in the control group. The authors concluded that Stretta was effective in the short-term for the management of GERD. This was a small study (n = 20) that provided interim (1-year) analysis; its findings need to be validated by well-designed studies.
The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) clinical spotlight review on “Endoluminal treatments for gastroesophageal reflux disease (GERD)” (Dimitrios et al, 2017) stated that “Based on existing evidence, Stretta significantly improves health related quality of life score, heartburn scores, the incidence of esophagitis, and esophageal acid exposure in patients with GERD, but does not increase lower esophageal sphincter basal pressure. In addition, it decreases the use of PPI by approximately 50 %. The effectiveness of the procedure diminishes some over time, but persistent effects have been described up to 10 years after the procedure in appropriately selected patients with GERD. Stretta is more effective than PPI, but less so than fundoplication. Stretta is safe in adults and has a short learning curve.
Coronel and associates (2018) stated that endoscopic anti-reflux treatments for GERD are still evolving, and most of the published studies address symptom relief in the short-term. These investigators performed a systematic review and meta-analysis focused on evaluating the efficacy of the different endoscopic procedures. Search was restricted to RCTs on Medline, Cochrane, SciELO, and Embase for patients with chronic GERD (greater than 6 months), over 18 years old and available follow-up of at least 3 months. The main outcome was to evaluate the efficacy of the different endoscopic treatments compared to sham, pharmacological or surgical treatment. Efficacy was measured by different subjective and objective outcomes. These researchers analyzed data from 16 RCT, totaling 1,085 patients. The efficacy of endoscopic treatments compared to sham and PPIs treatment showed a significant difference up to 6 months in favor of endoscopy with no heterogeneity (p < 0.00001) (I2: 0%). The subgroup analysis showed a statistically significant difference up to 6 months in favor of endoscopy: endoscopy versus PPI (p < 0.00001) (I2: 39%). Endoscopy versus sham (p < 0.00001) (I2: 0%). Most subjective and objective outcomes were statistically significant in favor of endoscopy up to 6 and 12 months follow-up. The authors concluded that the findings of this systematic review and meta-analysis showed a good short-term efficacy in favor of endoscopic procedures when comparing them to a sham and pharmacological or surgical treatment. However, they stated that long-term follow-up data are lacking and this should be examined in future studies.
Khidir and colleagues (2018) stated that GERD occurs de-novo or intensifies after sleeve gastrectomy (SG). These researchers evaluated the safety and efficacy of Stretta treatment post-LSG GERD, QOL, and PPI dose up to 6 months. They carried out a retrospective review of all patients' data who underwent Stretta procedure in their center. Demographics, pre-Stretta lower esophageal manometry, 24-hr pH monitoring, endoscopic and radiological findings, GERD symptoms using HRQOL questionnaire, and PPI doses at 0, 3, and 6 months were reviewed. A total of 15 patients had an initial BMI of 44.4 ± 9 kg/m2. Pre-Stretta BMI was 29.7 ± 6.3 kg/m2 with an EWL% of 44 ± 21.4%. Pre-Stretta endoscopic reflux esophagitis was found in 26.7%, and barium imaging showed severe reflux in 40%. The mean DeMeester score was 27.9 ± 6.7. Hypotensive LES pressure occurred in 93.3% of patients. Patients' mean HRQOL scores were 42.7 ± 8.9 pre-Stretta and 41.8 ± 11 at 6 months (p = 0.8); 1 case (6.7%) was complicated by hematemesis. At 6 months, 66.7% of patients were not satisfied, though the PPI medications were ceased in 20%; 2 patients (13.3%) underwent Roux-en-Y gastric bypass (RYGB) at 8 months post-Stretta to relieve symptoms. The authors concluded that the Stretta procedure did not improve GERD symptoms in patients post-SG at short-term follow-up, and about 6.7% complication rate was reported. Patients were not satisfied despite the decrease in PPI dose.
de Souza et al (2018) presented the first cases of endoscopic therapy for the treatment of GERD conducted in Brazil. This study entailed the use of RF with the Stretta procedure in symptomatic volunteers diagnosed with GERD. The technique was carried out in 3 patients. No patient had complications, and all patients were discharged on the same day, either without medication or taking it sporadically for symptom control. The authors concluded that endoscopic treatment for GERD using RF was effective in the cases presented with no technical complications. This was a small study (n = 3) and presented no follow-up data.
Viswanath et al (2019) noted that Stretta offers a therapeutic alternative for patients suffering from refractory GERD. Current evidence suggests that the treatment may improve symptoms of GERD and decrease requirement for PPI therapy. These investigators performed a prospective assessment of patients undergoing Stretta, between October 2014 and February 2016, in a U.K. tertiary referral center. All patients were examined for suitability using endoscopy, contrast studies, and pH and manometry studies. The GERD-Health-Related QOL (GERD-HRQL) was used to evaluate symptoms along with PPI dependency, pre-Stretta and post-Stretta treatment. Patients were followed-up by outpatient clinic appointment and telephone consultation. A total of 50 consecutive patients were followed-up for a median of 771 days (range of 499 to 1,162) following treatment with Stretta. The average GERD-HRQL score improved from 46.2/75 (± 14.2) pre-procedure to 15.2/75 (± 17.3) post-procedure. Dissatisfaction with GERD as measured in the GERD-HRQL decreased from 100 % to 10 % with 3 patients showing no improvement (non-responders) at follow up and 2 late failures at the time of this review. There were no complications; and all cases were performed as day cases. The authors concluded that there are currently few effective therapeutic alternatives to anti-reflux surgery for refractory GERD. This series corroborated the value and safety of Stretta as a viable option for selected patients who are unwilling or unable to undergo an operation. Stretta improved QOL and decreased PPI dependency in selected patients with GERD. These researchers stated that limitations of this study included its small numbers (n = 50) and pre-Stretta assessments were performed by various teams from all over the U.K. prior to the original referral.
Viswanath and Nevins (2020) noted that endoscopic anti-reflux radio-frequency therapy (STRETTA) is a NICE-approved treatment for the treatment of GERD. To obviate poor outcomes, there is a need for clinicians to select suitable patients who are likely to benefit. There are no published endoscopic scores, for use before endoscopic anti-reflux therapy, which predicts an outcome. These researchers produced an endoscopic score that predicts good outcome following STRETTA for GERD. All patients undergoing STRETTA therapy between July 2017 and January 2018 were scored at the time of their pre-STRETTA endoscopy by an expert endoscopist. The following criteria made up the score: Crural insufficiency; z line displacement; prolapse of the stomach; preservation of angle of His; depth of the fundus from gastro-esophageal junction (GEJ); on retroversion; erosive esophagitis. Patients were then independently scored by a specialist Upper GI trainee to ensure reproducibility. GERD Health-Related Quality of Life Questionnaires were obtained before STRETTA, and again at 12 months. Statistical analysis was performed comparing pre-STRETTA endoscopic scores and patients reported outcomes. A total of 19 patients were analyzed, 15 patients reported improvement in the symptom scores and 12 of then expressed full satisfaction at 12 months. There was no significant difference between scores produced by both endoscopists (> p.0.05), confirming reproducibility. No single endoscopic criterion was predictive of good outcome (p > 0.05). However, group A (completely satisfied) patients had significantly lower total scores than group B (improved and non-improved) patients, 3.42 versus 6.43 (p = 0.012). ROC curve analysis demonstrated a score less than or equal to 5 is likely to produce a good outcome (92 % sensitivity, 71 % specificity). The authors concluded that this is a novel endoscopic assessment score that may predict a successful outcome in patients undergoing STRETTA for GERD. They stated that this requires prospective validation in a new cohort of patients; this is ongoing. The authors stated that this study had several drawbacks. These researchers have only used a small number of patients (n = 19), and the score has not yet been prospectively validated (this is ongoing). However, this was the 1st study aiming to establish pre-procedure predictive factors as to who is likely to benefit from STRETTA therapy in order to improve outcomes and cost-effectiveness.
Sowa and Samarasena (2020) stated that GERD is the most frequent outpatient diagnosis in the U.S. There has been significant development in the endoscopic treatment of GERD, with several devices that have reached the market. One of the endoscopic devices for the management of GERD in the U.S. is the Stretta system. This procedure uses RF energy, which is applied to the muscles of the LES and the gastric cardia resulting in an improvement of reflux symptoms. The authors examined the most recent data on the safety, effectiveness, and mechanisms of action (MOA) of this procedure. These researchers stated that the underlying MOA of Stretta is unclear and controversial; but likely does not involve tissue fibrosis.
Ma et al (2020) noted that outcomes of GERD using Toupet fundoplication (TF) and Stretta radiofrequency (SRF) have not been compared. In a retrospective, single-center study, these researchers compared therapeutic efficacy of the 2 methods. This trial analyzed a total of 230 patients undergoing TF or SRF at the authors’ hospital. Baseline data, reflux symptoms, the DeMeester scores, LES pressure and AEs were compared over a 1-year period. A total of 226 patients were included in the study. The time and frequency of reflux and percentage of reflux time before and 12 months after therapy were not significantly different. There were significantly interactions between the therapy method and follow-up time on the DeMeester score and LES pressure. Twelve months post-therapy, the DeMeester score was significantly higher in SRF than in TF group, while the LES pressure was lower. At 12 months after therapy, multi-variate Cox proportional regression analysis showed that reflux frequency, the DeMeester score and LES pressure were risk factors for poor prognosis in TF group, while reflux frequency and the DeMeester score, and LES pressure were risk factors for poor prognosis in SFR group. The authors concluded that compared with TF, SFR could significantly improve the esophageal pH and pressure in GERD patients without increasing the risk of poor prognosis.
The authors stated that this study had several drawbacks. It was retrospective, single-center study with limited number of participants and relatively short follow-up time. The many adverse reactions and events may have not been included and only a few factors have been analyzed for their impact on prognosis. These researchers stated that large-scale, multiple-center studies with longer follow-up are needed to validate these findings.
He et al (2020) compared the Stretta procedure with PPIs for the treatment of non-erosive reflux disease (NERD). From July 2018 to April 2019, patients diagnosed with NERD and referred for treatment were enrolled. They were treated with either Stretta procedure or PPIs and followed-up for 6 months. The symptom control, QOL, lower esophageal sphincter (LES) pressure, 24-hour pH parameters, PPI usage and satisfaction rate were evaluated. The complications were assessed. The outcomes of the 2 groups were analyzed and compared. A total of 28 patients in the Stretta group and 21 patients in the PPI group completed the 6-month follow-up. No severe adverse events (AEs) occurred in either group. Both interventions were effective in improvement of symptom and QOL. The symptom score improvement was significantly superior in the Stretta group compared to the PPI group (6.3 ± 3.4 versus 8.5 ± 4.1, p = 0.03). LES pressure increased significantly in the Stretta group compared to the PPI group (14.2 ± 4.4 mm Hg versus 10.0 ± 4.0 mm Hg, p < 0.01). Although both interventions improved 24-hour pH parameters, including number of acid episodes (p = 0.27), acid exposure time (p = 0.39), and DeMeester score (p = 0.28), no difference was found between the 2 groups. Complete PPI cessation rate (82 % versus 52 %, p = 0.03) as well as satisfaction rate (89 % versus 57 %, p = 0.02) was much higher in Stretta group than those in the PPI group. The authors concluded that the Stretta procedure was safe and effective in the short-term for the management of NERD. The Stretta procedure resulted in higher LES pressure and achieved better improvement of symptom control and PPI cessation than did PPI in the short-term. Moreover, these researchers stated that a multi-center, randomized, controlled trial (RCT) with a larger sample size and long-term follow-up is needed to reach a conclusion regarding the superiority of the Stretta procedure for the management of NERD.
The authors stated that a major drawback of this trial was that it was a single-center, uncontrolled, non-randomized study, which made it impossible to control for baseline demographics. Although all of the patients underwent either the Stretta procedure or PPI therapy, the methods of therapy were not randomly chosen. In fact, the small number of enrolled patients and the intention of the patients to undergo the Stretta procedure did not allow these researchers to perform any kind of randomization. However, all of the patients included in the study were well-defined and homogenous. Another drawback of the study was its small sample size (n = 28 in the Stretta group) and the loss of subjects during follow-up. Only 87.5 % of patients completed the 6-month follow-up. However, the results were promising as there were few previous Chinese data that compared the Stretta procedure with PPI treatment for the management of NERD.
Xie et al (2021) stated that both transoral incisionless fundoplication (TIF) and Stretta are representative endoscopic treatments for GERD; however, they have not been directly compared. In a systematic review and network meta-analysis (NMA), these researchers evaluated the comparative effects of Stretta, TIF, and PPIs. PubMed, Cochrane Central Register of Controlled Trials, Web of Science, and Embase were searched for RCTs that compared the efficacy of either the Stretta, TIF, or PPIs/sham procedure for GERD treatment. The NMA was conducted using frequentist methods. A total of 516 participants from 10 RCTs were included in this NMA. Both Stretta (mean difference [MD] - 9.77, 95 % confidence interval [CI]: - 12.85 to - 6.70) and TIF (MD - 12.22, 9 5% CI: - 15.93 to - 8.52) were significantly superior to PPIs at improving HR-RQL scores and heartburn scores (Stretta: MD - 1.53, 95 % CI: - 2.98 to - 0.08; TIF: MD - 9.60, 95 % CI: - 17.79 to - 1.41). Stretta (MD - 3.77, 95 % CI: - 6.88 to - 0.65) was less effective at increasing LES pressure than TIF. Stretta was significantly superior to TIF (MD - 3.25, 95 % CI: - 5.95 to - 0.56) at improving esophageal acid exposure. Regarding the decrease in PPIs utility and esophagitis incidence, no significant differences were found between TIF and Stretta. The authors concluded that in terms of short-term reduction of the HR-RQL score and heartburn score in patients with GERD, TIF and Stretta may be comparable to each other, and both may be more effective than PPIs. TIF may increase the LES pressure in comparison with Stretta and PPIs. PPIs may reduce the percentage of time pH < 4.0 when compared with TIF. This evidence should be interpreted with caution given the small number of included studies and inherent heterogeneity.
Nevins et al (2021) noted that Stretta improves the QOL and reduces the need for anti-reflux medication in select patients, especially those with uncomplicated GERD. These investigators reviewed the outcomes of Stretta in patients with medically refractory GERD, who had undergone previous gastric surgery. This was a review of a prospective database in a British center. Since 2016, all GERD patients who underwent Stretta and had a history of previous gastric surgery were studied (n = 11). Anti-reflux medication pre- and post-Stretta was evaluated. The outcomes were assessed objectively by the change in anti-reflux medication and subjectively through a pre- and post-procedure HR-RQL questionnaire. The median length of follow-up was 23 months. A total of 9 patients demonstrated improved GERD-HRQL scores following Stretta (82 %). Of the 7 patients who underwent fundoplication, all reported improved symptoms, with 3 patients discontinuing the medication and 3 patients on a reduced dose of PPI; 4 patients underwent surgery other than fundoplication, of which 2 reported improvement and discontinued the PPI; 2 patients reported no improvement. The authors concluded that the findings of this study demonstrated that Stretta was successful in reducing refractory GERD in patients with previous gastric surgery. The outcomes were comparable to published outcomes in patients with uncomplicated GERD with no previous history of gastric surgery.
The authors stated that the small sample size (n = 11) was a limitation of this case series. Nevertheless, although STRETTA is not routinely used for recurrent or primary GERD after gastric surgery, these researchers believed this was the 2nd-largest cohort of patients on this topic. Another limitation was the lack of post-operative pH or manometry studies to help establish reasons for the success or failure of the Stretta procedure. These tests are not routinely performed post-operatively at the authors’ center. This was an initial study that demonstrated that Stretta was safe and likely to be beneficial in this cohort; however, further research is needed to predict treatment success. This includes correlation with additional measures for GERD-HRQL, such as symptom index or symptom association probability.
Enteryx
In addition to the EndoCinch and Stretta procedures, there are other endoscopic procedures being evaluated for the treatment of GERD. Enteryx (Boston Scientific Corp, Natick, MA) is a chemically inert, non-carcinogenic, hypoallergenic, non-antigenic, radio-opaque compound that is available in a liquid organic state but becomes solid on hydration (or placement in tissue). It has been used in the treatment of arterio-venous malformations, peripheral vascular disease, and hypervascular head and neck cancers. It can be injected into the LES under fluoroscopic and endoscopic guidance. The endoscopist can ensure that the injections are into the muscular layer because a ring appears at the LES on radiograph. This ring persists as long as the material is in the LES. On April 22, 2003, Enteryx was approved by the FDA for the treatment of patients with GERD who require and respond to PPIs. The pre-market approval (PMA) of Enteryx was recommended by the Gastroenterology and Urology Devices Advisory Panel of the FDA with 10 conditions including a post-market study to be performed as a placebo-sham controlled trial that also examine the effects of re-treatment.
In a pilot study of patients with GERD who required continuous therapy with a PPI (n = 15), Deviere et al (2002) examined the safety and effectiveness of Enteryx (ethylene-vinyl-alcohol polymer) in the management of these patients. Enteryx was injected into the muscle of the gastric cardia. Primary endpoints were the safety of the procedure, the effect on LES pressure and the stability of the injected material. A secondary endpoint was the effect on heartburn score after discontinuation of treatment with a PPI. The authors concluded that Enteryx implantation in the muscle of the cardia is feasible and safe. It leads to a sustained increase in resting LES pressure. This is associated with a sustained improvement in heartburn score for patients who previously required continuous therapy with a PPI. The authors stated that further studies are needed to delineate the potential clinical applications and long-term outcomes of this technique.
In a multi-center, single-arm study (n = 85), Johnson and associates (2003) evaluated the safety and effectiveness of Enteryx for the treatment of GERD. These patients had heartburn symptoms that were responsive to PPI therapy. At 6 months following Enteryx implantation, PPI use was eliminated in 74% and reduced by greater than 50% in 10% of patients. Mean total esophageal acid exposure time was 9.5% pre-therapy and 6.7% at 6 months. Mean LES length increased from 2.0 cm at baseline to 3.0 cm post-therapy. There were no clinically serious adverse events. Transient mild-to-moderate chest pain commonly occurred after implantation. These investigators concluded that endoscopic implantation of Enteryx is a safe and effective therapy for eliminating or decreasing the need for PPI medications, improving GERD symptoms and patient quality of life, and decreasing esophageal acid exposure among patients suffering from GERD. The authors stated that studies evaluating the benefits of Enteryx implantation compared with sham procedures as well as those that examine the long-term effectiveness and durability of Enteryx are in progress.
Although many patients had improvements in their symptoms and medication requirements, objective evaluations of the esophagus performed during the clinical trial showed evidence of persistent acid reflux in 61% of patients and low-grade inflammation in 37% of patients at 12 months. The most common adverse event observed in patients undergoing Enteryx treatment was pain beneath the breastbone that usually diminished within 2 weeks. Other common side effects included temporary difficulty with swallowing (20%), fever (12%), sore throat (11%), and gas/bloating/belching (7%).
