ndividuals in the TIF group were followed beyond 6 months as a nonrandomized case series, with additional individuals from the control group who crossed over to have TIF. Sixty individuals eventually underwent TIF, but there were losses to follow-up at 6 months (seven individuals) and 12 months (an additional eight individuals). Although GERD symptoms remained improved over baseline (P<0.05), EAE did not differ significantly from baseline. At least occasional use of PPI increased between 6 months and 12 months, from 34% to 61%. Three TIF individuals underwent fundoplication during this follow-up period. Endoscopy findings at 6 months and 12 months showed several findings indicating possible worsening of GERD in terms of esophagitis rating, Hill grade rating of the gastroesophageal valve, and size of hiatal hernia, but no formal statistical analysis of these changes was reported. Although this RCT met its principal end point at 6 months, and improvements in GERD symptoms appeared to be maintained to 12 months, long-term reflux control was not achieved, and due to findings observed between 6 months and 12 months in TIF individuals, the authors concluded that “TIF is no[t an] equivalent alternative for PPIs in GERD treatment, even in this highly selected population.” Limitations of the study include the small patient population; 2:1 randomization; short-term follow-up, and number of individuals lost to follow-up.
Randomized Controlled Trials Comparing TIF with EsophyX to Laparoscopic Fundoplication
In 2011, Svoboda et al. published the results from a RCT that compared TIF using either the Plicator method (n=18) or EsophyX (n=16) to NLF (n=18). Individuals were enrolled if they had chronic GERD symptoms, abnormal EAE test results, partial response to PPI therapy, hiatal hernia smaller than 2 cm, and no findings associated with severe esophagitis and/or complications. At 12-months' follow-up, 76% (26/34) of the individuals in the TIF group and 78% (14/18) of the individuals in the NLF group were available. GERD-HRQL scores improved in both groups to a similar extent at 3 months and 12 months (12-month scores, 6.6 for TIF vs 6.7 for NLF; P=0.7). In terms of the percentage of individuals with 50% or more improvement in GERD-HRQL scores at 12 months, results were similar (68% for TIF vs 71% for NLF; P=0.397). Fifty percent of the TIF group were off PPIs at 12 months versus 71% of the NLF group (P=0.2). The hospital stay was significantly shorter (P<0.0001) in TIF group (average, 2.9 ± 0.8 days) than in the NLF group (average, 6.4 ± 0.7). Four serious AEs occurred: one in the TIF group and three in the NLF group. The AE in the TIF group did not occur in an EsophyX subject. The AEs in the NLF group were unrelated to surgery. The authors stated that "longer follow-up is necessary to verify efficacy for more years." Using US Preventive Services Task Force criteria, this RCT was rated poor for the following reasons: TIF was performed using a different device in some individuals and the reporting lacked details on other aspects of the trial. Furthermore, more than half of the individuals who had TIF did so using a discontinued device. Therefore, the trial results may not generalize specifically to EsophyX. In addition, there was no separate analysis of individuals undergoing TIF with the EsophyX device. The limitations of this study are the small sample size and lack of long-term follow-up.
Nonrandomized Controlled Trials Comparing TIF with EsophyX to Laparoscopic Fundoplication
In a nonrandomized, case-controlled study, Toomey et al. (2014) compared three cohorts of individuals undergoing TIF using EsophyX (n=20), LNF (n=20), or Toupet fundoplication (TF; n=20). The authors stated that age, BMI, and preoperative DeMeester score were controlled, but it is not clear how this matching or control was achieved. The indications for each procedure resulted in an imbalance in important individual characteristics. For example, individuals with abnormal esophageal motility underwent TF, and only individuals who had a hiatal hernia of 2 cm or less were offered TIF. Due to these selection criteria, at baseline, 15% of the TIF group had a hiatal hernia versus 65% and 55% of the two fundoplication groups, limiting comparison of both treatments. Another incidental difference in baseline characteristics was the proportion of individuals undergoing a reoperation for GERD: 25% in the TIF group versus 5% and 5% in the two fundoplication groups. It is unclear from the article at what time postsurgery the outcomes were evaluated. An analysis plan was not provided, and it is unclear how statistical testing was performed. Results are displayed in the published article as preoperative and postoperative median values of various symptoms’ severity or frequency for each procedure. It appears as if, qualitatively, most measures of symptoms decreased to low levels (median ranges, 0−2) after all procedures. The authors stated that “… there was significant amelioration of symptom frequency and severity and with no significant difference among individuals who underwent TIF or … Nissen or Toupet fundoplications.” At follow-up, 83% of the individuals in the TIF group, 80% of the individuals in the LNF group, and 92% of the individuals in the TF group had symptoms less than once per month (P=0.12). Patient-rated satisfaction was 67% for TIF, 86% for LNF, and 92% for TF (P value not reported), but described as “similar.” Adverse events were not reported for any of the procedures.
In 2011, Frazzoni et al. reported the results from a nonrandomized study that compared 10 individuals who chose to undergo TIF using EsophyX with 10 individuals who chose to undergo LF. Eligible individuals had persisting symptoms despite at least 4 weeks of high-dose PPI therapy. Individuals with signs of severe esophagitis and extraesophageal manifestations of GERD were excluded. At baseline, individuals had similar levels of acid exposure and reflux as assessed by preprocedure endoscopy and manometry. Regarding clinical outcomes assessed at 3 months, seven individuals in the TIF group reported only partial or no symptom remission versus zero individuals in the LF group (P=0.003). Mild dysphagia was reported by two individuals after LF and one individual after TIF. Two individuals reported epigastric bloating after LF. Several measures of GERD as assessed by manometry and impedance pH monitoring showed greater improvement in the LF group than in the TIF group. This study reported that TIF is less effective than LF in improving symptoms of GERD.
Single-Arm Trials (Case Series)
In 2021, Bell et al. evaluated the durability of TIF with the EsophyX2 in 151 individuals via a single-institution prospective registry between November 2008 and July 2015. Of these individuals, the average duration of GERD symptoms was 11.3 years and 78% reported moderate to severe ongoing symptoms preoperatively despite PPI therapy. Eighty-six percent (n=131) were available for follow-up at a median of 4.92 years (0.7−9.7 years). Results revealed a reduction in the median GERD-HRQL scores from 21 (off PPI) and 14 (on PPI) at baseline to 4 (at 4.92 years) and 5 (at 5 to 9 years post-TIF). A successful (>50%) reduction in GERD-HRQL score at 4.92 years was seen in 64% of evaluable individuals and 68% of individuals followed for 5 or more years. Thirty-three (22%) of TIF individuals underwent laparoscopic revisional surgery at a median of 14.7 months after surgery. Approximately 70% of individuals remained free of daily PPI use throughout follow-up. The authors concluded that TIF provides durable relief of GERD symptoms for up to 9 years with a significant portion of individuals having a successful outcome by symptom response and PPI use.
In 2019, Testoni et al. reported the clinical outcomes up to 10 years of a prospective study evaluating TIF with EsophyX in individuals with GERD. Fifty-one procedures were performed in 50 individuals. All individuals entered a yearly clinical follow-up schedule including GERD HRQOL questionnaires, heartburn and regurgitation scores, and daily PPI consumption. The procedure was successfully performed in 49 of 50 individuals. Severe complications occurred in two of 51 procedures. The remaining 49 individuals were re-evaluated at 2 and 3 years, 41 after 5 years, 30 after 7 years, and 14 after 10 years. Seven individuals who were unresponsive to endoscopic fundoplication underwent surgical fundoplication. The mean scores at 2 years were significantly lower than before the procedure and did not change substantially during the follow-up. The rates of individuals who had stopped or halved antisecretory therapy 2, 3, 5, 7, and 10 years after the procedure were 86.7 %, 84.4 %, 73.5 %, 83.3 %, and 91.7 %, respectively. Limitations of the study include the small individual population and lack of a comparator.
In 2017, Stefanidis et al. reported the results of a prospective case series evaluating the long-term efficacy and safety of the TIF procedure in individuals with a history of esophagitis or proven chronic GERD who had achieved symptom control with the administration of PPIs but did not wish to continue receiving medications for life. Forty-five individuals (ages 18–60 years, BMI <36 kg/m2) with typical GERD symptoms (heartburn, regurgitation, chest pain) for more than 6 months for at least three times per week, and a history of esophagitis grade A and B or proven GERD by esophageal pH monitoring, underwent TIF using Esophyx. Individuals with esophagitis C and D or those with large hiatal hernias (>2 cm in length) were excluded. The primary clinical effectiveness measure was GERD symptom elimination at follow-up based on normalization of the GERD-HRQL questionnaire. After a median follow-up period of 59 months (range, 36−75 months) the median GERD-HRQL scores improved significantly from 27 (2−45) at baseline to 4 (0−26) (P<0.001) in the 44 individuals completing the study. Heartburn was eliminated in 12 of the 21 individuals included (57.1%), regurgitation was eliminated in 15 of the 17 individuals included (88.2%) and finally chest pain was eliminated in five individuals of the six individuals included (83.3%). Overall, 32 of the 44 individuals (72.7%) who completed the study follow-up reported elimination of their main symptoms without the need for PPI administration (no PPI usage). Furthermore, six more individuals (13.6%), five with heartburn and one with regurgitation, reported half PPI dose taken for less than 50% of the preceding follow-up period (occasional PPI usage), whereas six more individuals (four with heartburn, one with regurgitation, and one with chest pain) reported full or half PPI dose taken for more than 50% of the preceding follow-up period (daily PPI usage). Adverse events included one pneumothorax and one event of hematemesis. Other events included epigastric pain and pharynx irritation. Limitations of the study include the small individual population, short-term follow-up, and lack of a comparator. Randomized clinical trials are needed to validate these results in comparison with other treatments for GERD.
In 2017, Ebright et al. reported follow-up data on endoscopic TIF to treat GERD. For a 3-year period, TIF procedures were performed on 80 individuals. Preoperative workup routinely consisted of contrast esophagram and manometry. PH testing was reserved for individuals with either atypical symptoms or typical symptoms unresponsive to PPIs. Heartburn severity was longitudinally assessed using the GERD-HRQOL index. Safety analysis was performed on all 80 individuals, and an effectiveness analysis was performed on individuals with at least 6 months' follow-up. Mean procedure time was 75 minutes. There were seven (8.75%) grade 2 complications and one (1.25%) grade 3 complication (aspiration pneumonia). The median length of stay (LOS) was 1 day (mean, 1.4). Forty-one individuals had a minimum 6 months' follow-up (mean, 24 months; range, 6−68 months). The mean satisfaction scores at follow-up improved significantly from baseline (P<0.001). Sixty-three percent of individuals had completely stopped or reduced their PPI dose. Results were not impacted by impaired motility; however, the presence of a small hiatal hernia or a Hill grade 2/4 valve was associated with reduced GERD-HRQOL scores postoperatively. the authors concluded that at a mean follow-up of 24 months, TIF is effective. Although symptoms and satisfaction improved significantly, many individuals continued to take PPIs. Future studies should focus on longer-term durability and comparisons with laparoscopic techniques.
In 2015, Testoni et al. reported the clinical outcomes up to 6 years of a prospective study evaluating TIF with EsophyX2 in individuals with GERD. Fifty individuals 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. Individuals were followed for up to 6 years (mean 52.7 ± 19.7 months). In all, 83.7%, 79.6%, 87.8%, and 84.4% of individuals stopped or halved the PPI therapy 6, 12, 24, and 36 months after TIF. The 3-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 individuals, in 66.7% of grade II and 58.3% of grade III. This figure remained substantially unchanged at 12 and 24 months. 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 to II, no hiatal hernia or hernia smaller than 2 cm (P=0.03), absence of ineffective esophageal motility (P<0.0001), and number of fasteners deployed (P=0.01). Limitations of the study include the small individual population and lack of a comparator.
In 2013, Muls et al. prospectively evaluated the long-term safety and durability of TIF using EsophyX 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 gastrointestinal endoscopy, and pH-metry. Of 79 individuals previously reported at 1 year, 12 were lost to follow-up, and one died from an unrelated cause. The remaining 66 individuals were followed-up and analyzed (mITT). Of the 66 individuals, 12 underwent revisional procedures, leaving 54 individuals for PP analysis at a median of 3.1 years (range, 2.9−3.6). No AEs 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, 0−32) from both off (25 [13−38], P<0.0001) and on (9 [0−22], P<0.0001) PPIs. Discontinuation of daily PPIs was sustained in 61% (mITT) and 74% (PP) of individuals. Of 11 individuals with pH data at 3 years (PP), nine (82%) remained normal. Based on mITT analysis, nine of 23 (39%) remained normal at 3 years. The authors 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."
In 2012, Testoni et al. assessed the long-term effects of TIF using EsophyX2 (TIF 2.0) in individuals with symptomatic GERD. TIF 2.0 fundoplication was done in 42 consecutive individuals. All were studied with GERD-HRQL and GERD-QUAL questionnaires, upper gastrointestinal endoscopy, esophageal manometry, and 24-h pH impedance before and at 6, 12, and 24 months after TIF. In all, 35 individuals completed 6-month follow-up; 21 (60.0%) completely stopped PPI therapy, six (17.1%) more than halved it, and eight (22.9%) continued with the same dose as before the procedure. There were 26 individuals with complete 24-month follow-up; 11 (42.3%) completely stopped PPI therapy, seven (26.9%) more than halved it, and eight (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 major limitation of this small study was its uncontrolled design. Also, while 77% of individuals 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.
In 2012, Bell et al. reported the results from a multicenter, prospective, noncomparative study evaluating the safety and efficacy of TIF using the EsophyX2 system within different GERD subgroups (n=100) at 6-month follow-up. The authors also attempted to identify factors associated with clinical success in individuals undergoing TIF. Symptom improvement and objective outcomes of TIF were analyzed at 6-month follow-up compared with baseline. Primary outcomes measured included the elimination of daily typical or atypical GERD symptoms or clinically significant improvement in global symptoms. The secondary effectiveness endpoints were elimination of PPI usage; normalization or clinically significant improvement in EAE or number of reflux episodes measured objectively by 48-hour pH or 24-hour impedance/pH testing; healing of reflux esophagitis; and reduction of hiatal hernia. Intraoperative and postoperative serious AEs were evaluated and individuals were evaluated for common postfundoplication side effects of dysphagia, bloating, and flatulence. No complications were reported. Median GERD symptom duration was 9 years (range, 1–35 years) and median duration of PPI use was 7 years (1–20 years). Maximal medical therapy resulted in incomplete symptom control for 92% of individuals; GERD-HRQL total score was normalized in 73%. Median heartburn and regurgitation scores improved significantly, from 18 (range, 0–30) and 15 (range, 0–30) on PPIs before TIF to 3 (range, 0–25) and 0 (range, 0–25), respectively; P<0.001. Median RSI scores were reduced after TIF from 24 (range, 14–41) to 7 (range, 0–44); P<0.001. Eighty percent of individuals were completely off PPIs after TIF versus 92% of individuals on PPIs before TIF. Preoperative factors associated with clinical outcomes were less severe heartburn (total GERD-HRQL ≤30; P=0.02) and the presence of esophagitis (P<0.02). Reported limitations include the duration of follow-up and possibility of individual selection bias.
In 2012, Trad et al. reported the results from a retrospective study evaluating safety, symptom resolution, patient satisfaction, and medication use 1 to 2 years after TIF in individuals with GERD and/or laryngopharyngeal reflux (LPR) symptoms. Thirty-four individuals with a confirmed diagnosis of GERD symptoms that were inadequately controlled by antisecretory medications, and who where either dissatisfied with their current therapy or not willing to continue taking medication, underwent TIF using EsophyX2. Follow-up assessments were completed in 28 individuals (82%). Median age of the study group was 57 (range, 23–77) years, BMI was 25.7 (18.3–36.4 kg/m2, and 50% were female individuals. All individuals had documented chronic GERD for a median 5 (1–20) years and refractory symptoms to PPIs. Hiatal hernia was present in 75% (21/28) of individuals, and 21% (6/28) had erosive esophagitis (LA grade A or B). TIF was performed following a standardized TIF2 protocol and resulted in reducing hiatal hernia and restoring the natural anatomy of the gastroesophageal junction (GEJ) (Hill's grade I). There were no postoperative complications. At a median 14 months' follow-up, 82% (23/28) of individuals 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-HRQOL scores were significantly reduced to 4 (0–25) from 26 (0–45) before TIF (P<0.001). Heartburn was eliminated in 65% (17/26) and improved by more than 50% in 86% (24/28) of individuals. Regurgitation was eliminated in 80% (16/20) of individuals. Atypical LPR symptoms such as hoarseness, coughing, and throat clearing were eliminated in 63% (17/27) of individuals as measured by RSI scores. Limitations of this study included its retrospective, single-center design, small sample size and a lack of follow-up comparative pH/impedance monitoring data.
In 2011, Bell and Freeman retrospectively evaluated the efficacy and safety of a rotational/longitudinal esophagogastric TIF using EsophyX2 in individuals with GERD. Thirty-seven consecutive individuals on antisecretory medication and with proven gastroesophageal reflux and limited hiatal hernia underwent TIF for persistent GERD symptoms. Five cases were reoperations for failed LF. Of the 37 treated individuals, 57% were female. The median age was 58 (range, 20–81) years and BMI was 25.5 (range, 15.9–36.1 kg/m2). Sixty-eight percent indicated GERD-associated cough, asthma, or aspiration as a primary complaint and 32% complained of heartburn or regurgitation. Two complications occurred: one mediastinal abscess treated laparoscopically and one postoperative bleeding requiring transfusion. At 6 months' median follow-up (range, 3–14), TIF resulted in a significant improvement of both atypical and typical symptoms in 64% and 70% to 80% of individuals, respectively, as indicated by the corresponding GERD-HRQL and RSI score reduction by 50% or more compared with baseline on PPIs. No individual 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 individuals in terms of acid exposure, number of refluxates, and DeMeester scores, respectively. TIF was effective in treating GERD in 75% of individuals, among whom 54% were in a complete "remission" and 21% were "improved." The remaining 25% were considered failures, and five (13.5%) individuals underwent revision. This was a small, retrospective study with short-term follow-up; its findings need to be validated by well-designed studies.
In 2011, Barnes et al. reported the results from a retrospective study evaluating clinical outcomes in 124 consecutive individuals with GERD who underwent TIF using EsophyX2. Of 123 individuals treated successfully, 110 gave consent (74% female, median age 60 [range, 21–87] years, BMI 27.5 [19.0–47.9]). At a median 7-month follow-up (range, 5–17), typical and atypical symptom scores were normalized in 75% to 80% of individuals s, PPIs were completely discontinued by 93%, and 83% were satisfied with their current health condition. Endoscopy in 53 individuals revealed Hill's 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 individuals were in remission, 20% improved symptomatically, and only 8% had ongoing GERD. Limitations of the study include retrospective study design, short-term follow-up, and lack of a comparator.
In 2008, Cadiére et al. reported the results from a prospective, multicenter trial evaluating the safety and efficacy of TIF using the EsophyX system in the treatment of GERD. Eighty-six individuals with chronic GERD taking PPIs were enrolled. Exclusion criteria included an irreducible hiatal hernia larger than 2 cm. The TIF procedure (n=84) reduced all hiatal hernias (n=49) and constructed valves measuring 4 cm (2–6 cm) and 230 degrees (160–300 degrees). Serious AEs consisted of two esophageal perforations upon device insertion and one case of postoperative intraluminal bleeding. Other AEs were mild and transient. At 12 months, aggregate (n=79) and stratified Hill's grade I tight (n=21) results showed 73% and 86% of individuals with 50% or more improvement in GERD-HRQL scores, 85% discontinuation of daily PPI use, and 81% complete cessation of PPIs; 37% and 48% normalization of EAE; 60% and 89% hiatal hernia reduction; and 62% and 80% esophagitis reduction, respectively. More than 50% of individuals with Hill's grade I tight valves had a normalized cardia circumference. LES resting pressure was improved significantly (P<0.001) by 53%. EsophyX-TIF cured GERD in 56% of individuals based on their symptom reduction and PPI discontinuation.
In 2008, Bergman et al. reported the results from a retrospective study evaluating the safety and effectiveness of the first-generation EsophyX system in individuals with GERD who had undergone endoluminal fundoplication with the device. At follow-up, PPI usage was elicited and two validated questionnaires were administered measuring GERD-HRQL (range, 0–50) and symptom severity (range, 0–72). In limited preliminary evaluation, the initial North American experience with endoluminal fundoplication using the EsophyX device is that it appears to be safe and provides moderate effectiveness in treating the symptoms of GERD. The authors stated that further studies comparing this technique with conventional medical and surgical therapies are necessary.
Summary
For individuals who have GERD and a hiatal hernia of 2 cm or less that is not controlled by PPIs who receive TIF (e.g., EsophyX), the evidence includes two RCTs comparing TIF with PPI therapy, one RCT comparing TIF with fundoplication, nonrandomized studies comparing TIF with fundoplication, and case series with longer-term follow-up. The relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. The highest quality RCT (Hunter et al.) was sham-controlled that compared TIF with PPI therapy while the other RCT (Trad et al.) compared TIF with maximum PPI therapy. Both trials found a significant benefit of TIF on the primary outcome measure in about 65% of individuals. The sham-controlled trial reported improvement in 45% of the sham-controlled group and no benefit on secondary subjective outcome measures. The nonblinded RCT found significant improvements in subjective measures but no difference in objective outcome measures compared with PPI therapy. Together, these trial results would suggest a strong placebo effect of the surgery and a modest benefit of TIF in individuals whose symptoms were not controlled by PPIs. For these individuals, the most appropriate comparator would be LF. Studies comparing TIF with fundoplication have limitations that include earlier TIF procedures and unbalanced groups at baseline and are inadequate to determine relative efficacy. At present, the available evidence does not support the use of this intervention in individuals whose symptoms are not controlled by medical therapy.
