Medical Policy Gastroesophageal Reflux Disease (GERD): Endoscopic Treatments Effective Date: November, 2002: Revised [08/06; 10/08; 10/10; 10/12; 10/14; 10/16]

Subject: Gastroesophageal Reflux Disease (GERD): Endoscopic Treatments Overview: Several endoscopic treatments have been proposed for treating GERD, all of which focus on improving the function of the lower esophageal sphincter (LES). This is in response to the theory the LES relaxes too frequently in patients with GERD-related symptoms.

Policy and Coverage Criteria: Harvard Pilgrim does NOT cover the following treatments for gastroesophageal reflux disease (GERD), they are considered investigational/experimental and unproven:  Transesophageal radiofrequency to the gastroesophageal junction (Stretta System)  Endoscopic Suturing or transoral incisionless fundoplication (TIF) for GERD (including, but not limited to, EsophyX, StomaphyX, Plicator system, EDS system with Sew-Right, Endoscopic Gastroplasty)  Endoscopic Injection and Implantation (Implantation of PMMA microbeads, Gatekeeper, plexiglass implantation, Durasphere, Enteryx System and LINX Reflux Management System)

Exclusions: N/A Supporting Information: 1. Technology Assessment: Endoscopic, or endoluminal, therapies for gastroesophageal reflux disease (GERD) are designed to alter structures at the gastroesophageal junction to prevent reflux of gastric contents, eliminating symptoms, healing esophagitis, preventing recurrence of symptoms or progression of disease, and reducing the need for lifelong pharmacologic therapy. They may be classified into three basic categories: (1) endoscopic or plication suturing of the proximal stomach; (2) radiofrequency energy delivered to the gastroesophageal junction; and (3) polymer injection or implantation of bulking agents or devices into the cardia or distal esophagus. 2. Literature Review: There are a number of studies evaluating the relative safety and efficacy of endoscopic GERD treatments. While some have shown promising short-term results, long-term safety and efficacy remains unclear. Further well-designed studies are needed to support the positive, long-term outcomes in patients with GERD. One proposed treatment for GERD is transesophageal radiofrequency to the gastroesophageal junction. The Stretta System is an FDA cleared minimally invasive device for the treatment of refractory GERD. It uses a flexible catheter with needle electrodes for energy delivery down the patient’s esophagus. Precisely controlled radiofrequency 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. It is thought the tighter valve provides significantly increased resistance to gastric reflux. Dughera et al (2014) published 8-year-follow-up results for 26 patients who underwent Stretta procedures. The study’s endpoint was durability of the procedure at 8 years. Patients underwent clinical evaluation by upper endoscopy, esophageal pressure, and pH studies. Data at 8 years was compared to those recorded at baseline and at 4 year follow-up. There was a significant decrease in both heartburn and GERD HRQL scores at 4 years and at 8 years as well as a significant increase in quality of life scores at each follow-up. After 4 years, 21 patients were off PPI medication and after 8 years, 20 patients were completely off PPI medication. Median LES