Current evidence for the use of Enteryx is limited to pilot studies as well as small trials that lack appropriate control groups and long-term follow-up data. Thus, the clinical value of Enteryx is uncertain at this time. It should be noted that the FDA has issued a warning to physicians to stop using Enteryx because it has been connected to serious health problems and, in at least 1 case, death. On September 23, 2005, Boston Scientific Corporation initiated a voluntary recall of all Enteryx procedure kits and Enteryx single pack injectors because of reports that improper injection procedures can lead to serious patient injury and death.
An assessment conducted by the National Institute of Clinical Excellence (2004) concluded that current evidence on the safety and efficacy of endoscopic injection of bio-compatible polymer for GERD does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research. This is in agreement with that of 2004 Blue Cross Blue Shield Technology Evaluation Center (TEC)’s assessment on transesophageal endoscopic treatments for GERD, which stated that endoscopic suturing, radiofrequency energy delivery, or implantation of inert polymers for treatment of GERD do not meet the TEC criteria.
Gatekeeper
More recently, the National Institute for Health and Clinical Excellence (NICE, 2007) evaluated the Gatekeeper Reflux Repair System (Medtronic, Minneapolis, MN), a hydrogel prosthesis that is implanted endoscopically into the LES. The NICE guidance concluded that there is limited evidence of short-term efficacy on endoscopic augmentation of the LES using hydrogel implants for the treatment of GERD. This evidence also raises concerns about the procedure’s safety. "Therefore, this procedure should not be used without special arrangements for consent and for audit." The Gatekeeper Reflux Repair System clinical program was suspended in late 2005 before FDA approval due to concerns over efficacy.
The AGA's institute medical position statement on the use of endoscopic therapy for GERD (Falk et al, 2006) stated that "most studies of endoscopic therapy have only limited follow-up information of a relatively small number of patients. Thus, the durability of these technologies beyond 1 to 2 years remains unclear. Short-term and long-term safety issues are unresolved, but serious adverse events led to the voluntary withdrawal of Enteryx by the manufacturer in September 2005 and suspension of the Gatekeeper clinical program in late 2005. The economics of all techniques for the patient, practitioner, and society are unknown. While newer devices and improvements in endoscopic antireflux techniques may yield better and more durable treatment outcomes, current data suggest that there are no definite indications for endoscopic therapy for GERD at this time. Both practitioners and patients need to be aware of the limitations in the evidence that exist with these devices at present".
Spicak (2007) stated that 3 types of endoscopic methods in several modifications have been developed for the treatment of GERD:- radiofrequency therapy (Stretta procedure) is available both in Europe and the United States and more than 5,000 patients have been treated to date;
- injection therapy requires the injection of bulking agents or implantation of bioprosthesis into the LES zone. Both Enteryx was withdrawn from the market in 2005, and Gatekeeper was suspended before FDA approval;
- suturing/plication therapy is based on the plication at the level of the LES, and most of all techniques resemble the principle of surgical treatment.
Despite sophisticated technologies and promising short-term results, all these techniques are associated with inconsistencies, controversies, and relevant adverse affects. According to current practice, use of endoscopic methods is justifiable only as part of clinical trials.
In a prospective, randomized, sham-controlled, single-blinded, international multi-center study, Fockens et al (2010) evaluated if endoscopic implantation of an injectable esophageal prosthesis, the Gatekeeper Reflux Repair System (GK), is safe and effective for controlling GERD. A total of of 204 patients were assigned to 3 groups:
- 60 lead-in,
- 96 GK, and
- 48 sham patients.
The sham patients were allowed to cross-over to the GK treatment arm or exit the study at 6 months. The primary end points were
- reduction in serious device- and procedure-related adverse device effects compared with a surgical composite complication rate, and
- reduction in heartburn symptoms 6 months after the GK procedure compared with the sham procedure.
The secondary end point was improved esophageal pH (total time pH was less than 4) 6 months after the GK procedure compared with baseline. A planned interim analysis was performed after 143 patients were enrolled (25 lead-in, 75 GK, and 43 sham patients), and the GK study was terminated early due to lack of compelling efficacy data. Four reported serious adverse events had occurred (2 perforations, 1 pulmonary infiltrate related to a perforation, and 1 severe chest pain) at termination of the study with no mortality or long-term sequelae. Heartburn symptoms had improved significantly at 6 months compared with baseline in the GK group (p < 0.0001) and the sham group (p < 0.0001), but no significant between-group difference in improvement was observed (p = 0.146). Esophageal acid exposure had improved significantly at 6 months compared with baseline in the GK group (p = 0.021) and the sham group (p = 0.003), but no significant between-group difference in improvement was observed (p = 0.27). The authors concluded that the GK procedure was associated with some serious but infrequent complications. No statistically significant difference in outcomes was observed between the treatment and control groups at 6 months compared with baseline.
Durasphere
In a pilot study, Ganz et al (2009) evaluated the long-term safety and effectiveness of Durasphere (Carbon Medical Technologies, St Paul, MN), a new injectable bulking agent, in the treatment of mild-moderate GERD. A total of 10 GERD subjects, confirmed by pH monitoring, on daily PPI therapy, hiatal hernia less than 3 cm, and no or mild erosive esophagitis were enrolled in this study. Subjects received endoscopic injection with Durasphere at the gastro-esophageal junction. Outcome measures included change in symptom scores, PPI use, pH scores, and endoscopic findings; safety profile was monitored. Nine of 10 patients completed the 12-month trial. There were no adverse events. The procedure was well-tolerated with minimal patient discomfort and no dysphagia. At 12 months 70% of patients discontinued all antacid medication completely; 90% of patients reduced PPI use by greater than 50%. DeMeester scores improved from a mean of 44.5 at baseline to 26.5 at 12 months; 4 patients achieved normal pH scores. There was no esophagitis at 12 months, and no erosion, ulceration or sloughing of material was noted at any injection site. The Durasphere material did not appear to migrate. The authors concluded that Durasphere appears to be a promising new injectable bulking agent for the treatment of mild-moderate GERD, with demonstrable efficacy and no significant adverse events in a small cohort. Drawbacks of this study were its non-randomized study design without a control group and small number of subjects.
Plexiglas Polymethylmethacrylate (PMMA) Microbeads
Feretis et al (2001) noted that a gelatinous implant containing polymethylmethacrylate (PMMA) beads is successfully used to augment the diminished thickness of the chorium in patients with skin defects and wrinkles. These investigators examined if submucosal injection of PMMA microspheres into the lower esophageal folds decreases the severity of symptoms and acid reflux in patients with GERD. Endoscopic submucosal implantation of PMMA was carried out in 10 patients with GERD who were either refractory to or dependent on PPIs. Symptom severity score, 24-hour pH monitoring, upper GI endoscopy, and endoscopic ultrasonography were performed to evaluate the efficacy of implantation. A significant decrease in the symptom severity score and mean total time with esophageal pH less than 4 was noted after the implantation of PMMA (p < 0.05); 7 of 10 patients were taking no medication after PMMA implantation. There were no serious procedure-related complications. The authors concluded that endoscopic implantation of PMMA into the submucosa of the lower esophageal folds may be a new method for treating GERD. Moreover, they stated that further studies are needed to determine the long-term effectiveness of the procedure.
Neuhauser et al (2003) stated that therapeutic options for GERD include lifestyle modifications, medical therapy, laparoscopic anti-reflux surgery, and 3 more recent options:- injection therapy to the LES,
- endoscopic sewing procedures, and
- radio frequency ablation therapy.
Medical therapy is effective in most patients but not always successful with advanced disease. Up to 70% of subjects do not have adequate nocturnal control of gastric acid secretion with 20 mg of omeprazole given twice-daily. Patients who do not tolerate medical therapy, who respond inadequately, or who want to avoid life-long drug therapy are candidates for alternate treatments. Studies on endoscopic procedures such as PMMA injection, the Stretta procedure, and endoscopic suturing techniques all suffer from having small study groups for each procedure, unknown durability, short follow-up, and the absence of randomized, controlled trilas. Limitations on endoscopic techniques are esophageal motility disorders, severe esophagitis, and larger hiatal hernias. Laparoscopic anti-reflux surgery remains a well-established, durable alternative to long-term medical therapy. It has the benefits of convenience, safety, minimal complications, improved quality of life, and low cost. Alternative methods will have to earn their place against this gold standard.
Plicator
The Plicator System (NDO Surgical Inc., Mansfield, MA) is another new treatment option for GERD. It consists of the reusable Plicator instrument, a single-use cartridge containing a suture-based implant, and a specially designed endoscopic tissue retractor. This system allows the physician to create a full-thickness plication at the gastro-esophageal junction, permitting serosa-to-serosa tissue healing and a re-structuring of the normal anti-reflux barrier. The Plicator procedure is an outpatient procedure performed using direct endoscopic visualization and under conscious sedation. The Plicator System was cleared by the FDA in April 2003 through a 510(k) application. The most common side effect associated with the Plicator procedure is pharyngitis (41%), which resolved spontaneously within several days after the procedure.
There is only limited clinical data on the effectiveness of the Plicator System. In a pilot study, Chuttani et al (2003) reported that full-thickness plication (the Plicator procedure) was performed successfully in 6 of 7 patients, with 1 procedure aborted because of difficulty in sedating the patient. Mean procedure time was 21 mins. Mild epigastric pain was reported by 2 patients and difficulty with eructation by 1 patient; all symptoms resolved spontaneously within 7 days of the procedure. Endoscopy at 6 months revealed an intact plication in all patients. At 1 year after the procedure, patients reported sustained reduction in heartburn scores. One patient, who did not experience significant relief of symptoms, ultimately underwent successful laparoscopic Nissen fundoplication at 6 months after the procedure. At 1 year after the procedure, 3 of 5 patients were not taking anti-GERD medications. The authors concluded that endoscopic full-thickness plication is feasible, safe and, and appeared to reduce symptoms and medication use associated with GERD. Findings of this study need to be validated by prospective, randomized controlled studies.
An assessment prepared for the California Technology Assessment Forum (CTAF) concluded that the Stretta, Endocinch, and Enterx endoluminal treatments for GERD do not meet CTAF's assessment criteria (Feldman, 2004). The assessment explained that, in the case of Enterx and Bard EndoCinch, the current literature does not include any randomized trial data, so it is not possible to fully evaluate the safety and efficacy of these procedures. In addition, with the Bard EndoCinch, questions remain about the safety of the procedure and the training required to perform it under conditions of routine clinical practice. CTAF found that, although the Stretta procedure had been evaluated in a randomized, controlled clinical trial (Corley et al, 2003), the trial did not enroll patients who were refractory to medical therapy, so it is not possible to conclude from this trial if Stretta will be an acceptable alternative to surgery for patients with refractory symptoms on appropriate medical therapy. Although the study showed that the Stretta procedure was successful in returning patients back to a similar level of symptoms they had at baseline on medications, the procedure did not improve esophageal acid exposure, esophageal erosions or LES pressure, all presumably risk factors for developing later complications from GERD. The assessment found that it does not seem advisable to recommend that patients discontinue a safe and effective treatment that has been proven to reduce acid exposure (i.e., medications) in favor of one that does not (Stretta).
Ozawa et al (2005) stated that endoscopic treatments (e.g., the EndoCinch method, the NDO Plicator method, the Wilson-Cook Medical's Endoscopic Suturing Device, the Stretta System, the Enteryx procedure, and Medtronic's Gatekeeper Reflux Repair System) for GERD are still in the development phase. They further noted that the safety, effectiveness, durability, cost-effectiveness, indications of endoscopic treatments, and possible combination with other treatments must be thoroughly evaluated in randomized controlled trials. This is in agreement with the observations of Annese et al (2005) who stated that the use of endoscopic treatment for GERD should be limited to clinical trials, which should incorporate the provision of comprehensive and unbiased information to study patients as well as de Hoyos and Fernando (2005) who noted that endoscopic therapies for GERD are being rapidly introduced, despite lack of long-term follow-up and randomized trials.
Rothstein et al (2006) examined the effectiveness of endoscopic full-thickness plication for the treatment of GERD in comparison with a sham procedure. Patients with symptomatic GERD requiring maintenance PPI therapy were entered into a randomized, single-blind, prospective, multi-center trial. A total of 78 patients were randomly assigned to undergo endoscopic full-thickness restructuring of the gastric cardia with transmural suture, while 81 patients underwent a sham procedure. Group assignments were revealed following the 3-month evaluation. The primary end point was greater than or equal to 50% improvement in GERD HRQL score. Secondary end points included medication use and esophageal acid exposure. By intention-to-treat analysis, at 3 months, the proportion of patients achieving greater than or equal to 50% improvement in GERD-HRQL score was significantly greater in the active group (56%) compared with the sham group (18.5%; p < 0.001). Complete cessation of PPI therapy was higher among patients in the active group than in the sham group by intention-to-treat analysis (50% versus 24%; p = 0.002). The percent reduction in median percent time pH less than 4 was significantly improved within the active group versus baseline (7 versus 10, 18%, p < 0.001) but not in the sham group (10 versus 9, -3%, p = 0.686). Between-group analysis revealed the active therapy to be superior to the sham in improving median percent time pH less than 4 (p = 0.010). There were no perforations or deaths. The authors concluded that endoscopic full-thickness plication more effectively reduces GERD symptoms, PPI use, and esophageal acid exposure than a sham procedure.
An editorial (Shaheen, 2006) accompanying the study by Rothstein and colleagues outlined the limitations of the study. It stated that the Plicator procedure shows promise as a treatment option for patients with mild GERD seeking an alternative to long-term acid-suppressive therapy. Furthermore, Shaheen stated there are issues to be dealt with concerning the acceptance of endoscopic anti-reflux devices such as safety, efficacy and durability. In regards to the study, Shaheen also stated that some head-to-head data with alternative treatment measure would be helpful. No study has truly compared the results of PPI therapy to endoscopic anti-reflux devices. Shaheen concluded that the study still leaves uncertainty as to where to position endoscopic anti-reflux procedures in the patient with GERD. Since there is a lack of data, there is no claim to superiority, or even equivalency, of these devices to the best medical or surgical therapy for GERD. Until the questions regarding safety, efficacy, and durability outlined above become clearer, the routine use of these devices in PPI responsive patients outside the realm of clinical studies can not be recommended.
In an open-label, prospective, multi-center study, von Renteln and colleagues (2008) evaluated the safety and effectiveness of placing multiple transmural sutures for the treatment of GERD. Subjects with symptomatic GERD who require daily maintenance PPI therapy. Study exclusions were hiatal hernia greater than 3 cm, grades III and IV esophagitis, Barrett's epithelium, and esophageal dysmotility. A total of 41 patients received 2 or more transmural sutures placed linearly in the anterior gastric cardia approximately 1 cm below the gastro-esophageal junction. Six months following the procedure, median GERD-health-related quality of life (HRQL) improved 76% compared with off-medication baseline (6.0 versus 25.0, p < 0.001), with 75% of patients (32/40) achieving over 50% improvement in their baseline GERD-HRQL score. Six months after the procedure, daily PPI therapy was eliminated in 70% of patients (28/40). Heartburn symptoms improved 80% compared with off-medication baseline (16.0 versus 84.0, p < 0.001). Median esophagitis grade improved 75% compared with baseline (0.0 versus 1.0, p = 0.005). Esophageal pH assessed as median distal esophageal-acid exposure (percentage time pH less than 4.0) improved 38% compared with baseline (9.0 versus 11.0, p < 0.020; nominal p value for a single statistical test: significance removed upon the Bonferroni adjustment for multiple testing of data) and manometric outcomes were also improved compared with baseline (median LES resting pressure improved 25% [10.0 versus 6.0, p < 0.017; nominal p value for a single statistical test: significance removed upon the Bonferroni adjustment for multiple testing of data]) and median amplitude of contraction improved 11% (70.0 versus 62.0, p < 0.037; nominal p value for a single statistical test: significance removed upon the Bonferroni adjustment for multiple testing of data). The authors concluded that endoscopic full-thickness plication with multiple serially placed implants was safe and effective in reducing GERD symptoms, medication use, esophageal-acid exposure, and esophagitis. The limitations of this study were small sample size, and a lack of randomized comparison with a single implant group.
Angelchik Anti-Reflux Prosthesis
The Angelchik anti-reflux prosthesis was approved (PMA) by the FDA in 1979. It is a soft, collar-shaped, silicone elastomer shell filled with silicone gel, with an internal diameter of 3.1 cm. It is placed around the esophagus under the diaphragm and above the stomach, and is secured by 2 reinforced Teflon straps around the gastro-esophageal junction. The alleged advantage of the Angelchik device is the simplicity of the procedure -- its placement requires only limited dissection, thus decreasing the operating time. Since its introduction, more than 25,000 prostheses have been inserted into patients worldwide. Early faulty design had caused breakage of the circumferential strap, and led to migration of the device. Modification of the original strap to 2 re-inforced, non-circumferential straps by the manufacturer appears to have minimized the migration problem. However, complications as a consequence of implantation of the Angelchik prosthesis have been reported in as many as 10 to 20% of patients. An American Medical Association's DATTA evaluation of the Angelchik prosthesis found that this device has not been established as safe and effective for routine use in the treatment of GERD. Long-term studies concluded that the Angelchik device causes long-term dysphagia in many patients, severe enough to require its removal in 25% of these patients. Thus, its continual use can not be recommended.
LINX Reflux Management System
LINX Reflux Management System uses a small flexible band of interlinked titanium beads with magnetic cores that are laparoscopically placed around the esophagus, just above the stomach. The LINX system purportedly expands by swallowing, allowing food and liquid to pass normally into the stomach. The magnetic attraction then closes the LES, supposedly preventing reflux.
In a feasibility study, Bonavina et al (2010) evaluated the safety and efficacy of the LINX Reflux Management System (Ethicon, Bridgewater, NJ), a laparoscopically implanted sphincter augmentation device, for the treatment of GERD. The device, designed to prevent reflux due to abnormal opening of the LES, was laparoscopically implanted at the gastro-esophageal junction in 44 patients. At baseline, all patients had abnormal esophageal acid exposure on 24-hr pH monitoring and improved, but persistent, typical GERD symptoms while on acid suppression therapy with PPIs. The device comprises a miniature string of inter-linked titanium beads, with magnetic cores, placed around the gastro-esophageal junction. The magnetic bond between adjacent beads augments sphincter competence. The beads temporarily separate to accommodate a swallowed bolus, allow belching or vomiting, and re-approximate to augment the LES in the closed position. Patients were evaluated after surgery by GERD Health-Related Quality of Life symptom score, PPI usage, endoscopy, esophageal manometry, and 24-hr esophageal pH monitoring. The total mean GERD Health-Related Quality of Life symptom scores improved from a mean baseline value of 25.7 to 3.8 and 2.4 at 1- and 2-year follow-up, representing an 85% and 90% reduction, respectively (p < 0.0001). Complete cessation of PPI use was reported by 90% of patients at 1 year and by 86% of patients at 2 years. Early dysphagia occurred in 43% of the patients and self-resolved by 90 days. One device was laparoscopically explanted for persistent dysphagia without disruption of the anatomy or function of the cardia. There were no device migrations, erosions, or induced mucosal injuries. At 1 and 2 years, 77% and 90% of patients had a normal esophageal acid exposure. The mean percentage time pH was less than 4 decreased from a baseline of 11.9% to 3.1% (p < 0.0001) at 1 year and to 2.4% (p < 0.0001) at 2 years. Patient satisfaction was 87% at 1 year and 86% at 2 years. The authors concluded that the new laparoscopically implanted sphincter augmentation device eliminates GERD symptoms without creating undue side effects and is effective at 1 and 2 years of follow-up. The findings of this small feasibility study need to be validated by well-designed studies.