For individuals who have GERD and a hiatal hernia of 2 cm or less that is controlled by PPIs who receive TIF (e.g., EsophyX), the evidence includes two RCTs and observational studies with longer term follow-up. The relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. A sham-controlled trial found that the time to resume PPI therapy was longer following TIF and the remission rate was higher, indicating that TIF is more effective than no therapy. The nonblinded RCT found a benefit of TIF compared with continued PPI therapy for subjective measures, but not for the objective measures of pH normalization and esophagitis. These results raise questions about a possible placebo effect for the procedure. Also, observational studies have indicated a loss of treatment effectiveness over time. Adverse events associated with the procedure (e.g., perforation) may be severe. At present, the available evidence does not support the use of this intervention in individuals whose symptoms are adequately controlled by medical therapy.
The published, peer-reviewed scientific literature evaluating TIF using EsophyX contains numerous case series studies with small patient populations. Whereas these case series report improvements in outcomes following treatment with EsophyX, the lack of control group precludes the ability to generalize findings and draw strong conclusions regarding the impact on health outcomes. RCTs with longer follow-up periods are needed to determine whether EsophyX improves outcomes compared to alternative treatment modalities.
StomaphyX
StomaphyX is a weight-loss procedure in which the volume of the stomach is reduced resulting in decreased food intake and early satiety. The procedure involves folding and fastening parts of the stomach pouch and is performed in an endoscopic manner without the need for incisions.
No studies evaluating the use of StomaphyX for the treatment of GERD were identified.
Medigus Ultrasonic Surgical Endostapler or MUSE System (formerly the SRS Endoscopic Stapling System)
The MUSE System (MediGus Ltd., Omer, Israel) creates a TIF. According to the FDA, the system enables the operator to staple the fundus of the stomach to the esophagus, in two or more locations around the esophageal circumference, entirely through the mouth, without incisions. The system consists of three main parts: the endoscopic stapler, the control console, and several accessories.
In 2014, the MUSE was cleared for marketing by the FDA through the 510(k) process. The system is intended for endoscopic placement of surgical staples in soft tissue of the esophagus and stomach in order to create anterior partial fundoplication for treatment of symptomatic chronic GERD in individuals who require and respond to pharmacological therapy. The predicate device to the MUSE System is the Medigus SRS Endoscopic Stapling System (MediGus Ltd., Omer, Israel), which has the same indication as the MUSE System.
Systematic Reviews and Meta-Analyses
In a 2015 clinical review, Lo and Mashimo stated the following regarding the MUSE System: "Initial 6-month follow-up data for MUSE are promising, although the presence of 2 early severe adverse events including esophageal leak and postprocedural upper gastrointestinal bleeding necessitated changes to the procedure protocol and to the device. Questions about safety and long-term durability of symptom relief remain."
Clinical Trials
In 2016, Kim et al. reported the long-term outcomes from the Zacherl et al. (2015) MUSE study using the MUSE. Efficacy and safety data from 37 individuals with GERD were analyzed at baseline, 6 months, and 4 years postprocedure. In one center, efficacy and safety data were evaluated at baseline, 6 months postprocedure, and then annually up to 4 years. No new complications were reported. The proportions of individuals who remained off daily PPI were 83.8% (31/37) at 6 months and 69.4% (25/36) at 4 years postprocedure. GERD-HRQL scores (off PPI) were significantly decreased from baseline to 6 months and 4 years postprocedure. The daily dosage of GERD medications, measured as omeprazole equivalents (mean ± SD, mg), decreased from 66.1 ± 33.2 at baseline to 10.8 ± 15.9 at 6 months and 12.8 ± 19.4 at 4 years postprocedure (P<0.01). The authors stated that "[f]uture studies with larger patient series, sham control group, and greater number of staples are awaited."
In 2015, Roy-Shapira et al. reported the results of an Institutional Review Board (IRB)-approved pilot study of 13 individuals who received a transoral anterior partial fundoplication for the treatment of GERD using a MUSE. All individuals had a history of PPI use, objective evidence of GERD, and no significant comorbidity. Primary follow-up at 6 weeks included pH-metrics, GERD-HRQL scores, and PPI use. The protocol allowed annual telephone interviews for the following 5 years to collect GERD-HRQL scores, PPI use, satisfaction with the procedure, and willingness to have the procedure again. At 6 weeks, mean total acid exposure was significantly reduced, and 12 of 13 individuals reduced GERD-HRQL scores by 50% or more. Twelve of 13 individuals had stopped daily GERD medications, and nine of 13 had stopped all GERD medications. Each year, 11 of the 13 individuals could be reached with all 13 individuals having at least 4-year follow-up. Throughout the follow-up period, GERD-HRQL scores were normal (<10) in all but one individual. All individuals would agree to do the procedure again. The median satisfaction score is 8 (range, 6–10) on a scale of 1 to 10. None reported dysphagia. At 1 year, 54% of respondents (6/11) had eliminated PPI use, with another 27% (3/11) taking a reduced dose. Combining respondents at 4 and 5 years to account for all individuals, 54% (7/13) had eliminated and another 23% (3/13) reduced PPI use at least 50%.
In 2015, Zacherl et al. reported the results from a multicenter, prospective study that evaluated the clinical experiences of 69 individuals who received the MUSE. Individuals with well-categorized GERD were enrolled at six international sites. Efficacy data were compared at baseline and at 6 months postprocedure. The primary endpoint was a 50% or more improvement in GERD-HRQL score. Secondary endpoints were elimination or 50% or more reduction in dose of PPI medication and reduction of total acid exposure on esophageal pH probe monitoring. A safety evaluation was performed at time 0 and weeks 1, 4, 12, and 6 months. Sixty-six individuals completed follow-up. Six months after the procedure, the GERD-HRQL score improved by more than 50% off PPI in 73% (48/66) of individuals (95% CI, 60%–83%). Forty-two individuals (64.6%) were no longer using daily PPI medication. Of the 23 individuals who continued to take PPI following the procedure, 13 (56.5%) reported a 50% or more reduction in dose. The mean percent of total time with esophageal pH less than 4.0 decreased from baseline to 6 months (P<0.001). Common AEs were perioperative chest discomfort and sore throat. Two severe AEs requiring intervention occurred in the first 24 subjects, and no further esophageal injury or leaks were reported in the remaining 48 enrolled subjects. From their results, the authors concluded that "[t]he initial 6-month data reported in this study demonstrate safety and efficacy of this endoscopic plication device. Early experience with the device necessitated procedure and device changes to improve safety, with improved results in the later portion of the study. Continued assessment of durability and safety are ongoing in a three-year follow-up study of this patient group."
In 2014, Danalioglu et al. compared the safety and efficacy of the SRS Endoscopic Stapling System (SRS) to laparoscopic antireflux surgery (LARS). Twenty-seven individuals enrolled in the study. Eleven underwent SRS and 16 underwent LARS. Symptoms were assessed using Velanovich GERD-HRQL scores. The groups were compared in reference to operation time, improvement in GERD-HRQL scores, and postoperative course. Chi-squared and Mann-Whitney U-tests were used for statistical analysis. Both groups were statistically similar. An esophageal perforation observed in the SRS group completely resolved after over-the-scope clipping. Procedure times for SRS and LARS were 89 and 47 minutes, respectively (P<0.05). Mean discharge time was longer for SRS than LARS (3 days vs 1.2 days; P<0.05). However, this difference disappeared with the exclusion of a complicated case with long hospitalization in the SRS group. During 6 months mean follow up, PPI use was higher in the SRS group compared to the LARS group, but the difference was not significant. Mean GERD-HRQL scores dropped in 87% and in 64% of individuals (P>0.05) from 29.3 to 4.1 and from 24.8 to 8.9 (P=0.016) in LARS and SRS groups, respectively.
Summary
There is a lack of studies in the peer-reviewed literature investigating the safety and efficacy of the MUSE system or SRS. The studies in the peer-reviewed literature are primarily in the form of case series with small patient populations. RCTs with long-term follow-up are needed to determine whether the MUSE system or SRS improves outcomes compared with alternative treatment modalities.
TRANSESOPHAGEAL ENDOSCOPIC SUTURING OR PLICATION
Apollo OverStitch Endoscopic Suturing System
The Apollo OverStitch Endoscopic Suturing System (Apollo Endosurgery, Austin, Texas) provides full-thickness sutures over a flexible endoscopic platform. The current version, which received FDA approval for endoscopic suturing and tissue apposition in 2011, has found use in a variety of settings such as primary endoscopic obesity surgery, postbariatric surgery endoscopic stoma reduction, perforation closure, covered self-expanding metal stent fixation, gastrointestinal fistula/leak closure, and closure after endoscopic mucosal resection.
In 2018, Han et al. reported the results from a preliminary study evaluating the feasibility and safety of endoscopic augmentation of the GEJ using the Apollo OverStitch Endoscopic Suturing System in individuals with GERD symptoms. Endoscopic augmentation of the GEJ was performed on 10 consecutive individuals 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 two layers in order to create a narrowed and elongated GEJ. Technical success was achieved in all individuals, including those with a history of previous antireflux procedures (n = 7) and those with a hiatal hernia (n = 6). The median follow-up duration was 5 months (range, 2 – 12). The median preprocedure GERD-HRQL improved from 20 (range, 11– 45) to a postprocedure score of 6 (range, 3– 25) (P = 0.001). The median duration of GERD symptom improvement after the procedure was 1 month (range, 0.5– 4). Adverse events were limited to one individual who developed nausea and vomiting, which was self-limited. The authors concluded that the use of the Apollo OverStitch Endoscopic Suturing System for the treatment of GERD is feasible and safe. The procedure resulted in short-term GERD symptom improvement. The authors stated that further prospective studies including those with routine pre- and postprocedure ambulatory pH testing, in a larger number of individuals are needed to evaluate the optimal technique and long-term outcomes of this novel procedure. The authors stated that there were several limitations in this study: (1) the trial included a heterogeneous group of individuals with GERD, (2) eight individuals had prior surgical or endoscopic treatment of GERD and one individual had prior esophagectomy, and (3) six individuals had a hiatal hernia, the largest being 5 cm. These confounding factors may hinder evaluation of the efficacy of the procedure. Additionally, not all individuals underwent objective GERD testing with pH monitoring before and after the procedure, thus relying on the GERD-HRQOL questionnaire, which may not be reliable. Finally, while the procedure appeared to have improved GERD symptoms initially, at longer follow-up the improvement seemed to disappear; i.e., the effect of the procedure was not durable.
Bard EndoCinch Suturing System / Bard Endoscopic Suturing System
In this procedure, a metal guidewire with a spring tip is passed through the endoscope into the pylorus and the endoscope is removed. A polyvinyl dilator and overtube are passed over the guidewire. The dilator and guidewire are removed and the overtube serves as a conduit for subsequent instrument passage. Another gastroscope with the mounted sewing capsule is advanced to the level of the Z-line. A minimum of two plications are placed for each procedure. One or two of these plications is placed along the lesser and the other below the Z-line. Stitches to form the plication are placed in a circumferential pattern.
In 2001, the Bard EndoCinch Suturing System (Bard Endoscopic Technologies, Billerica, MA) was cleared for marketing by the FDA through the 510(k) process. The system is intended for endoscopic placement of sutures in the soft tissue of the esophagus and stomach and for approximation of tissue for the treatment of symptomatic GERD. The predicate device to the Bard EndoCinch Suturing System is the Bard Endoscopic Suturing System, which has the same indication as the Bard EndoCinch Suturing System.
Clinical Trials
In 2013, Schwartz et al. reported the results obtained from 50 individuals who were recruited from an initial randomized, placebo-controlled, single-center study (Schwartz et al. 2007) and followed for 4 years. Three individuals were lost to follow-up. At 4 years, symptom scores and four of six QOL subscales were improved (all P<0.01 compared to baseline). However, 80% of the individuals required PPIs for their GERD symptoms. Ultimately, 64% of the cases were classified as treatment failures. In 60%, a postprocedural endoscopy was carried out, in which 16% were diagnosed with reflux esophagitis. The authors concluded that during the 4-year follow-up period, the number of individuals who benefited from endoscopic gastroplication (EndoCinch) gradually declined, and nearly half of the individuals chose re-treatment and 80% eventually required PPIs.
In a single-center, double-blind, randomized, sham-controlled trial, Schwartz et al. (2007) reported the findings of 60 individuals with GERD. In this study, 20 individuals were randomly assigned to EndoCinch, 20 underwent a sham procedure, and 20 received no intervention (observation group). After 3 months, open-label active treatment was offered to all patients. The primary outcome measures were PPI use and GERD symptoms, and secondary measures were QOL, 24-hour EAE, esophageal manometry, and AEs. Follow-up assessments were performed at 3, 6, and 12 months. At 3 months' follow-up, the proportion of individuals who had reduced their PPI use by at least greater than 50% was significantly higher in the treatment group (65%) than in either the sham (25%) or observation groups (0%) (P<0.02). Symptoms (heartburn and to a lesser extent regurgitation) improved more in the active group than in the sham group. Three Short Form-20 QOL subscales (role function, general health, and bodily pain perception) improved in the active group versus sham. EAE was modestly decreased after active treatment (P<0.02), but not significantly greater than after the sham procedure (P=0.61). The active treatment effects on PPI use, symptoms, and QOL persisted after 6 and 12 months of open-label follow-up (n=41), but 29% of individuals were retreated in this period. No serious AEs occurred. The authors concluded that endoscopic gastroplication using EndoCinch reduces PPI use and improves general GERD symptoms and QOL. However, the reduction in EAE was not greater after endoscopic treatment than after a sham procedure. The study is limited by a small sample size and limited follow-up time.
In 2006, Montgomery et al. reported the results from a single-center, randomized, sham-controlled trial evaluating the effects of the EndoCinch plication technique in a randomized, placebo-controlled setting. Forty-six otherwise healthy subjects with objectively verified GERD requiring regular use of PPIs were enrolled in the study. Individuals were randomly assigned to the EndoCinch plication technique or a sham procedure. Pre- and postprocedure assessments included gastroesophageal endoscopy, esophageal manometry, and 24-hour pH recording, QOL assessment, and use of PPIs. Reflux-specific symptoms and use of PPIs (total intake as well as number of individuals not taking PPIs) improved in both groups at 6 weeks and at 3 and 12 months postprocedure (P<0.05) with an increased improvement in the treatment group at 3 months compared to controls (P<0.05 vs. sham). There were no inter- or intragroup differences in endoscopic findings, esophageal manometry, or acid exposure before or at 3 or 12 months postprocedure. Gastroesophageal endoscopy showed that 71% and 67% of sutures remained at 3 and 12 months, respectively. The authors concluded that "[a]lthough some short-term effects were achieved, it was found that there were no differences between the treatment and control groups after 12 months and the lack of reduction of EAE suggests that, in its present form, the EndoCinch plication technique is not to be recommended for use in clinical practice. It is suggested that the lack of long-term effects is primarily due to detachment of the sutures."
In 2006, Domagk et al. reported the results of a prospective, randomized trial that compared the efficiency and safety of endoluminal gastroplasty (EndoCinch) to polymer injection (Enteryx) in the treatment of GERD. Fifty-one consecutive individuals dependent on PPI therapy were enrolled. Follow-up evaluation included drug consumption, symptoms, QOL scoring, endoscopy, pH monitoring, manometry, and documentation of AEs. Twenty-six individuals were assigned to EndoCinch treatment, 23 individuals received Enteryx implantation, and two individuals dropped out before applying endoscopic therapy. At 6 months, PPI therapy could be stopped or dosage was reduced by 50% or more in 20 of 26 (77%) EndoCinch-treated individuals and in 20 of 23 individuals treated by Enteryx (87%, P=0.365), which differed significantly in both groups compared with the preinterventional status (P<0.0001). Esophageal acid reflux (pH <4) decreased from 14.5% to 9.6% in EndoCinch-treated individuals (P=0.071) and from 15.5% to 13.9% in individuals treated by Enteryx (P=0.930). Heartburn symptom score, modified DeMeester score, gastrointestinal life quality index, and SF-36 physical health survey score improved significantly in both groups postinterventionally (P<0.0001). Approximately 25% of the individuals in both groups required re-treatment in an attempt to achieve symptom control. The authors concluded that EndoCinch and Enteryx seem to be equally successful in the treatment of GERD, significantly reducing the PPI dosages, and also by improving symptoms of individuals. Both endoluminal antireflux procedures may be promising therapeutic options; long-term evaluation will have to show if the positive initial results can be maintained.
In a nonrandomized comparative study, Mahmood et al. (2006) reported on outcomes in 27 individuals undergoing endoscopic plication with EndoCinch and 24 individuals undergoing LNF. Many of those receiving endoscopic procedures were referred to a gastroenterologist, whereas those undergoing LNF were often referred directly to a surgeon. At follow-up, symptom control had improved in both groups but was better for the LNF group. In terms of objective indices, 91% of individuals in the LNF group achieved normal esophageal pH compared with 48% in the endoscopic group. The study is limited by a small sample size and short follow-up time.
In 2005, Chen et al. published the results from a prospective, multicenter trial evaluating 85 individuals with GERD who were treated with endoluminal gastroplication (EndoCinch). Inclusion criteria were three or more heartburn or regurgitation episodes per week, more than 4.2% time in 24 hours with esophageal pH lower than 4, and dependency on antisecretory medications. Exclusion criteria were the presence of varices, achalasia, aperistalsis, or previous gastric resection. Individuals underwent manometry, 24-hour pH monitoring, and symptom severity scoring before and after the procedure. Patient diaries were used to assess medication use and to estimate annual medication cost. At 1- and 2-year follow-up, individuals had significant reductions in median heartburn symptom scores (72 at baseline vs. 4 at 12 months and 16 at 24 months; P<0.0001 vs. baseline) and median regurgitation symptoms (2 at baseline vs. 0 at 12 months and 1 at 24 months; P<0.0001 vs. baseline). Fifty-nine percent and 52% of the individuals showed heartburn symptom resolution at 12 and 24 months, respectively (P<0.0001 vs. baseline). Also, 83% and 77% had regurgitation symptom resolution at 12 and 24 months, respectively (P<0.0001 vs. baseline). PPI use also was significantly reduced at 12 and 24 months after the procedure. Endoluminal gastroplication significantly reduced the duration and the number of episodes of EAE (P<0.0001 vs. baseline). Seven individuals experienced AEs. The authors stated that individuals with classic GERD symptoms who are responsive to antisecretory medications are good candidates for endoluminal gastroplication if an alternative to long-term medical therapy or surgery is being considered. Additional studies will be needed to evaluate whether the procedure should be routinely offered to individuals in whom medical therapy fails or who have other unfavorable parameters.
In a prospective study of 38 individuals with GERD, Abou-Rebyeh et al. (2005) performed a total of 43 endoscopic gastroplications (EndoCinch). Two or three EndoCinch gastroplications were constructed at the level of the gastric cardia in each individual; five individuals were treated twice within 6 to 12 months. Postprocedure data after 2 months and after 1 year were compared with preoperative data, focusing on symptoms, medication requirements, endoscopic findings, and pH-metry results. In contrast to the findings at 2 months (which showed that 72% of the sutures were present and that there was a reduction in the percentage of time when the esophageal pH was <4 from 15.4% to 8.7%), the results 1 year after EndoCinch were considered to indicate failure of the treatment in all 38 individuals because none of them still had all of the initially placed gastroplications in situ (90% of gastroplications were lost). The percentage of individuals who did not require PPI medication decreased from 52% at 2 months to only 20% at 1 year and even more individuals had evidence of reflux esophagitis at 1 year (56%) than had initially demonstrated signs of this (41%). The authors concluded that endoscopic gastroplications (EndoCinch) "has some short-term beneficial effects on clinical symptoms and pH-metry. However, mainly due to the loss of the endoscopically placed sutures, these effects were not maintained at the 1-year follow-up. EGP cannot therefore be recommended for routine clinical use. Better endoscopic methods need to be developed, and they should be adequately tested before being marketed."
In a prospective case series, Schiefke et al. (2005) evaluated the long-term (18 months) outcomes of 70 individuals treated with EndoCinch. All individuals were interviewed using a standardized questionnaire regarding their symptoms and medication prior to and 18 months after EndoCinch. In addition, follow-up included endoscopy, 24-hour pH monitoring, and esophageal manometry. At 18 months' follow-up, 80% of the cases were considered treatment failures because the heartburn symptoms did not improve or PPI medication exceeded 50% of the initial dose. Endoscopy showed all sutures in situ in 17% of the individuals, while no remaining sutures could be detected in 26% of the individuals. In 54 and 50 individuals examined, respectively, no significant changes in 24-hour pH monitoring or LES pressure were observed while median LES length slightly increased. The authors concluded that "[e]ndoscopic gastroplication (EndoCinch) is a safe and minimally invasive endoscopic treatment for GORD with reasonable short term results. In contrast, long-term outcome is disappointing, probably due to suture loss in the majority of patients. Therefore, technical improvements to ensure suture durability are mandatory before endoscopic suturing can evolve as a therapeutic option for GORD treatment."
Summary
Comparative studies evaluating EndoCinch have failed to show improvement in acid exposure time when compared to sham controls. Prospective case series studies report that at follow-up there is a high rate of suture loss. Therefore, large, well-designed RCTs are needed to show long-term safety and efficacy of EndoCinch. In addition, the manufacturer, Bard, has discontinued the EndoCinch Suturing System.