pressure did not show significant amelioration at 4 and 8 years and mean esophageal acid exposure significantly improved at 4 years but returned to baseline after 8 years. The authors concluded that RF energy delivery for GERD provides durable improvement in symptoms and in quality of life and reduces antireflux drug consumption. A 2010 study by Aziz et al. reported on trial of the Stretta device for GERD. 36 patients were randomized into three treatment groups. 12 patients underwent a single Stretta session, 12 underwent a sham procedure and 12 underwent a single Stretta session follow by a repeat session if GERD heal-related quality of life was not 75% improved after 4 months. In each patient treated with the Stretta, 56 lesions were created per session. The primary outcome measure was HRQL improvement. Secondary outcomes included medication use, lower esophageal sphincter basal pressure, endscopic grade of esophagitis, and esophageal acid exposure by pH probe. Analysis of the results showed Stretta significantly reduced GERD HRQL, use of PPI drugs, esophageal acid exposure, LES pressure, and grade of esophagitis compared with the sham. Double Stretta had significantly more frequent normalization of HRQL scores compared with the single Stretta. Dundon et al. (2008) reported on long-term outcomes of patients who underwent the Stretta procedure for GERD symptom control. 32 patients with a mean follow-up of 53 months were included in the study. 19 then proceeded onto anti-reflux surgery. Those not undergoing surgery showed a significant improvement in their GERD satisfaction from 3.14 to 1.46 but had significantly lower pre-procedure heartburn score than those who proceeded to surgery. The Stretta procedure was effective in reducing symptoms in 40% of patients. Responders had less sever preoperative heartburn. RF energy delivery to the LES may be effective in selected aptients for the treatment of GERD. A 2007 review by Schwartz and Smout looked at studies evaluating a number of endoscopic GERD treatments. Endocinch, Stretta and Enteryx all have studies comparing them with sham treatments. Schwartz and Smout found although the three techniques were able to improve symptoms, quality of life and PPI use, the acid reduction was unremarkable. The review also found there were durability concerns over the Endocinch system and the Enteryx and gel prosthesis implantation systems were recalled for severe complications and lack of efficacy. They concluded the widespread clinical use of endotherapy for GERD should wait until further developments and studies made to determine what modifications are required to produce optimal efficacy and durability. A 2003 review by Galmiche and des Varannes, reviewed literature on endoluminal therapies for GERD and concluded studies of the Stretta System have been largely uncontrolled, none show long-term effectiveness of procedure, no studies compared the Stretta System with other established medical or surgical therapies, and, though few, some severe complications have been observed after the Stretta procedure. Another review by Hochberger et al. (2003), reached similar conclusions about the Stretta procedure. The authors found even with promising results in preliminary studies, there were no long-term results available and as a result, the procedure would be considered experimental. A more recent 2007 review by Spicak evaluated three types of endoscopic treatment for GERD and found the Stretta procedure to be lacking in long-term results and would only be justifiable as use as part of a clinical trial. Endoscopic suturing of areas around the LES aims to tighten the valve and prevent reflux. Submucosal stitching devices and deep transmural placating devices are the two basic techniques used to place sutures or staples at the cardia. They both create pleats of tissue just beneath the gastroesophageal junction. Bell et al. (2011) reported on the efficacy and safety of a case series study on the EsophyX system. 37 patients on antisecretory medication and with GERD and limited hiatal hernia underwent TIF for persistent symptoms. Five patients were reoperations for failed laparoscopic fundoplication. One mediastinal abscess treated laparoscopically and one postoperative bleeding requiring transfusion were reported as complications. A median follow up period of six months found a significant improvement of both atypical and typical symptoms in 64% and 70–80% 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). There were no reports of dysphagia, bloating, or excess flatulence, and 82% of patients were not taking PPIs. 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 five (13.5%) patients underwent revision. The study had a small sample size and lacked long-term follow-up. Barnes et al. (2011) retrospectively evaluated 124 GERD patients who underwent EsophyX fundoplication. All patients had chronic GERD for a median of nine years, were on daily double-dose of PPIs for a median of eight years, and 97% reported ineffective symptom control on medical therapy. 110 patients completed GERD-specific questionnaires following the procedure. At a median seven-month follow-up (range 5-17), typical and atypical