Ganz and colleagues (2013) evaluated the safety and effectiveness of a new magnetic device to augment the LES. These investigators prospectively assessed 100 patients with GERD before and after sphincter augmentation. The study did not include a concurrent control group. The primary outcome measure was normalization of esophageal acid exposure or a 50% or greater reduction in exposure at 1 year. Secondary outcomes were 50% or greater improvement in quality-of-life related to GERD and a 50% or greater reduction in the use of PPIs at 1 year. For each outcome, the pre-specified definition of successful treatment was achievement of the outcome in at least 60% of the patients. The 3-year results of a 5-year study were reported. The primary outcome was achieved in 64% of patients (95% confidence interval [CI]: 54 to 73). For the secondary outcomes, a reduction of 50% or more in the use of PPIs occurred in 93% of patients, and there was improvement of 50% or more in quality-of-life scores in 92%, as compared with scores for patients assessed at baseline while they were not taking PPIs. The most frequent adverse event was dysphagia (in 68% of patients post-operatively, in 11% at 1 year, and in 4% at 3 years). Serious adverse events occurred in 6 patients, and in 6 patients the device was removed. The authors concluded that in this single-group evaluation of 100 patients before and after sphincter augmentation with a magnetic device, exposure to esophageal acid decreased, reflux symptoms improved, and use of PPIs decreased. Moreover, they stated that follow-up studies (prospective, randomized trials with appropriate controls) are needed to confirm these preliminary findings and evaluate longer-term safety.
In a multi-center, prospective, single-arm study, Lipham et al (2012) examined the long-term safety and effectiveness of the LINX reflux management system. A total of 44 patients underwent a laparoscopic surgical procedure for placement of the LINX System around the gastro-esophageal junction (GEJ). Each patient's baseline GERD status served as the control for evaluations post-implant. Long-term efficacy measures included esophageal acid exposure, GERD quality-of-life measures, and use of PPIs. Adverse events and long-term complications were closely monitored. For esophageal acid exposure, the mean total% time pH less than 4 was reduced from 11.9% at baseline to 3.8% at 3 years (p < 0.001), with 80% (18/20) of patients achieving pH normalization (less than or equal to 5.3%). At greater than or equal to 4 years, 100% (23/23) of the patients had improved quality-of-life measures for GERD, and 80% (20/25) had complete cessation of the use of PPIs. There have been no reports of death or long-term device-related complications such as migration or erosion. The authors concluded that sphincter augmentation with the LINX Reflux Management System provided long-term clinical benefits with no safety issues, as demonstrated by reduced esophageal acid exposure, improved GERD-related quality of life, and cessation of dependence on PPIs, with minimal side effects and no safety issues. Patients with inadequate symptom control with acid suppression therapy may benefit from treatment with sphincter augmentation. The major drawbacks of this study were its small sample size (only 23 patients were available at 4 years) and the lack of a comparison group.
Moreover, the NICE’s guidance on “Laparoscopic insertion of a magnetic bead band for gastro-oesophageal reflux disease” (2012) considered insertion of a magnetic bead band for the treatment of GERD to be an innovative concept which, if shown to be safe and effective in further studies, could be a useful addition to the treatment options. The report stated that “The evidence on the safety and efficacy of laparoscopic insertion of a magnetic bead band for gastro-oesophageal reflux disease (GORD) is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research …. NICE encourages further research and collaborative data collection on laparoscopic insertion of a magnetic bead band for GORD”.
A technology brief on the LINX device for the Australian Safety and Efficacy of New Interventional Procedures - Surgical (ASENIP-S, 2013) concluded: "The findings of the two clinical trials reported in this Technology Brief illustrate promising results for the use of the LINX® Reflux Management System in treating patients with GORD. In particular, the device’s ability to be removed if required and the lower rate of side effects, compared with conventional surgical intervention, make the device a favourable treatment alternative (provided its utility in patients with significant oesophagitis and hiatal hernia can be determined). However, the evidence base for this technology is in its infancy and it is not currently possible to determine the safety and effectiveness of the LINX® device. Future studies should be comparative (ideally randomised), with broader patient populations and without industry sponsorship. Particular outcomes of interest for future studies should include the durability of the device (i.e. the lifespan of the magnets), its ability to reduce the likelihood of complications of GORD (i.e., Barrett’s oesophagus and cancer) and patient QoL. In addition, regulatory approval of the LINX® Reflux Management System in Australia does not appear to be imminent, and the cost of the device is likely to be a barrier to its uptake in clinical practice at this time."
Ganz et al (2013) prospectively assessed 100 patients with GERD before and after sphincter augmentation. The study did not include a concurrent control group. The primary outcome measure was normalization of esophageal acid exposure or a 50% or greater reduction in exposure at 1 year. Secondary outcomes were 50% or greater improvement in quality of life related to GERD and a 50% or greater reduction in the use of PPIs at 1 year. For each outcome, the pre-specified definition of successful treatment was achievement of the outcome in at least 60% of the patients. The 3-year results of a 5-year study were reported. The primary outcome was achieved in 64% of patients (95% CI: 54 to 73). For the secondary outcomes, a reduction of 50% or more in the use of PPIs occurred in 93% of patients, and there was improvement of 50% or more in quality-of-life scores in 92%, as compared with scores for patients assessed at baseline while they were not taking PPIs. The most frequent adverse event was dysphagia (in 68% of patients post-operatively, in 11% at 1 year, and in 4% at 3 years). Serious adverse events occurred in 6 patients, and in 6 patients the device was removed. The authors concluded that the current study was designed so that the direct effects of the sphincter augmentation device on each patient's exposure to esophageal acid, use of PPIs, and symptom control could be measured before and after the implantation. This design was limited in that it did not allow direct comparisons with other forms of therapy. These researchers stated that prospective, randomized trials with larger samples and longer-term follow-up are needed to confirm these early results and assess longer-term safety.
Bonavina et al (2013a) stated that the LINX Reflux Management System is designed to provide a permanent solution to GERD by augmenting the sphincter barrier with a standardized, reproducible laparoscopic procedure that does not alter gastric anatomy and is easily reversible. Two single-group trials confirmed that a magnetic device designed to augment the LES can be safely and effectively implanted using a standard laparoscopic approach. The device decreased esophageal acid exposure, improved reflux symptoms and quality of life, and allowed cessation of PPIs in the majority of patients.
The expert panel convened by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Technology and Value Assessment Committee (2013) concluded the following:
- The incidence of initial dysphagia following LINX implantation is high. Difficulty swallowing was more commonly reported at 12 and 24 months following LINX implantation than at baseline. Patients should be advised about the possibility that it may be more difficult to swallow following surgery, and that this symptom may persist.
- The LINX device may provide an option currently lacking in clinical practice for patients with medically refractory GERD who have not yet progressed to end-stage reflux disease with associated complications.
- Direct comparative studies between the LINX procedure and Nissen fundoplication will be needed.
- On the basis of the available evidence, the LINX device should be an option available to patients and providers for the management of medically refractory GERD.
On the other hand, the American College of Gastroenterology (ACG)’s guidelines on “Diagnosis and management of gastroesophageal reflux disease” (Katz et al, 2013) did not agree with the expert opinion rendered by the SAGES Technology and Value Assessment Committee. The ACG guidelines stated that “Endoscopic therapies for GERD have been developed but have not demonstrated long-term efficacy. These therapies included radiofrequency augmentation to the lower esophageal sphincter, silicone injection into the lower esophageal sphincter, and endoscopic suturing of the LES. None of these therapies demonstrated long-term improvement in esophageal pH levels or the ability for patients to stop antireflux therapy and were subsequently removed from the US marketplace. Recent alternative approaches have included transoral incisionless fundoplication, a suturing device designed to create a full thickness gastroesophageal valve from inside the stomach. Unfortunately long-term data regarding efficacy of this device are limited to a small number of subjects and short duration of follow-up. A recent study suggested that at 36 months of follow-up, the majority of patients had required additional medical therapy or a revisional fundoplication. Sphincter augmentation using the LINX Reflux system constructed of titanium beads has shown efficacy up to 4 years in the reduction of the amount of pathologic esophageal acid exposure in a small number of subjects. This device has been approved by the FDA based on a clinical study in 100 GERD patients. This study found that performance of LINX resulted in consistent symptom relief and pH control with markedly fewer side effects than traditional laparoscopic fundoplication in well-selected patients. More data are required before widespread usage can be recommended. The usage of current endoscopic therapy or transoral incisionless fundoplication cannot be recommended as an alternative to medical or traditional surgical therapy”.
In a randomized, multi-center, open label, cross-over study, Trad et al (2014) examined if transoral fundoplication (TF) could further improve clinical outcomes in partial responders to high-dose (HD) proton-pump inhibitor (PPI) therapy and evaluated durability of TF. In 7 United States centers, patients with hiatal hernia less than or equal to 2 cm and abnormal esophageal acid exposure (EAE) were randomized to TF (n = 40) or HD PPIs (n = 23) group. At 6-month follow-up, PPI patients underwent cross-over. These researchers assessed clinical outcomes 6-month post TF in cross-over patients (COP), as compared to 6-month of HD PPI therapy, and 12-month outcomes in patients initially randomized to TF. The primary outcome was symptom control evaluated by Reflux Disease Questionnaire and Reflux Symptom Index. Secondary outcomes included healing of esophagitis, normalization of EAE and PPI use after TF. These investigators analyzed 21 COP and 39 TF patients. McNemar’s test or Fisher exact test was used to compare proportions. Of 63 randomized patients, 3 were lost to follow-up, leaving 39 TF and 21 COP for analyses. In the COP, TF further improved control of regurgitation and of atypical symptoms achieved after 6 months of HD PPIs. Of 20 patients with GERD symptoms after 6 months of high-dose PPI therapy, 6 5% (13/20) reported global elimination of troublesome regurgitation and atypical symptoms post TF off PPIs; 67% (6/9) reported no troublesome regurgitation. Esophagitis further healed in 75% (6/8) of patients; 71% of COP patients were off PPIs 6 months following TF. Normalization of EAE decreased from 52% after HD PPIs (on PPIs) to 33% after TF (off PPIs), p = 0.388. In the original TF group, 12-month post TF, 77% of patients achieved complete symptom control, 82% ceased PPI therapy, 100% healed esophagitis and 45% normalized EAE. The authors concluded that these findings indicated that in patients with incomplete symptom control on high-dose PPI therapy TF may provide further elimination of symptoms and esophagitis healing. In the original TF group, the clinical outcomes of TF remained stable between 6- and 12-month follow-up.
This was a relatively small study (n = 60 including 21 cross-over patients). Furthermore, the authors noted that there were several limitations to this study:- this was an open-label, pre-planned cross-over, non-blinded trial, which may carry a certain unintended bias;
- although symptomatic control in the TF group improved at 12-month compared to 6-month, a residual placebo effect could still have impacted the reported results,
- the lack of pH impedance testing and systematic high-resolution manometry data prevented these researchers from clarifying the presumed effects of TF on patients with non-acid and proximal reflux, and on number of TLESRs, and
- for the association analysis, these researchers combined the TF and the cross-over patient to increase the sample size.
They believed that these analyses should be repeated on a larger patient population.
In a single-center, prospective case-series study, Bonavina et al (2013b) evaluated their clinical experience during a 6-year period with an implantable device that augments the lower esophageal sphincter for gastro-esophageal reflux disease (GERD). The device uses magnetic sphincter augmentation (MSA) to strengthen the anti-reflux barrier. A total of 100 consecutive patients underwent laparoscopic MSA for GERD between March 2007 and February 2012 were included in this report. Clinical outcomes for each patient were tracked post implantation and compared with pre-surgical data for esophageal pH measurements, symptom scores, and PPI use. Median implant duration was 3 years (range of 378 days to 6 years). Median total acid exposure time was reduced from 8.0% before implant to 3.2% post implant (p < 0.001). The median GERD Health Related Quality of Life score at baseline was 16 on PPIs and 24 off PPIs and improved to a score of 2 (p < 0.001). Freedom from daily dependence on PPIs was achieved in 85% of patients. There have been no long-term complications, such as device migrations or erosions. Three patients had the device laparoscopically removed for persistent GERD, odynophagia, or dysphagia, with subsequent resolution of symptoms. The authors concluded that magnetic sphincter augmentation for GERD in clinical practice provides safe and long-term reduction of esophageal acid exposure, substantial symptom improvement, and elimination of daily PPI use. For candidates of anti-reflux surgery who have been carefully evaluated before surgery to confirm indication for MSA, MSA has become a standard treatment at these researchers’ institution because control of reflux symptoms and pH normalization can be achieved with minimal side effects and preservation of gastric anatomy. The main drawback of this study was its single-center, case-series design.
Louie et al (2014) stated that in 2012 the United States Food and Drug Administration approved implantation of a magnetic sphincter to augment the native reflux barrier based on single-series data. These researchers sought to compare their initial experience with magnetic sphincter augmentation (MSA) with laparoscopic Nissen fundoplication (LNF). A retrospective case-control study was performed of consecutive patients undergoing either procedure who had chronic gastrointestinal esophageal disease (GERD) and a hiatal hernia of less than 3 cm. A total of 66 patients underwent operations (34 MSA and 32 LNF). The groups were similar in reflux characteristics and hernia size. Operative time was longer for LNF (118 versus 73 mins) and resulted in 1 return to the operating room and 1 re-admission. Pre-operative symptoms were abolished in both groups. At 6 months or longer post-operatively, scores on the Gastroesophageal Reflux Disease Health Related Quality of Life scale improved from 20.6 to 5.0 for MSA versus 22.8 to 5.1 for LNF. Post-operative DeMeester scores (14.2 versus 5.1, p = 0.0001) and the percentage of time pH was less than 4 (4.6 versus 1.1; p = 0.0001) were normalized in both groups but statistically different. MSA resulted in improved gassy and bloated feelings (1.32 versus 2.36; p = 0.59) and enabled belching in 67% compared with none of the LNFs. The authors concluded that MSA resulted in similar objective control of GERD, symptom resolution, and improved quality of life compared with LNF. MSA appeared to restore a more physiologic sphincter that allows physiologic reflux, facilitates belching, and creates less bloating and flatulence. This device has the potential to allow individualized treatment of patients with GERD and increase the surgical treatment of GERD. The main drawbacks of this study were its retrospective nature, small sample size and short follow-up.
Loh et al (2014) examined if the LINX Reflux management system is an effectives treatment for patients with symptoms of GERD not controlled by PPI. A total of 48 LINX-related papers were identified using the reported search, of which 3 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group, study type, relevant outcomes and results of these papers were tabulated. All 3 studies were prospective case studies. They demonstrated that LINX is an effective treatment for GERD patients with good short- and medium-term outcomes and an acceptable safety profile. The authors concluded that further studies are needed to determine its long-term outcomes and its relative efficacy as compared to other established treatments.
Min and Ganz (2014) noted that GERD is a common and progressive condition manifested by heartburn or regurgitation. Although Nissen fundoplication has been and remains the gold standard for procedural therapy for GERD, 2 newer interventions have gained popularity:- magnetic sphincter augmentation (MSA), which entails the placement of a self-expanding magnetic ring around the GE junction, and
- TIF, an endoscopic approach that creates a neogastroesophageal valve near the fundus.
Collective data gathered from 4 studies published within the past year suggested that the 3 modalities share comparable effectiveness in pH monitoring and patient satisfaction, TIF may have a lower PPI cessation rate, and Nissen fundoplication required longer recovery time and had a more serious adverse effects profile. The authors stated that large, prospective, randomized controlled studies are needed to reliably compare the 3 procedures.
Lipham et al (2015) stated that anti-reflux surgery with a magnetic sphincter augmentation device (MSAD) restores the competency of the LES with a device rather than a tissue fundoplication. As a regulated device, safety information from the published clinical literature can be supplemented by tracking under the Safe Medical Devices Act. These investigators examined the safety profile of the MSAD in the first 1,000 implanted patients. They compiled safety data from all available sources as of July 1, 2013. The analysis included intra- and peri-operative complications, hospital re-admissions, procedure-related interventions, re-operations, and device malfunctions leading to injury or inability to complete the procedure. Over 1,000 patients worldwide had been implanted with the MSAD at 82 institutions with median implant duration of 274 days. Event rates were 0.1% intra- and peri-operative complications, 1.3% hospital re-admissions, 5.6% endoscopic dilations, and 3.4% re-operations. All re-operations were performed non-emergently for device removal, with no complications or conversion to laparotomy. The primary reason for device removal was dysphagia. No device migrations or malfunctions were reported. Erosion of the device occurred in 1 patient (0.1%). The authors concluded that the safety analysis of the first 1,000 patients treated with MSAD for GERD confirmed the safety of this device and the implantation technique. The overall event rates were low based on data from 82 institutions. They stated that the MSAD is a safe therapeutic option for patients with chronic, uncomplicated GERD. The main drawbacks of this study included:
- typical patients treated with MSAD generally do not have a large hiatal hernia or other co-morbidities, such as Barrett’s esophagus, strictures, or motility disorders to the same extent as patients who typically undergo fundoplication, and
- the reliance on health professionals to consistently report events occurring outside of a clinical study to the manufacturer and/or FDA.
In a multi-center, prospective, observational study, Riegler et al (2015) evaluated the magnetic sphincter augmentation device (MSAD) and laparoscopic fundoplication (LF) in clinical practice. Data collection included baseline characteristics, reflux symptoms, PPI use, side effects, and complications. Post-surgical evaluations were collected at 1 year. At report, 249 patients (202 MSAD patients and 47 LF patients) had completed 1-year follow-up. The LF group was older and had a greater frequency of large hiatal hernias and Barrett's esophagus than the MSAD group (p < 0.001). The median GERD-health related quality of life score improved from 20.0 to 3.0 after MSAD and 23.0 to 3.5 after LF. Moderate or severe regurgitation improved from 58.2 to 3.1% after MSAD and 60.0 to 13.0% after LF (p = 0.014). Discontinuation of PPIs was achieved by 81.8% of patients after MSAD and 63.0% after LF (p = 0.009). Excessive gas and abdominal bloating were reported by 10.0% of patients after MSAD and 31.9% following LF (p ≤ 0.001). Following MSAD, 91.3% of patients were able to vomit if needed, compared with 44.4% of those undergoing LF (p < 0.001). Re-operation rate was 4.0% following MSAD and 6.4% following LF. The authors concluded that anti-reflux surgery should be individualized to the characteristics of each patient, taking into consideration anatomy and propensity and tolerance of side effects. Both MSAD and LF showed significant improvements in reflux control, with similar safety and re-operation rates. In the treatment continuum of anti-reflux surgery, MSAD should be considered as a first-line surgical option in appropriately selected patients without Barrett's esophagus or a large hiatal hernia in order to avoid unnecessary dissection and preserve the patient's native gastric anatomy. MSAD is an important treatment option and will expand the surgeon's role in treating GERD. This was an observational study; its findings need to be validated by randomized controlled trials.