GERDx System (G-SURG)
The GERDx System (G-SURG) combines advanced endoscopic and microhydraulic technologies for the treatment of reflux and the resection of tumors.
In 2018, Weitzendorfer et al. assessed the clinical safety and efficiency of the GERDx device by evaluating clinical parameters, reflux symptom scores, and QOL. The study was a prospective one-arm trial evaluating the outcome of 40 individuals with GERD subjected to endoscopic plication with the GERDx device. Individuals with at least one typical reflux symptom despite treatment with a PPI for more than 6 months, pathologic EAE, hiatal hernia of size less than 2 cm, and endoscopic Hill's grade II to III were included. Evaluation of Gastrointestinal Quality of Life Index (GIQLI), symptom scores, esophageal manometry, and impedance-pH-monitoring were performed at baseline and at 3 months after surgery. There were no intraoperative complications. Four of 40 individuals (10%) experienced postoperative complications requiring intervention. Seven of 40 individuals (17.5%) underwent LF 3 months after endoscopic plication because of persistent symptoms and were lost to further follow-up. Thirty of 40 individuals (75%) were available at 3-month follow-up. There was an improvement of the GIQLI score, from a mean of 92.45 ± 18.47 to 112.03 ± 13.11 (P<0.001). The general reflux-specific score increased from a mean of 49.84 ± 24.83 to 23.93 ± 15.63 (P< 0.001), and the DeMeester score from a mean of 46.48 ± 30.83 to 20.03 ± 23.62 (P< 0.001). There was no significant change in manometric data after intervention. Three of 30 individuals (10%) continued daily antireflux medication. The authors concluded that endoscopic plication with the GERDx device reduced distal acid exposure of the esophagus, reflux-related symptoms, and improved GIQLI scores with minimal side effects in a selected cohort of individuals and may be a safe alternative in the treatment of GERD. Limitations of this study include small sample size (n=40), short-term follow-up (3 months), and no comparator. Randomized clinical trials with larger patient populations and longer follow-up periods are needed to further assess GERDx.
In 2017, Weitzendorfer et al. reported the results of a prospective study investigating the clinical efficiency of the GERDx device for individuals with GERD. Outcomes of interest included the GIQLI, symptoms scores, as well as esophageal manometry and impedance-pH-monitoring data at baseline and 3 months after endoscopic full-thickness plication with the GERDx device. In total, 28 individuals underwent the procedure. Mean GIQLI scores, DeMeester scores, and general and reflux-specific scores improved (P<0.01). Three of six individuals, who were treated with converted sutures, experienced postoperative complications. The authors concluded that endoscopic plication using the GERDx device may be effective in improving QOL and GERD symptoms. Suture length between pledgets and suture material may have an impact on procedure outcomes. Limitations of this preliminary study include small sample size (n=28), short-term follow-up (3 months), and no comparator.
NDO Surgical Endoscopic Plication System / NDO Plicator
In this procedure, the Plicator and gastroscope assembly are passed into the stomach and the stomach is distended with air. The Plicator is retroflexed to within 1 cm below the GEJ, and the helical tissue retractor is advanced deeply into the gastric wall. The gastric wall is retracted into the Plicator instrument arms. The arms are then closed, and the suture-implant is deployed to secure the full-thickness plication. The tissue retractor is then disengaged and the suture-implant released from the instrument. Additional sutures are placed in the same manner described above, with each additional implant placed incrementally closer to the GEJ in a linear configuration along the anterior gastric cardia. A search of online site www.ClinicalTrials.gov in February 2020 found several studies with the NDO Plicator listed as terminated, because the sponsoring company (NDO Surgical Inc.) was acquired by Johnson & Johnson and has ceased business operations.
The NDO Surgical Endoscopic Plication System and the NDO Plicator (NDO Surgical, Inc., Mansfield, MA) were cleared for marketing by the FDA through the 510(k) process in 2003 and 2007, respectively. Both systems are indicated for the treatment of the symptoms of chronic GERD in individuals who require and respond to pharmacological therapy.
Clinical Trials
In 2018, De Moura et al. investigated the efficacy of endoscopic polymer injection and endoluminal full-thickness plication in the long-term control of GERD. Forty-seven individuals with GERD who underwent an endoscopic procedure were followed up for 60 months and evaluated for total response (TR), partial response (RP) and no response (SR) to endoscopic treatment with reintroduction of PPIs. Twenty-one individuals received polymer injection (G0) and 26 endoluminal plication (G1). The number of individuals with no response to endoscopic treatment with reintroduction of PPIs increased in time for both techniques (G0 P = 0.006; G1 P < 0.001). There was symptomatic improvement up to 12 months, with progressive loss of this trending up to 60 months in G0 and G1 (P< 0.001). GERD-HRQL demonstrated TR in G0 and G1 at 1, 3, 6 and 12 months. The 60-month analysis showed an increased number of individuals with SR in both groups. The QOL assessment (SF-36) showed benefit in G0 up to 3 months. G0 showed a higher rate of complications. There were no deaths. There was healing of esophagitis at 3 months in 45 % of individuals in G0 and 40 % in G1. There was no improvement in manometric or pH findings. The authors concluded that endoscopic therapies were ineffective in long-term GERD control.
In a randomized comparative study, Antoniou et al. (2012) evaluated the effectiveness of endoscopic plication and LF in terms of QOL and symptom control. Sixty individuals with GERD were randomly assigned to undergo either endoscopic plication or LF. QOL scores and symptom grading were recorded before treatment and at 3- and 12-month follow-up. Twenty-nine individuals from the endoscopic group and 27 individuals from the operative group were available at follow-up. QOL scores showed a substantial and similar increase for both groups after treatment. Symptoms of heartburn, regurgitation, and asthma were significantly improved in the endoscopic group, whereas LF was more effective in controlling symptoms of heartburn and regurgitation compared to the endoscopic procedure. Limitations of this study include small sample size and lack of long-term follow-up.
In an open-label, prospective multicenter postmarket registry study, Birk et al. (2009) evaluated the safety and efficacy of the Plicator procedure in individuals with GERD. The study included 131 individuals who were evaluated at 12 months after plication. At 12 months, 81 individuals (62%) were available for assessment. The mean GERD-HRQL score had improved significantly compared with the baseline score, with 66% of the individuals showing an GERD-HRQL score improved 50% or more. Statistically significant improvements also were observed in median heartburn and regurgitation symptom scores. The need for daily PPI therapy was eliminated for 58% of the individuals. At baseline, 18% of the individuals had been satisfied with their GERD symptom control while on antisecretory therapy. At 12 months, 75% of the individuals were satisfied with their GERD symptom control after undergoing the Plicator procedure, and 86% would recommend the procedure to family or friends. Limitations of the study include a lack of a control or comparison group.
In 2009, Renteln et al. reported the 12-month results from their prospective multicenter study evaluating the safety and efficacy of placing multiple transmural sutures for the treatment of GERD. Twelve months after treatment, 74% of individuals demonstrated improvement in GERD-HRQL scores by 50% or more, with mean decrease of 17.6 points compared with baseline (7.8 vs. 25.4; P<0.001). Using an intention-to-treat model, 63% of individuals had symptomatic improvements of 50% or more, with mean GERD-HRQL decrease of 15.0 (11.0 vs. 26.0; P<0.001). The need for daily PPI therapy was eliminated in 69% of individuals at 12 months on a per-protocol basis, and 59% on an intention-to-treat basis. Adverse events included postprocedure abdominal pain (44%), shoulder pain (24%), and chest pain (17%). No long-term AEs occurred. The authors stated that the long-term durability of the endoscopically restructured GEJ and the long-term effects on esophagitis and pH-metry should be compared with surgical therapy. These data are necessary to define the value of the Plicator compared with established GERD therapies.
The safety and efficacy of the Plicator procedure was evaluated in a prospective multicenter study, and the 6, 12, 36, and 60 months follow-up results were reported by Pleskow et al. in 2004, 2005, 2007, and 2008. Sixty-four individuals initially underwent plication to assess the safety and efficacy of endoscopic full-thickness plication. At 6 months after plication, PPI therapy had been eliminated in 74% of previously medication-dependent individuals. Twenty-nine individuals completed the 12-month and 36-month follow-up. At 36 months, 57% of baseline PPI-dependent individuals remained off daily PPI therapy. Treatment effect remained stable from 12 to 36 months, with 21 of 29 individuals off daily PPI at 12 months compared with 17 of 29 individuals at 36 months. Median GERD-HRQL scores remained significantly improved at 36 months versus baseline off meds scores. Furthermore, the proportion of individuals achieving 50% or higher improvement in GERD-HRQL score was consistent from 12 months (59%) to 36 months (55%). No long-term procedural adverse effects were reported. The results of the prospective, uncontrolled studies suggest that endoscopic full-thickness plication is effective, reducing symptoms and medication use associated with GERD. The treatment effect was stable for at least 5 years postprocedure. The limitations of the studies included small sample size, lack of a control group, and the studies' exclusion criteria. In addition, only a subset of the individuals who had originally undergone the Plicator procedure were enrolled in the 60-month follow-up study; therefore there is the potential for referral bias.
In 2008, Renteln et al. reported the results of a prospective multicenter study evaluating the safety and efficacy of placing multiple transmural sutures for the treatment of GERD. The study included individuals with symptomatic GERD who require daily maintenance PPI therapy. Study exclusions were hiatal hernia larger than 3 cm, grades III and IV esophagitis, Barrett epithelium, and esophageal dysmotility. Forty-one individuals received two or more transmural sutures placed linearly in the anterior gastric cardia approximately 1 cm below the GEJ. Six months after the procedure, median GERD-HRQL improved 76% compared with off-medication baseline (6.0 vs 25.0; P<0.001), with 75% of individuals (32/40) achieving more than 50% improvement in their baseline GERD-HRQL score. Daily PPI therapy was eliminated in 70% of individuals (28/40). Heartburn symptoms improved 80% compared with off-medication baseline (16.0 vs 84.0; P<0.001). Median esophagitis grade improved 75% compared with baseline (0.0 vs. 1.0; P=0.005). Esophageal pH assessed as median distal esophageal-acid exposure (percentage time pH <4.0) improved 38% compared with baseline (9.0 vs 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 vs, 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 vs 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 reported that further studies and long-term data regarding the safety and efficacy of this procedure will be necessary to define the value of the Plicator compared with already established GERD therapies. Other limitations of this study are the small sample size and lack of a comparison with a single implant group.
In a randomized, single-blind, prospective, multicenter, sham-controlled study, Rothstein et al. (2006) reported the outcomes of 159 individuals with GERD undergoing full-thickness plication (Plicator). Seventy-eight individuals were randomly assigned to undergo endoscopic full-thickness restructuring of the gastric cardia with transmural suture. Eighty-one individuals underwent a sham procedure. Group assignments were revealed following the 3-month evaluation. The primary endpoint was 50% or greater improvement in GERD-HRQL score. Secondary endpoints included medication use and EAE. At 3-month follow-up, the proportion of individuals achieving 50% or higher improvement in GERD-HRQL score was significantly greater in the treatment group (56%) compared with the sham group (18.5%; P<0.001). Complete cessation of PPI therapy was higher among those in the treatment group than in the sham group (50% vs. 24%, respectively; P=0.002). QOL scores also improved more in the active group. The percent reduction in median percent time the pH was less than 4 was improved more in the treatment group versus baseline (7% vs. 10%, respectively; P<0.001) but did not change in the sham group (10% vs. 9%, respectively; P=0.686). Between-group analysis revealed the treatment therapy to be superior to the sham in improving median percent time pH less than 4 (P=0.010). The authors noted that the single full-thickness plication normalized the distal esophageal acid contact for fewer than one third of the individuals and was not effective in healing esophagitis. Also, radiating shoulder pain and abdominal pain were more frequent AEs in the active treatment group (12% vs. 0% and 9% vs. 0%, respectively). Twenty-four individuals randomly assigned in the study were lost to follow-up or excluded from further study because they were ruled ineligible by entry criteria. The authors stated, “Further studies, including those with longer term follow-up, will help clarify the role of this promising procedure across a broader range of patients with GERD."An editorial by Shaheen (2006) accompanying the study by Rothstein et al. (2006) outlined the limitations of the study. It stated that the Plicator procedure shows promise as a treatment option for individuals 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 antireflux devices such as safety, efficacy, and durability. Regarding 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 antireflux devices. Shaheen concluded that the study still leaves uncertainty as to where to position endoscopic antireflux procedures in the individual with GERD. Because 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 individuals outside the realm of clinical studies cannot be recommended.In 2003, Chuttani et al. reported the results from a pilot study assessing the safety and feasibility of endoscopic full-thickness plication (i.e., the Plicator system) for the treatment of Chuttanis with GERD symptoms. Individuals with chronic heartburn and pathologic reflux requiring maintenance antisecretory therapy were included. The primary endpoints of the study were procedure safety and feasibility, as well as long-term durability of the full-thickness tissue fixation. Secondary endpoints included medication use and the GERD-HRQL questionnaire and Gastrointestinal Symptom Rating Scale. Full-thickness plication was performed successfully in six of seven individuals, with one procedure aborted because of difficulty in sedating the individual. Mean procedure time was 21 minutes. Mild epigastric pain was reported by two individuals and difficulty to belch by one individual; all symptoms resolved spontaneously within 7 days of the procedure. Endoscopy at 6 months revealed an intact plication in all individuals. At 1 year after the procedure, individuals reported sustained reduction in heartburn scores. One individual, who did not experience significant relief of symptoms, ultimately underwent successful LNF at 6 months after the procedure. At 1 year after the procedure, three of five individuals were not taking anti-GERD medications. The authors concluded that endoscopic full-thickness plication is feasible, safe and, in this pilot study, appeared to reduce symptoms and medication use associated with GERD.SummaryStudies in the peer-reviewed literature investigating endoscopic plications systems are primarily in the form of case series. Large, well-designed, controlled trials showing long-term safety and efficacy are lacking.Syntheon ARD PlicatorThe Syntheon ARD delivers a single titanium implant into the cardia of the stomach, creating a serosa-to-serosa apposition and altering the anatomy of the proximal stomach in a fashion similar to that of the NDO Plicator device. Unlike the NDO Plicator device, the ARD instrument and an endoscope can be passed independently of each other. This feature permits any upper endoscope to be used, placed alongside the ARD and retroflexed to view the cardia. A catheter-based tissue retractor is passed through the endoscope biopsy channel to pull the proximal stomach into the open arms of the ARD. As the arms close upon the retracted tissue of the distal GEJ, the titanium implant is deployed to create a full-thickness "pleat."No studies evaluating the use of the Syntheon ARD Plicator for the treatment of GERD were identified.ENDOSCOPIC SUBMUCOSAL IMPLANTATION OR INJECTION OF A BULKING AGENTIn these procedures, a biomaterial is injected/implanted in the submucosa of the LES augmenting the sphincter and reducing gastric reflux into the esophagus. Commonly used products include Enteryx, Durasphere GR, Gatekeeper Reflux Repair System, and plexiglass polymethylmethacrylate (PMMA) microbeads.
Enteryx (Ethylene-Vinyl Alcohol)
In this procedure, a nonresorbable biocompatible polymer is endoscopically implanted in the distal esophagus and proximal gastric cardia.
The FDA issued a preliminary health notification on October 14, 2005, regarding the recall of the ethylene vinyl alcohol (Enteryx) Procedure Kits and ethylene vinyl alcohol (Enteryx) Injector Single Packs by the manufacturer (Boston Scientific Corp., Natick, MA) on September 23, 2005, due to the occurrence of AEs, including death. The FDA instructed physicians to stop injecting ethylene vinyl alcohol (Enteryx) and to follow the manufacturer's procedures for returning unused products. In September 2005, Enteryx was voluntarily removed from the market because of serious adverse effects.
In a randomized, single-blind, prospective, multicenter clinical trial, Deviere et al. (2005) reported on 64 individuals with GERD whose symptoms were well controlled by PPI therapy and rapidly recurred after cessation of PPI therapy. Individuals were randomly assigned to either Enteryx implantation (n=32) or a sham procedure consisting of standard upper endoscopy (n=32). Individuals in both groups with unsatisfactory symptom relief after 3 months were eligible for re-treatment by Enteryx implantation. The primary study endpoint was 50% or more reduction in PPI use. Secondary endpoints included 50% or more improvement in GERD score and the proportion of individuals not undergoing re-treatment procedure. Follow-up evaluations were performed at 3 and 6 months. The percentage of Enteryx-treated individuals achieving a 50% or more reduction in PPI use (81%) was greater than that of the sham group (53%), with a rate ratio of 1.52 (CI, 1.06–2.28; P=0.023). A higher proportion of the Enteryx (68%) than sham group (41%) ceased PPI use completely (rate ratio, 1.67; CI, 1.03–2.80; P=0.033). GERD-HRQL heartburn score improvement of 50% or higher was achieved by 67% of the Enteryx group versus 22% of the sham group (rate ratio, 3.05; CI, 1.55–6.33; P<0.001). More Enteryx-treated (81%) than sham-treated (19%) individuals did not undergo re-treatment (rate ratio, 4.33; CI, 2.23–9.29; P<0.001). The small sample size and short follow-up time of the study limit interpretation of findings.
In 2005, Cohen et al. reported the results from an open-label, international clinical trial evaluating Enteryx in 144 PPI-dependent individuals with GERD with follow-up at 6 and 12 months. In addition, the durability and the safety of the treatment were assessed for 24 months in 64 individuals enrolled in a postapproval study. The primary study outcome measure was usage of PPI. Secondary outcomes in the multicenter trial were GERD-HRQL symptom score and EAE. At 12 months, PPI use was reduced 50% or more in 84% (95% CI, 76%–90%) and was eliminated in 73% (95% CI, 64%–81%) of evaluable individuals (intent-to-treat analysis 78% [95% CI, 70%–84%] and 68% [95% CI, 60%–76%], respectively). A GERD-HRQL of less than or equal to 11 was attained in 78% (95% CI, 69%–85%) of evaluable individuals. Esophageal acid exposure (total time pH <4) was reduced by 31% (95% CI, 17%–43%). At 24 months, a 50% or greater reduction in PPI use was achieved in 72% (95% CI, 59%–82%) and PPI use was eliminated in 67% (95% CI, 54%–78%) of individuals. The authors concluded that the study provides evidence for sustained effectiveness and safety of implantation of Enteryx in the esophagus in PPI-dependent individuals with GERD.
Also in 2003, Johnson et al. reported 6-month follow-up results from a prospective, multicenter, single-arm study evaluating the safety and efficacy of the endoscopic implantation of Enteryx for the treatment of GERD. Eighty-five individuals with heartburn symptoms responsive to PPI use were enrolled. Inclusion requirements were HRQL score of 11 or less on PPI and 20 or higher off PPI, and 24-hour PH probe with at least 5% total time at PH of 4 or under. Patients with a hiatus hernia larger than 3 cm, grade 3 or 4 esophagitis, or esophageal motility disorder were excluded. Use of PPI medications, pH-metry, manometry, GERD symptoms, and patient QOL were assessed over a 6-month follow-up period. At 6 months, PPI use was eliminated in 74% and reduced by more than 50% in 10% of patients. The median HRQL score improved from 24.0 pre-implant (baseline off PPIs) to 4.0 at 6 months (P<0.001). Mean total EAE time was 9.5% pretherapy and 6.7% at 6 months (P<0.001). Mean LES length increased from 2.0 cm at baseline to 3.0 cm posttherapy (P=0.003). There were no clinically serious AEs. Transient mild-to-moderate chest pain commonly occurred after implantation. The authors 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 QOL, and decreasing EAE among individuals suffering from GERD.
Also in 2003, the same authors published the 12-month follow-up results. At 12 months, 80.3% (95% CI, 69.9%–88.3%) of 81 evaluable individuals were treatment responders. Of the responders, 87.7% completely discontinued PPIs, and 12.3% reduced PPI dosage by 50% or more. Treatment response was more likely in patients with residual implant volume of 5 mL or higher (P=0.027). Other patient and treatment variables were not predictive. Both GERD heartburn and regurgitation symptom scores significantly improved at 12 months compared with baseline (P<0.001). There were significant reductions in median supine, upright, and total percent time of esophageal exposure to pH less than 4. Endoscopically assessed esophagitis grades were unchanged. No serious AEs were encountered. Transient retrosternal chest pain was experienced by 91.8% of individuals. This pain was seldom severe and was typically successfully managed with prescription pain medication. The authors concluded that Enteryx implantation allows most patients to discontinue PPI therapy, improves their symptoms, and reduces EAE. The effects of implantation are long-lasting, and morbidity is transient and minimal. The procedure requires basic endoscopic skills and seems to provide a useful option in the effective clinical management of GERD.
In 2002, Deviere et al. published the results of a pilot study evaluating the safety and effectiveness of Enteryx in individuals with GERD, who required continuous therapy with a PPI. Enteryx was injected into the muscle of the gastric cardia. Primary endpoints were the safety of the procedure, the effect on LESP, and the stability of the injected material. A secondary endpoint was the effect on heartburn score after discontinuation of treatment with a PPI. Ethylene-vinyl-alcohol injection into the cardia resulted in circular diffusion of the product in 10 of 15 cases, suggesting that implantation into the muscle is feasible. LESP was increased in 13 of 15 cases at 1 month and was sustained at a median follow-up of 6 months (range, 4–12 months). Mean ± SEM of LESP (15 individuals) were 12.2 ± 0.9, 18.7 ± 1.5 (P=0.001 at baseline), and 16.7 ± 1.3 mm Hg (P=0.038 from baseline) at, respectively, baseline, 1 month follow-up, and final follow-up. There was also a sustained reduction in heartburn score (off PPI) (3.40 ± 0.13 vs. 1.53 ± 0.24 and 1.87 ± 0.26 at baseline vs. 1 month and final follow-up, respectively; P<0.01). Nine of the 15 individuals had more than 50% of the injected material in place at second follow-up (at 6 months for eight individuals; at 12 months for one individual). In only two individuals was there loss of more than 75% of injected ethylene-vinyl-alcohol. Persistence of greater than 50% of the material was associated with achievement of a circular injection. Only four individuals had to resume therapy with a PPI. Mild retrosternal discomfort was observed in eight individuals; this disappeared in all cases after a maximum of 3 days. The authors concluded that Enteryx implantation in the muscle of the cardia is feasible and safe. It leads to a sustained increase in resting LESP. This is associated with a sustained improvement in heartburn score for individuals who previously required continuous therapy with a PPI. The authors also stated that further studies are needed to delineate the potential clinical applications and long-term outcomes of this technique.