symptom scores were normalized in 75―80% of patients, PPI use stopped in 93%, and 83% were satisfied with their current health condition. Analysis showed only 8% of treated patients had ongoing GERD. The study did not report long-term success and did not measure pH. A 2010 study from von Renteln et al. reported on 23 patients on maintenance PPI therapy that underwent endoscopic full-thickness placation for GERD. Multichannel intraluminal impedimence monitoring was used before and 6-motnhs after the procedure. Results showed the total median number of reflux episodes significantly reduced from 1-5 to 65. Median number of acid reflux episodes decreased from 73 to 43; non-acid reflux episodes decreased from 23 to 21; median bolus clearance time was 12s before treatment and 11s at 6 months. Based on the small set of patients, the authors concluded the full-thickness placation significantly reduced total reflux episodes, acid reflux episodes, and total reflux exposure time. An earlier study by von Renteln (2009) showcased the 12-month results of 41 patients treated with the full-thickness placation for GERD. The studies results showed the need for daily PPI therapy was eliminated in 69% of patients at 12 months on a per-protocol basis, and 59% on an intent to treat basis. Adverse events included post-procedure abdominal pain (44%), shoulder pain (24%), and chest pain (17%). Von Renteln et al. concluded from these results the Plicator implants can be used safely and effectively to improve GERD symptoms and reduce medication use. Schwartz et al. (2007) reported on endoscopic gastroplication using the EndoCinch suturing system. 60 patients were randomly assigned to three endoscopic gastroplications, a sham procedure or observation. Follow up was monitored until one year. While GERD symptoms improved in the active group more than in the sham or observation groups, the improvement was not significantly different than the improvement in the sham group. These results led Schwartz et al. to conclude the device and technique should be improved and efficacy needs to be proven in a sham-controlled fashion. A 2011 NICE guidance for endoluminal gastroplication for GERD noted “Evidence from a number of randomised controlled trials (RCTs) shows a degree of efficacy in terms of reduced medication requirement in the short term, but changes in other efficacy outcomes are inconsistent and there is no good evidence of sustained improvement in oesophageal pH measurements. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.” Bredenoord (2010) noted while many endoscopic anti-reflux treatments have been introduced over the years, endoluminal plication techniques and endoluminal RF ablation therapy remain based in research centers because more data of safety and efficacy is needed before the procedures can become standard. Montgomery et al. (2006) also found no significant change in esophageal acid exposure after 12 months in 46 patients enrolled in a sham-controlled study of EndoCinch. The Plicator System consists of an instrument containing a suture-based implant and a endoscopic tissue retractor. It allows for restructuring of the normal anti-reflux barrier. A 2007 prospective study by Pleskow et al. reported on safety and efficacy of endoscopic fullthickness placation for the treatment of GERD. 29 patients completed the 12 and 36 month follow-up. Median GERD- Health Related Quality of Life score remained significantly improved at 36 months versus baseline off meds scores. However, even with the noted improvements, the authors acknowledged the small number of patients in the study and the lack of a comparative sham group. A pilot study by Chuttani et al. (2003) reported 6 patients were treated with the full-thickness placation procedure. At one year after the procedure, authors reported 3 of 5 patients were not taking anti-GERD medications. They concluded the procedure to be feasible and safe, but conceded the findings need to be validated by prospective randomized controlled studies. A 2012 retrospective study by Trad et al. evaluated long-term outcomes of TIF in GERD and LPR symptomatic patients. Follow up was completed on 28 patients who underwent TIF using EsophyX. The median follow-up time was 14 months. Results showed 23/28 patients were off daily PPIs and 19/28 were satisfied with their current health condition. Heartburn was eliminated in 17/26 and improved by greater than 50% in 24/28 patients. The authors found the results of the 28 patients confirm the safety and efficacy of TIF. Testoni et al. (2012) reported long-term results up to 24 months for patients who underwent TIF with EsophyX. Results included GERD-HRQL, GERD-QUAL, GI endoscopy, esophageal manometry, and 24h pH impedance before and at 6, 12, and 24 months after the TIF procedure. 35 patients completed 6 month follow up and 26 completed 24 months. At 6 months, results showed 60% completed stopped PPI therapy. At 24 months, 42.3% completed stopped PPI therapy. Hiatal hernia and ineffective esophageal motility seemed to raise the risk of symptom recurrence. The authors concluded the larger amount of fasteners deployed during TIF was predictive of positive outcome. Also, 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. Antoniou et al. (2012) compared the effectiveness of endoscopic plication and laparoscopic fundoplication to other GERD surgical treatment. 60 GERD patients underwent either endoscopic plication or laparoscopic