Furthermore, an UpToDate review on " Surgical management of gastroesophageal reflux in adults" (Schwaitzberg, 2014) states that " LINX prosthesis -- In 2013, the US Federal Drug Administration (FDA) approved the LINX Reflux Management System for lower esophageal sphincter augmentation. Eligible patients for the procedure include those with inadequate symptom control with acid suppression therapy, including those patients with mild to moderate GERD and a hiatal hernia less than 3 cm. The device is a ring made up of a series of rare earth magnets that have sufficient attraction to increase the LES closure pressure, but allow for food passage with swallowing. Results from early studies at four years are encouraging".
An assessment by the ECRI Institute (2013) of the Linx procedure judged the quality of studies to be low. Commenting on the pivotal studies by Ganz, et al., and Lipham, et al., the ECRI report stated that weaknesses of these studies include inconsistent and incomplete results reporting (Ganz et al. reported intent-to-treat [ITT] at one year, not at subsequent follow-ups, patients were lost to follow-up; Lipham reported findings on the basis of patients left at follow-up, not ITT), and post-hoc analyses on an unclear number of patients. Both studies took baseline esophageal pH level measurements while patients were off PPI therapy, so no pre-post pH comparison data for PPI therapy and Linx are available. The ECRI reported also noted that results in the text of articles did not consistently correspond to results in tables.
An AHRQ Horizon Scanning Report on peptic ulcer disease and dyspepsia (ECRI, 2013) commented that: "Experts thought this intervention has potential to improve patient health, although comparative studies evaluating Linx with other minimally invasive GERD procedures have not been conducted. Experts noted that although this intervention is likely to be accepted by patients, clinicians may be hesitant because of the small amount of data on safety and efficacy and the lack of long-term data on safety and efficacy."
Sheu and Rattner (2015) evaluated the current data on the safety, effectiveness, and indications for MSA using the LINX device to treat GERD. The LINX device has demonstrated excellent safety and GERD efficacy in several recent non-blinded, single-arm studies with strict inclusion criteria and up to 3 years follow-up. Dysphagia has been the most common adverse effect occurring after LINX. Other gastro-intestinal side-effects seen after laparoscopic fundoplication (bloating, gas, and inability to belch) may be less common after LINX. The authors concluded that the LINX device is a safe, well-tolerated, and effective therapy for GERD in the short-term. They stated that MSA should be considered for selected GERD patients without significant anatomic or motility defects; however, the long-term safety and effectiveness of LINX -- both alone and in comparison to current GERD therapies -- remains to be determined.
In a prospective, multi-center, pilot study, Saino et al (2015) evaluated safety and effectiveness of the magnetic sphincter augmentation device (MSAD) for 5 years. Prior to MSAD placement, patients had abnormal esophageal acid and symptoms poorly controlled by proton pump inhibitors (PPIs). Patients served as their own control, which allowed comparison between baseline and post-operative measurements to determine individual treatment effect. At 5 years, gastro-esophageal reflux disease (GERD)-Health Related Quality of Life (HRQL) questionnaire score, esophageal pH, PPI use, and complications were evaluated. Between February 2007 and October 2008, a total of 44 patients (26 males) had an MSAD implanted by laparoscopy, and 33 patients were followed-up at 5 years. Mean total percentage of time with pH less than 4 was 11.9% at baseline and 4.6% at 5 years (p < 0.001), with 85% of patients achieving pH normalization or at least a 50% reduction. Mean total GERD-HRQL score improved significantly from 25.7 to 2.9 (p < 0.001) when comparing baseline and 5 years, and 93.9% of patients had at least a 50% reduction in total score compared with baseline. Complete discontinuation of PPIs was achieved by 87.8% of patients. No complications occurred in the long-term, including no device erosions or migrations at any point. The authors concluded that based on long-term reduction in esophageal acid, symptom improvement, and no late complications, the findings of this study showed the relative safety and effectiveness of magnetic sphincter augmentation (MSA) for GERD.
The main drawbacks of this study included no comparison treatment group and loss of patients during the 5-year follow-up (only 33 patients were available for 5-year follow-up). Esophageal pH data were completed by all sites at 1 year, but not all sites continued to perform esophageal pH monitoring past the 1-year follow-up. Long-term manometric data to characterize any changes in esophageal motility would have been informative; but were not part of the protocol past the 1-year follow-up. No significant findings were found during follow-up to make continued manometric evaluations clinically necessary. For the clinical study, only patients with normal motility were eligible for MSAD implantation, defined as esophageal amplitude of at least 35 mm Hg and at least 70% effective swallows. In clinical practice, these investigators have adhered to implanting only patients with normal motility. Normal esophageal motility is necessary to facilitate propulsion of a food bolus through the esophageal body in order to push open the magnetic device and allow passage through the LES and into the stomach. In clinical practice, one author has developed a barium esophagram protocol to evaluate for adequate motility related to MSAD and limited the use of manometry to those patients found to have abnormal passage of a solid bolus by video esophagram. The protocol involves evaluations in the upright, prone, and supine positions while the patient swallows liquid as well as solid food bolus (i.e., contrast-coated hamburger). These preliminary findings from a pilot study need to be validated by well-designed studies.
Ganz et al (2016) performed a prospective study of the safety and efficacy of a magnetic device in 100 adults with GERD for 6 months or more, who were partially responsive to daily PPIs and had evidence of pathologic esophageal acid exposure, at 14 centers in the United States and The Netherlands. The magnetic device was placed using standard laparoscopic tools and techniques; 85 subjects were followed up for 5 years to evaluate quality of life, reflux control, use of PPIs, and side effects. The GERD-HRQL questionnaire was administered at baseline to patients on and off PPIs, and after placement of the device; patients served as their own controls. A partial response to PPIs was defined as a GERD-HRQL score of 10 or less on PPIs and a score of 15 or higher off PPIs, or a 6-point or more improvement when scores on versus off PPI were compared. Over the follow-up period, no device erosions, migrations, or malfunctions occurred. At baseline, the median GERD-HRQL scores were 27 in patients not taking PPIs and 11 in patients on PPIs; 5 years after device placement this score decreased to 4. All patients used PPIs at baseline; this value decreased to 15.3% at 5 years. Moderate or severe regurgitation occurred in 57% of subjects at baseline, but only 1.2% at 5 years. All patients reported the ability to belch and vomit if needed. Bothersome dysphagia was present in 5% at baseline and in 6% at 5 years. Bothersome gas-bloat was present in 52% at baseline and decreased to 8.3% at 5 years. The authors concluded that augmentation of the lower esophageal sphincter with a magnetic device provided significant and sustained control of reflux, with minimal side effects or complications. No new safety risks emerged over a 5-year follow-up period. They stated that these findings validated the long-term safety and effectiveness of the MSA device for patients with GERD.
The major drawbacks of this study were:- all of the centers were high-volume esophageal center, and high-volume surgeons with extended proficiency in dissection of the diaphragmatic hiatus, performing laparoscopic fundoplication and early adopters of magnetic sphincter augmentation (MSA) technology. This may limit the applicability of the results outside of high-volume esophageal centers,
- the lack of an objective post-operative GERD control measure -- esophageal pH testing and manometry were not performed beyond 1 year. Manometry data have been reported previously with no significant change in any manometric parameter. Esophageal pH results at 1 year showed that the majority of the patients had normalization of esophageal acid exposure along with symptomatic improvement and discontinuation of PPIs. Longer-term pH data would have strengthened the conclusions, and
- the lack of a comparison group.
While the studies by Saino et al (2015) and Ganz et al (2016) provided long-term outcomes, both of them had limitations. Moreover, they do not address the critical issues that comparisons of LINX with either fundoplication or comparisons with medical therapy are needed.
In a retrospective, case-control study, Warren et al (2017) evaluated the manometric changes, function, and impact of MSA on the LES (n = 121). Inclusion criteria consisted of a confirmed diagnosis of GERD by an abnormal esophageal pH study (BMI less than 35 kg/m2, hiatal hernia less than 3 cm, and absence of endoscopic Barrett disease). Manometric changes, pH testing, and PPI use were assessed preoperatively and 6 and 12 months after MSA. MSA was associated with an overall increase in the median LES resting pressure (18 pre-MSA versus 23 mm Hg post-MSA; p = 0.0003), residual pressure (4 versus 9 mm Hg; p < 0.0001), and distal esophageal contraction amplitude (80 versus 9 0mm Hg; p = 0.02). The percent peristalsis remained unaltered (94% versus 87%; P = 0.71). Overall, patients with a manometrically defective LES were restored 67% of the time to a normal sphincter with MSA. Those with a structurally defective or severely defective LES improved to a normal LES in 77% and 56% of patients, respectively. Only 18% of patients with a normal pre-operative manometric LES deteriorated to a lower category. The authors concluded that MSA results in significant manometric improvement of the LES without apparent deleterious effects on the esophageal body. A manometrically defective LES can be restored to normal sphincter, whereas a normal LES remains stable. The authors noted that this study had several drawbacks:- the data were pooled and, though prospectively collected and retrospectively analyzed, it is from several different studies and multiple organizations,
- there was no standardized protocol for conducting or interpreting manometry. Also, it is recognized that assessment of LES length with high resolution manometry is controversial as it may not be as reliable as stationary pull through manometry. However, given its broad utilization in many centers the data should be applicable,
- the original manometry files were not reviewed and re-interpreted due to the complexity of acquiring files from multiple systems in multiple centers over time. Nevertheless, the centers contributing data were experienced esophageal centers and have experienced personnel interpreting these files, and
- this was an evaluation of median and mean values and may not be directly applicable to a 1-on-1 comparison.
As well, collective differences likely average out in a large group, but when applied to a specific patient, may have a greater error for clinical decision-making.
Warren et al (2016) stated that magnetic sphincter augmentation (MSA) has emerged as an alternative surgical treatment of GERD. The safety and effectiveness of MSA has been previously demonstrated, although adequate comparison to Nissen fundoplication (NF) is lacking, and required to validate the role of MSA in GERD management. A multi-institutional retrospective cohort study of patients with GERD undergoing either MSA or NF was carried out. Comparisons were made at 1 year for the overall group and for a propensity-matched group. A total of 415 patients (201 MSA and 214 NF) underwent surgery. The groups were similar in age, gender, and GERD-HRQL scores but significantly different in pre-operative obesity (32 versus 40%), dysphagia (27 versus 39%), DeMeester scores (34 versus 39), presence of microscopic Barrett's (18 versus 31%) and hiatal hernia (55 versus 69%). At a minimum of 1-year follow-up, 354 patients (169 MSA and 185 NF) had significant improvement in GERD-HRQL scores (pre to post: 21-3 and 19-4); MSA patients had greater ability to belch (96 versus 69%) and vomit (95 versus 43%) with less gas bloat (47 versus 59%). Propensity-matched cases showed similar GERD-HRQL scores and the differences in ability to belch or vomit, and gas bloat persisted in favor of MSA. Mild dysphagia was higher for MSA (44 versus 32%). Resumption of daily PPIs was higher for MSA (24 versus 12, p = 0.02) with similar patient-reported satisfaction rates. The authors concluded that MSA for uncomplicated GERD achieved similar improvements in quality of life and symptomatic relief, with fewer side effects, but lower PPI elimination rates when compared to propensity-matched NF cases. They stated that in appropriate candidates, MSA is a valid alternative surgical treatment for GERD management. The main drawbacks of this study were its retrospective design, short-term ( 1 year) follow-up, lack of an objective post-operative GERD control measure (e.g., post-operative pH), higher dysphagia, and lower PPI elimination rates, and all of the centers were high-volume esophageal centers, and high-volume surgeons with extended proficiency in dissection of the diaphragmatic hiatus, performing laparoscopic fundoplication, and early adopters of MSA technology. This may limit the applicability of the results outside of high-volume esophageal centers.
Reynolds et al (2016) compared charges, complications, and outcome of MSA versus laparoscopic Nissen fundoplication (LNF) at 1 year. This was a retrospective analysis of all patients who underwent MSA or LNF for the treatment of GERD between January 2010 and June 2013. Patient charges were collected for the surgical admission. These researchers also collected data on 30-day complications and symptom control at 1 year assessed by GERD-HRQL score and PPI use. There were 119 patients included in the study, 52 MSA and 67 LNF. There was no significant difference between the mean charges for MSA and LNF ($48,491 versus $50,111, p = 0.506). There were significant differences in OR time (66 minutes MSA versus 82 minutes LNF, p < 0.01) and LOS (17 hours MSA versus 38 hours LNF, p < 0.01). At 1-year follow-up, mean GERD-HRQL was 4.3 for MSA versus 5.1 for LNF (p = 0.47) and 85% of MSA patients versus 92% of LNF patients were free from PPIs (p = 0.37). MSA patients reported less gas bloat symptoms (23 versus 53%, p ≤ 0.01) and inability to belch (10 versus 36%, p ≤ 0.01) and vomit (4 versus 19%, p ≤ 0.01). The authors concluded that the side effect profile of MSA was better than LNF as evidenced by less gas bloat and increase ability to belch and vomit. They stated that LNF and MSA are comparable in symptom control, safety, and overall hospital charges. The charge for the MSA device is offset by less charges in other categories as a result of the shorter operative time and LOS. The main drawbacks of this study were its retrospective design, short-term ( 1 year) follow-up, the primary outcome was a difference in charges, and the study was not adequately powered for the secondary outcome – it was not powered to detect a difference in PPI use of less than 10%.
- the GERD-HRQL is a validated, but still subjective test, and the LINX procedures were not standardized regarding crural repair,
- hidden bias typical of an observational study cannot be excluded due to unmeasured and unmeasurable confounding factors, and
- the PS model could be biased, and these researchers did not consider possible measurable time-dependent confounders.
Moreover, the authors stated that “Despite the sensitivity analysis showed negligible residual bias, we need to be cautious in interpreting the overall study results … Further research is needed to investigate correlation between longitudinal quality of life data with objective long-term outcome of these procedures”.
- data were gathered retrospectively and is potentially subject to both selection and information biases as this review spanned over a 6-year period,
- after successful introduction of the LINX device into their clinical practice, their understanding of its potential for patients with large hiatal hernias evolved and they began expanding their patient selection to those with hiatal hernias of greater than or equal to 3 cm over the last 2 years of the study.
Thus, patients in their large hiatal hernia group had a shorter follow-up time compared to those in their control group. Consequently, the improved post-operative outcomes with respect to PPI requirement and GERD-HRQL scores seen in the large hiatal hernia group may be secondary to a relatively shorter follow-up period. Long-term follow-up with objective post-operative measures of reflux and screening for hiatal hernia recurrence are needed to confirm the durability of MSA in this patient population. These investigators stated that although their results were encouraging and may broaden the application of MSA, prospective trials comparing MSA and Nissen fundoplication are needed to reveal the optimal surgical therapy in patients with gastro-esophageal reflux and large hiatal hernias.
Patti (2016) reviewed the pathophysiology, clinical presentation, diagnostic evaluation, and treatment of GERD. A search of PubMed was conducted for the years spanning 1985 to 2015 and included the following terms: heartburn, regurgitation, dysphagia, gastroesophageal reflux disease, cough, aspiration, laryngitis, GERD, GORD, endoscopy, manometry, pH monitoring, proton pump inhibitors, open fundoplication, and laparoscopic fundoplication. Only articles in English were included. The author concluded that lifestyle modifications, PPIs, and laparoscopic fundoplication are proven treatment modalities for GERD; endoscopic procedures have not been proven as effective.
An UpToDate review on "Approach to refractory gastroesophageal reflux disease in adults" (Fass, 2016) states that “Another surgical approach is laparoscopic sphincter augmentation using a device comprised of a string of magnetized beads. The device is implanted at the lower esophageal sphincter to maintain closure of a weak lower esophageal sphincter, preventing reflux. The beads then separate when the patient swallows to allow passage of a food or liquid bolus. In one prospective study, 100 patients with GERD that was partially responsive to PPIs underwent implantation of a magnetic esophageal sphincter device. At 3-year follow-up, a 50% or greater reduction in esophageal acid exposure was achieved in 64% of patients and 87% of patients reported complete cessation of PPI use. The most frequent adverse event was dysphagia, which occurred in 68% of patients. Serious side effects occurred in 6% of individuals. However, randomized controlled trials are needed to confirm these results and to assess the long-term safety of magnetic devices to treat refractory GERD”.
Chen and colleagues (2017) noted that the efficacy of MSA and its outcomes for GERD are uncertain. These researchers analyzed the efficacy of 2 treatments:- NF, and
- MSA for GERD.
They carried out a meta-analysis using 4 databases. All studies from 2005 to 2016 were included. Pooled effect was calculated using either the fixed or random effects model. A total of 4 trials included 624 patients and aimed to evaluate the differences in PPI use, complications, and adverse events. MSA had a shorter operative time (MSA and NF: RR = -18.80, 95% CI: -24.57 to -13.04, and p = 0.001) and length of stay (RR = -14.21, 95% CI: -24.18 to -4.23, and p = 0.005). Similar PPI use, complication (p = 0.19), and severe dysphagia for dilation were shown in both groups. Although there was no difference between the MSA and NF in the number of adverse events, the incidence of post-operative gas or bloating (RR = 0.71, 95% CI: 0.54 to 0.94, and p = 0.02) showed significantly different results. However, there was no significant difference in ability to belch and ability to vomit. The authors concluded that MSA can be recommended as an alternative treatment for GERD according to their short-term studies, especially in main-features of gas-bloating, due to shorter operative time and less complication of gas or bloating. Moreover ,they stated that there are still many unanswered questions whether MSA is still appropriate for hiatal hernias that are more than 3 cm, whether the long-term outcomes of MSA are same as the short-time outcomes, whether the incidence of LINX device removed and erosion will increase as time goes on, and so on. They stated that it is very important and necessary to perform RCTs to compare the efficacy of MSA compared to NF in short-term and long-term. These investigators stated that the main drawbacks of this study included 2 trials that did not match the size of hiatal hernias, the less number of tails included, and none of RCT trials.