Durasphere GR (Zirconium Oxide Spheres)
Durasphere GR (Carbon Medical Technologies, Inc., St. Paul, MN) is a bulking agent approved by the FDA for use in the treatment of adult women with stress urinary incontinence (SUI) due to intrinsic sphincter deficiency (ISD). Use of this product for the treatment of GERD would be considered an off-label use. Carbon Medical Technologies' website states that Durasphere GR is an investigational device in the United States, and is “intended to treat problems associated with Gastroesophageal Reflux Disease (GERD).”
The available evidence consists of a single case series evaluating the long-term safety and effectiveness of Durasphere in the treatment of mild to moderate GERD (Ganz et al., 2009). Ten individuals with GERD were injected with Durasphere. Outcomes measured included change in symptom scores, PPI use, pH scores, and endoscopic findings; monitoring of safety profile. Nine of 10 individuals completed the 12-month trial. There were no AEs. The procedure was well tolerated with minimal patient discomfort and no dysphagia. At 12 months, 70% of individuals 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; four individuals 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. Noted limitations in the study included nonrandomized study design without a control group and small number of subjects.
Gatekeeper Reflux Repair System
The Gatekeeper Reflux Repair System (Medtronic, Shoreview, MN) uses a soft, pliable, expandable prosthesis made of a polyacrylonitrile-based hydrogel. The prosthesis is implanted into the esophageal submucosa, and with time, the prosthesis absorbs water and expands, creating bulk in the region of implantation. The Gatekeeper Reflux Repair System is not FDA approved for the treatment of symptomatic chronic GERD.
The available evidence base for this system consists of a single RCT evaluating the safety and effectiveness of the Gatekeeper Reflux Repair System for controlling gastroesophageal reflux disease (Fockens et al., 2010). A prospective, randomized, sham-controlled, single-blinded, international multicenter study planned final enrollment of 204 individuals in three groups: up to 60 lead-in, 96 Gatekeeper, and 48 sham subjects. The sham subjects were allowed to cross over to the Gatekeeper treatment arm or exit the study at 6 months. The primary endpoints were (1) reduction in serious device- and procedure-related adverse device effects compared with a surgical composite complication rate and (2) reduction in heartburn symptoms 6 months after the Gatekeeper procedure compared with the sham procedure. The secondary endpoint was improved esophageal pH (total time pH <4) 6 months after the Gatekeeper procedure compared with baseline. A planned interim analysis was performed after 143 individuals were enrolled (25 lead-in, 75 Gatekeeper, and 43 sham subjects), and the Gatekeeper study was terminated early due to lack of compelling efficacy data. The individuals initially received four Gatekeeper prostheses. At 3 months, 44% of implanted subjects received re-treatment with up to four additional prostheses due to unsatisfactory symptom control. Four serious AEs were reported (two perforations, one pulmonary infiltrate related to a perforation, one severe chest pain). Heartburn symptoms had improved significantly at 6 months compared with baseline in the Gatekeeper group (P<0.0001) and the sham group (P<0.0001), but no significant between-group difference in improvement was observed (P=0.146). EAE had improved significantly at 6 months compared with baseline in the Gatekeeper 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 Gatekeeper 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.
Plexiglass or Polymethylmethacrylate (PMMA) Microbeads
In this procedure, PMMA microspheres are submucosally injected in the LES. This process augments the LES and helps to reduce gastric reflux in to the esophagus.
In a case series, Feretis et al. (2001) reported on 10 individuals with GERD who underwent transesophageal submucosal implantation of PMMA beads. Symptom severity score, 24-hour pH monitoring, upper GI endoscopy, and EUS were performed to evaluate the efficacy of implantation. Seven of 10 individuals were taking no medication after PMMA implantation. While a significant decrease in symptom severity score and mean total time with esophageal pH less than 4 was noted at posttreatment follow-up (time not specified), the small number of subjects and lack of long-term follow-up preclude scientific analysis. The authors noted that "further studies are required to determine the long-term efficacy of the procedure." No additional studies have been identified evaluating this treatment option.
ELECTRICAL STIMULATION THERAPY
EndoStim Lower Esophageal Sphincter Stimulation System
The EndoStim LES Stimulation System (EndoStim, Dallas, TX) is a minimally invasive implantable device designed to provide long-term reflux control by restoring normal esophageal function through neurostimulation. The therapy directly targets an individual's weak or dysfunctional LES muscle between the stomach and the esophagus, often the underlying cause of reflux. The EndoStim LES Stimulation System is not FDA approved for the treatment of symptomatic chronic GERD.
In 2016, Rodriguez et al. reported 3-year follow-up results of an open-label pilot trial evaluating the safety and efficacy of long-term LES stimulation using a permanently implanted LES stimulator in individuals with GERD. GERD individuals with partial response to PPI, with percent 24-hr esophageal pH lower than 4.0 for more than 5%, with hiatal hernia smaller than 3 cm and with esophagitis LA grade C or under were treated with LES stimulation in an open-label 2-year trial. All individuals were on fixed stimulation parameter of 20 Hz, 220 μs, 5 mA delivered in 12, 30-minute sessions. After completing the 2-year open-label study, they were offered enrollment into a multicenter registry trial and were evaluated using GERD-HRQL, symptom diaries, and pH testing at their 3-year follow-up. Fifteen participants completed their 3-year evaluation [mean (SD) age, 56.1 (9.7) years; men, 8] on LES stimulation. At 3 years, there was a significant improvement in their median (IQR) GERD-HRQL on electrical stimulation compared with both their on PPI [9 (6–10) vs. 1 (0–2), P=0.001] and off PPI [22 (21–24) vs. 1 (0–2), P<0.001]. Median 24-hour distal EAE was significantly reduced from 10.3% (7.5–11.6) at baseline versus 3% (1.9–4.5) [P<0.001] at 3 years. Seventy-three percent (11/15) of participants had normalized their distal EAE at 3 years. The remaining four individuals had improved their distal EAE by 39% to 48% from baseline. All but four individuals reported cessation of regular PPI use (>50% of days with PPI use); three had normal esophageal pH at 3 years. There were no unanticipated device- or stimulation-related AEs or untoward sensation reported during the 2- to 3-year follow-up. The authors concluded that LES-EST is safe and effective for treating GERD over long-term, 3-year duration. There was a significant and sustained improvement in EAE and reduction in GERD symptoms and PPI use. Further, no new gastrointestinal side effects or AEs were reported. Limitations of this study include open-label, single-center design (lack of a control group) and small study size (15 individuals evaluated). Furthermore, this study excluded individuals with moderate and large (>3 cm) hiatal hernias, LES end-expiratory pressures less than 5 mm Hg, and those with severe (grade D) esophagitis or long-segment Barrett esophagus. These individuals tend to have more severe esophageal motor dysfunction and are more likely to suffer from medically refractory GERD. Thus, effectiveness of LES stimulation in these subgroups needs to be established.
In 2016, Soffer et al. evaluated the efficacy of LES-electrical stimulation therapy (EST) in a subgroup of individuals who reported only partial response to PPI therapy, compared to a group of individuals with complete response. Bipolar stitch electrodes were laparoscopically placed in the LES and connected to an implantable pulse generator (EndoStim BV, the Hague, the Netherlands), placed subcutaneously in the anterior abdominal wall. Stimulation at 20 Hz, 215 μsec, 3-8 mAmp in 30 min sessions was delivered starting on day 1 post-implant. Individuals were evaluated using gastroesophageal reflux disease (GERD)-HRQL, symptom diaries; esophageal pH and esophageal manometry before and up to 24 months after therapy and results were compared between partial and complete responders. Twenty-three individuals with GERD on LES-EST were enrolled and received continuous per-protocol stimulation through 12 months and 21 patients completed 24 months of therapy. Of the 23 individuals, 16 (eight male, mean age 52.1 ± 12 years) had incomplete response to PPIs prior to LES-EST, while seven individuals (five male, mean age 52.7 ± 4.7) had complete response to PPIs. In the sub-group with incomplete response to PPIs, median (IQR) composite GERD-HRQL score improved significantly from 9.5 (9.0-10.0) at baseline on-PPI and 24.0 (20.8-26.3) at baseline off-PPI to 2.5 (0.0-4.0) at 12-months and 0.0 (0.0-2.5) at 24-months follow-up (P < 0.05 compared to on-and off-PPI at baseline). Median (IQR) % 24-h esophageal pH < 4.0 at baseline in this sub-group improved significantly from 9.8% (7.8-11.5) at baseline to 3.0% (1.9-6.3) at 12 months (P < 0.001) and 4.6% (2.0-5.8) at 24 months follow-up (P < 0.01). At their 24-month follow-up, nine of 11 individuals in this subgroup were completely free of PPI use. These results were comparable to the sub-group that reported complete response to PPI therapy at baseline. No unanticipated implantation or stimulation-related AEs, or any untoward sensation due to stimulation were reported in either group and LES-EST was safely tolerated by both groups The authors concluded that LES-EST is safe and effective in controlling symptoms and EAE in GERD individuals with incomplete response to PPIs. These results were comparable to those observed PPI responders.
In 2015, Rodriguez et al. reported 2-year follow-up results of an open-label pilot trial evaluating the safety and efficacy of long-term LES stimulation using a permanently implanted LES stimulator in individuals with GERD. GERD individuals responsive partially to PPI with off-PPI GERD-HRQL of 20 or higher, 24-hour esophageal pH 4.0 or less for more than 5% of the time, hiatal hernia 3 cm or smaller, 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 stimulation was delivered at 20 Hz, 215 μs, 3 to 8 mAmp over 30-minute sessions, six to 12 sessions per day, starting on day 1 after implantation. Individuals were evaluated using GERD-HRQL, symptom diaries, SF-12, and esophageal pH testing at regular intervals. Stimulation sessions were optimized based on residual symptoms and esophageal pH at follow-up. Twenty-five individuals (mean age [SD] , 52 [12] years; 14 men) underwent implantation successfully; 23 individuals 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 stimulation compared with both their on-PPI (9 vs 0; P=0.001) and off-PPI (23.5 vs. 0; P<0.001) baseline scores. Median 24-hour distal EAE improved from 10% at baseline to 4% (per-protocol analysis; P<0.001) at 2 years with 71% demonstrating either normalization or a 50% or more decrease in their distal EAE. All except five individuals (16/21) reported complete cessation of PPI use; only two individuals were using a PPI regularly (≥50% of days). There was significant improvement in sleep quality and daily symptoms of heartburn and regurgitation on LES stimulation. 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 stimulation. There were no device- or therapy-related serious AEs and no untoward sensation or dysphagia reported with LES stimulation. The authors concluded that LES stimulation is safe and effective for treating individuals with GERD for over 2 years. LES stimulation resulted in a significant and sustained improvement in GERD symptoms, and EAE eliminated PPI use in majority of individuals (16 of 21). Further, LES stimulation was not associated with any gastrointestinal side effects or AEs. Limitations of this study include open-label, single-center design (lack of a control group) and small study size (21 individuals evaluated). Furthermore, this study excluded individuals with moderate and large (>3 cm) hiatal hernias, LES end-expiratory pressures less than 5 mm Hg, and those with severe (grade D) esophagitis or long segment Barrett esophagus. These individuals tend to have more severe esophageal motor dysfunction and are more likely to suffer from medically refractory GERD. Thus, effectiveness of LES stimulation in these subgroups needs 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 2013, Rodriguez et al. reported 12 month follow-up results of an open-label pilot trial evaluating the safety and efficacy of long-term LES stimulation using a permanently implanted LES stimulator in individuals with GERD. Individuals with GERD who were at least partially responsive to PPIs and who had hiatal hernia of smaller than 3 cm and esophagitis of Los Angeles Grade A, B, or C were included in the study. Stimulation electrodes were placed in the LES and a pulse generator (EndoStim LES Stimulation System; EndoStim BV, The Hague, The Netherlands) was implanted laparoscopically. LES stimulation was delivered at 20 Hz, 215 μs, 3 to 8 mA in multiple 30-minute sessions. Individuals were evaluated at follow-up using the GERD-HRQL questionnaire, daily symptom and medication diaries, the SF-12 Health Survey, esophageal pH testing, and high-resolution manometry. Twenty-four individuals (mean age, 53 ± 12 years; 14 men) underwent implantation and 23 completed the 12-month evaluation. No serious implantation- or stimulation-related adverse effects or sensations were reported. Median composite GERD-HRQL score at 12 months was 2.0 (interquartile range [IQR] 0–3.0), which was significantly better than baseline scores both on PPI therapy (median 9.0, IQR 6.0–10.0; P=0.002) and off PPIs (median 23.5, IQR 21–25.75; P<0.001). The median percentage of the 24-hour period with esophageal pH under 4.0 at baseline was 10.1% (IQR 7.7–15.5), which was reduced to 3.3 % (1.8–6.9) at 12 months (P<0.001), with 69% of individuals showing either normalization or greater than 50% improvement in their distal esophageal pH. At 12 months, 96% of individuals (22/23) were completely off PPI medication. The authors concluded that at 12 months, LES electrical stimulation therapy was safe and effective for the treatment of GERD. There was a significant and sustained improvement in GERD symptoms, reduction in EAE with elimination of daily PPI usage, and no stimulation-related adverse effects. Limitations of this study included open-label, single-center design (lack of a control group) and small study size (23 individuals evaluated). Furthermore, this study excluded individuals with moderate and large (>3 cm) hiatal hernias, LES end-expiratory pressures less than 5 mm Hg, and those with severe (grade D) esophagitis or long segment Barrett esophagus. These individuals tend to have more severe esophageal motor dysfunction and are more likely to suffer from medically refractory GERD. Thus, effectiveness of LES stimulation in these subgroups needs to be established.
In 2013, Rodriguez et al. reported 6-month follow-up results of an open-label pilot trial evaluating the safety and efficacy of long-term LES stimulation using a permanently implanted LES stimulator in individuals with GERD. GERD individuals who were at least partially responsive to PPI with abnormal esophageal pH, hiatal hernia 3 cm or smaller, and esophagitis LA grade C or less were included. Bipolar stitch electrodes were placed in the LES and an IPG was placed in a subcutaneous pocket. Electrical stimulation was delivered at 20 Hz, 215 μs, 3 to 8 mA in 30-minute sessions. The number and timing of sessions was tailored to each individual's GERD profile. Individuals were evaluated using GERD-HRQL, daily symptom and medication diaries, SF-12, esophageal pH, and high-resolution manometry. Twenty-four individuals (mean age, 53 years; SD, 12 years; 14 men) received the implant; 23 completed their 6-month evaluation. Median GERD-HRQL scores at 6 months was 2.0 (IQR, 0–5.5) and was significantly better than both baseline on-PPI [9.0 (range, 6.0–10.0); P<0.001] and off-PPI [23 (21–25); P<0.001]. Median percent 24-hour esophageal pH less than 4.0 at baseline was 10.1 and improved to 5.1 at 6 months (P<0.001). At their 6-month follow-up, 91% (21/23) of the individuals were off PPI and had significantly better median GERD-HRQL on LES stimulation compared to their on-PPI GERD-HRQL at baseline (9.0 vs. 2.0; P<0.001). There were no unanticipated implantation- or stimulation-related AEs or untoward sensation due to stimulation. There were no reports of treatment-related dysphagia, and manometric swallow was also unaffected. The authors concluded that electrical stimulation of the LES is safe and effective for treating GERD. There is a significant and sustained improvement in GERD symptoms, esophageal pH, and reduction in PPI usage without any side effects with the therapy. Furthermore, the therapy can be optimized to address an individual's disease. Limitations of this study include open-label, single-center design (lack of a control group) and small study size (23 individuals evaluated). Furthermore, this study excluded individuals with moderate and large (>3 cm) hiatal hernias, LES end-expiratory pressures less than 5 mm Hg, and those with severe (grade D) esophagitis or long segment Barrett esophagus. These individuals tend to have more severe esophageal motor dysfunction and are more likely to suffer from medically refractory GERD. Thus, effectiveness of LES stimulation in these subgroups needs to be established.
MAGNETIC ESOPHAGEAL RING IMPLANTATION
LINX Reflux Management System
The LINX Reflux Management System (Torax Medical, Shoreview, MN) consists of a small flexible band of 10 to 18 interlinked titanium beads with magnetic cores that is laparoscopically inserted around the esophagus at the GEJ. The magnetic attraction between the beads is intended to help the LES resist opening due to gastric pressure, and preventing the backflow of refluxate into the esophagus. The magnetic attraction of the device also closes the LES immediately after swallowing, restoring the body’s natural barrier to stomach content reflux. The system is intended for individuals who have GERD despite maximum medical therapy (e.g., PPIs), but who do not want to risk the adverse effects of a surgical procedure like NLF. Adverse events of the system include dysphagia or odynophagia.
Systematic Reviews and Meta-Analyses
In 2020, ECRI issued a product brief re-evaluating the LINX Reflux Management System for treating GERD. Their brief indicated that the evidence is very favorable for the LINX Reflux Management System; they focused on systematic reviews and comparative studies and before-and-after studies not included in the systematic reviews that reported on 500 or more individuals. The authors reviewed the full text of two systematic reviews, one RCT, one prepost study, and two economic studies reporting on 13,437 individuals. One systematic review (Guidozzi et al., 2019; 19 studies, n=12,697) compared PPI use, QOL, GERD symptoms, and re-treatment up to 4-year follow-up with LINX or LF and reported on PPI use, retreatment, and AEs with LINX up to 5 years. A second systematic review (Riva et al. 2019; seven studies, n=35) reported on QOL, GERD symptoms, and deaths up to 2-year follow-up in individuals with persistent GERD symptoms after gastric or bariatric surgery who underwent MSA with LINX. The RCT (Bell et al., 2019; n=152) compared LINX with PPI dose escalation and reported on individuals at 6 months after PPI group crossover to LINX; the authors reported on GERD symptoms, QOL, PPI use, and AEs. A retrospective before-and-after study (Ayazi et al. 2020; n=553) reported on patient satisfaction, QOL, GERD symptoms, AEs, and re-treatment at mean 10-month follow-up in individuals with GERD treated with LINX. Two economic studies (Ayazi et al., 2019; Pandolfino et al., 2019) compared LINX and LF from a United States payer perspective. ECRI noted the following limitations in the evidence:
Studies in the SRs are at risk of bias from small sample size, retrospective design, single-center focus, or lack of randomization. However, findings support conclusions because results are consistent across studies and validated in a meta-analysis of controlled studies and 1 independent RCT.
ECRI stated that "evidence from 2 systematic reviews (SRs) of nonrandomized studies, 1 randomized controlled trial (RCT), and 1 before-and-after study shows that LINX works as well as LF for improving symptoms and QOL up to 4 years. Longer follow-up and comparisons of LINX with other GERD devices would be useful; 3 ongoing trials may partially address these evidence gaps."In 2020, Schizas et al. published a systematic review investigating the safety and efficacy of magnetic sphincter augmentation (MSA) using the LINX® Reflux Management System in resolving GERD symptoms. The systematic review was conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Overall, 35 studies with a total number of 2511 individuals undergoing MSA were included and analyzed. Postoperative 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) also showed promising results. The most common postoperative complication was dysphagia, ranging between 6% and 83%. Dilation due to dysphagia occurred in 8% of individuals with typical inclusion criteria. Esophageal erosion may occur in up to 0.03% of individuals. Furthermore, the authors noted that a recent trial indicated MSA as an efficient alternative to double-dose PPIs in moderate to severe GERD. The authors concluded that their 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.
In 2019, Guidozzi et al. conducted a systematic review and meta-analysis evaluating clinical outcomes following MSA for GERD control in comparison with LF. A systematic electronic search for articles was performed in Medline, Embase, Web of Science, and the Cochrane Library for single-arm cohort studies or comparative studies (with fundoplication) evaluating the use of MSA. A random-effects meta-analysis for postoperative PPI use, GERD-HRQL, gas bloating, ability to belch, dysphagia, and reoperation was performed. The systematic review identified six comparative observational studies of MSA versus fundoplication (n=1099; range, 24–415) and 13 single-cohort studies. Follow-up in the comparative observational studies ranged between 6 and 44 months. Following MSA, only 13.2% of individuals required postoperative PPI therapy, 7.8% required dilatation, 3.3% needed device removal or reoperation, and esophageal erosion was seen in 0.3% of individuals. There was no significant difference among the groups in requirement for postoperative PPI therapy (pooled OR, 1.08; 95% CI, 0.40–2.95; P=0.877), GERD-HRQOL score (weighted mean difference, 0.34; 95% CI, −0.70 to 1.37; P=0.525), dysphagia (POR, 0.94; 95% CI, 0.57–1.55; P=0.822), and need for reoperation (PORm 1.23; 95% CI, 0.26–5.8; P=0.797). However, when compared to fundoplication, MSA was associated with significantly less gas bloating (POR, 0.34; 95% CI, 0.16–0.71) and a greater ability to belch (POR, 12.34; 95% CI, 6.43–23.7). The authors concluded that "magnetic sphincter augmentation achieves good GERD symptomatic control similar to that of fundoplication, with the benefit of less gas bloating. The safety of MSA also appears acceptable with only 3.3% of individuals requiring device removal. 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."