fundoplication. 29 endoscopic patients and 27 laparoscopic patients were available at the 12 month follow up. The authors found both the procedures resulted in significant symptom improvement with similar quality of life improvements. Small sample size and the lack of long-term follow up limit the conclusions. Treatments for GERD that entail endoscopic injection and implantation have a limited amount of supporting evidence. The injection of bulking agents like expandable hydrogel prosthesis, ethylene vinyl alcohol copolymer with tantalum dissolved in dimethyl sulfoxide, and plexiglas plymethylmethacrylate microspheres (PMMA), aim to impede reflux at the level of the esophagastric junction. A 2004 assessment conducted by the National Institute of Clinical Excellent (NICE) concluded that available evidence on the safety and efficacy of endoscopic injection of bio-compatible polymer for GERD does not appear to be adequate for the procedure. A 2009 study reported on an initial human pilot study of Durasphere, an injectable bulking agent proposed to treat mild to moderate GERD. The authors found Durasphere to be a promising new injectable agent for GERD with few adverse events, and demonstrable efficacy. 10 GERD patients on daily PPI therapy were endoscopically injected with Durasphere at the gastroesophageal junction. 9 of the 10 patients completed the 12-moth followup. 70% the patients discontinued antacid medication complete, 90% reduced PPI use by greater than 50%. There was no esophagitis at 12 months, no erosion, ulceration or sloughing o material was noted at any injection site. The Durasphere material did not appear to migrate. Fockens et al. (2010) assessed the endoscopic injectable prosthesis, the Gatekeeper Reflux Repair System, for GERD. Researchers performed a prospective, randomized, sham-controlled, single-blinded, international multicenter study. An interim analysis was performed after 143 patients were enrolled (25 lead in, 75 GK, and 43 sham patients). The Gatekeeper study was terminated early due to lack of compelling efficacy data. At six months there was not statistically significant difference between the treatment and control groups. Fry et al. (2007) conducted a systematic review of the evidence on the effect of endoscopic therapies for GERD. Forty-three studies met their inclusion criteria including four randomized controlled trials. Many of the studies were small feasibility studies, with follow-ups of less than one year. No study comparing endoscopic techniques with other established treatment options such as PPIs existed. All endoscopic therapies were associated with a small percentage of mild to severe complications, which included perforation, abscess and death. The authors concluded that the data from most of the short-term follow-up and the few sham-controlled studies demonstrate that subgroups of patients experienced improvement or resolution of typical GERD symptoms and decreased PPI usage. The authors stated that there is limited data on safety, efficacy and durability to support the use of endoluminal therapies for GERD in routine clinical practice. Torquati et al. (2007) conducted an evidence-based review of the literature of FDA-approved modalities of endoluminal treatment of GERD. Sixteen studies met the inclusion criteria, representing 787 patients. The studies were categorized according to the guidelines for levels of evidence and grades of recommendation supplied by the Oxford Centre for Evidence-Based Medicine. The authors concluded there is grade 1b and 2b evidence demonstrating the EndoCinch plication is effective in reducing GERD symptoms at short-term follow up. However, in the majority of the studies analyzed, the procedure does not significantly reduce the acid exposure in the distal esophagus. The majority of the studies with long-term outcome showed disappointing outcomes, probably due to suture loss in the majority of patients. There is grade 1b and 2b evidence demonstrating that the Stretta procedure is effective in reducing GERD symptoms at short- and mid-term follow-up. However, in the majority of the studies analyzed, the procedure did not reduce significantly the acid exposure in the distal esophagus. There is grade 1b and 2b evidence demonstrating that full-thickness plication is effective in reducing GERD symptoms, and acid exposure in the distal esophagus. The LINX System is a device placed at the LES designed to augment a weak sphincter and minimize GERD-related symptoms. There is not enough evidence in clinical literature to support its long-term safety and efficacy. Smith et al. (2014) reported results of 66 GERD patients implanted with the device. The average length of follow up was 5.8 months. Approximately 92% reported they were satisfied or neutral with their GERD condition. 83% were PPI free. The authors found outcomes improved over time after implantation. They found the device to be a promising new offering for patients with GERD. Bonavina et al. (2013) reported two single-group trials confirmed the LINX device can be safely and effectively implanted using the standard laparoscopic approach. Results for the trials found decreased esophageal acid exposure, improved reflux symptoms and quality of life, and decrease in PPI use in the majority of patients.