Skubleny and associates (2017) stated that the LINX® magnetic sphincter augmentation system (MSA) is a surgical technique with short-term evidence demonstrating efficacy in the treatment of medically refractory or chronic GERD. Currently, the Nissen fundoplication is the gold-standard surgical treatment for GERD. These investigators noted that they were the first to systematically review the literature and perform a meta-analysis comparing MSA to the Nissen fundoplication. A comprehensive search of electronic databases (e.g., Medline, Embase, SCOPUS, Web of Science and the Cochrane Library) using search terms "Gastroesophageal reflux or heartburn" and "LINX or endoluminal or magnetic" and "fundoplication or Nissen" was completed. All randomized controlled trials (RCTs), non-randomized comparison study and case series with greater than 5 patients were included. A total of 547 titles were identified through primary search, and 197 titles or abstracts were screened after removing duplicates. Meta-analysis was performed on post-operative quality of life (QOL) outcomes, procedural efficacy and patient procedural satisfaction; 3 primary studies identified a total of 688 patients, of whom 273 and 415 underwent Nissen fundoplication and MSA, respectively. MSA was statistically superior to LNF in preserving patient's ability to belch (95.2 versus 65.9%, p < 0.00001) and ability to emesis (93.5 versus 49.5%, p < 0.0001). There was no statistically significant difference between MSA and LNF in gas/bloating (26.7 versus 53.4%, p = 0.06), post-operative dysphagia (33.9 versus 47.1%, p = 0.43) and proton pump inhibitor (PPI) elimination (81.4 versus 81.5%, p = 0.68). The authors concluded that magnetic sphincter augmentation appeared to be an effective treatment for GERD with short-term outcomes comparable to the more technically challenging and time-consuming Nissen fundoplication. Moreover, they stated that long-term comparative outcome data past 1 year are needed in order to further understand the efficacy of magnetic sphincter augmentation.
An assessment of the procedure by the National Institute for Health and Care Excellence (NICE, 2017) found that there were no safety concerns but that available data were short term.. "There is limited evidence of short-term efficacy, but evidence of long-term efficacy is inadequate in quality and quantity."
Czosnyka et al (2017) reported the early experience of MSA for the treatment of GERD from 2 community-based health systems. The first 102 post-trial cases of MSA were reviewed. Outcomes were compared to those in the initial clinical trial. Mean follow-up duration was 7.6 months; GERD medication use decreased from 98% pre-operative to 8% post-operative (p < 0.001). Median GERD health-related quality of life (HRQL) improved from 27 pre-operative to 5 post-operative (p < 0.001). Patient satisfaction increased from 8% pre-operative to 84% post-operative (p < 0.001). Results were similar to the trial data. The authors concluded that MSA was a safe and effective treatment for GERD, with significant improvement in quality of life. GERD-HRQL, medication reduction, operative times, and dysphagia rates were similar to other reports, showing the reproducibility of MSA. Lower dilation rates may be due to refinements in technique and postoperative dietary management. This study provided short-term follow-up (7.6 months).
Mermelstein et al (2018) listed LINX as one of the novel procedures for the treatment of PPI-refractory GERD. These investigators stated that data are limited to short-term case series, but multiple prospective studies have demonstrated the safety and efficacy of LINX in treating patients with refractory GERD symptoms.
Zadeh et al (2018) reviewed the current literature regarding indications, surgical technique, efficacy, and complications of MSA using the LINX device. These investigators carried out a standardized literature search that yielded 367 abstracts. After elimination due to duplicates between databases and irrelevance, 96 articles remained. The information found to be significant and non-redundant was included in this review. The authors concluded that after several years of clinical application, the LINX device has been shown to not only be effective for the management of GERD but also be as effective as fundoplication. With respect to safety, the most common complication of MSA is dysphagia. This often resolved without intervention, but esophageal dilation or device explanation are occasionally necessary. Not fully appreciated in earlier reviews, erosion of the device into the esophagus appears to be the most significant complication of the device after extended follow-up. While very rare, the potentially severe consequences of this phenomenon suggest that the device should be used with some restraint and that patients should be made aware of this potential morbidity. Fortunately, in the few cases of device erosion described in the literature reviewed, the LINX device was easily and safely removed. These researchers stated that while outcomes thus far have generally been favorable, further evaluation of the long-term safety and efficacy of MSA is needed as this device is often used in patients with decades of life ahead of them.
Nicolau et al (2018) noted that GERD has become one of the most frequent pathology of the upper GI tract. It is a spectrum disease and is a progressive disease as well. Serious and severe complications are possible. The main treatment in most of the patients is pharmacotherapy with PPI's. The most severe cases with an impaired LES function as well as important anatomical disruptions are of surgical indication, the gold standard being laparoscopic fundoplication, an elective therapy with long-term follow-up outcomes at the expense of de-novo symptoms associated with fundoplication in general; 30% to 40% of the patients are PPI refractory with partial symptom control, but they are not willing to go for the laparoscopic fundoplication because of the invasive character and because of potential post-fundoplication syndromes. There is a "treatment gap" for these patients with GERD. For a selected patient population with GERD, with mild forms of the disease, without complications and without major anatomical disruptions (patients with small hiatal hernias), patients who are refractory on PPI medication, there are today new alternative minimally invasive treatments, which are less aggressive and basically with no side effects or new onset symptoms. These are endoscopic therapies that improve the LES function: Stretta utilizes RF therapy, a novel technique describes mucosal resection at the level of the cardia, while a partial fundoplication from within the stomach could be realized with EsophyX, Muse or Gerd-X. For all these procedures, EsophyX is the most advanced with more than 20,000 patients treated worldwide, with good clinical outcomes and with no de-novo symptoms. The laparoscopic techniques treat hiatal hernias larger than 2 cm. LINX utilizes a magnetic ring at the LES level; EndoStim utilizes electrodes in order to stimulate the LES muscle. The authors concluded that these procedures are effective on short-term and there are few patients treated with LINX or EndoStim; and more research with randomized clinical trials for LINX and EndoStim is needed, with improvement of the devices and with long-term follow-up.
Rebecchi et al (2018) stated that a total laparoscopic fundoplication has become the procedure of choice for the surgical treatment of GERD patients with normal esophageal motility, with reduced post-operative pain, faster recovery and similar long-term outcomes compared to conventional open total fundoplication. Most controversial surgical aspects are the division of the short gastric vessels and the insertion of a bougie to calibrate the wrap. The anterior 180° and the posterior partial fundoplication led to similar control of heartburn when compared to total fundoplication with lower risk of dysphagia. However, when performed, 24-hour pH monitoring showed pathologic reflux more frequently after partial than total fundoplication. Disappointing results were achieved by anterior 90° partial fundoplication. More recently, a magnetic sphincter augmentation with the LINX Reflux Management System and LES electrical stimulation (EndoStim) have been developed, seeking for a durable and effective minimally invasive alternative to laparoscopic fundoplication for the treatment of GERD. The authors concluded that both devices appeared to be promising, with very low post-operative complications and good short-term functional outcomes. Moreover, they stated that large RCTs comparing them with laparoscopic fundoplication over a long period of follow-up are needed to verify their indications and outcomes.
Buckley et al (2018) noted that MSA of the LES restores the anti-reflux barrier in patients with hiatal hernias of less than or equal to 3 cm. In a prospective, multi-center study, these researchers examined the use of MSA with the LINX device during repair of para-esophageal and hernias over 3 cm axial component. A total of 200 patients (110 women) were treated between March 2014 and February 2017 via laparoscopic hernia repair and MSA. Mean age was 59.5 years, mean BMI 29.4; 40% had esophagitis, 20% intestinal metaplasia, 72 of 77 tested had abnormal pH studies. Pre-operative PPI use was reported by 87%; 18 patients had prior hiatal hernia/fundoplication. All had normal function; 78% of patients had axial hiatal hernia of greater than or equal to 5 cm or large para-esophageal component. Mean operative time was 81 mins (38 to 193), estimated blood loss (EBL) was 10 cc. Non-permanent mesh reinforcement of hiatal repair was performed in 83% of the patients. There were 2 re-admissions for dehydration; 2 patients with pulmonary embolism, and 1 patient with cardiac ischemia; 19 patients required dilation; 156 patients were followed at a median of 8.6 months. GERD-HRQL scores improved from 26 pre-operatively to 2 post-operatively. Complete PPI independence was achieved in 94% (147/156). Videoesophagram in 51 patients at median 11 months found 3 asymptomatic hernias of less than 3 cm; 1 symptomatic patient underwent successful repair of the hernia without MSA manipulation. There have been no device explants, erosions, or migrations to-date. The authors concluded that the findings of this prospective study of 200 patients with greater than 3 cm hernias undergoing MSA with hiatoplasty resulted in favorable outcomes with median of 9 months follow-up. Comparing this to published reports of MSA in patients with less than 3 cm hernias, the safety and clinical efficacy of MSA are independent of initial hernia size.
The authors stated that this study had several drawbacks. Although all patients had greater than 3 cm axial component to the hernia by pre-operative or intra-operative findings, no single measurement of hernia size was used uniformly. The 2 institutions performed slightly different prospective data collection and surgical techniques. These researchers could be criticized for not obtaining pre-operative pH testing on all patients; however, the false-negative rate seen in patients with large hernias limited the utility of pH testing. These investigators did not directly compare outcomes of patients in this study with outcomes of their patients with less than or equal to 3 cm hernias. Outcomes from patients undergoing MSA with less than or equal to 3 cm hernias have been reported elsewhere, were remarkably consistent, and the authors thought adequate to serve as a benchmark against which to compare this study’s results. The authors would have preferred to obtain more complete objective post-operative data, especially on asymptomatic patients; this was not possible insofar as many asymptomatic patients refused objective testing for cost and/or travel reasons. These researchers intend to continue reporting outcomes up to 5 years and will continue to collect as much objective data as possible.
Bell and colleagues (2019) compared effectiveness of increased PPI dosing with laparoscopic magnetic sphincter augmentation (MSA) in patients with moderate-to-severe regurgitation despite once-daily PPI therapy. A total of 152 patients with GERD, aged greater than or equal to 21 years with moderate-to-severe regurgitation despite 8 weeks of once-daily PPI therapy, were prospectively enrolled at 21 U.S. sites. Participants were randomized 2:1 to treatment with twice-daily (BID) PPIs (n = 102) or to laparoscopic MSA (n = 50). Standardized foregut symptom questionnaires and ambulatory esophageal reflux monitoring were performed at baseline and at 6 months. Relief of regurgitation, improvement in foregut questionnaire scores, decrease in esophageal acid exposure and reflux events, discontinuation of PPIs, and adverse events (AEs) were the measures of efficacy. Per protocol, 89% (42/47) of treated patients with MSA reported relief of regurgitation compared with 10% (10/101) of the BID PPI group (p < 0.001) at the 6-month primary end-point. By intention-to-treat (ITT) analysis, 84% (42/50) of patients in the MSA group and 10% (10/102) in the BID PPI group met this primary endpoint (p < 0.001); 81% (38/47) of patients with MSA versus 8% (7/87) of patients with BID PPI had greater than or equal to 50% improvement in GERD-health-related quality of life (QOL) scores (p < 0.001), and 91% (43/47) remained off of PPI therapy. A normal number of reflux episodes and acid exposures was observed in 91% (40/44) and 89% (39/44) of MSA patients, respectively, compared with 58% (46/79) (p < 0.001) and 75% (59/79) (p = 0.065) of BID PPI patients at 6 months. No significant safety issues were observed. In MSA patients, 28% reported transient dysphagia; 4% reported ongoing dysphagia. The authors concluded that patients with GERD with moderate-to-severe regurgitation, especially despite once-daily PPI treatment, should be considered for minimally invasive treatment with MSA rather than increased PPI therapy. This was a relatively small study (n = 50 for the MSA group) with short-term follow-up (6 months).
The drawbacks of this study included the inherent subjective nature of the questionnaires used as end-points, although impedance-pH added some objective measure of the control of reflux. Also, there was potential referral bias insofar as recruitment began with patients presenting to a surgical clinic. Attempting to minimize this bias, these researchers chose standardized measures of GERD symptoms such as the FSQ and GERD-HRQL that could be applied across a broader range of patients such as those observed in a medical clinic. A precise but practical definition of moderate-to-severe regurgitation was used to characterize better the patient population being studied. Another drawback might be the choice of 20-mg omeprazole BID as the control treatment, given that 40-mg BID PPI is commonly considered for refractory GERD symptoms. The choice of 20-mg BID omeprazole dosing was chosen because- the FDA-recommended adult oral dose is 20 mg daily,
- a 20-mg BID dose of omeprazole appeared to be more effective than 40-mg daily, and (
- a dosage of 40 mg omeprazole BID has not been demonstrated to provide better gastric acid control than 20 mg BID.
The authors also chose not to monitor patient compliance or gastric acid control with the dosing because their intent was to mimic a real-world scenario in patients already familiar with taking PPIs. Despite these drawbacks, this prospective, randomized, controlled trial comparing control of regurgitation symptoms demonstrated the ability of MSA to control regurgitative symptoms while illustrating the lack of benefit achieved from increasing the dosage of PPI therapy to BID. In this population of GERD patients with regurgitation refractory to daily PPI therapy, MSA was far more effective at alleviating regurgitation and improving GERD-related quality of life than was increased dosing of PPIs.
Hawasli and co-workers (2019) noted that management of severe reflux after SG is often done by conversion to RYGB. The LINX system could be an alternative treatment. Between 2015 and 2017, a total of 13 patients had the LINX system placed to manage their reflux after SG. Pre-operative evaluation included a barium swallow, endoscopy with pH monitor and esophageal motility. A total of 10 women and 3 men with mean age of 49 ± 13 years were evaluated. Their mean weight before placing the LINX system was 193 ± 45 lbs. and mean BMI of 33 ± 6 kg/m2. The mean time between SG and placing the LINX system was 43 ± 19 months. The mean Bravo score was 46 ± 26 (normal 14.7). One patient developed severe dysphagia post-operatively requiring removal of the LINX after 18 days and 1 patient was lost to follow-up. The mean follow-up in the remaining 11 patients was 26 ± 12 months. The mean GERD-HRQOL score dropped significantly from 47/75 ± 17/75 to 12/75 ± 14/75 (p = 0.0003). The authors concluded that the LINX system may be used as an alternative to RYGB conversion in managing refractory post-SG reflux. This was a small study (n = 11 evaluable subjects) with only mid-term follow-up (26 months). These findings need to be validated by well-designed studies.
Guidozzi and colleagues (2019) stated that MSA has been proposed as a less invasive, more appealing alternative intervention to fundoplication for the treatment of GERD. These researchers examined clinical outcomes following MSA for GERD control in comparison with laparoscopic fundoplication. A systematic electronic search for articles was performed in Medline, Embase, Web of Science, and Cochrane Library for single-arm cohort studies or comparative studies (with fundoplication) evaluating the use of MSA. A random-effects meta-analysis for post-operative PPI use, GERD-HRQOL, gas bloating, ability to belch, dysphagia, and re-operation was performed. The systematic review identified 6 comparative studies of MSA versus fundoplication and 13 single-cohort studies. Following MSA, only 13.2% required post-operative PPI therapy, 7.8% dilatation, 3.3% device removal or re-operation, and esophageal erosion was observed in 0.3%. There was no significant difference between the groups in requirement for post-operative PPI therapy (pooled OR [POR] = 1.08; 95% CI: 0.40 to 2.95), GERD-HRQOL score (weighted mean difference [WMD] = 0.34; 95% CI: -0.70 to 1.37), dysphagia (POR = 0.94; 95% CI: 0.57 to 1.55), and re-operation (POR = 1.23; 95% CI: 0.26 to 5.8). However, when compared to fundoplication MSA was associated with significantly less gas bloating (POR = 0.34; 95% CI: 0.16 to 0.71) and a greater ability to belch (POR = 12.34; 95% CI: 6.43 to 23.7). The authors concluded that MSA attained good GERD symptomatic control similar to that of fundoplication, with the benefit of less gas bloating. The safety of MSA also appeared acceptable with only 3.3% of patients requiring device removal. These researchers stated that there is an urgent need for randomized data directly comparing fundoplication with MSA for the treatment of GERD to truly evaluate the efficacy of this treatment approach.
The authors noted that a random-effects model was used in this study to correct for the heterogeneity of the analyzed data. However, there remain several other drawbacks to consider when interpreting these findings. Magnetic sphincter augmentation studies may potentially under-report complications associated with device implantation, leading to publication bias. The reported complications were reliant on health-care professionals efficiently following up patients after device insertion, identifying both early and late complications, and reporting these complications to the device manufacturer. This process evidently has many potential pitfalls. Associated with this potential limitation is the fact that many MSA studies and comparative studies have relatively small recruitment populations, leading to numerous under-powered studies. Reporting bias was also a limitation to consider in the current literature available, as insertion of the MSA device is a novel procedure, which some surgeons may be technically invested in, driving promising outcomes. Meta-analysis of data regarding re-operation rates was based upon comparative studies with limited follow-up, and may be expected to change substantially over time with more extended follow-up. There was also significant variation in the follow-up protocols and specifically length of follow-up between individual studies. These limitations highlighted the need for a well-designed, multi-center, RCT to fully evaluate the effectiveness of MSA in comparison to laparoscopic fundoplication.
Stanak and colleagues (2018) stated that electric stimulation therapy (EST) and magnetic sphincter augmentation (MSA) represent novel methods for the surgical treatment of GERD. These investigators examined the safety and effectiveness of EST and MSA device (MSAD) compared to laparoscopic fundoplication (LF) and PPI therapy (in case of EST). They carried out a systematic literature search without restrictions on publication dates in 5 electronic databases (Medline, Embase, the Cochrane library, PubMed, and Centre for Reviews and Dissemination), complemented by hand-search, search in trial registries, and documentation provided by the manufacturers. No study passed inclusion criteria for analyzing EST effectiveness. Concerning safety, lead erosion through the esophagus and trocar perforation of the small bowel occurred in 2.4% of patients (in 1 study). Only the registry study fulfilled inclusion criteria for effectiveness analysis of MSAD. The crucial outcome of GERD-HRQOL score improved from 20 to 3 points in MSAD patients, and from 23 to 3.5 points in LF patients. However, the LF patients were in a more severe stage of the disease. The authors concluded that these findings yielded indefinite conclusions regarding the use of both MSAD and EST. These researchers stated that the safety and effectiveness of both MSAD and EST are not sufficiently proven and are yet to be supported by high quality evidence from RCTs.