In 2019, Riva et al. conducted a systematic review investigating the effect of MSA in the treatment of GERD after a previous gastric/bariatric surgery. The authors searched multiple databases (PubMed, Cochrane, Embase, Scopus) for studies published between 2008 and May 2019 and reporting outcomes of MSA with LINX after any type of gastric surgery. They also queried the prospectively collected database of individuals who underwent MSA at their tertiary-care hospital and compared postsurgical to surgery-naïve individuals operated on during the same time period. Seven studies (three case series and four case reports), for a total of 35 individuals, met the inclusion criteria in the systematic review. The most common index operation was a bariatric procedure, either sleeve gastrectomy or Roux-en-Y gastric bypass. After MSA implant, the GERD-HRQL score significantly improved compared to baseline (5.6 ± 4.4 vs 35.2 ± 16.5; P=0.005). However, 12 (34.3%) individuals reported persistent symptoms after MSA. Seven (20.0%) of them reported recurrent reflux symptoms, but only three (8.6%) resumed daily PPI therapy. Overall, five (14.3%) individuals reported persistent dysphagia; three of them underwent successful endoscopic dilatation, and two (5.7%) required laparoscopic device removal 18 days and 4 months after implantation, respectively. There was no mortality and the postoperative follow-up ranged between 1 and 38 months. In the local institutional cohort series of 67 individuals treated by MSA, the prevalence of preoperative grade B esophagitis, operative time, size of MSA, and LOS were greater in individuals with prior gastric surgery compared to surgery-naïve individuals. The authors conclude that "MSA is a safe, simple, and standardized antireflux procedure. It is also feasible in patients with refractory GERD following gastric/bariatric surgery. Further prospective and comparative studies are needed to validate the preliminary clinical experience in this subset of patients."
In 2019, ECRI issued a Product Brief evaluating the LINX Reflux Management System for treating GERD. In their brief, ECRI indicated that the evidence is somewhat favorable for the LINX Reflux Management System. ECRI stated that "the LINX Reflux Management System appears to work as intended to alleviate GERD symptoms and improve QOL, although some data are at high risk of bias. Higher-quality studies that directly compare the LINX device to standard medical and surgical management of GERD are needed. Long-term data on device failure and reductions in efficacy over time are still accumulating. No deaths have been reported with LINX use, and serious adverse events (AEs) are rare." The brief noted that "most of the available studies are at high risk of bias due to single-arm design and lack of parallel control groups, randomization, and blinding. Higher-quality studies are needed that directly compare the LINX system with medication and surgical approaches. While it may not be feasible to implement placebo controls for implanted devices such as LINX, controlled studies could be conducted that blind outcomes data analysts to the intervention group assignment to generate data at lower risk of bias. However, these studies would not account for potential placebo effects because patients and clinicians administering the treatment could not be blinded."
In 2018, Aiolfi et al. conducted a systematic review and meta-analysis to compare early outcomes of laparoscopic Nissen and Toupet fundoplication (LF) to MSA using the LINX device. Seven observational cohort studies, published between 2014 and 2017, matched the inclusion criteria. No RCTs were found. The patient populations of the individual studies ranged from 24 to 415. A total of 686 individuals (56%) received the LINX and 525 (44%) individuals underwent laparoscopic total (Nissen) or partial (Toupet) fundoplication. Postoperative morbidity ranged from 0% to 3% in the MSA group and from 0% to 7% in the LF group, and there was no mortality. The hospital LOS was 13 to 48 hours in the MSA group and 26 to 48 hours in the LF group. The postoperative follow-up ranged from 6 to 12 months. Compared to preoperative baseline, a statistically significant improvement was noted for both procedures. Reoperation was required in 13 MSA individuals including 12 device removals: one for erosion and one crural release. There were 11 reoperations in the LF group. Dysphagia requiring endoscopic dilatation occurred in 9.3% (MSA) and 6.6% (LF) of individuals (OR, 1.56, 95% CI, 0.61–3.95; P=0.119), not statistically significant. The pooled OR of gas/bloat symptoms, ability to vomit, and ability to belch were 0.39 (95% CI, 0.25–0.61; P< 0.001), 10.10 (95% CI, 5.33–19.15; P<0.001), and 5.53 (95% CI, 3.73–8.19; P<0.001), respectively. The postoperative GERD-HRQL was similar (P=0.101). The pooled OR of PPI suspension, endoscopic dilation, and reoperation were similar in the two patient groups (P=0.548, P=0.119, P=0.183, respectively). The authors noted that the difference in outcomes between the two patient groups should be interpreted with caution because no comparative randomized clinical trials existed to provide strong evidence, and subgroup analysis according to baseline variables was not possible because all outcomes were aggregated in the analyzed studies. This analysis is also limited by the retrospective and registry study designs, small patient populations, and short-term follow-ups. Prospective RCTs with large patient populations and long-term follow-ups are needed to support the safety and efficacy of LINX.
In 2018, Hayes, Inc. updated their technology brief on MSA (LINX Reflux Management System) for the treatment of GERD. Hayes concluded that there was an overall low-quality body of evidence that suggested that MSA is associated with improved QOL and GERD symptoms. However, substantial uncertainty exists due to limited follow-up beyond 1 year and unclear patient selection criteria. Studies were included if they evaluated LINX for the treatment of GERD and compared LINX with alternative treatments (e.g., changes in PPI use, patient-reported GERD symptoms, QOL) or harms data. Seven clinical studies (n=66 to 415 patients) met the inclusion criteria. One RCT that compared MSA with twice-daily PPI treatment and four poor and two very, poor quality cohort studies comparing MSA with LF were included. Outcomes assessed generally included indicators of EAE before and after treatment, changes in PPI usage, patient-reported symptoms, and complications. Hayes also noted that definitive patient selection criteria have not been established for MSA with the LINX. There is a lack of data on patients with moderate-to-severe esophageal disease and moderate-to-severe obesity, a risk factor for GERD. Limitations of individual studies included small patient populations, lack of long-term data, lack of power, analysis, variable follow-up durations among patient populations, and significant differences in baseline characteristics between groups. MSA appeared to be moderately well tolerated; there were no reports of deaths, and serious AEs were uncommon. MSA resulted in fewer individuals experiencing the inability to belch or vomit. Additional prospective comparative studies with large patient populations and long-term follow-up are needed to establish the effectiveness of LINX for the treatment of GERD.
In 2018, Zadeh et al. reviewed the current literature regarding indications, surgical technique, efficacy, and complications of MSA using the LINX device. A standardized literature search was performed yielding 367 abstracts. After elimination due to duplicates between databases and irrelevance, 96 articles remained. The information found to be significant and nonredundant was included in this review. From their review of the published evidence, 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. Regarding 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. Although very rare, the potentially severe consequences of this phenomenon suggest that the device should be used with some restraint and that individuals 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. The authors 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 individuals with decades of life ahead of them.
In 2017, Chen et al. reported the results from a systematic review and meta-analysis comparing the safety and efficacy of the LINX Reflux Management System to Nissen fundoplication. The meta-analysis search was performed using four databases. All studies between 2005 and 2016 were included. Pooled effect was calculated using either the fixed or random effects model. Four retrospective studies included 624 individuals and aimed to evaluate the differences in PPI use, complications, and AEs. A total of 299 individuals were in the LINX group and 325 were in the Nissen Fundoplication group. LINX had a shorter operative time (LINX and Nissen fundoplication: RR, −18.80, 95% CI, −24.57 to −13.04; P=0.001) and LOS (RR, −14.21; 95% CI, −24.18 to −4.23; P=0.005). There were no significant differences between the groups in resumption of PPIs (P=0.23), severe dysphagia for dilation (P=0.74), ability to belch (P=0.13), ability to vomit (P=0.38) and AEs (P=0.49). Although there is no difference between LINX and Nissen fundoplication in the number of AEs, the incidence of postoperative gas or bloating (RR, 0.71; 95% CI, 0.54–0.94; P=0.02) showed significantly different results. However, there is no significant difference in ability to belch and ability to vomit. Limitations of the studies included the retrospective study design, small patient populations; and two trials did not match the size of hiatal hernias. Prospective studies with long-term follow-ups are needed to establish the safety and efficacy of the LINX Reflux Management System for the treatment of GERD.
In 2017, Skubleny et al. reported the results from a systematic review and meta-analysis comparing MSA using the LINX Reflux Management System to Nissen fundoplication for the treatment of GERD. All RCTs, nonrandomized comparison studies, and case series with more than five individuals were included. A total of 547 titles were identified through primary search, and 197 titles or abstracts were screened after removing duplicates. Primary outcomes included GERD-HRQL scores, DeMeester scores, operative times, ability to belch, ability to vomit, discontinuation of PPI, need for endoscopic dilation, procedural satisfaction, presence of gas/bloating and dysphagia. Secondary outcomes included mortality and morbidity. Three primary studies (two retrospective cohort comparative studies and one case series) identified 688 individuals, of whom 273 and 415 underwent Nissen fundoplication and MSA, respectively. Mean duration of follow-up ranged between 7 and 16 months for Nissen fundoplication and 7 and 12 months for MSA. MSA was statistically superior to Nissen fundoplication in preserving an individual's ability to belch (95.2 vs 65.9%; P<0.00001) and ability to vomit (93.5% vs. 49.5%; P<0.0001). There was no statistically significant difference between MSA and Nissen fundoplication in gas/bloating (26.7% vs. 53.4%, P=0.06), postoperative dysphagia (33.9 vs. 47.1%; P=0.43) and PPI elimination (81.4% vs. 81.5%; P=0.68). Six individuals required endoscopic balloon dilation following MSA compared with zero dilations post-Nissen fundoplication. Major morbidity for Nissen fundoplication included one case of intraoperative pleural injury, two cases of retroesophageal abscesses, and four cases of revision due to hiatal hernia recurrence. The MSA group morbidity included one pleural injury, two episodes of intraoperative bleeding, one pneumothorax, and one GEJ obstruction. Two MSA devices were removed because of treatment failure and device erosion 20 months after surgery. Limitations of the studies included lack of randomization, short-term follow-up, loss to follow-up (7.7%–10.6%), and heterogeneity in the size of hiatal hernia and grade of esophagitis accepted within treatment arms. The authors noted that the validity of many of the primary outcomes was decreased due to their subjective nature and lack of clear medical definition. The authors further stated that long-term comparative outcome data past 1 year are needed in order to further understand the efficacy of MSA.
In 2017, ECRI issued an update to their 2015 Emerging Technology Evidence Report evaluating MSA (LINX Reflux Management System) for treating GERD. In their evidence report, ECRI addressed three key questions: (1) How do the safety and effectiveness of MSA compare with those of optimal medical therapy for treating medically refractory GERD? (2) How do the safety and effectiveness of MSA compare with those of other endoscopic or surgical interventions for treating medically refractory GERD? (3) What AEs are reported in studies of MSA for medically refractory GERD?
For key question number 1, ECRI wrote the following:
- The evidence does not clearly indicate whether MSA reduces GERD symptom prevalence compared with optimal medical therapy because a single prepost study assessed this outcome at 1- and 6-month, and 1-, 2-, 3-, and 5-year follow-up. Strength of evidence: very low.
- MSA reduces heartburn and regurgitation prevalence compared with optimal medical therapy after 1-year follow-up. Strength of evidence: low.
- The evidence does not clearly indicate whether MSA improves overall QOL compared with optimal medical therapy because a single prepost study assessed this outcome at 1- or 6-month follow-up. Strength of evidence: very low.
- MSA improves overall GERD-HRQL scores compared with optimal medical therapy after 1- and 5-year follow-up. Strength of evidence: low.
- The evidence does not clearly indicate whether MSA reduces PPI medication use compared with optimal medical therapy because a single prepost study assessed this outcome at 1-month, 6-month, and 5-year follow-up. Strength of evidence: very low.
- The evidence does not clearly indicate whether MSA reduces PPI medication use compared with optimal medical therapy because a prepost study at high risk of bias reported findings of unclear statistical significance at 1-year follow-up. Strength of evidence: very low.
For key question number 2, ECRI wrote the following:
- The evidence does not clearly indicate how GERD symptom prevalence compares in individuals treated with MSA and individuals treated with LF because a single nonrandomized study compared this outcome at 6-month and 1-year follow-up. Strength of evidence: very low.
- The evidence does not clearly indicate how QOL compares in individuals treated with MSA and individuals treated with LF because a single nonrandomized study compared this outcome at 1-month, 6-month, and 1-year follow-up. Strength of evidence: very low.
- The evidence does not clearly indicate how PPI medication use compares in individuals treated with MSA and individuals treated with LF because studies disagree on the outcome at 1-year follow-up. Strength of evidence: very low.
- The evidence does not clearly indicate how rates of retreatment for recurring GERD compare in individuals treated with MSA and individuals treated with LF because a single nonrandomized study compared this outcome at 1-year and 2-year follow-up. Strength of evidence: very low
- The evidence does not clearly indicate how the rate of serious AEs in individuals treated with MSA compares to that in individuals treated with LF because a single nonrandomized study compared this outcome at 6-month and 1-year follow-up. Strength of evidence: very low
For key question number 3, ECRI wrote the following:
Mild or moderate dysphagia, odynophagia and epigastric pain are expected and common in patients who undergo MSA and typically resolve without additional treatment after a few days. Dysphagia may occur in up to 85% of patients, gas or bloating in up to 41%, odynophagia in up to 35%, inability to belch or vomit in up to 33%, and chest or epigastric pain in pain up to 20%. One small study (n=12) reported that 50% of patients required endoscopic esophageal dilation to relieve ongoing dysphagia; however, the reported rates of dilation among patients in 10 other studies (n=818, range 23 to 169) ranged between 1% and 19%. Furthermore, other SAEs are infrequent. Severe pain, severe nausea and vomiting, esophageal erosion or obstruction, food impaction, pneumothorax, or surgical bleeding occurred in less than 5% of patients in studies of the LINX system.
In 2015, ECRI published an emerging technology evidence report evaluating MSA (LINX Reflux Management System) for treating GERD. Their report considered the quantity of evidence to be low "given the large number of patients affected by medically refractory GERD and the need for comparative data on procedures and patient-oriented outcomes." Regarding the quality of the evidence, ECRI was unable to find any well-designed controlled trials. Regarding the available evidence, the authors stated that "[t]he case series lack many comparisons of interest, were sponsored by the manufacturer, and led by manufacturer consultants. These studies suffered from incomplete and vague results reporting: inconsistent results reporting (e.g., Ganz et al. (2013) reported intent-to-treat [ITT] at one year, not at subsequent follow-ups, and did not report numbers lost to follow-up; Lipham et al (2012) reported findings on the basis of individuals left at follow-up, not ITT). Both studies took baseline esophageal pH level measurements while individuals were off PPI therapy, so no pre-post pH comparison data for PPI therapy and LINX are available. Results reported after one year were post hoc analyses with an unclear number of individuals lost to follow-up—as many as half were unaccounted for in the Lipham et al. (2012) study. Results in the text of articles did not consistently correspond to results in tables." In their evidence report, ECRI addressed three key questions: (1) How does the LINX Reflux Management System compare with medical therapy for treating medically refractory GERD regarding esophageal pH, GERD symptom frequency, GERD-related QOL, medication use, and patient satisfaction? (2) How does the LINX Reflux Management System compare with any other surgical or endoscopic treatment for medically refractory GERD regarding esophageal pH, GERD symptom frequency and severity, GERD-QOL, hospital length-of-stay (LOS), medication use, and patient satisfaction? (3) What AEs are reported in studies of the LINX Reflux Management System? (4) How do the AEs reported with the LINX Reflux Management System compare with AEs reported in studies of any other surgical or endoscopic treatments for GERD?For key question number 1, ECRI wrote the following:
Generally, because of the small evidence base and other quality factors, the available evidence is insufficient to firmly conclude that device implantation resolves GERD symptoms, obviates the need for medication, or definitively improve QOL and patient satisfaction. See details below.
Ganz et al. (2013) reported data on an intent-to-treat basis for some outcomes of interest, as follows, at 1 year (100 individuals were enrolled; 98 had the device at 1 year); 85 patients provided data at year 3:
- GERD-HRQL: At year 3, some individuals who received the LINX device reported improved scores on this measure, which rates symptoms on a scale of 0 (no symptoms) to 50 (incapacitated by GERD). Patients' median baseline HRQL score of 11 had declined to a score of 2 over 3 years. The clinical significance of this change is not well defined.
- Esophageal pH: No studies reported esophageal pH of individuals while on PPI therapy at baseline compared with post-LINX esophageal pH. Esophageal pH measures acid reflux decline and is primarily measured using 24-hour pH monitoring. Thus, the impact on esophageal pH of LINX relative to medication could not be determined.
- Length of stay (LOS): No data on LOS relative to other procedures are available, but LOS for LINX in the studies was one to two days.
- Medication use: No data on medication use after LINX relative to other surgical or endoscopic procedures are available. PPI medication use before and after LINX are available. Ganz et al. (2013) reported that at 1 year, 93% (93/100; 95% CI, 86 to 97) of individuals had a 50% reduction in average daily dose of PPIs compared with PPI use before LINX. Authors also reported that 14% of individuals were still taking PPIs one year after LINX but did not provide actual patient numbers at follow-up. Lipham et al. reported that 80% (20/25) of patients were not taking PPIs at ≥4 years, but the table in the published article of this study shows the number of individuals evaluated as 23, not 25. Thus, while medication use declined in many individuals, many individuals still required medication; one cannot conclude from these data that LINX obviates the need for GERD medication.
For key question number 2, ECRI reported that no studies were available to address the question.For key question 3, ECRI stated the following:
Ganz et al. 2013 and Lipham et al. 2012 reported AEs. Dysphagia was the most commonly reported AE, occurring in 88 of the 144 individuals enrolled, although some individuals were lost to follow-up in these studies. In most individuals reporting dysphagia, the condition resolved within a few months. However, study authors reported that "serious AEs" occurred in eight patients: four cases of persistent dysphagia required device removal; one case of persistent vomiting requiring device removal; two cases requiring hospitalization from nausea and vomiting, but no device removal; and one case in which the patient experienced pain requiring hospitalization. One FDA Manufacturer and User Facility Device Experience database report indicated that endoscopy revealed a LINX bead inside a patient's esophagus and required surgery, during which surgeons removed three beads from the device.
For key question number 4, ECRI noted that no studies were available to address the question.In 2015, Sheu and Rattner evaluated the current data on the safety, efficacy, and indications for MSA using the LINX device to treat GERD. The authors stated that the LINX device has demonstrated excellent safety and GERD efficacy in several recent nonblinded, 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 gastrointestinal side effects seen after LF (bloating, gas, 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 further stated that MSA should be considered for selected GERD individuals without significant anatomic or motility defects. However, the authors also stated that long-term safety and efficacy of LINX—both alone and in comparison to current GERD therapies—remains to be determined.In 2014, Loh et al. addressed whether the LINX Reflux management system is an efficacious treatment for individuals with symptoms of GERD not controlled by PPIs. Forty-eight LINX-related papers were identified using the reported search, of which three represented the best evidence to answer the clinical question. All three studies were prospective case studies. They demonstrated that LINX is an efficacious treatment for individuals with GERD, with good short and medium term outcomes and an acceptable safety profile. The authors concluded that further studies are required to determine its long-term outcomes and its relative efficacy as compared to other established treatments.In 2013, the Australian Safety and Efficacy of New Interventional Procedures - Surgical (ASENIP-S) issued a technology brief on the LINX device. The brief came to the following conclusions: "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 individuals 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 favorable treatment alternative (provided its utility in individuals with significant esophagitis 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 randomized), 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 esophagus 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."
Randomized Controlled Trials
No RCTs comparing MSA (i.e., LINX Reflux Management System) to LNF were identified.
In 2019, Bell et al. reported the 6-month (Bell 2019a) and 1 year (Bell 2019b) results of a randomized, controlled, prospective, double-arm, crossover study comparing the effectiveness of increased PPI dosing with laparoscopic MSA in individuals with moderate to severe regurgitation despite once-daily PPI therapy. A total of 152 individuals with GERD, aged 21 years or older with moderate to severe regurgitation despite 8 weeks of once-daily PPI therapy were prospectively enrolled. Participants were randomly assigned 2:1 to treatment with twice-daily PPIs (n=102) or to laparoscopic MSA (n=50). At 6 months, eligible individuals in the PPI arm could cross over to the MSA arm; both groups then underwent additional evaluation at 12 months. Individuals answered questions from the foregut-specific reflux disease questionnaire and GERD-HRQOL survey about regurgitation, heartburn, dysphagia, bloating, diarrhea, flatulence, and medication use, at baseline and 6 and 12 months after treatment.