Lipham et al. (2012) conducted a follow-up to the original Bonavina study. The researcher used initial GERD baseline as the control for post implant evaluations. 80% of patients achieved pH normalization. At greater than 43 years, 100% of patients reported improved QOL measures for GERD and 80% had reduced PPI use. 3. Professional/Governmental Agencies: Agency for Healthcare Research and Quality: A 2011 Comparative Effectiveness Review for management of gastroesophageal reflux disease noted the following limitations and conclusions: “Studies directly comparing surgery to medical therapy generally had high dropout rates in long-term follow-up. There was a great deal of variability in the rigor with which the outcomes were evaluated across studies, particularly in subjective endpoints. Conclusions. Medical therapy and laparoscopic fundoplication were similarly effective in improving GERD symptoms in patients whose symptoms were already well controlled by medical therapy for at least the first 1 to 3 years following surgery. Serious adverse events were more common after surgery. The effectiveness of endoscopic procedures remains substantially uncertain.” http://www.effectivehealthcare.ahrq.gov/ehc/products/165/755/CER29GERD_20110926.pdfhttp://www.effectivehealthcare.ahrq.gov/ehc/products/165/755/CER29-GERD_20110926.pdf FDA:  Stretta® System: Received PMA 501k approval April 18, 2000 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm?ID=199  Endoscopic Plication System: Received PMA 501k approval May 23, 2003; modified October 18, 2007  http://www.accessdata.fda.gov/cdrh_docs/pdf7/k072125.pdf  EsophyX™ System: Received PMA 501k approval September 14, 2007; modified November 6, 2009  http://www.accessdata.fda.gov/cdrh_docs/pdf9/k092400.pdfNDO Plicator: Received PMA 501k approval September 18, 2007  http://www.accessdata.fda.gov/cdrh_docs/pdf7/k071553.pdfLINX System: PMA approval March 22, 2012 http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100049a.pdf CMS: No National Coverage Determination Local Coverage Determination: “Not proven effective” https://www.cms.gov/medicare-coverage-database/details/lcddetails.aspx?LCDId=35080&ContrId=310&ver=6&ContrVer=1&CntrctrSelected=310*1&Cntrctr=310&name=Natio nal+Government+Services%2c+Inc.+%28National+Government+Services%2c+Inc.+%2814212%2c+A+and+B +and+HHH+MAC%2c+J+-+K%29%29&LCntrctr=310*1&DocType=Active&bc=AgACAAQAAAAAAA%3d%3d&

Codes: 43257 – Upper Gastrointestinal Endoscopy with delivery of thermal energy to the muscle of lower esophageal sphincter and/or gastric cardia, for treatment of gastroesophageal reflux disease 43999 – Unlisted procedure 43236 – Esophagogastroduodenoscopy, flexible, transoral; with directed submucosal injection(s), any substance 43201 – Esophagoscopy, flexible, transoral; with directed submucosal injection(s), any substance 43210 – Esophagogastroduodenoscopy, flexible, transoral; with esophagogastric fundoplasty, partial or complete, includes duodenoscopy when performed 0392T - Laparoscopy, surgical, esophageal sphincter augmentation procedure, placement sphincter augmentation device - i.e. magnetic band

References:

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