Ferrari et al (2020) stated that the magnetic sphincter augmentation (MSA) device has been proven safe and effective in controlling typical reflux symptoms and esophageal acid exposure for up to 6-year follow-up. Longer term outcomes have not been reported yet. In a retrospective, single-center study, these researchers examined a prospectively maintained database to evaluate long-term safety and efficacy of the laparoscopic MSA procedure at a single referral center. Gastro-Esophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL), use of proton-pump inhibitors (PPI), and esophageal acid exposure were compared to baseline. Favorable outcomes were defined as greater than or equal to 50% improvement of GERD-HRQL total score and PPI discontinuation. Between March 2007 and March 2020, 335 patients met the study inclusion criteria, and 124 of them were followed from 6 to 12 years after surgery (median of 9 years, inter-quartile range [IQR] 2). Mean total GERD-HRQL score significantly improved from 19.9 to 4.01 (p < 0.001), and PPI were discontinued by 79% of patients. The mean total percent time with pH of less than 4 decreased from 9.6% at baseline to 4.1% (p < 0.001), with 89% of patients achieving pH normalization. Independent predictors of a favorable outcome were age at intervention of less than 40 years (odds ratio [OR] 4.17) and GERD-HRQL score of greater than 15 (OR 4.09). The authors confirmed long-term safety and efficacy of MSA in terms of symptom improvement, decreased drug dependency, and reduced esophageal acid exposure. Moreover, these researchers stated that MSA may represent a true paradigm shift that has the potential to fill the current therapy gap in GERD; a randomized clinical trial comparing MSA and either total or partial fundoplication could provide more robust and definitive conclusions
The authors stated that the main limitations of this study were the retrospective design, the fact that there was no comparison treatment group, and the possible selection bias. However, despite the fact that criteria for patient selection, surgical technique, and type of device and sizer have evolved during the study period, the patient population of this study was homogeneous and indications for surgical therapy were consistent based on the pre-operative pH study confirming GERD. Finally, this was the first report of a cohort of patients who completed the 6 to 12 years follow-up after MSA.
In a prospective, multi-center, observational registry study, Bonavina et al (2020) reported the 3-year outcomes for MSA and laparoscopic fundoplication (LF) in patients with GERD. Data collection included baseline characteristics, reflux symptoms, medication use, satisfaction and complications. Post-surgical evaluations were collected at yearly intervals. Between December 2009 and December 2014, a total of 631 patients (465 MSA and 166 LF) were enrolled in the registry. Both MSA and LF resulted in improvements in total GERD-HRQL score (mean reduction in GERD-HRQL from baseline to 3 years post-surgery: MSA 22.0 to 4.6 and LF 23.6 to 4.9) and in satisfaction (GERD-HRQL satisfaction increase from baseline to 3 years: MSA 4.6% to 78.2% and LF 3.7% to 76.5%). Most patients were able to belch as needed with both therapies (MSA 97.6% and LF 91.7% at 3 years). MSA allowed a higher percentage of patients the ability to vomit as needed (MSA 91.2% and LF 68.0% at 3 years). PPI usage declined from baseline to 3 years for both groups after surgery (MSA 97.8% to 24.2% and LF 95.8% to 19.5%). The mean procedure time was shorter for MSA than for LF . Intra-operative and procedure-related complication rates (less than or equal to 2%) were low for both therapies. The authors concluded that this 3-year prospective observational registry study contributed to the mounting evidence for the effectiveness of MSA and LF. Despite the more severe nature of GERD in the LF group, the clinical outcomes for MSA and LF were favorable from an effectiveness and safety stand-point.
The authors stated that there were limitations associated with this analysis. MSA and LF effectiveness estimates were derived from 22 medical centers in 4 European countries and were not necessarily representative of all settings of care. All investigators performed fundoplication routinely and in addition, were trained specifically on the implantation of MSA, which is only available in select centers. Within the LF group, there were different procedures performed at the discretion of the surgeon. While this individualized the treatment to the patient, it made the analysis more complex. This was a non-randomized study and was not intended to detect statistically significant clinical outcomes between MSA and LF. This registry was intended to capture everyday clinical practice and patients were screened based upon the current Instructions for Use (IFU) for MSA as those who met the MSA criteria. The final decision for the type of surgery was made by the surgeon at the time of laparoscopy, based upon a variety of patient-specific factors. Comparisons of baseline characteristics indicated that patients in the LF group were older, had a higher body mass index (BMI), and had a greater frequency of large hiatal hernias and Barrett’s esophagus. It was possible that results were confounded and observed differences between groups were due to these and other variables. Due to the noted differences in the 2 populations, the results must be carefully considered. Furthermore, the procedure to implant MSA has since evolved to include full crural and gastro-esophageal junction dissection as opposed to the minimal dissection utilized in this investigation. The time-frame for this study will determine if the procedural modifications are relevant to the outcomes in this study population. The current procedure theoretically may provide better outcomes for patients as compared to those done under the “minimal dissection” protocol as the hiatal hernia is often addressed.
In commentaries/responses on a study entitled “Three-year clinical experience with magnetic sphincter augmentation and laparoscopic fundoplication -- Bonavina et al, 2020”, the editorialists, Blencowe et al (2020), noted that they were delighted that the authors agreed that a well-designed RCT comparing the effectiveness of MSA and anti-reflux surgery is needed to inform clinical decision-making. Blencowe et al (20200 stated that their review of the published literature regarding MSA took a novel approach. They undertook a detailed analysis over time of reporting of study design, clinical indications, technique standardization, governance arrangements and outcome selection, as an evaluation of how the innovative procedure progressed. These researchers hoped to see the acquisition of incremental evidence. However, they identified deviations from FDA eligibility criteria, heterogeneity of outcome reporting, and limited and inconsistent technique descriptions. This meant it was difficult to decide how to select patients and replicate the procedure in future studies and clinical practice. Therefore, these investigators continued to believe that their conclusion that “there is a need for robust assessment and reporting to improve the rigor with which innovative surgical procedures are evaluated, to optimize transparency, maximize patient benefit and reduce harms” is justified. These researchers hoped that swift and scientific evaluations of MSA will now take place.
Bell et al (2020) noted that regurgitative GERD refractive to medical treatment is common and caused by mechanical failure of the anti-reflux barrier. In a randomized trial, these researchers compared the effects of MSA with those of PPIs. Patients with moderate-to-severe regurgitation (assessed by the foregut symptom questionnaire) despite once-daily PPI therapy (n = 152) were randomly assigned to groups given twice-daily PPIs (n = 102) or laparoscopic MSA (n = 50) at 20 sites, from July 2015 through February 2017. Patients answered questions from the foregut-specific reflux disease questionnaire and GERD-HRQL survey about regurgitation, heartburn, dysphagia, bloating, diarrhea, flatulence, and medication use, at baseline and 6 and 12 months after treatment. Six months after PPI therapy, MSA was offered to patients with persistent moderate-to-severe regurgitation and excess reflux episodes during impedance or pH testing on medication. Regurgitation, foregut scores, esophageal acid exposure, and adverse events (AEs) were evaluated at 1 year. Patients in the MSA group and those who crossed-over to the MSA group after PPI therapy (n = 75) had similar outcomes. MSA resulted in control of regurgitation in 72/75 patients (96%); regurgitation control was independent of pre-operative response to PPIs. Only 8/43 patients receiving PPIs (19%) reported control of regurgitation. Among the 75 patients who received MSA, 61 (81%) had improvements in GERD-HRQL improvement scores (greater than 50%) and 68 patients (91%) discontinued daily PPI use. Proportions of patients with dysphagia decreased from 15% to 7% (p < 0.005), bloating decreased from 55% to 25%, and esophageal acid exposure time decreased from 10.7% to 1.3% (p < 0.001) from study entry to 1-year after MSA (combined p < 0.001); 70% (48/69) of patients had pH normalization at study completion. MSA was not associated with any peri-operative events, device explants, erosions, or migrations. The authors concluded that they found MSA to reduce regurgitation in 95% of patients with moderate-to-severe regurgitation despite once-daily PPI therapy; MSA was superior to twice-daily PPIs therapy in reducing regurgitation. Relief of regurgitation is sustained over 12 months.
The authors concluded that potential limitations in this study included the relatively limited duration of follow-up (1 year). Other studies of MSA have documented little decrease in efficacy between 1 and 5 years of follow-up, and additional long-term studies of MSA are ongoing. This study compared medical and surgical therapy, and lacking evidence to suggest that medical therapy results improve over time, longer-term follow-up comparison of the 2 arms was deemed unnecessary. Another consideration was the use of trans-nasal impedance or pH testing at the 6-month end-point but 48-hour telemetry capsule pH testing at the 12-month end-point. Trans-nasal impedance or pH testing was the only method to evaluate ongoing nonacid regurgitation in the double-dose PPI cohort, as it measured both acidic and acid-neutralized reflux episodes and was appropriate to determine cross-over eligibility. Telemetry capsule pH testing was utilized at 12 months when all patients were evaluated off PPIs and were undergoing follow-up endoscopy. Also, this study did not compare MSA with Nissen fundoplication.
In a systematic review, Schizas et al (2020) examined the safety and efficacy of MSA using the LINX Reflux Management System in resolving GERD symptoms. This review conducted in accordance to the PRISMA guidelines. These investigators searched Medline, Clinicaltrials.gov, Embase, Cochrane Central Register of Controlled Trials CENTRAL databases from inception until September 2019. Overall, 35 studies with a total number of 2,511 MSA patients were included and analyzed. Post-operative PPI cessation rates reached 100%, with less bloating symptoms and a better ability to belch or vomit in comparison to LF. Special patient groups (e.g., bariatric or large hiatal-hernias) had promising results too. The most common post-operative complication was dysphagia ranging between 6% and 83%. Dilation due to dysphagia occurred in 8% of patients with typical inclusion criteria. Esophageal erosion may occur in up to 0.03% of patients. Furthermore, a recent trial (Bell et al, 2020) indicated MSA as an efficient alternative to double-dose PPIs in moderate-to-severe GERD. The authors concluded that the findings of this review suggested that MSA has the potential to bridge the treatment gap between maxed-out medical treatment and LF. However, further studies with longer follow-up are needed for a better elucidation of these results.
Kirkham et al (2020) stated that MSA is reported to be an innovative alternative to anti-reflux surgery for patients with GERD. Although used in practice, little is known about how it has been evaluated. These researchers systematically evaluated the reporting of MSA and its introduction into clinical practice, in the context of guidelines (such as IDEAL) for evaluating innovative surgical devices. Systematic searches were used to identify all published studies reporting MSA insertion. Data collected included patient selection, governance arrangements, surgeon expertise, technique description and outcome reporting. Searches identified 587 abstracts; 39 full-text papers were included (1 randomized controlled trial [RCT], 5 cohort, 3 case-control, 25 case-series, and 5 case reports); 21 followed Food and Drug Administration (FDA) eligibility criteria for MSA insertion; 26 documented that ethical approval was obtained; 2 reported that participating surgeons received training in MSA; 18 provided information regarding how MSA insertion was performed, although techniques varied between studies. Follow-up ranged from 4 weeks to 5 years; in 14 studies, it was less than 1 year. The authors concluded that most studies on MSA lacked information regarding patient selection, governance, expertise, techniques and outcomes, or varied between studies. These researchers stated that MSA is currently being used despite a lack of robust evidence for its effectiveness. They noted that the long‐term safety of MSA has not been sufficiently demonstrated in the existing 39 published studies owing to inconsistent reporting of outcomes, especially those detailing long‐term follow‐up. There is a lack of standardized, transparent reporting of how the MSA device should optimally be inserted, making adoption into practice difficult and hampering comparisons between studies. These investigators stated that there is a need for robust assessment and reporting to improve the rigor with which innovative surgical procedures are evaluated, to optimize transparency, maximize patient benefit and reduce harms.
The Editor shared the authors' conclusion that “magnetic sphincter augmentation is being used in clinical practice despite a lack of robust evidence to support its effectiveness, placing surgeons and patients at risk”. There is a clear need for international registries that evaluate indications and outcomes of new devices and techniques. National surgical bodies and governments should support these registries so they are independent of the industry/companies and surgeons involved in the manufacturing and promotion of new devices, because there will always be a conflict of interest.
Leeds and Ward (2020) determined how often surgical experts agree on the technical aspects of the MSA procedure. A 12-question survey examined various technical aspects of the MSA procedure. The survey was sent to all certified MSA surgical proctors. Consensus on individual questions was defined as greater than or equal to70% agreement among the responding surgeons. The survey was sent to 37 certified MSA surgical proctors, 24 of whom responded (65%). The mean number of MSA procedures performed by the responders was 210. There was consensus on 4 of the 12 questions. The consensus was achieved indicating it is safe for MSA implantation in any size hiatal hernia, and that tension on the hiatal repair is not a factor to implant the MSA device. There was no consensus for 3 mediastinal dissection questions and only consensus on 2 of the 5 questions regarding MSA implantation. Once the device is implanted, there was no consensus for the appearance of the MSA device. The authors concluded that there is a need for procedure standardization to improve teaching and to maintain excellent efficacy and safety outcomes when the device is used in the community.
Furthermore, an UpToDate review on “Surgical management of gastroesophageal reflux in adults” (Schwaitzberg, 2020) states that “MSA with the LINX device has been compared with laparoscopic Nissen fundoplication (LF) in several meta-analyses. Clinical control of reflux was comparable after the two procedures in both the short and longer term. In the longer term, there was less gas bloat associated with MSA than LF. Presently, however, there is insufficient evidence that would allow surgeons to choose between the two procedures. Ten to 20 year results of MSA are not yet available; given the location where device is placed, such data would ultimately alleviate concerns about possible esophageal complications”.
In a systematic review and meta-analysis, Rausa and colleagues (2021) examined the effectiveness of MSA in the management of patients with GERD. These researchers carried out an electronic systematic search using Medline databases (PubMed), Embase, and Web of Science. An electronic systematic search of articles comparing pre-operative and post-operative GERD-HRQL scores in patients who underwent MSA placement for management of GERD following bariatric surgery. A total of 3 retrospective studies (n = 33 patients) met the inclusion criteria and were included in this meta-analysis. The pooled MD in change from pre-operative GERD-HRQL score was 17.5 (95 % CI: -22.88 to -12.20) and it was statistically significant. The between-study variability was 3.621 (95 % HPD: 1.39 to 4.99) with low heterogeneity (I2 = 15 %; 95 % HPD: 2.1 to 26.2 %). The authors concluded that MSA for refractory GERD following bariatric surgery appeared feasible. Moreover, these researchers stated that prospective RCTs with standardized surgical technique and objective follow-up evaluation are needed to better assess short- and long-term effectiveness.
O'Neill et al (2022) stated that while short-term outcomes of MSA compare favorably to those of laparoscopic Nissen fundoplication (LNF), direct comparisons of long-term outcomes are lacking. These researchers hypothesized that the long-term patient-reported outcomes of MSA would be similar to those achieved with LNF. They tested this hypothesis in a retrospective cohort undergoing primary LNF or MSA between March 2013 and July 2015. The primary outcome was GERD-HRQL score at long-term follow-up relative to baseline. Secondary outcomes included dysphagia and bloating scores, PPI cessation, re-operations, and overall satisfaction with surgery. A total of 70 patients (25 MSA, 45 LNF) met criteria for study inclusion. MSA patients had lower baseline BMI (median of 27.1 [IQR: 22.7 to 29.9] versus 30.4 [26.4 to 32.8], p = 0.02), lower total GERD-HRQL (26 [19 to 32] versus 34 [25 to 40], p = 0.02), and dysphagia (2 [0 to 3] versus 3 [1 to 4], p = 0.02) scores. Median follow-up interval exceeded 5 years (MSA: 68 [65 to 74]; LNF: 65 months [62 to 69]). Total GERD-HRQL improved from 26 to 9 after MSA (p < 0.001) and from 34 to 7.5 after LNF (p < 0.01); these scores did not differ between groups (p = 0.68). Dysphagia (MSA: 1 [0 to 2]; LNF: 0 [0 to 2], p = 0.96) and bloating (MSA: 1.5 [0.5 to 3.0]; LNF: 3.0 [1.0 to 4.0], p = 0.08) scores did not show any statistically significant differences. Device removal was carried out in 4 (16 %) MSA patients and re-operation in 3 (7 %) LNF patients; 89 % of LNF patients reported satisfaction with the procedure, compared to 70 % of MSA patients (p = 0.09). The authors concluded that MSA appeared to offer similar long-term improvement in disease-specific QOL as LNF. For MSA, there was a trend toward reduced long-term bloating compared to LNF; however, the need for re-operation and device removal may be associated with patient dissatisfaction.
The ACG clinical guideline on “The diagnosis and management of GERD” (Katz et al, 2022) recommended consideration of MSA as an alternative to laparoscopic fundoplication for patients with regurgitation who fail medical management. (Quality of Evidence = moderate; Strength of Recommendation = strong).
On behalf of the CGIT GERD Consensus Conference participants, Yadlapati et al (2022) updated the American Gastroenterological Association (AGA)’s clinical practice guideline on “The evaluation and management of GERD”. These investigators outlined a personalized diagnostic and therapeutic approach to GERD symptoms. They presented Best Practice Advice statements that were developed from expert review of existing literature combined with extensive discussion and expert opinion to provide practical advice. Formal rating of the quality of evidence or strength of recommendations was not the intent of this clinical practice update.
- Best Practice Advice 12: In patients with proven GERD, laparoscopic fundoplication and magnetic sphincter augmentation are effective surgical options, and transoral incisionless fundoplication is an effective endoscopic option in carefully selected patients.
- Best Practice Advice 13: In patients with proven GERD, Roux-en-Y gastric bypass is an effective primary anti-reflux intervention in obese patients, and a salvage option in non-obese patients, whereas sleeve gastrectomy has potential to worsen GERD.
- Best Practice Advice 14: Candidacy for invasive anti-reflux procedures includes confirmatory evidence of pathologic GERD, exclusion of achalasia, and assessment of esophageal peristaltic function.
The Austrian Institute for Health Technology Assessment (AIHTA) GmbH (2022) stated that “Due to the very low quality of the currently available evidence and the lack of studies with relevant comparators, the inclusion of the three laparoscopic approaches (magnetic sphincter augmentation with a magnetic ring implant (LINX Reflux Management System); a non-active implant made of medical silicone (RefluxStop) and electro-stimulation therapy (EndoStim)) in the Austrian hospital service catalogue is currently not recommended. Higher quality evidence and longer follow-up times (greater than 2 to 3 years) will be required in the future to clarify the currently uncertain evidence situation and to complement the current findings on the safety profile”.
Khaitan et al (2023) noted that patients with medically intractable GERD following laparoscopic sleeve gastrectomy (LSG) have limited surgical options. Fundoplication is difficult post-LSG. Roux-en-Y gastric bypass may be used as a conversion procedure but is more invasive with potential for serious complications. Magnetic sphincter augmentation is a less invasive GERD treatment alternative. In a prospective, observational, single-arm, multi-center study, these researchers examined safety and effectiveness of MSA following LSG. The primary outcome of this trial was the rate of serious device and/or procedure-related AEs. The effectiveness of the LINX device was measured comparing baseline to 12-month post-implant reductions in distal acid exposure, GERD-HRQL score, and average daily PPI usage. A total of 30 subjects who underwent MSA implantation were followed 12 months post-implant. No unanticipated device-associated AEs were observed. There were 2 AEs deemed serious (dysphagia, pain, 6.7 %) that resolved without sequelae. GERD-HRQL scores showed significant improvement (80.8 %, p < 0.001), and reduction in daily PPI usage was observed (95.8 %, p < 0.001); 44 % of subjects reported normalization or 50 % or greater reduction of total distal acid exposure time (baseline 16.2 %, 12 months 11 %; p = 0.038). The authors concluded that post-LSG, MSA showed an overall improvement of GERD symptoms, and reduction in PPI use with explants within anticipated range along with improvement in distal esophageal acid exposure time. Thus, MSA appeared to be safe and effective with comparable morbidity in the treatment of GERD in patients who previously underwent sleeve gastrectomy.