6-Month Results
At 6 months, 94% (47/50) of individuals in the MSA arm and 85% (87/102) of individuals in the PPI arm were available for analysis. Per protocol, 89% (42/47) of individuals treated with MSA reported relief of regurgitation compared with 11% (10/87) of the PPI group at the 6-month primary endpoint. By intention-to-treat analysis, 84% (42/50) of individuals in the MSA group and 10% (10/102) in the PPI group met this primary endpoint (P<0.001). Eighty-one percent (38/47) of individuals with MSA versus 8% (7/87) of individuals with PPI had 50% or more improvement in GERD-HRQOL 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 individuals, respectively, compared with 58% (46/79) (P<0.001) and 75% (59/79) (P=0.065) of PPI individuals at 6 months. No significant safety issues were observed. In MSA individuals, 28% reported transient dysphagia; 4% reported ongoing dysphagia. A major limitation of the study was that the individuals had not received optimal medical treatment prior to enrollment. Additional limitations included the use of subjective outcome measures along with an open-label design, although this limitation is less of a concern because results were supported by better results for MSA on some objective measures. For individuals who have not responded to optimal medical treatment, an appropriate comparator would be Nissen fundoplication. The study was also relatively small (n=50 for the MSA group) with short-term follow-up (6 months).
1-Year Results
Seventy-five individuals (49% [75/152]) were followed up for 1 year. Of the 75, 44 (59%) were originally treated with MSA, and 31 (41%) were crossover cases from the original PPI group. Individuals in the MSA group and those who crossed over to the MSA group after PPI therapy had similar outcomes. MSA resulted in control of regurgitation in 72 of 75 individuals (96%); regurgitation control was independent of preoperative response to PPIs. Only eight of 43 individuals receiving PPIs (19%) reported control of regurgitation. Among the 75 individuals who received MSA, 61 (81%) had improvements in GERD-HRQOL improvement scores (>50%) and 68 individuals (91%) discontinued daily PPI use. Proportions of individuals with dysphagia decreased from 15% to 7% (P<0.005), bloating decreased from 55% to 25%, and EAE time decreased from 10.7% to 1.3% (P<0.001) from study entry to 1 year after MSA (Combined P<0.001). Seventy percent (48/69) of individuals had pH normalization at study completion. MSA was not associated with any per-operative events, device explants, erosions, or migrations.
Nonrandomized Comparative Trials
In 2021, Bonavina et al. published 3-year outcomes from a prospective, multicenter, observational registry study evaluating MSA and LF in 631 individuals (465 MSA; 166 LF) with GERD. Individuals had a diagnosis of GERD confirmed by abnormal EAE and chronic reflux symptoms despite daily use of PPIs. Individuals with severe GERD marked by hiatal hernia larger than 3 cm, Barrett esophagus, motility disorder, and Grade C or D esophagitis by Los Angeles classification were also included. MSA was recommended when individuals met labeling requirements for MSA (hiatal hernia ≤3 cm, esophagitis <Grade C, absence of Barrett esophagus, and absence of motility disorders); however, the final choice of procedure was made by the surgeon at the time of laparoscopy. Various forms of laparoscopic fundoplication were performed, including Nissen (62%), Toupet (31%), and Other/Unspecified (e.g., Dor; 7%). Data collection included baseline characteristics, reflux symptoms, medication use, satisfaction and complications. Postsurgical evaluations were collected at yearly intervals. Improvements in total GERD-HRQL scores were observed in both MSA (22.0 to 4.6) and LF (23.6 to 4.9) groups with similar increases in GERD-HRQL satisfaction (GERD-HRQL satisfaction increase from baseline to 3 years: MSA 4.6% to 78.2% and LF 3.7% to 76.5%). Most individuals 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 individuals 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. Intraoperative and procedure-related complication rates (≤ 2%) were low for both therapies. Limitations of the study include lack of randomization and blinding, heterogeneity in LF techniques, and selection bias, because individuals with less severe symptoms received MSA. It is unclear to what extent study results are generalizable to US populations and broader settings of care. The authors concluded that "this 3-year prospective observational registry study contributes 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 standpoint."
In 2016, Warren et al. reported the 1-year results of a multi-institutional retrospective cohort study of individuals with GERD undergoing either MSA (n=201) or Nissen fundoplication (NF; n=214). The groups were similar in age, gender, and GERD-HRQL scores but significantly different in preoperative obesity (32% vs. 40%), dysphagia (27% vs. 39%), DeMeester scores (34 vs. 39), presence of microscopic Barrett esophagus (18% vs. 31%), and presence of hiatal hernia (55% vs. 69%). Given the differences in baseline groups, the authors used propensity score matching to generate 114 matched pairs based on preoperative esophagitis, presence of Barret esophagus, hiatal hernia, and BMI. Mean follow-up differed for matched-pair MSA and NF groups (11 months vs. 16 months, respectively; P<0.001). At a minimum of 1-year follow-up, 354 individuals (169 MSA and 185 NF) had significant improvement in GERD-HRQL scores (pre to post: 21–3 and 19–4). MSA individuals had greater ability to belch (96% vs 69%) and vomit (95% vs 43%) with less gas bloat (47% vs 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% vs 32%). Resumption of daily PPIs was higher for MSA (24 vs 12; P=0.02) with similar patient-reported satisfaction rates. The authors concluded that MSA for uncomplicated GERD achieves similar improvements in QOL and symptomatic relief, with fewer side effects, but lower PPI elimination rates when compared to propensity-matched NF cases. In appropriate candidates, MSA is a valid alternative surgical treatment for GERD management. Limitations of this study included retrospective design, short-term follow-up, and lack of an objective postoperative GERD control measure (e.g., postoperative pH).
In 2016, Asti et al. reported 1-year data from an observational cohort study comparing MSA (n=135) using the LINX Reflux Management System and LTF (n=103). Eligible individuals had GERD symptoms despite PPI for at least 6 months, and normal esophageal motility. Criteria of exclusion were greater than 3 cm hiatal hernia, grade C-D esophagitis, ineffective esophageal motility, BMI greater than 35, and previous upper abdominal surgery. The primary study outcome was QOL measured with the GERD-HRQL questionnaire. Secondary outcomes were PPI use, presence of gas-related symptoms or dysphagia, and reoperation-free probability. In a generalized estimating equations model for GERD-HRQL, there was no significant difference at 1 year in GERD-HRQL between MSA and LTF groups (OR, 1.04; 95% CI, 0.89–1.27; P=0.578). Similarly, there was no significant difference between the MSA and LTF groups at 1 year in PPI use (OR, 1.18, 95% CI, 0.81–1.70; P=0.388), gas-related symptoms (OR, 0.69; 95% CI, 0.21–2.28; P= 0.542), dysphagia (OR, 0.62; 95% CI, 0.26–1.30; P = 0.241), and reoperation-free probability (stratified log-rank test = 0.556). Author-noted limitations of the study included the fact that the GERD-HRQL is a subjective test and the MSA procedures were not standardized regarding large hernia repair (crural repair). There is also a risk of bias due to the observational design of the study. Further research is needed to investigate correlation between longitudinal QOL data with objective long-term outcomes of these procedures.
In 2016, Reynolds et al. reported the results of a retrospective analysis that compared the charges, complications, and outcomes of MSA to LNF. There were 119 individuals included in the study: 52 MSA and 67 LNF. Patient charges were collected for the surgical admission. The authors also collected data on 30-day complications and symptom control at 1 year assessed by GERD-HRQL score and PPI use. There was no significant difference between the mean charges for MSA and LNF ($48,491 vs. $50,111; P=0.506). There were significant differences in OR time (MSA, 66 minutes; LNF, 82 minutes; P<0.01) and LOS (MSA, 17 hours vs. LNF, 38 hours; 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 individuals versus 92% of LNF individuals were free from PPIs (P=0.37). Individuals who underwent MSA reported less gas bloat symptoms (23% vs. 53%; P≤0.01) and inability to belch (10% vs. 36%; P≤0.01) and vomit (4% vs. 19%; P≤0.01). The authors concluded that the side effect profile of MSA is better than LNF as evidenced by less gas bloat and increased ability to belch and vomit. 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 limitations of this study included retrospective design, short-term 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%.
Reynolds et al. (2015) reported their findings from a retrospective analysis of 1-year outcomes of 50 individuals who underwent MSA using the LINX Reflux Management System and 50 individuals who underwent LNF. At 1 year after surgery, both groups had similar GERD-HRQL scores (MSA=4.2, LNF=4.3; P=0.897) and PPI use (MSA, 17%; LNF, 8.5%; P=0.355). There was no difference in the number of individuals reporting mild gas and bloating (MSA, 27.6%; LNF, 27.6%; P=1.000), but more LNF individuals reported severe gas and bloating compared to the MSA individuals (10.6% vs 0%; P=0.022). Furthermore, more LNF individuals were unable to belch (MSA, 8.5%; LNF, 25.5%; P=0.028) or vomit when needed (MSA, 4.3%; LNF, 21.3%; P=0.004). The incidence of postoperative dysphagia was similar between the groups (MSA, 46.8%; LNF, 44.7%; P=0.766).
In 2015, Riegler et al. reported the results of a prospective, multicenter registry that compared MSA (n=202) to LF (n=47). Data collection included baseline characteristics, reflux symptoms, PPI use, side effects, and complications. Outcomes were evaluated 1 year after surgery. The LF group had a greater frequency of large hiatal hernias (>3 cm, 45.7% vs 1.6%), and was older and had a greater frequency of Barrett esophagus (19.1% vs. 1.0%; P<0.001) compared to the MSA group. Improvements in GERD-HRQL scores were similar for the two groups (MSA, 20.0 to 3.0; LF, 23.0 to 3.5). Individuals who underwent LF had greater regurgitation (13% vs 3.1%; P=0.014) and fewer individuals who discontinued PPIs after treatment (63% vs 81.8%; P=0.009). Excessive gas and abdominal bloating (31.9% vs 10%; P<0.001) and inability to vomit (55.6% vs 8.7%; P<0.001) were significantly higher after LF than MSA. Reoperation rate was 4.0% following MSA compared to 6.4% following LF. This was an observational study; its findings need to be validated by RCTs.
In another retrospective, case-controlled study, Sheu et al. (2015) compared outcomes from 12 MSA (LINX Reflux Management System) individuals with a contemporaneous case-matched cohort of individuals who underwent LNF. Over half of the MSA individuals were self-referred, compared with none who underwent LNF (P<0.001). Both procedures were effective for reflux (MSA, 75%; LNF, 83%). Severe dysphagia requiring endoscopic dilation was more frequent after MSA (MSA, 50%; LNF, 0%; P=0.01), while there was a trend for a reduction in bloating, flatulence, and diarrhea after MSA compared to LNF.
In a retrospective case-controlled study, Louie et al. (2014) reported on 66 individuals with GERD who had undergone either MSA using the LINX Reflux Management System (n=34) or LNF (n=32). The outcomes of interest were subjective and objective indices of GERD and follow-up data were collected between 6 and 10 months postprocedure. At follow-up, the study found a statistically significant improvement in GERD-HRQL scores in both groups: 20.6 to 5.0 in the MSA group and 22.8 to 5.1 in the LNF group. DeMeester scores were also significantly normalized postoperatively in both groups, with greater improvements occurring in the LNF group: 14.2 in the MSA group versus 5.1 in the LNF group (P=0.0001). They also found that the MSA procedure resulted in improved gassy and bloated feelings (1.32 vs 2.36; P=0.59) and enabled belching in 67% of individuals compared to none of the LNF individuals. Limitations of this study included retrospective design, small sample size, and short follow-up.
Single-Arm Trials (Case Series)
In 2021, DeMarchi et al. analyzed the FDA Manufacturer and User Facility Device Experience (MAUDE) reports and manufacturer complaint databases between 2013 and 2020 to determine rates of surgical device erosion and explants. Overall, 7-year cumulative risk of removal was 4.81% (95% CI, 4.31%–5.36%), with 2.2% of devices (609/27779) having been reported as removed. Primary reasons for device removal included dysphagia/odynophagia (47.9%), persistent GERD (20.5%), and unknown/other (11.2%). The 7-year cumulative risk of erosion was 0.28% (95% CI, 0.17%–0.46%), with 27 reports of erosion. Smaller device size was found to be associated with increased removal and erosion rates.
In 2020, Ayazi et al. evaluated the outcomes of MSA in a large cohort of individuals with GERD and to determine the factors predicting a favorable outcome. This was a retrospective, single-center, prepost review of prospectively collected data of 553 individuals who underwent MSA in a 5-year period. Preoperative clinical, endoscopic, manometric, and pH data were used in a univariate analysis. This was followed by a regression multivariable analysis to determine the factors predicting a favorable outcome. Favorable outcome was defined as freedom from PPIs and 50% or greater improvement in GERD-HRQL total score. At a mean (SD) follow-up of 10.3 (10.6) months after MSA, 86.7% of the individuals were satisfied with the outcome of surgery, 92.7% of the individuals were free of PPI use, and 84% reported at least 50% improvement in their GERD-HRQL total score. The GERD-HRQL total score was improved from a mean (SD) baseline value of 33.8 (18.7) to 7.2 (9.0) (P<0.001) and 76.1% of the individuals had normalization of their EAE. RSI total score was improved from 22.2 (10.9) to 8.7 (8.8) (P<0.001). Twenty-three (4.2%) of the individuals were readmitted within 30 days from surgery and another eight (1.4%) were readmitted within 90 days from surgery. There were only two (0.4%) major complications. These consisted of CO2 retention requiring reintubation (n=1) and mediastinal abscess requiring drainage and IV antibiotic (n=1). Minor complications were observed in 49 (8.9%) of the individuals. There was one death from causes unrelated to placement of the LINX device. Thirty-seven (6.7%) individuals required removal of their device. Of these, 20 (3.6%) were due to significant dysphagia or chest pain. Independent predictors of a favorable outcome after MSA included age younger than 45 years (OR, 4.2; 95% CI, 1.1–15.2; P=0.0305), male sex (OR, 2.5; 95% CI, 1.1–5.7; P=0.0301), GERD-HRQL total score greater than 15 (OR, 7.5; 95% CI, 3.3–16.8; P<0.0001), and abnormal DeMeester score (OR, 2.6; 95% CI, 1.1–5.7; P=0.0225). The authors concluded with the following: "In this largest single-institution series, we demonstrate that MSA implantation is associated with very good clinical and objective outcomes. Age younger than 45 years, male sex, GERD-HRQL total score >15, and abnormal DeMeester score are the 4 preoperative factors predicting a favorable outcome and can be used in patient counseling and MSA use."
Also in 2020, Ayazi et al. (2020) published a retrospective review of 380 individuals treated with MSA with a mean follow-up duration of 11.5 ± 8.7 months. Persistent dysphagia was reported in 59 (15.5%) individuals with 31% requiring at least one dilation for dysphagia or chest pain. The overall response rate to dilation was 67%, with seven (1.8%) individuals requiring device removal for dysphagia. Independent predictors of persistent dysphagia included the absence of a large hiatal hernia (P=0.035), the presence of preoperative dysphagia (P=0.037), and having less than 80% peristaltic contractions on high-resolution impedance manometry (P=0.031).
In 2019, Hawasli et al. reported the results from 13 individuals that had the LINX system placed to manage their reflux after sleeve gastrectomy. Preoperative evaluation included a barium swallow, endoscopy with pH monitor, and esophageal motility. Ten female and three male individuals with mean age of 49 ± 13 years were evaluated. Their mean weight before receiving the LINX system was 193 ± 45 pounds and mean BMI of 33 ± 6 kg/m2. The mean time between sleeve gastrectomy and placing the LINX system was 43 ± 19 months. The mean Bravo score was 46 ± 26 (normal, 14.7). One individual developed severe dysphagia postoperatively requiring removal of the LINX® after 18 days and one individual was lost to follow-up. The mean follow-up in the remaining 11 individuals was 26 ± 12 months. The mean GERD-HRQL 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 Roux-en-Y gastric bypass conversion in managing refractory post–sleeve gastrectomy reflux. Limitations of this study include small sample size (11 individuals were evaluated) and mid-term follow-up (26 months). These findings need to be validated by well-designed studies.
In 2019, Louie et al. reported the 1-year results from a 5-year mandated multicenter, prospective study of individuals with pathologic acid reflux confirmed by esophageal pH testing undergoing MSA using the LINX Reflux Management System. Predefined clinical outcomes were assessed at the annual visit including a validated, disease-specific questionnaire, esophagogastroduodenoscopy and esophageal pH monitoring, and use of PPI. A total of 200 individuals with a mean age of 48.5 years were treated with MSA. At 1 year, the mean total acid exposure time decreased from 10.0% at baseline to 3.6%, and 74.4% of individual had normal EAE time. GERD-HRQL scores improved from a median score of 26.0 at baseline to 4.0 at 1 year, with 84% of individuals meeting the predefined success criteria of at least a 50% reduction in total GERD-HRQL score compared with baseline. The device removal rate at 1 year was 2.5%. One erosion and no serious AEs were reported.
In 2018, Alicubin et al. (2018) published a retrospective review, which identified a risk of device erosion of 0.3% at 4 years after device placement. Twenty-nine reported cases of erosion occurred among 9453 device placements. The median time to erosion was 26 months, and most cases occurred between 1 and 4 years after device placement.
In 2018, Buckley et al. published the results from a multicenter, prospective study in consecutive individuals undergoing MSA with the LINX device during repair of paraesophageal and hernias over 3 cm axial component. Two-hundred individuals (110 female) were treated via laparoscopic hernia repair and MSA. Mean age was 59.5 years, mean BMI was 29.4, 40% had esophagitis, 20% had intestinal metaplasia, and 72 of 77 tested had abnormal pH studies. Preoperative PPI use was reported by 87%. Eighteen individuals had prior hiatal hernia/fundoplication. All individuals had normal function, and 78% of individuals had axial hiatal hernia 5 cm or larger paraesophageal component. Mean operative time was 81 minutes (38–193), estimated blood loss was 10 cc. Nonpermanent mesh reinforcement of hiatal repair was performed in 83% of the individuals. There were two readmissions for dehydration; two individuals with pulmonary embolism, and one individual with cardiac ischemia. Nineteen individuals required dilation. One-hundred and fifty-six individuals were followed up for a median of 8.6 months. GERD-HRQL scores improved from 26 preoperatively to two postoperatively. Complete PPI independence was achieved in 94% (147/156). Videoesophagram in 51 individuals at median 11 months found three asymptomatic hernias smaller than 3 cm. One symptomatic individual underwent successful repair of the hernia without MSA manipulation. There have been no device explants, erosions, or migrations to date. The authors concluded that this prospective study of 200 individuals with hernias larger than 3 cm undergoing MSA with hiatoplasty resulted in favorable outcomes with median of 9 months follow-up. Comparing this to published reports of MSA in individuals with smaller than 3 cm hernias, the safety and clinical efficacy of MSA are independent of initial hernia size. The authors stated that the study had several limitations: (1) although all individuals had greater than 3 cm axial component to the hernia by preoperative or intraoperative findings, no single measurement of hernia size was used uniformly; (2) the two institutions performed slightly different prospective data collection and surgical techniques; (3) the authors did not obtain preoperative pH testing on all individuals; however, the false-negative rate seen in individuals with large hernias limited the utility of pH testing; (4) the authors did not directly compare outcomes of individuals in this study with outcomes of their individuals 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 it adequate to serve as a benchmark against which to compare this study’s results; and (5) the authors would have preferred to obtain more complete objective postoperative data, especially on asymptomatic individuals; this was not possible insofar as many asymptomatic individuals 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.
In 2017, Warren et al. reported the results from a retrospective case control study evaluating the manometric changes, function, and impact of MSA on the LES in 121 individuals with GERD. Inclusion criteria consisted of a confirmed diagnosis of GERD by an abnormal esophageal pH study (BMI <35 kg/m, hiatal hernia <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 mm Hg pre-MSA vs. 23 mm Hg post-MSA; P = 0.0003), residual pressure (4 mm Hg vs. 9 mm Hg; P<0.0001), and distal esophageal contraction amplitude (80 mm Hg vs. 90 mm Hg; P=0.02). The percent peristalsis remained unaltered (94% vs 87%; P=0.71). Overall, a manometrically defective LES was 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 individuals, respectively. Only 18% of individuals with a normal preoperative 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.
In 2017, Rona et al. assessed outcomes of MSA in individuals with hiatal hernias 3 cm or larger. The authors retrospectively reviewed all individuals who underwent MSA over a 6-year period. Information obtained consisted of patient demographics, symptoms of GERD, preoperative GERD-HRQOL scores, perioperative details, and implantation of the MSA device. Primary endpoints included postoperative GERD-HRQL scores, PPI use, symptom change, and procedure-related complications. A large hiatal hernia was defined as a hernia measuring 3 cm or more by intraoperative measurement. A total of 192 individuals were reviewed. Median follow-up was 20 months (3–75 months). Mean GERD-HRQL scores in the overall population before and after MSA were 18.9 and 5.0, respectively (P<0.001). In the majority of individuals, symptoms improved or resolved (N=177; P<0.001). Fifty-two individuals (27.0%) had a hiatal hernia 3 cm or greater (range, 3–7 cm). Their mean GERD-HRQL score decreased from 20.5 to 3.6 (P<0.001) following MSA. When compared with individuals with smaller hernias, individuals with large hiatal hernias had decreased postoperative PPI requirement (9.6 vs. 26.6 %; P=0.011) and lower mean postoperative GERD-HRQL scores (3.6 vs. 5.6; P=0.027). The percentage of individuals requiring postoperative intervention for dysphagia was similar (13.5 vs. 17.9%; P=0.522), as was the incidence of symptom resolution or improvement (98.1 vs. 91.3%; P=0.118). The authors concluded that "MSA in patients with large hiatal hernias demonstrates decreased postoperative PPI requirement and mean GERD-HRQL scores compared to patients with smaller hernias. The incidence of symptom resolution or improvement and the percentage of patients requiring intervention for dysphagia are similar. Short-term outcomes of MSA are encouraging in patients with gastroesophageal reflux disease and large hiatal hernias." The authors stated that there were several limitations to this study: (1) data were gathered retrospectively and is potentially subject to both selection and information biases as this review spanned over a 6-year period; (2) after successful introduction of the LINX device into their clinical practice, their understanding of its potential for individuals 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. As a result, individuals in their large hiatal hernia group had a shorter follow-up time compared with those in their control group. Thus, the improved postoperative 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 postoperative measures of reflux and screening for hiatal hernia recurrence are needed to confirm the durability of MSA in this patient population. The authors 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 individuals with GERD and large hiatal hernias.