The authors stated that 1 main drawback of this trial was the small subject number (n = 30) who were observed for a relatively short observation period (i.e., 12 months). Although the risk of device erosion was low, the median time to explant was 26 months with most occurring between 1 and 4 years after placement. Furthermore, non-bariatric literature suggested that more than 80 % of explants (rate less than 10 %) occurred 1 to 2 years post-implant. This study was constrained by the inclusion/exclusion criteria of the pivotal study; therefore, there was an element of selection bias in that all cases had successful weight loss (BMI less than 35), with no (37 %) or small (less than 3 cm) hiatal hernias, and no grade-C or grade-D esophagitis. Thus, the study population did not fully represent the post-sleeve GERD population. Additionally, this technology is not intended to treat all GERD after sleeve as the causality is multi-factorial.
NICE’s interventional procedures guidance on “Laparoscopic insertion of a magnetic ring for GERD” (2023) provides the following information:
- Evidence on the safety and efficacy of laparoscopic insertion of a magnetic ring for GERD is adequate to support using this procedure provided that standard arrangements are in place for clinical governance, consent and audit.
- Patient selection, and the procedure, should be done by clinicians who have specific training in the procedure, and experience in upper GI laparoscopic surgery and managing GERD.
Bariatric Surgical Procedures for GERD
Laparoscopic adjustable gastric banding (LAGB) involves the surgical insertion of a hollow band around the stomach near its upper end, creating a small pouch and a narrow passage into the larger remainder of the stomach. The band is inflated with a saline solution and can be tightened or loosened over time to change the size of the passage by increasing or decreasing the amount of saline. The procedure has been suggested to ease the symptoms of GERD. Examples of US Food and Drug Administration (FDA) approved adjustable bands include LAP-BAND and Realize.
Roux-en-Y Gastric Bypass (RYGBP) (open or laparoscopic) is commonly known as "gastric bypass." A small stomach pouch is created to restrict food intake. A Y-shaped section of the small intestine is attached to the pouch to allow food to bypass the lower stomach, the duodenum and the first portion of the jejunum. This reduces the amount of calories and nutrients the body absorbs. Long-limb Roux-en-Y gastric bypass is similar to standard RYGBP, except that the limb through which food passes is long, which purportedly eases symptoms of GERD.
REZA Band
REZA Band is a non-medication, non-surgical device that was designed to reduce the symptoms of acid reflux. The device is worn around the neck while sleeping and reportedly applies slight external pressure to the cricoid cartilage region (right below the Adam’s apple). This purportedly increases the internal pressure in the upper esophageal sphincter (UES); thereby decreasing acid reflux into the esophagus.
Medigus
Medigus Ultrasonic Surgery Endostapler (MUSE) utilizes a disposable flexible endoscope that is inserted through the mouth. The system combines a miniaturized video camera, a surgical stapler and ultrasonic sights for alignment. It has been suggested that the use of this device can help restore a normal gastroesophageal valve through anterior fundoplication via endoluminally placed staples.
Electrical Stimulation of the Lower Esophageal Sphincter (EndoStim)
In an open-label, single-center trial, Rodríguez and colleagues (2015) examined the 2-year safety and effectiveness of LES electrical stimulation therapy (EST) in GERD patients. Subjects responsive partially to PPIs with off-PPI GERD HRQL of greater than or equal to 20, 24-hour esophageal pH less than or equal to 4.0 for greater than 5% of the time, hiatal hernia less than or equal to 3 cm, and esophagitis LA grade C or lower participated in this trial. Bipolar stitch electrodes and a pulse generator (EndoStim BV, The Hague, The Netherlands) were implanted laparoscopically; LES-EST at 20 Hz, 215 μs, 3to 8 mAmp was delivered over 30-minute sessions, 6 to 12 sessions per day, starting on day 1 after implantation. Patients were evaluated using GERD-HRQL, symptom diaries, Short Form-12, and esophageal pH testing at regular intervals. Stimulation sessions were optimized based on residual symptoms and esophageal pH at follow-up. A total of 25 patients (mean age of [SD] = 52 [12] years; 14 men) were implanted successfully; 23 patients participated in the 2-year extension trial, and 21 completed their 2-year evaluation. At 2 years, there was improvement in their median GERD-HRQL on LES-EST compared with both their on-PPI (9 versus 0; p = 0.001) and off-PPI (23.5 versus 0; p < 0.001) baseline scores. Median 24-hour distal esophageal acid exposure improved from 10% at baseline to 4% (per-protocol analysis; p < 0.001) at 2 years with 71% demonstrating either normalization or a greater than or equal to 50% decrease in their distal esophageal acid exposure. All except 5 patients (16/21) reported complete cessation of PPI use; only 2 patients were using a PPI regularly (greater than or equal to 50% of days). There was significant improvement in sleep quality and daily symptoms of heartburn and regurgitation on LES-EST. At baseline, 92% of the subjects (22/24) reported that they were "unsatisfied" with their condition off-PPI and 71% (17/24) on-PPI compared with 0% (0/21) "unsatisfied" at the 24-month visits on LES-EST. There were no device- or therapy-related serious adverse events and no untoward sensation or dysphagia reported with LES-EST. The authors suggested that LES-EST is safe and effective for treating patients with GERD over a period of 2 years; LES-EST resulted in a significant and sustained improvement in GERD symptoms, and esophageal acid exposure and eliminated PPI use in majority of patients (16 of 21). The main drawbacks of this study were its open-label, single-center design (lack of a control group) and its small sample size (n = 25). Furthermore, this study excluded patients with moderate and large (greater than 3 cm) hiatal hernias, LES end-expiratory pressures less than 5 mmHg, and those with severe (grade D) esophagitis or long segment Barrett esophagus. These patients tend to have more severe esophageal motor dysfunction and are more likely to suffer from medically refractory GERD. Thus, effectiveness of LES-EST in these subgroups need to be established. The authors stated that “Sham-controlled trials comparing EST with no stimulation and comparative effectiveness trials compared with maximal medical therapy and anti-reflux surgery may help to better establish the role of LES stimulation in the management of GERD”.
In an editorial that accompanied the afore-mentioned study, Attwood (2015) stated that “So is Endostim too good to be true? Only controlled clinical trials will fully reveal the truth”.
Apollo OverStitch Endoscopic Suturing System
Han and colleagues (2018) determined the feasibility and safety of endoscopic augmentation of the GEJ using the Apollo OverStitch endoscopic suturing system in patients with GERD. Endoscopic augmentation of GEJ was performed on 10 consecutive patients and the data were analyzed retrospectively. Using a double-channel gastroscope affixed to the endoscopic suturing platform, interrupted sutures were placed on the gastric side of the GEJ in 2 layers in order to create a narrowed and elongated GEJ. Technical success was achieved in all patients, including those with a history of previous anti-reflux procedures (n = 7) and those with a hiatal hernia (n = 6). The median follow-up duration was 5 months (range of 2 - to 12). The median pre-procedure GERD-HRQOL Questionnaire improved from 20 (range of 11 to 45) to a post-procedure score of 6 (range of 3 - to 25) (p = 0.001). The median duration of GERD symptom improvement after the procedure was 1 month (range of 0.5 to 4). Adverse events were limited to 1 patient who developed nausea and vomiting, which was self-limited. The authors concluded that the use of a novel endoscopic suturing technique for the treatment of GERD was feasible and safe. The procedure resulted in short-term GERD symptom improvement. These researchers stated that further prospective studies including those with routine pre- and post-procedure ambulatory pH testing, in a larger number of patients are needed to evaluate the optimal technique and long-term outcomes of this novel procedure.
The authors stated that this study had several drawbacks. First, this trial included a heterogeneous group of patients with GERD; 8 patients had prior surgical or endoscopic treatment of GERD and 1 patient had prior esophagectomy; 6 patients had a hiatal hernia, the largest being 5 cm. These confounding factors may hinder evaluation of the efficacy of the procedure. Second, not all patients underwent objective GERD testing with pH monitoring before and after the procedure, thus relying on the GERD-HRQOL questionnaire, which may not be reliable. Third, while the procedure appeared to have improved GERD symptoms initially, at longer follow-up the improvement seemed to disappear. In other words, the effect of the procedure was not durable.
C-BLART (Clip Band Ligation Anti-Reflux Therapy)
Liu and colleagues (2020) noted that C-BLART (clip band ligation anti-reflux therapy) has been reported as a new alternative endoscopic treatment for refractory GERD. These researchers examined the short-term efficacy of C-BLART for controlling GERD symptoms, esophageal acid exposure, esophagitis, and QOL. Patients with refractory GERD were recruited for a non-randomized concurrent comparison, with 60 patients in the C-BLART with tailored PPI use group and 43 patients in the BID PPI group. The primary outcomes were esophageal acid exposure and the LES pressure. The GERD-Q score, esophagitis grade, and adherence degree were also recorded. Cross-over from the BID PPI group to the C-BLART with tailored PPI use group was allowed after 6 months. The LES pressure and GERD-Q score improved more in the C-BLART with tailored PPI use group (p < 0.001) after 6 months, with no significant difference in the decrease in esophagitis compared with the baseline endoscopic results (p = 0.268). Treatment with PPIs had been halted in 43% of the patients at 6 months following C-BLART. At 12 months after C-BLART, the DeMeester score showed a significant improvement compared with the baseline measurements (p = 0.025). The GERD-Q score and LES pressure did not significantly improve compared with the baseline values (p = 0.102, p = 0.184) in C-BLART with tailored PPI use group. At 6 to 12 months, n = 6 (10%) patients had undergone laparoscopic fundoplication to control their symptoms in all the patients following C-BLART. The authors concluded that C-BLART is a novel treatment for controlling refractory GERD symptoms, esophageal acid exposure, and LES pressure according to this short-term analysis, safely performed endoscopically to create an anti-reflux barrier with ligated bands. Despite improvements in DeMeester score, LES pressure, and GERD-Q scores in the C-BLART with tailored PPI use group, many patients continue to demonstrate objective evidence of GERD. These preliminary findings need to be further investigated in well-designed studies.
Osteopathic Visceral Treatment
Eguaras and colleagues (2019) stated that osteopathic manual treatment has been recommended as a non-pharmacological therapy for GERD. However, to-date, no study has supported the effectiveness of this intervention with respect to the symptoms of the disease. In a randomized, double-blind, placebo-controlled trial, these researchers examined the effect of an osteopathic manual technique for the LES on GERD symptoms, cervical mobility and on the C4 spinous process pressure pain threshold (PPTs). A total of 60 subjects suffering from GERD participated in this study and were randomly assigned to either an experimental group (EG) (n = 29), who received the osteopathic technique for the LES, or to a control group (CG) (n = 31), who received a manual contact, which mimicked the osteopathic technique without exerting any therapeutic force. Randomization was computer-generated, with allocation concealed by sequentially numbered, opaque, sealed envelopes. The GERDQ questionnaire was used to assess symptom changes the week following intervention. Cervical range of motion (CROM) and algometer were used to evaluate cervical mobility and PPTs before and after both treatments. Before-after between groups comparison (t-test) was used for statistical analysis of the outcome, with 2 measurement points (ERDQ), while repeated-measures ANOVA was used for those outcomes with 4 measurement points (CROM and PPT). The application of the osteopathic manual treatment in subjects with GERD produced a significant improvement in symptoms 1 week after the intervention (p = 0.005) with a between-groups difference of 1.49 points in GERDQ score (95% CI: 0.47 to 2.49). PPT C4 improved in the EG after the treatment (p = 0.034; η2 = 0.048) (between-groups difference 8.78 Newton/cm2; 95% CI: 0.48 to 17.09). CROM also increased in the EG compared to the CG (p < 0.001; η2 = 0.108) (between-groups difference 33.89 degrees; 95% CI: 15.17 to 52.61). The authors concluded that the manual osteopathic technique produced an improvement in GERD symptoms 1 week after treatment, cervical mobility, and PPTs. This may mean that osteopathic treatment is useful for improving symptoms of GERD.
The authors stated that the main drawback of this study was its short-term (1 week) follow-up. It would be interesting to determinate the duration of improvement for all the outcomes. Actual osteopathic practice usually applies a combination of multiple techniques, during several sessions. However, this study was limited to 1 technique for 2 sessions, because these researchers wanted to know the specific effects of a single visceral osteopathic technique, without the influence of other manual procedures. A more comprehensive osteopathic treatment might achieve even better results. Furthermore, despite the absence of statistical significance, baseline GERDQ differences must be considered to analyze the results. The absence of practitioner blinding must be taken into account, as well as the fact that whether subject blinding was convincing or not was not checked.
Partial Gastrectomy for the Treatment of GERD
Davis and colleagues (2015) noted that treatment of GERD with hiatal hernia in obese patients has proven difficult, as studies demonstrate poor symptom control and high failure rates in this patient population. Recent data have shown that incorporating weight loss procedures into the treatment of reflux may improve overall outcomes. These investigators retrospectively reviewed 28 obese and morbidly obese patients who presented from December 2007 through July 2013 with large or recurrent type 3 or 4 para-esophageal hernia. All of the patients underwent combined para-esophageal hernia repair and partial longitudinal gastrectomy. Charts were retrospectively reviewed, and the patients were contacted to determine symptomatic relief. Mean pre-operative BMI was 38.1 ± 4.9 kg/m2. Anatomic failure of prior fundoplication occurred in 7 patients (25%). The remaining 21 had primary para-esophageal hernia, 3 of which were type 4. Post-operative complications included pulmonary embolism (n = 1), pulmonary decompensation (n = 2), and wound infection (n = 1). Mean hospital stay was 5 ± 3 days. Upper GI esophagogram was carried out in 21 patients with no immediate recurrence or staple line dehiscence. Mean excess weight loss (EWL) was 44 ± 25%. All of the patients surveyed experienced near-to-total resolution of their pre-operative symptoms within the 1st month. At 1 year, symptom scores decreased significantly. At 27 months, however, there was a mild increase in the scores. Return of severe symptoms occurred in 2 patients, both of whom underwent conversion to gastric bypass. The authors concluded that combined laparoscopic para-esophageal hernia repair with longitudinal partial gastrectomy offered a safe, feasible approach to the management of large or recurrent para-esophageal hernia in well-selected obese and morbidly obese patients. Short-term results were promising; however, intermediate results showed increasing rates of reflux symptoms that required medical therapy or conversion to gastric bypass. Moreover, these researchers stated that further analysis of larger groups of bariatric patients with reflux is needed to examine the efficacy of this combined approach. Longer-term follow-up will aid in observing the natural history of the anti-reflux aspect of this surgery and will provide a better understanding of the recurrence of reflux after repair.
The authors stated that this study, although novel in its approach to combined GERD and obesity treatment, was limited by its small patient group and retrospective design. As a follow-up to the initial short-term study, these investigators observed a change in trajectory in symptom score that tended toward a lifespan for this procedure; however, this scoring system was a subjective interpretation by the patient without any correlation with diagnostic imaging or objective follow-up testing. Greater proof of the efficacy of this procedure may be that only 1 patient experienced symptom recurrence severe enough to return for re-evaluation. A limitation specific to the accumulation of data via survey was the inability to account for outside factors that may have contributed to return of symptoms. The surveys did not include data on adherence to diet and lifestyle modification, exercise involvement, or smoking status - all factors that may increase reflux, even after successful surgical repair. As well, patients were not included in the routine post-bariatric surgery study protocols and follow-up schedule.
Le Page and Martin (2015) stated that a difficult management problem for the upper GI surgeon exists when a patient presents with symptomatic and refractory severe delayed gastric emptying. Surgical treatment is further complicated by co-existing gastro-esophageal reflux. No universal surgical strategy exists for this problem. Novel surgical strategy combines partial sleeve gastrectomy (SG) and hiatus hernia (HH) repair with fundoplication. A review of treating 4 such patients was described with objective outcome data. Overall, solid gastric emptying improved in all, from median 350 (163 to 488) mins pre-operatively to 108 (84 to 135) mins at 10 months (3 to 24) post-operatively, corresponding to 67% improvement. Primary symptoms resolved in all; however, 1 patient had recurrent symptoms. GERD-HRQL also improved in all, from median 23 (3 to 25) to 4 (0 to 8) at 21 months (6 to 30, 83% improvement). Gas bloat improved in 3; all had post-operative gastroscopies showing intact repair and absent esophagitis, with no patient requiring post-operative PPI. Patient weight reduced by median 11% (7 to 20) post-operatively; and there was no significant peri-operative morbidity. The authors concluded that with careful patient selection and work-up, SG and HH repair with fundoplication may improve QOL by coupling adequate reflux control with improved gastric emptying.
Furthermore, an UpToDate review on “Surgical management of gastroesophageal reflux in adults” (Schwaitzberg, 2020) does not mention partial gastrectomy as a management / therapeutic option.
Optical Endomicroscopy for the Evaluation of Gastro-Esophageal Reflux Disease (GERD)
Chu et al (2012) noted that objectively diagnosing non-erosive reflux disease (NERD) is still a challenge. These researchers evaluated the use of in-vivo confocal laser endomicroscopy (CLE) to examine the micro-alterations of the esophagus in patients with NERD and its relationship with reflux episodes monitored by multiple intra-luminal impedance-pH (MII-pH). Patients with gastro-esophageal reflux symptoms completed reflux disease questionnaires. NERD was determined by negative gastroscopy. Patients without reflux symptoms were recruited as controls. Pilot clinical study was followed by prospective controlled blinded study. All subjects were examined by white-light mode of the endoscopy followed by the standard CLE mode and then MII-pH monitoring. The micro-alterations observed on CLE images and the correlation between CLE features and reflux episodes were evaluated, the correlation between CLE and transmission electron microscope (TEM) data were also analyzed. On CLE images, NERD patients had more intra-papillary capillary loops (IPCLs) per image than did controls (8.29 ± 3.52 versus 5.69 ± 2.31, p = 0.010), as well as the diameter of IPCLs (19.48 ± 3.13 versus 15.87 ± 2.21 μm, p = 0.041) and intercellular spaces of squamous cells (3.40 ± 0.82 versus 1.90 ± 0.53 μm, p = 0.042). The receiver operating characteristic (ROC) analysis indicated that IPCLs number (optimal cut-off greater than 6 per image, area under the curve (AUC) 0.722, 9 5% confidence interval (CI): 0.592 to 0.853, sensitivity 67.7%, specificity 71.6%), IPCLs diameter (optimal cut-off greater than 17.2 μm, AUC 0.847, 95% CI: 0.747 to 0.947, sensitivity 81%, specificity 76%), and the intercellular spaces of squamous cells (optimal cut-off greater than 2.40 μm, AUC 0.935, 95% CI: 0.875 to 0.995, sensitivity 85.7%, specificity 90.5%) diagnosed NERD with reasonable accuracy. Combined features of dilatation of intercellular space plus increased IPCLs provided 100% specificity in the diagnosis of NERD patients. The intercellular spaces of squamous cells observed on CLE were highly related to that on TEM findings (r = 0.75, p < 0.001). Multi-variate progressive regression analysis showed that acidic reflux, especially in the supine position, was related to the increased number and dilation of IPCLs in the squamous epithelium (β = 0.063, t = 2.895, p = 0.038 and β = 0.156, t = 1.023, p = 0.04). The authors concluded that CLE represented a useful and potentially significant improvement over standard endoscopy to examine the micro-alterations of the esophagus in-vivo. Acidic reflux is responsible for the micro-alterations in the esophagus of patients with NERD.