In 2017, Czosnyka et al. reported their early experience in using MSA from two 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% preoperatively to 8% postoperatively (P<0.001). Median GERD-HRQL improved from 27 preoperatively to 5 postoperatively (P<0.001). Patient satisfaction increased from 8% preoperatively to 84% postoperatively (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 QOL. GERD-HRQL, medication reduction, operative times, and dysphagia rates were similar to other reports, demonstrating the reproducibility of MSA. Lower dilation rates may be due to refinements in technique and postoperative dietary management.
In 2016, Ganz et al. reported the final 5-year results for the 100 individuals enrolled in the pivotal Investigational Device Exemption (IDE) study described in Ganz et al. (2013). Eighty-five individuals were followed up for 5 years to evaluate QOL, reflux control, use of PPIs, and side effects. The GERD-HRQL questionnaire was administered at baseline to individuals 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 six-point or more improvement when scores on versus off PPI were compared. Of those 85, 83% achieved had a 50% reduction in the GERD-HRQL score (95% CI, 73%–91%), and 89.4% had a reduction of 50% or more in average daily dose of PPI (95% CI, 81%–95%). At baseline, the median GERD-HRQL scores were 27 in individuals not taking PPIs and 11 in individuals on PPIs; 5 years after device placement this score decreased to 4. Moderate or severe heartburn decreased from 89% to 11.9%, and moderate or severe regurgitation decreased from 57% to 1.2% without use of PPIs at baseline and 5 years. Daily use of PPIs decreased from 100% at baseline to 15.3% at 5 years. At 5 years, 75.3% of individuals reported complete cessation of PPIs, and 9.4% reported PPI use only as needed. Thus, 84.7% were either completely off PPIs or reported use as needed at 5 years. All individuals 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. Over the follow-up period, there were no device erosions, migrations, or malfunctions. The device was removed in seven individuals. The limitations of this study included the following: (1) all of the centers were high-volume esophageal center, and high-volume surgeons with extended proficiency in dissection of the diaphragmatic hiatus, performing LF and early adopters of MSA technology. This may limit the applicability of the results outside of high-volume esophageal centers; (2) the lack of an objective postoperative 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 individuals had normalization of EAE along with symptomatic improvement and discontinuation of PPIs. Longer term pH data would have strengthened the conclusions; 15 of the original 100 individuals were lost to follow-up (15%), and there was no comparison group.
In 2015, Lipham et al. reported the results of a study that examined the safety profile of MSA in the first 1048 implanted individuals (82 institutions). Median device implantation was 274 days. Of these, 144 were implanted as part of premarket clinical trials (previously described), 332 had been enrolled in the postmarket registry, and 572 were implanted outside of a postmarket registry. Published clinical literature along with the device’s Summary of Safety Effectiveness Data, the FDA database for device-related complications (MAUDE database), and information provided by the manufacturer were used to identify AEs. Event rates were 0.1% intra- or perioperative complications, 1.3% hospital readmissions, 5.6% endoscopic dilations, and 3.4% reoperations for device removal. The primary reason for device removal was dysphagia. No device migrations or malfunctions were reported. Erosion of the device occurred in one (0.1%) individual. The overall event rates were low based on data from 82 institutions. The authors stated that the MSA device is a safe therapeutic option for individuals with chronic, uncomplicated GERD. The main limitations of this study included the fact that typical individuals treated with the MSA device generally do not have a large hiatal hernia or other comorbidities, such as Barrett esophagus, strictures, or motility disorders to the same extent as individuals 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 2015, Saino et al. reported the 5-year results from 33 of the 44 individuals enrolled in the multicenter, prospective, single-arm IDE feasibility study described in Bonavina et al. (2010) evaluating the safety and efficacy of a MSA device. Prior to MSA device placement, these individuals had abnormal esophageal acid and symptoms poorly controlled by PPIs. Patients served as their own control, which allowed comparison between baseline and postoperative measurements to determine individual treatment effect. At 5 years, GERD-HRQL questionnaire score, esophageal pH, PPI use, and complications were evaluated. Mean total percentage of time with pH below 4 was 11.9% at baseline and 4.6% at 5 years (P<0.001), with 85% of individuals 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 individuals had at least a 50% reduction in total score compared with baseline. Complete discontinuation of PPIs was achieved by 87.8% of individuals. The reoperation rate was 6.8% and due to dysphagia, continued reflux symptoms, and planned MRI imaging. No complications occurred in the long term, including no device erosions or migrations at any point. Limitations of the study include the small patient population, lack of a comparator; loss of patients from the original pilot study (only 33 patients were available for the 5-year follow-up); failure of all sites to perform pH monitoring after the first year and no manometric evaluations were performed after the first year.
In 2015, Desart et al. reported the results of a retrospective review to determine if the LINX MSA system is a safe and effective option for individuals with new GERD following LSG. Seven consecutive individuals with refractory GERD who had a laparoscopic LINX magnetic sphincter device placement after LSG were included. All individuals were noted to have self-reported greatly improved gastroesophageal reflux symptoms 2 to 4 weeks after their procedure. They were all noted to have statistically significant improved severity and frequency of their reflux, regurgitation, epigastric pain, sensation of fullness, dysphagia, and cough symptoms in their postoperative GERD symptoms compared with their preoperative evaluation. The authors concluded that the LINX device is a safe and effective option in individuals with de novo refractory GERD after a LSG despite appropriate weight loss. The study was limited by small sample size and short follow-up period. In addition, there was lack of information about use of PPIs prior to or after the procedure.
In 2014, Smith et al. reported data from 66 individuals who underwent MSA using the LINX Reflux Management System. All individuals had objectively confirmed GERD with pH testing, acceptable esophageal motility, and no significant hiatal hernia (>3 cm). All individuals experienced clinical improvement on antisecretory medication, but incomplete symptom control or medication intolerance. There were no reported intra- or perioperative complications. Average length of hospital stay was 0.7 days. At an average follow-up of 5.8 months (range, 1–18.6 months), 92% of individuals were satisfied or neutral with their GERD condition, and 83% were PPI free. The GERD-HRQL scores were similar to those of individuals without GERD. There were no device ulcers or erosions and no devices explanted. Thirteen individuals underwent additional testing for dysphagia or persistent symptoms. Dysphagia and regurgitation were the most common concerns.
In a prospective observational study, Reynolds et al. (2014) evaluated 67 individuals who were implanted with the LINX Reflux Management System at two institutions. There were no intraoperative complications and only four mild postoperative complications, which included three individuals with urinary retention and one readmission for dehydration. The mean operative time was 60 minutes (range, 31–159 minutes) and mean LOS was 11 hours (range, 5–35 hours). Sixty-three individuals were at least 3 months postoperative and eligible for follow-up at the time of data analysis. Follow-up information was obtained for 83% of individuals with a median follow-up of 5 months (range, 3–14 months). The median GERD-HRQL score at follow-up was 4 (range, 0–26). A total of 76.9% of individuals were no longer taking PPIs. The most common postoperative complaint was dysphagia, which was seen in 82.7% of individuals, and was resolved in 79.1% of individuals with a median time to resolution of 8 weeks. Eight individuals had persistent dysphagia that required balloon dilation with improvement in symptoms.
In a prospective case series, Schwameis et al. (2014) evaluated the safety and effectiveness of the LINX Reflux Management System in improving outcomes in 23 individuals with GERD. Primary outcome measures were overall feasibility of the procedure, short-term procedure safety, and effectiveness. Secondary outcomes were subjective individual indices assessed with the GERD-HRQL questionnaire. All laparoscopic procedures were performed within a median operative time of 23 minutes and there were no intraoperative complications. At 4-week follow-up, PPI cessation was achieved in 71.4% of individuals and a significant number of individuals experienced reduction of primary GERD symptoms: [heartburn (96%–22%; P<0.001); bloating (70%–30%; P=0.006); respiratory complaints (57%–17%; P=0.039); and sleep disturbance (56%–4%; P<0.001)]. Median GERD-HRQL scores (lower scores better) also improved from 29 to 4 (P<0.001) after the LINX procedure and the proportion of individuals who were satisfied with their HRQL increased from 0% to 74%. Dysphagia was the only reported side effect and only one individual required endoscopic dilation.
In 2013, Bonavina et al. published longer follow-up from individuals in the pilot and multicenter registry studies. This study was a single-center, prospective case series of 100 individuals who received MSA for GERD. Clinical outcomes for each patient were tracked postimplantation and compared with presurgical data for esophageal pH measurements, symptom scores, and PPI use. Median implant duration was 3 years (range, 378 days to 6 years). Thirty of the individuals had data beyond 5 years. Median total acid exposure time was reduced from 8% before implant to 3.2% post implant (P<0.001). The median GERD-HRQL score at baseline was 16 on PPIs and 24 off PPIs. The median GERD-HRQL score improved to a score of 2 (P<0.001). Freedom from daily dependence on PPIs was achieved in 85% of individuals. Three individuals had the device removed for persistent GERD, odynophagia, or dysphagia; however, there were no occurrences of device migration or erosion.
Three-year results of the pivotal IDE study were published by Ganz et al. in 2013. In this study, 100 consecutive individuals received the LINX Reflux Management System. The primary outcome measure was normalization of or a 50% or greater reduction in EAE at 1 year. The secondary outcome measures were 50% or greater improvement in QOL and a 50% or greater reduction in PPI use at 1 year. Successful treatment was pre-specified as achievement of the outcome in at least 60% of individuals. The primary outcome was achieved in 64% of study participants. Mean total acid exposure time was reduced from 11.6% at baseline to 5.1% at 12 months (56% reduction). For the secondary outcomes, a reduction of 50% or more in the use of PPIs occurred in 93% of individuals (79% and 83% of individuals were free from daily dependence at 12 and 24 months, respectively, vs. 0% at baseline), and there was improvement of 50% or more in QOL scores in 92% of individuals (the mean QOL total score decreased from 28.4 at baseline to 5.9 and 5.5 at 12 and 24 months, respectively). The most frequent AE was dysphagia (in 68% of individuals postoperatively, 11% at 1 year, and in 4% at 3 years). Nineteen individuals underwent esophageal dilation for dysphagia. There were six serious adverse effects, and the device had to be removed in 6 individuals. The authors concluded that the LINX Reflux Management System improves outcomes in individuals and is safe; however, they added that studies with larger sample size and longer-term follow-up are needed to confirm these findings. The preliminary and positive results of this study are hampered by the poor quality design, which includes lack of an adequate control or comparator group, and lack of randomization and blinding.
Lipham et al. (2012) reported the 4-year results from 44 individuals enrolled in the multicenter, prospective, single-arm IDE feasibility study described in Bonavina et al. (2010). Long-term efficacy measures included EAE, GERD quality-of-life measures, and use of PPIs. For EAE, the mean total percent time pH below 4 was reduced from 11.9% at baseline to 3.8% at 3 years (P<0.001), with 80% (18/20) of individuals achieving pH normalization (≤5.3%). At 4 or more years, 100% (23/23) of the individuals had improved QOL measures for GERD, and 80% (20/25) had complete cessation of the use of PPIs. There were no reports of death or long-term device-related complications such as migration or erosion. Limitations of this study include small sample size (only 23 individuals were available at 4 years) and the lack of a comparison group.
In 2010, Bonavina et al. reported the 1- and 2-year results from a multicenter, prospective, single-arm feasibility study evaluating the safety and efficacy of the LINX Reflux Management System. The LINX device was laparoscopically implanted at the GEJ in 44 individuals. Individuals served as their own controls. At baseline, all individuals had abnormal EAE on 24-hour pH monitoring and improved, but persistent, typical GERD symptoms while on acid suppression therapy with PPIs. Individuals were evaluated after surgery by GERD-HRQL symptom score, PPI usage, endoscopy, esophageal manometry, and 24-hour esophageal pH monitoring. The total mean GERD-HRQL 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 individuals at 1 year and by 86% of individuals at 2 years. Early dysphagia occurred in 43% of the individuals 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 individuals had a normal EAE. 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 findings of this small feasibility study need to be validated by well-designed studies.
In 2008, Bonavina et al. reported the results from a multicenter feasibility trial that was performed to evaluate the safety and efficacy of a MSA device. Individuals enrolled in the study had typical heartburn (at least partially responding to PPIs), abnormal EAE, and normal esophageal peristalsis. Individuals with hiatal hernia smaller than 3 cm were excluded from the study. Over a 1-year period, 38 of 41 enrolled individuals underwent this procedure in three hospitals. No operative complications were recorded. A free diet was allowed since postoperative day 1, and 97% of the individuals were discharged within 48 hours. The mean follow-up was 209 days (range, 12–434 days). The GERD-HRQL score decreased from 26.0 to 1.0 (P<0.005). At 3 months postoperatively, 89% of individuals were off antireflux medications, and 79% of individuals had a normal 24-hour pH test. All individuals preserved the ability to belch. Mild dysphagia occurred in 45% of individuals. No migrations or erosions of the device occurred. The small study population limits the validity of the conclusion of this study.
Economic Studies
In 2020, Pandolfino et al. assessed the economic impact of introducing MSA technology (i.e., LINX Reflux Management System) into current practice from a US-payer perspective. An economic budget impact model was developed over a 1-year time horizon that compared current treatment of individuals with GERD who are medically managed (but refractory) or receiving LNF to future treatment of individuals with GERD that included a mix of patients treated with medical management only, LNF, or MSA. Resources included within the analyses were index procedures (inpatient and outpatient use), reoperations (revisions and removals), readmissions, healthcare visits, diagnostic tests, procedures, and medications. Medicare payment rates were typically used to inform unit costs. Assuming a hypothetical commercial insurance population of 1 million members, the base-case analysis estimated a net cost savings of $111,367 with introduction of the MSA. This calculation translates to a savings of $0.01 per member per month. Results were largely driven by avoided inpatient procedures with use of the MSA device. Alternative analyses exploring the potential impact of increasing surgical volumes predicted that results would remain cost saving if the proportion of MSA market share taken from LNF was 90% or more. The authors concluded the following: "This study predicts that the introduction of the MSA device would lead to favorable budget impact results for the treatment of medication-refractory mechanical GERD for commercial payers. Future analyses will benefit from inclusion of middle-ground treatments as well as longer time horizons."
In 2019, Ayazi et al. performed an economic evaluation to report the clinical outcome and QOL measures in individuals after MSA and to compare the pharmaceutical and procedure payer costs and the disease-related and overall expense of MSA compared to LNF from a payer perspective. Data were collected on individuals who underwent MSA over a 2-year period beginning in September 2015 at the study network hospitals. The LNF comparison group was procured from members' claims data of the payer. Inclusion was predicated by individuals having continuous coverage during study period. The total procedural reimbursement and the disease-related and overall medical claims submitted up to 12 months prior to surgery and up to 12 months following surgery were obtained. The payer reimbursement data are presented as allowed cost per member per month (PMPM). These values were then compared between groups. There were 195 individuals who underwent MSA and 1131 that had LNF. The median (IQR [interquartile range]) reimbursement of surgery was $13,522 (13,195-14,439) for those who underwent MSA and $13,388 (9951–16,261) for individuals with LNF (P=0.02). In individuals who underwent MSA, the median reimbursement related to the upper gastrointestinal disease was $305 PMPM, at 12 months prior to surgery and $104 at 12 months after surgery, representing 66% decrease in cost. These values were $233 PMPM and $126 PMPM for individuals who underwent LNF, representing a 46% decrease (P=0.0001). At 12 months following surgery, the reimbursement for overall medical expenses had decreased by 10.7% in the MSA group and 1.4% in the LNF group when compared to the preoperative baseline reimbursement. The reimbursement for PPI use after surgery showed a 95% decrease in the MSA group and 90% among LNF group when compared to the preoperative baseline (P=0.10). The authors concluded that "when compared with LNF, MSA results in a reduction of disease-related expenses for the payer in the year following surgery. While MSA is associated with a higher procedural payer cost compared to LNF, payer costs may offset due to reduction in the expenses after surgery."
Summary
The evidence base evaluating MSA (i.e., the LINX Reflux Management System) for treating GERD includes one RCT comparing MSA to PPI therapy, comparative observational studies of MSA versus LF, single-arm case series studies, and systematic reviews/meta-analyses of observational studies. Outcomes of interest include symptoms, change in disease status, medication use, and treatment-related morbidity.
Evidence from systematic reviews and meta-analyses, an RCT, comparative observational studies, and single-arm case series studies shows that MSA (i.e., the LINX Reflux Management System) works as well as LF for improving symptoms and QOL in individuals with GERD.
The systematic reviews and meta-analyses included studies that are at high risk of bias due to small sample size, retrospective design, single-center focus, and lack of randomization and blinding. In addition, patient-reported outcomes of QOL and patient satisfaction are at a risk of bias because blinding is not feasible in the individuals or clinicians, although the data analysts assessing outcomes data could potentially be blinded from group assignment. However, the evidence allows for the drawing of conclusions because the results are consistent across studies and were validated through meta-analyses, an independent RCT, and single-arm case series studies. Larger, multicenter RCTs comparing the LINX Reflux Management System to other minimally invasive GERD treatment options and studies reporting more than 5-year follow-up would be useful to further characterize the long-term safety and effectiveness of the LINX Reflux Management System. Ongoing clinical trials may address these issues.
ANTI-GASTROESOPHAGEAL REFLUX DEVICE IMPLANTATION
Angelchik Anti-Reflux Prosthesis
The Angelchik Antireflux Prosthesis (Allergan, Inc., Santa Barbara, CA) is a C-shaped silicon ring (i.e., Angelchik prosthesis) that is surgically implanted around the esophagus at the GEJ. It is secured in place by a circumferential tie strap that is designed to reduce and prevent further sliding of hiatal hernias and to prevent reflux of gastric contents into the esophagus. The device was cleared for marketing by the FDA through the PMA process in 1979.
Because follow-up assessment of individuals with the antigastroesophageal reflux device implantation revealed poor long-term results and complications, including dysphagia, erosion, perforation, obstruction, and migration of the prosthesis, use of the device has been largely abandoned. In addition, the American Medical Association’s (AMA) Diagnostic and Therapeutic Technology Assessment (DATTA) evaluation of the Angelchik prosthesis has determined that the safety and effectiveness of this device have not been established; therefore, its routine use is discouraged. Long-term studies concluded that the Angelchik device causes long-term dysphagia in many individuals, severe enough to require its removal in 25% of these individuals. Thus, its continual use cannot be recommended.
TECHNOLOGY ASSESSMENTS/SYSTEMATIC REVIEWS/META-ANALYSES OF MULTIPLE PROCEDURES
In 2018, Coronel et al. published the results of a systematic review and meta-analysis focused on evaluating the efficacy of different endoscopic procedures for the treatment of GERD. Endoscopic therapies included TIF using EsophyX; surgical plication by NDO surgical device; Stretta radiofrequency therapy; EndoCinch endoscopic suturing system; injectable esophageal prostheses by Gatekeeper device, and biocompatible nonresorbable copolymer Enteryx device. Controls included sham procedure, PPIs, or laparoscopic antireflux surgery (LARS). The authors restricted their search to RCTs evaluating individuals with chronic GERD (>6 months), who were over 18 years old, and follow-up of at least 3 months. Efficacy was measured by different subjective and objective outcomes. Data from 16 RCTs, totaling 1085 individuals, was analyzed. A total of 221 individuals underwent TIF2, 145 surgical plications, 81 Stretta; 42 endoscopic suturing, 32 injectable esophageal prostheses, and 75 biocompatible nonresorbable copolymer. Control groups (n=312) included 294 individuals who underwent a sham procedure, 120 received PPIs, and 63 underwent LARS. Overall, there was a statistically significant difference in treatment efficacy in favor of endoscopic treatment (P<0.00001). At 3 months' follow-up, three trials (n=263) showed a significant difference in two endoscopic groups (P<0.00001). At 6 months, six trials (n=377) also showed a statistically significant difference for endoscopic subjects (P<0.00001). At 12 months' follow-ups in two trials (n=67), no statistically significant difference (P<0.06) was shown. Regarding efficacy of endoscopic treatments versus pharmacological (PPI), four studies (n=320) were analyzed. At 6 months (n=277) statistically significant difference was seen in favor of endoscopic treatments (Stretta, TIF2) (P<0.00001). One trial (n=43) showed no difference at the 12-month follow-up. In studies comparing endoscopic treatments with sham, at 6 months, two RCTs (n=100) showed a significant difference (P<0.0001) but at 12 months there was no significant difference (one RCT; n=24). The outcomes of normalization of esophageal acid pH (P<0.03); LES resting pressure (P<0.00001); mean percent of total time of esophageal pH less than 4 (P<0.00001); and mean number of reflux episodes (P<0.00001) were statistically significant in favor of endoscopic treatments. Overall, there was high heterogeneity between the trials in up to 12 months of follow up. The time in remission (P<0.00001), number of individuals with GERD HRLQ score greater than 50% improvement (P<0.00001), elimination of troublesome regurgitation (P<0.00001) were statistically significant in favor of endoscopic treatments with very low heterogeneity between the trials at 6 and 12 months' follow-up. The mean GERD-HRQL score (P<0.00001), the heartburn score (P<0.00001) and DeMeester score (P<0.00001) showed statistically significant improvement following endoscopic treatment up to 6 and 12 months but there was high heterogeneity. The SF-36 score showed improvement in favor of controls at 12 months follow up, but also with high heterogeneity between studies. When comparing endoscopic therapies only to sham, the results were similar. Most studies reported clinically significant moderate to severe postprocedure-related AEs (n=312 events) such as epigastric pain, musculoskeletal pain, dysphagia, sore throat, chest pain, nausea and vomiting, bloating, and flatulence that were treated clinically, with complete resolution and no major sequelae. The event rate was 38% for endoscopic treatments, 24% for sham, 4% for PPI and 2% for the LARS group. The author noted that limitations included a high degree of heterogeneity in outcomes, short-term follow-ups (<6 months) and many individuals were offered alternative interventions during follow-ups, thus the actual benefit of the endoscopic intervention was compromised. The authors noted that to date, there are no randomized studies evaluating the efficacy of endoscopic procedures with over 12 months of follow-up. The role of endoscopic therapies for the treatment of GERD remains unclear.