Dunbar et al (2016) stated that the histologic changes associated with acute gastro-esophageal reflux disease (GERD) have not been studied prospectively in humans. Recent studies in animals have challenged the traditional notion that reflux esophagitis develops when esophageal surface epithelial cells are exposed to lethal chemical injury from refluxed acid. These researchers examined histologic features of esophageal inflammation in acute GERD to study its pathogenesis. Patients from the Dallas Veterans Affairs Medical Center who had reflux esophagitis successfully treated with proton pump inhibitors (PPIs) began 24-hour esophageal pH and impedance monitoring and esophagoscopy (including CLE) with biopsies from non-eroded areas of distal esophagus at baseline (taking PPIs) and at 1 week and 2 weeks after stopping the PPI medication. Enrollment began May 2013 and follow-up ended July 2015; PPIs stopped for 2 weeks. A total of 12 patients (men, 11; mean age of 57.6 year [SD, 13.1]) completed the study. Primary outcome was change in esophageal inflammation 2 weeks after stopping the PPI medication, determined by comparing lymphocyte, eosinophil, and neutrophil infiltrates (each scored on a 0 to 3 scale) in esophageal biopsies. Also evaluated were changes in epithelial basal cell and papillary hyperplasia, surface erosions, intercellular space width, endoscopic grade of esophagitis, esophageal acid exposure, and mucosal impedance (an index of mucosal integrity). At 1 week and 2 weeks after discontinuation of PPIs, biopsies showed significant increases in intra-epithelial lymphocytes, which were predominantly T cells (median [range]: 0 (0 to 2) at baseline versus 1 (1 to 2) at both 1 week [p = 0.005] and 2 weeks [p = 0.002]); neutrophils and eosinophils were few or absent. Biopsies also showed widening of intercellular spaces (confirmed by CLE), and basal cell and papillary hyperplasia developed without surface erosions. Two weeks after stopping the PPI medication, esophageal acid exposure increased (median of 1.2% at baseline to 17.8% at 2 weeks; Δ, 16.2% [95% CI: 4.4% to 26.5%], p = 0.005), mucosal impedance decreased (mean of 2,671.3 Ω at baseline to 1,508.4 Ω at 2 weeks; Δ, 1,162.9 Ω [95% CI: 629.9 to 1,695.9], p = 0.001), and all patients had evidence of esophagitis. The authors concluded that in this preliminary study of 12 patients with severe reflux esophagitis successfully treated with PPI therapy, stopping PPI medication was associated with T lymphocyte-predominant esophageal inflammation and basal cell and papillary hyperplasia without loss of surface cells. If replicated, these findings suggested that the pathogenesis of reflux esophagitis may be cytokine-mediated rather than the result of chemical injury.
Jeong et al (2021) noted that to-date, there is no standard tool to diagnose GERD. Typically, GERD is a NERD that does not present endoscopic abnormalities. These investigators examined the cellular and vascular changes in-vivo and ex-vivo through CLE in patients with GERD. Patients with refractory GERD who underwent mucosectomy were recruited. The distal esophagus was observed in-vivo using CLE. Mucosectomy tissue was stained with acriflavine and CLE image was obtained ex-vivo. They compared cellular and vascular changes in CLE between erosive reflux disease (ERD), NERD, and a control group. A total of 11 patients who underwent anti-reflux mucosectomy and 5 control patients were enrolled in the study. Patients with ERD and NERD presented greater dilated intercellular space than patients in the control group on CLE image. The diameter, number, and cross-sectional area (CSA) of the intra-papillary capillary loops (IPCLs) were significantly larger in the ERD group than in the NERD group. The irregular shape of the IPCLs were observed in both patients with ERD and NERD. The authors concluded that the irregular shape of the IPCLs were significantly correlated with a positive diagnosis of GERD; CLE may diagnose NERD with high sensitivity and accuracy.
The authors stated that this study had limitations that may restrict the interpretation of the study. First, the probe-based CLE (pCLE) technology allows for observation of only a narrow area. To overcome this problem, the endoscopy procedure time was lengthened. This way, the endoscopist searched the wide area of the distal esophagus with the narrow scope of pCLE; thus, the procedure time was about 3 times longer than that of a standard endoscopy procedure. It appeared that this technology may not be suitable for daily practice. Artificial intelligence (AI) has gained popularity in clinical medicine; and applications of AI may be useful to detect early neoplastic or dysplastic lesions in GI endoscopy. Computer-based algorithms may be added to the existing technology of pCLE. Detecting dilatation of dilated intercellular space (DIS) in the epithelium, counting the number of IPCLs, measuring the diameter and CSA of IPCLs, and detecting the irregularly shaped IPCL may be coded as the tasks of the software of pCLE. AI may shorten the time for diagnosing ERD or NERD via pCLE. Many clinical pilot studies must be performed before development of this technology. Another limitation of this study was the small sample size for each group. The reason for the small sample size may be due to a reduced number of patients requiring anti-reflux mucosectomy (ARMS) for the treatment of refractory GERD despite PPI. Another explanation could be the cost of the CLE probe and the procedure of ARMS, since these are not yet covered by the insurance companies in South Korea, and some patients could not afford the associated cost. Furthermore, ARMS has emerged as a new method, and it is not accepted as a standard treatment method for refractory GERD; thus, some patients did not give informed content due to the possible adverse effects associated with the ARMS procedure.
Furthermore, UpToDate reviews on “Clinical manifestations and diagnosis of gastroesophageal reflux in adults” (Kahrilas, 2020), “Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents” (Winter, 2020), and “Approach to refractory gastroesophageal reflux disease in adults” (Fass, 2020) do not mention optical endomicroscopy as a diagnostic / management option.
Anti-Reflux Mucosal Interventions (e.g., Anti-Reflux Band Ligation / Anti-Reflux Mucosectomy / Anti-Reflux Mucosal Ablation) for the Treatment of Refractory Gastroesophageal Reflux Disease
de Santiago et al (2021) stated that anti-reflux mucosectomy (ARMS) and anti-reflux mucosal ablation (ARMA) are new endoscopic procedures for patients with GERD. In a meta-analysis, these investigators examined the feasibility, clinical success, and safety of these procedures. They searched Embase, PubMed, and Cochrane Central from inception to October 2020. Overlapping reports, animal studies, and case reports were excluded. The primary outcomes were clinical success and AEs. Secondary outcomes included technical success, endoscopic esophagitis, 24-hour pH monitoring, and PPI use. A random effects model was used to pool data. A total of 15 non-randomized studies (12 ARMS, n = 331; 3 ARMA, n = 130) were included; 10 were carried out in patients with refractory GERD. The technical success rate was 100 %. The pooled short-term (1st assessment within the first 6 months), 1-year, and 3-year clinical success rates were 78 % (95 % CI: 70 % to 85 %), 72 % (95 % CI: 47 % to 92 %), and 73 % (95 % CI: 65 % to 81 %), respectively. ARMS and ARMA yielded similar clinical success. The proportion of patients off PPIs at 1 year was 64 % (95 % CI: 52 % to 75 %). There were significant reductions (p < 0.01) in validated clinical questionnaires scores, presence of esophagitis, and acid exposure time. The most common AE (11 %, 95 % CI: 8 % to 15 %) was dysphagia requiring dilation (7 %, 95 % CI: 5 % to 11 %); 4 cases of perforation were recorded, all in patients undergoing ARMS. The authors concluded that this meta-analysis of non-randomized studies suggested that ARMS and ARMA were safe and effective for the treatment of patients with GERD. Moreover, these researchers stated that these findings indicated that these techniques deserve further examinations in RCTs.
The authors stated that this study had 2 main drawbacks. First, it could be argued that the definition of clinical success was not uniform, which could be explained by the lack of expert consensus on how to measure success in GERD therapies. To overcome this drawback, these researchers also pooled data from validated clinical questionnaires, PPI use, endoscopic esophagitis, and 24-hour pH monitoring and performed a sensitivity analysis using a commonly used definition in recent studies. All analyses supported the effectiveness of ARMS and ARMA. Second, all studies were of single-arm design and no RCTs were found. The placebo effect could not be ruled out, although it appeared unlikely that this would account for ARMA/ARMS effectiveness, considering that the response rate to placebo in GERD clinical trials was around 20 %. Nevertheless, these investigators agreed with guidelines from the European Society of Gastrointestinal Endoscopy recommending that these techniques be performed within research protocols due to the lack of long-term and controlled data.
Garg et al (2022) noted that ARMS is an emerging endoscopic treatment for refractory GERD. In a systematic review and meta-analysis, these researchers examined the safety and effectiveness of ARMS in refractory GERD. These investigators carried out a comprehensive search of multiple databases (through March 2020) to identify studies that reported outcomes of ARMS for the treatment of refractory GERD. Outcomes assessed included technical success, clinical response, and AEs. Clinical response was defined as discontinuation (complete) or reduction (partial) of PPIs post-ARMS at follow-up. A total of 307 patients (mean age of 46.9 [8.1] years, 41.5 % women) were included from 10 studies. The technical success and clinical response rates were 97.7 % (95 % CI: 94.6 % to 99.0 %) and 80.1 % (95 % CI: 61.6 % to 91.0 %), respectively. The pooled rate of complete and partial clinical response was 65.3 % (95 % CI: 51.4 % to 77.0 %) and 21.5 % (95 % CI: 14.2 % to 31.2 %), respectively. The rate of AEs was 17.2 % (95 % CI: 13.1 % to 22.2 %) with most common AE being dysphagia/esophageal stricture followed by bleeding with rates of 11.4 % and 5.0 %, respectively. GERD-HRQL (MD = 14.9, p < 0.001), GERD questionnaire (GERD-Q) (MD = 4.85, p < 0.001) and mean acid exposure time (MD = 2.39, p = 0.01) decreased significantly post-ARMS as compared to pre-procedure. There was no difference in terms of clinical response and AEs between ARMS and ARMS with banding on subgroup analysis. The authors concluded that ARMS was a safe and effective procedure for the treatment of refractory GERD with high rates of clinical response, acceptable safety profile and significant improvement in GERD-HQOL. These researchers stated that future prospective studies with long-term follow-up are needed to validate these findings.
The authors stated that this study had several drawbacks, most of which are inherent to any meta-analysis. The included studies were not entirely representative of the general population and community practice, with most studies being conducted in tertiary-care referral centers. The cost associated with the procedure was not examined in this analysis. These investigators were also unable to compare ARMS with the current standard of care (SOC) for refractory GERD and laparoscopic fundoplication. Furthermore, the endoscopic procedure is highly operator-dependent. The success and safety profile are dependent on the expertise of the person performing the procedure. These investigators also could not compare procedure time between the 2 techniques. Additionally, follow-up was quite variable in included studies, which added to heterogeneity for clinical success along with small sample size. There was limited precision in these investigators’ estimates as evidenced by wide CIs. They also could not directly compare outcomes of ARMS with other endoscopic techniques such as TIF and MSA as data are not available. Additional subgroup analyses were also not possible due to lack of data.
Yeh et al (2022) stated that endoscopic treatments are increasingly being employed for the treatment of refractory GERD. Three procedures have similar concepts and techniques: ARMS, ARMA, and anti-reflux band ligation (ARBL); these investigators have collectively termed them anti-reflux mucosal intervention (ARMI). These researchers systematically reviewed the clinical outcomes and technical aspects. The PubMed, Embase, and Cochrane Library databases were searched from inception to October 2021. The primary outcome was the clinical success rate. The secondary outcomes were acid exposure time, DeMeester score, need for PPIs, endoscopic findings, and AEs. A total of 15 studies were included. The pooled clinical success rate was 73.8 % (95% CI: 69 % to 78 %) overall, 68.6 % (95 % CI: 62.2 % to 74.4 %) with ARMS, 86.7 % (95 % CI: 78.7 % to 91.9 %) with ARMA, and 76.5 % (95 % CI: 65 % to 85.1 %) with ARBL. ARMI resulted in significantly improved acid exposure time, DeMeester score, and degree of hiatal hernia. In addition, 10 % of patients had dysphagia requiring endoscopic dilatation following ARMS or ARMA, and ARMS was associated with a 2.2 % perforation rate. In contrast, no bleeding, perforation, or severe dysphagia was noted with ARBL. Severe hiatal hernia (Hill grade-III) may predict treatment failure with ARMA. The authors concluded that the 3 ARMI procedures were safe and effective for PPI-refractory GERD -- ARMA and ARBL may be preferred over ARMS because of fewer AEs and similar effectiveness. Moreover, these researchers stated further investigation is needed to determine the optimal technique and candidates of the ARMI procedures.
The authors stated that this study had several drawbacks. First, most of the included articles were retrospective and lacked control groups. Second, the outcome parameters were not complete in all studies because these researchers only included the up-to-date report for each specific cohort, and a few lost-to-follow-up cases were not accounted for. Third, apparent clinical heterogeneity and marked variations in patient numbers and outcome parameters precluded performing meta-analyses for most outcomes. However, these investigators examined the clinical success rate, PPI usage, and dysphagia rate to better demonstrate the safety and effectiveness of ARMI procedures. Moreover, although nearly all studies claimed symptomatic improvement by questionnaire-based evaluation, these researchers used the clinical success rate that was clearly defined (patients had 50 % or more symptomatic improvement compared with baseline) as the primary outcome, in order to have more validated assessment. Fourth, most of the studies analyzed included only PPI-refractory patients; only 1 involved PPI-dependent patients. Therefore, the interpretation of outcomes for PPI-dependent patients should be viewed with caution. Fifth, no included study examined the feasibility of the procedures in patients who underwent SG, and only a few cases with prior anti-reflux surgery were included. Nearly 1/3 of such patients developed GERD following surgery, and the response to radiofrequency ablation (RFA) was unsatisfactory, possibly due to altered anatomy. However, ARMI procedures may still provide improvement in symptomatic relief by tightening GEJ. Moreover, these researchers stated that with more emerging studies and RCTs, more validated evidence and approaches for ARMI are needed as part of GERD treatment.
Laparoscopic Magnetic Sphincter Augmentation for Patients with Medically-Refractory Gastroesophageal Reflux After Sleeve Gastrectomy
Bona et al (2022) stated that the development of GERD has been shown to be not infrequent following laparoscopic SG (LSG). Management may vary from medical therapy to Roux-en-Y gastric bypass (RYGB) conversion. Magnetic sphincter augmentation device has been shown to be a promising option with excellent results. These researchers presented an intra-operative video to demonstrate the laparoscopic management of post-LSG GERD with MSA device implant. The procedure started with the lysis of the peri-gastric adhesions to free the distal esophagus circumferentially. The posterior vagus nerve was identified, and a small window was created between the posterior esophageal wall anteriorly and the vagus nerve posteriorly. A hiatoplasty was carried out using 2 non-resorbable interrupted 2.0 Prolene sutures. The system's sizer was placed to measure the junctional circumference. A 15-mm MSA device was implanted. The authors concluded that the MSA device placement appeared technically feasible and safe with promising results in term of improved LES resting pressure and esophageal acid exposure. These investigators stated that while future, large-scale studies are needed to corroborate these preliminary indications, MSA device may possibly become a valid option in surgeon armamentarium. Specific indications and universally accepted guidelines are needed to identify patients that might benefit from this approach.
Patel et al (2022) noted that the use of the MSA in patients with de-novo or persistent GERD after SG has not been thoroughly examined. In a retrospective study, these investigators examined the effectiveness of MSA device placement in improving GERD symptoms and reducing anti-reflux medication usage in patients with persistent or de-novo GERD after SG. This trial included patients who underwent laparoscopic MSA device placement between January 2018 and July 2020 after SG. A total of 22 patients met inclusion criteria; 20 patients were female (91 %) and 2 patients were male (9 %). All patients were taking anti-reflux medications daily to control GERD symptoms before MSA device placement. There was a significant improvement in the mean GERD-HRQL survey scores when comparing scores before (43.8) and after (16.7) MSA device placement (p < 0.0001). Majority of the patients did well without any post-operative complications (77 %). Nearly 82 % of patients were no longer taking any anti-acid medications following MSA device placement (p < 0.0485). There were no patients who required MSA device removals. There were no AEs such as MSA device erosions or device-related mortalities. The authors concluded that MSA device placement in patients with medically refractory GERD after SG was a safe and viable alternative to Roux-en-Y gastric bypass without conferring additional risks. These investigators showed an improvement in reflux symptoms following MSA device placement as evidenced by decreased post-operative GERD-HRQL scores, decreased anti-acid medication usage, and overall patient satisfaction with the procedure. Moreover, these researchers stated that further prospective and comparative studies with longer term follow-up are needed to validate the use of MSA in patients who have undergone SG.
Nasal Continuous Positive Airway Pressure for the Treatment of Nocturnal Gastroesophageal Reflux
Schuitenmaker et al (2022) stated that nocturnal GER symptoms have a major impact on sleep quality and are associated with complicated GERD. In a systematic review, these investigators examined the data on the effectiveness of the currently available treatments for nocturnal reflux symptoms. They searched PubMed, Embase, and the Cochrane Library. All prospective, controlled, and uncontrolled clinical trials in adult patients describing interventions (lifestyle modifications, surgical and pharmacological) for nocturnal GER symptoms were assessed for eligibility. A narrative descriptive summary of findings was presented together with summary tables for study characteristics and quality assessment. The initial reference search yielded 3,067 citations; 66 citations were screened in full text, of which 31 studies were included. Studies on lifestyle modifications include head-of-bed elevation (n = 5), prolonging dinner-to-bed time (n = 2); as well as promoting left lateral decubitus position (n = 2). Placebo-controlled clinical trials examining PPIs (n = 11) showed success rates ranging from 34.4 % to 80.8 % in the PPI group versus 10.4 % to 51.7 % in the placebo group. Laparoscopic fundoplication was reserved for severe disease only. There was insufficient evidence for a recommendation on the use of nasal continuous positive airway pressure (nCPAP), hypnotics, baclofen and adding bedtime H2 receptor antagonists for reducing nocturnal reflux. The authors recommended sequential treatment strategy, including head-of-bed elevation, prolonging dinner-to-bed time, promoting left lateral decubitus position and treatment with acid-suppressive medication for nocturnal GER symptoms. Currently, there is insufficient evidence for the use of nCPAP, hypnotics, baclofen and adding bedtime H2 receptor antagonists.
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