In 2018, Nicolau et al. published a review of new minimally invasive endoscopic and surgical therapies for the treatment of GERD. In their review the authors stated the following: "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 mainstream therapy in most of the patients is the medical therapy 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 LF, an elective therapy with long term follow up outcomes at the expense of de novo symptoms associated with fundoplications in general. 30% to 40% of the patients are PPI refractory with partial symptom control, but they are not willing to go for the LF because of the invasive character and because of potential postfundoplications syndromes. There is a "treatment gap" for these patients with GERD. For a well 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 therapies, minimally invasive. These therapies are less aggressive and basically with no side effects or new onset symptoms that Laparoscopic Fundoplications will give. These are endoscopic therapies which improve the LES function: Stretta utilizes radiofrequency therapy, a novel technique describes mucosal resection at the level of the cardia, while a partial fundoplication from within the stomach can be realized with EsophyX, Muse or Gerd-X. Form 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. These procedures are effective on short term and there are few patients treated with LINX or EndoStim. More research for LINX and EndoStim is necessary with randomized clinical trials, with improvement of the devices and with long term follow up."
In 2018, Rebecchi et al. published a review of laparoscopic procedures for the treatment of GERD. In their review the authors stated the following: "A total laparoscopic fundoplication has become the procedure of choice for the surgical treatment of GERD in individuals with normal esophageal motility, with reduced postoperative 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 fundoplications lead to similar control of heartburn when compared to total fundoplication with lower risk of dysphagia. However, when performed, 24-h pH monitoring shows pathologic reflux more frequently after partial than total fundoplication. Disappointing results are achieved by anterior 90° partial fundoplication. More recently, a MSA with the LINX Reflux Management System (Torax Medical) and the LES Electrical Stimulation (EndoStim) have been developed, seeking for a durable and effective minimally invasive alternative to laparoscopic fundoplication for the treatment of reflux. Both devices seem to be promising, with very low postoperative complications and good short-term functional outcomes. Large RCTs comparing them with laparoscopic fundoplication over a long period of follow-up are needed to verify their indications and outcomes."
In 2017, Hayes Inc. issued a Medical Technology Directory Report regarding endoscopic therapy for the treatment of GERD. The report included Stretta, EsophyX, and Medigus Ultrasonic Surgical Endostapler (MUSE). Fourteen comparative studies met the inclusion criteria (five RCTs and five noncomparative studies were included). The report included comparative studies with follow-up for 6 months or more and noncomparative studies with 100 or more individuals and 12 or more months follow-up. Twelve Stretta studies (n=36–217), five EsophyX studies (n=44–129) and two MUSE studies (n=27–66) were reviewed. The authors reported that there was insufficient evidence to support the use of MUSE for GERD individuals. The authors further stated that although the findings for Stretta and EsophyX suggested improvement in clinical and patient-reported outcomes compared to baseline for GERD individuals who were unsatisfied with or uncontrolled on PPIs, the evidence was of low quality. Long-term data are lacking for these two procedures. Limitations of the studies included lack of randomization and/or blinding, small sample size, short-term follow-up, lack of and inconsistent comparators, loss to follow-up (especially for pH measures), retrospective study designs, inconsistent use of outcome measures, and potential lack of generalizability.
In 2016, Testoni et al. reviewed the techniques and outcomes of TIF, using the EsophyX device and the MUSE system. The authors reported that based on their analysis, the overall complication rates for TIF with the EsophyX device range from 3% to 10%. Major complications arose rarely and included bleeding, mucosal tears or perforation requiring endoscopic intervention or surgery, pneumothorax, and mediastinal abscesses. Bleeding requiring transfusions has been reported in about 3% to 5% of cases. Mediastinal abscesses have been reported in fewer than 2% of cases. No procedure-related deaths have occurred. Concerning outcomes, the authors' findings show that patient selection is one determinant in achieving clinical success. The operator’s experience is also key in the success, noting that in the majority of included studies, the procedure was done early in the operator’s learning curve. From a technical point of view, in the authors’ opinion, the number of fasteners deployed and the rotational technique were associated with a better outcome; a larger number of fasteners increased by four-folds the success rate. Other factors associated with a higher rate of unsuccessful results include Hill grades III and IV, hiatal hernia larger than 2 cm, and ineffective esophageal motility. An impaired esophageal clearance may induce epithelial sensitization and reflux-related symptoms, even in presence of a low-volume reflux. The authors conclude that long-term efficacy of TIF needs to be further assessed, mainly for the MUSE technique through RCTs. However, the role of TIF in the management of GERD still needs to occur for both procedures. Preoperative anatomical and functional findings and technical procedural aspects that will help select individuals and predict a successful outcome still need to be identified, as well.
In 2015, Hopkins et al. published a review of two endoscopic treatments (EsophyX and Stretta) for GERD. Regarding EsophyX, long-term data suggest that transoral incisional fundoplication (TIF) with EsophyX may be effective for symptom control and PPI reduction or cessation for up to 2 to 6 years. There is no evidence that EsophyX is more effective than surgical intervention. TIF may be most effective for individuals with hiatal hernia smaller than 2 cm and Hill Grade I/II valves. Regarding Stretta, the authors noted 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 QOL scores up to 8 years postintervention. 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. Furthermore, treatment modalities for GERD, as a field, suffer from a lack of standardization in primary and secondary outcomes. Although many studies have looked at health-related QOL, the tools used to do so are markedly heterogeneous.
In 2014, Min and Ganz stated 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, two newer interventions have gained popularity: MSA, which entails the placement of a self-expanding magnetic ring around the GEJ, and TIF, an endoscopic approach that creates a neogastroesophageal valve near the fundus. Collective data gathered from four studies published within the past year suggest that the three 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. Large prospective RCTs are needed to reliably compare the three procedures.
In 2013, Yew and Chuah discussed the past and present status of endoluminal therapy. Currently, there are three commonly employed antireflux 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 radiofrequency ablation of LES and cardia. EndoCinch plication requires further study and modification of technique before it can be recommended because of durability issues. Esophynx, 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 AEs. 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.
The Agency for Healthcare Research and Quality (AHRQ) published a systematic review of management strategies for GERD in 2005 that was updated in 2011. The 2005 comparative effectiveness review evaluated studies on the EndoCinch Suturing System, Stretta, Enteryx, and the NDO Plicator. The 2011 update excluded Enteryx and the NDO Plicator, because they were no longer available in the United States, and added the EsophyX procedure (endoscopic fundoplication), which was commercialized after the 2005 review. The 2011 report, which is now archived (meaning that the findings may be used for research purposes but should not be considered current), concluded that, for the three available endoscopic procedures (EndoCinch, Stretta, EsophyX), effectiveness remained substantially uncertain for the long-term management of GERD. The study noted that while some clinical benefits were observed in individuals who had undergone these procedures, these studies had been generally small, of variable quality, and of short duration. In addition, all of these procedures have been associated with complications, including dysphagia, infection/fever, and bloating, although bloating and dysphagia are also AEs of LF. They concluded that higher quality studies are needed to determine the role and value of endoscopic procedures in the treatment of individuals with GERD. A review of endoscopic treatment of GERD by Hummel and Richards (2015) noted that EndoCinch is no longer manufactured.
In 2011, Zagol and Mikami evaluated transoral fundoplication devices for GERD that have been commercially available within the past 5 years. Literature databases including Medline and PubMed were searched from January 2005 to November 2010. Both blinded and unblinded randomized studies were evaluated. The authors 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 individuals were evaluated to assess the efficacy and safety of transoral fundoplication devices. These endoluminal devices were primarily matched against sham procedures. The EndoCinch and Stretta procedures were the only devices compared to LF, the current standard for surgical management of GERD. The authors came to the following conclusions: "The field of endoluminal treatment of gastro-oesophageal reflux disease has gained popularity over the last several years. Endoluminal treatment of gastro-oesophageal reflux disease has been shown to be safe and effective in recent studies. We still believe more randomized prospective studies need to be carried out to determine if endoluminal therapies will be a durable option for patients with gastro-oesophageal reflux disease. Continuing research will further the advancement of endoluminal gastro-oesophageal reflux disease procedures in the future."
In 2010, Watson and Immanuel published a review on endoscopic and laparoscopic treatments for GERD. In their review they state that for selected individuals, there is an established role for the surgical treatment of reflux, and possibly an emerging role for endoscopic antireflux 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 cohort studies with short-term follow-up. Laparoscopic fundoplication has been shown to be an effective antireflux operation. It facilitates quicker convalescence and is associated with fewer complications, but has a similar longer term outcome compared with open antireflux surgery. In most randomized trials, antireflux 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 antireflux 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 gastroesophageal reflux, and no endoscopic procedure has achieved equivalent reflux control to that achieved by surgical fundoplication.
In 2010, Bredenoord published a review of new therapies for GERD. In the review the author states that over the last decade various endoscopic antireflux 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 radiofrequency ablation therapy are still available and being evaluated in research centers, but more data on safety and efficacy are required before a more widespread use can be advised.
In 2009, Chen et al. published a systematic review assessing the safety and efficacy of endoscopic procedures for GERD. RCTs and nonrandomized comparative studies with at least 10 individuals in each study arm, and case series studies of at least 10 individuals, were included. Thirty-three studies examining seven 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 three procedures that were tested against sham controls (Stretta procedure, Bard EndoCinch and Enteryx), outcomes in the treatment group were either as good as, or significantly better than, those of control subjects in terms of heartburn symptoms, QOL, and medication usage. However, for the two procedures that were tested against laparoscopic fundoplication (Stretta procedure and Bard EndoCinch), outcomes for individuals in the endoscopic group were either as good as, or inferior to, those for the laparoscopic group. The authors concluded that there is "insufficient evidence to determine the safety and efficacy of endoscopic procedures for gastro-oesophageal reflux disease, particularly in the long term."
In 2009, Jofri et al. critically analyzed existing endoscopy-based interventions for GERD. The focus was on the effectiveness of available procedures and to delineate goals for future research. The authors stated that recent evaluations of the EndoCinch system revealed poor long-term results and no significant improvement over sham therapy due to poor apposition of mucosa with stitches. Recent studies with TIF demonstrate improvement in GERD symptoms, QOL, EAE, esophagitis, resting LESP, 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 radiofrequency energy to the GEJ. A large prospective series demonstrates sustained improvement in GERD symptoms, QOL, and PPI therapy elimination after radiofrequency ablation at the GEJ. 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. TIF is a very promising procedure in its early stages of development. Further evaluation of procedure safety and durability is needed. Radiofrequency ablation therapy has been reintroduced and may have potential in individuals with refractory GERD.
In 2008, Pace et al. published a review of endoscopic antireflux procedures. From their review the authors concluded that none of the proposed antireflux therapies has fulfilled the criteria of efficacy, safety, cost, durability and, possibly, of reversibility. There is at present no definite indication for endoscopic therapy for GERD.
In 2007, Fry et al. published a systematic review evaluating the evidence on the effect of endoscopic therapies for the treatment of GERD. Retrospective and prospective open-label and randomized, sham-controlled trials were taken into account. The exclusion criteria included the following: case series that included fewer than 10 individuals, abstracts, studies involving children or those with a follow-up shorter than 3 months. Forty-three studies were included, including four randomized, sham-controlled trials that met the inclusion criteria. The primary endpoint in most studies was the reduction of the use of PPIs by more than 50%. In view of these findings, the majority of studies suggested the efficacy of endoluminal therapies for the control of symptoms in GERD. In the sham-controlled studies, the effect of placebo was, nevertheless, as high as 50%. Most studies were small feasibility studies, with follow-ups of less than 1 year. No study comparing endoscopic techniques with other established treatment options such as PPIs existed. All endoscopic therapies were associated with a small but important percentage of mild to severe complications, which included perforation, abscess and death. The authors concluded that "there are not enough scientific and clinical data on safety, efficacy and durability to support the use of endoluminal therapies for GORD in routine clinical practice."
In 2007, Torquati and Richards performed an evidence-based analysis of the literature regarding three FDA-approved modalities used for endoluminal treatment of GERD. The authors searched for RCTs and controlled clinical trials of currently available endoluminal treatments of GERD. Sixteen studies met the inclusion criteria, representing 787 individuals. The methodological quality of most of the included studies was average; four studies were grade 1b (individual randomized trial), 10 were grade 2b (individual cohort study), and two were grade 3b (individual case-control study). There was grade 1b and 2b evidence demonstrating that 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 was grade 1b and 2b evidence demonstrating that the Stretta procedure was 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 was grade 1b and 2b evidence demonstrating that full-thickness plication was effective in reducing GERD symptoms, and acid exposure in the distal esophagus.
In 2007, Schwartz and Smout systematically reviewed the literature evaluating the clinical efficacy of endoscopic antireflux procedures for GERD. The authors reported that "endotherapy has shown the potential to treat (uncomplicated) GORD. However, some early procedures have failed or proven unsafe. 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."
In 2007, Spicák published a review stating that three types of endoscopic methods in several modifications have been developed for the treatment of GERD: (1) Radiofrequency therapy (Stretta procedure) is available both in Europe and USA and more than 5000 individuals have been treated to date. (2) Injection therapy requires the injection of bulking agents or implantation of bioprosthesis into the LES zone. Enteryx was withdrawn from the market in 2005, and Gatekeeper was suspended before FDA approval. (3) 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 effects. According to current practice, use of endoscopic methods is justifiable only as part of clinical trials.
In 2006, the Australian Safety and Efficacy Register of New Interventional Procedures - Surgical (ASERNIP-S) published a systematic review about endoscopic treatments of GERD (McLoughlin et al., 2006). From their review of the published evidence, the authors concluded that "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 LF. Doubts about the durability of the therapeutic effect remain since the follow-up period in most studies was short."
In a review by Ozawa et al. (2005), the authors state that endoscopic treatments for GERD, such as Bard's EndoCinch, NDO Plicator, Wilson-Cook Medical's Endoscopic Suturing Device, the Stretta System, Enteryx, and the Gatekeeper Reflux Repair System, are still in the development phase. The efficacy, safety, durability, cost-effectiveness, indications, and possible combination with other treatments must be thoroughly assessed in RCTs.
In a review by Annese et al. (2005), the authors state that a variety of endoscopic techniques have been developed for the treatment of GERD, and these have shown apparently encouraging results, at least in the short term. However, promising results have been obtained in only around two thirds of individuals over a short-term follow-up period of about 6 months. Moreover, several inconsistencies have emerged regarding the efficacy of this form of treatment in improving symptoms and QOL and a lack of improvement of objective parameters, such as LESP and EAE. The authors strongly endorse the need for comprehensive evaluation of clinical evidence on this topic. After an extensive evaluation of existing literature, the authors suggest that controlled studies are urgently needed in order to clarify the potential of endoscopic therapy, either in terms of cost-effectiveness or in comparison with standard therapy. Meanwhile, with regard to current practice, the use of endoscopic treatment should be limited to clinical trials, which should incorporate the provision of comprehensive and unbiased information to study subjects.
A technology assessment prepared for the California Technology Assessment Forum (CTAF) concluded that the Stretta, Bard 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 an RCT (Corley et al., 2003), the trial did not enroll individuals 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 individuals with refractory symptoms on appropriate medical therapy. Although the study showed that the Stretta procedure was successful in allowing individuals to reach a similar level of symptoms they had at baseline on medications, the procedure did not improve EAE, esophageal erosions or LES pressure, which are all presumably risk factors for developing later complications from GERD. Therefore, it does not seem advisable to recommend that individuals 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).
A review by Neuhauser et al. (2003) stated that therapeutic options for the treatment of GERD include lifestyle modifications, medical therapy, laparoscopic antireflux surgery, and three more recent options: injection therapy to the LES, endoscopic sewing procedures, and radiofrequency ablation therapy. Medical therapy is effective in most individuals but not always successful with advanced disease. Up to 70% of individuals do not have adequate nocturnal control of gastric acid secretion with 20 mg of omeprazole given twice per day. Individuals 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 procedures. Limitations on endoscopic techniques are esophageal motility disorders, severe esophagitis, and larger hiatal hernias. Laparoscopic antireflux surgery remains a well-established, durable alternative to long-term medical therapy. It has the benefits of convenience, safety, minimal complications, improved QOL, and low cost. Alternative methods will have to earn their place against this gold standard.
PRACTICE GUIDELINES AND POSITION STATEMENTS
American College of Gastroenterology (ACG)
In 2013, the ACG updated their Practice Guidelines for GERD. Under the section on surgical options for GERD, the guidelines state that “The usage of current endoscopic therapy or transoral incisionless fundoplication cannot be recommended as an alternative to medical or traditional surgical therapy (Strong recommendation, moderate level of evidence)” (Katz et al., 2013).
American Foregut Society (AFS)
The AFS issued a statement on appropriate patient selection and use of MSA, and noted that "patient selection criteria for MSA do not differ in principle from those of any other surgical procedure for reflux disease." Indications for MSA include:
- Typical GERD symptoms (i.e., heartburn, regurgitation) with break-through symptoms, intolerance to medical therapy, and/or unwillingness to take anti-reflux medications long term.
- Regurgitation despite optimized medical therapy and lifestyle modification.
- Extraesophageal symptoms with objective evidence of significant reflux disease (i.e., endoscopic evidence of [Los Angeles] Class C or D esophagitis, Barrett's esophagus or positive pH study."
The statement additionally notes that "MSA candidacy largely mirrors that for laparoscopic fundoplication. Low dysphagia rates for MSA have been found when performed in patients with normal esophageal motility." The AFS also recommends that a full hiatal dissection and cruroplasty be performed prior to implantation of an MSA device.
The AFS Bariatric Committee also issued a statement regarding the concurrent use of MSA at the time of primary bariatric surgery, noting that this practice "violates many basic surgical principles and is not considered judicious use by the American Foregut Society." The statement also notes that prospective trials demonstrating the safety and efficacy of concurrent MSA are needed.
American Gastroenterological Association (AGA)
In 2008, the AGA Medical Position Statement on the Management of Gastroesophageal Reflux Disease stated that due to insufficient information they can make no recommendation for or against the use of currently commercially available endoluminal antireflux procedures in the management of individuals with an esophageal syndrome (Kahrilas et al., 2008).
In 2006, the AGA's 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 individuals. Thus, the durability of these technologies beyond 1 to 2 years remains unclear. Short-term and long-term safety issues are unresolved, but serious AEs 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 individual, 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 individuals need to be aware of the limitations in the evidence that exist with these devices at present."
American Society for Gastrointestinal Endoscopy (ASGE)
The ASGE (2025) published guidelines for the diagnosis and management of GERD. In the guidelines, the following recommendations regarding TIF are made:
- In individuals with confirmed GERD and a small hiatal hernia (≤2 cm) and Hill grade 1 or 2 who meet any of the following criteria, the ASGE suggests evaluation for TIF as an alternative to chronic medical management:
- Chronic GERD (≥6 months)
- Chronic PPI use (≥6 months) for management for GERD symptoms
- Refractory GERD
- Regurgitation-predominant GERD
- Patient preference for avoidance of long-term PPI use
(Conditional recommendation, low-quality evidence).
- In individuals with confirmed GERD and a large hiatal hernia (>2 cm) and Hill grade III or IV, the ASGE suggests evaluation for combined hiatal hernia repair and TIF (cTIF) in a multidisciplinary review. (Conditional recommendation, very low-quality evidence)
The guideline explains that the evidence for TIF is of mixed populations and varying outcome definitions, which limits the understanding of safety and effectiveness. Yet, the evidence does show a short-term improvement in symptoms. However, for combined TIF, the evidence base is even lower, and high-quality comparison studies are needed for establishing combined TIF into routine clinical care.
Additionally, ASGE provides the following recommendation regarding Stretta:
- In individuals with confirmed GERD, a small hiatal hernia (<2 cm), and Hill grade I or II, radiofrequency energy to the LES can be considered when other alternatives (endoscopic/surgical fundoplication) are not available or feasible.
ASGE notes that the evidence base for Stretta is low and that there may be a lack of net health benefit as a result of its use.
Finally, ASGE describes the use of GERDx as a “novel and emerging intervention" and did not provide a recommendation regarding its use.
In a 2015 the ASGE Practice Guideline on the role of endoscopy in the management of GERD, ASGE stated that there are only two endoluminal GERD therapies being used in the United States: the Stretta procedure and the TIF (EsophyX device). Following a discussion of the studies for these two procedures, the Society noted some positive findings but discrepancies between subjective and objective outcome measures or a lack of objective outcome measures in reported trials. ASGE stated that the endoluminal antireflux procedures represent potentially, new therapeutic indications for gastrointestinal endoscopy and that appropriate patient selection and endoscopist experience and training should be “carefully considered” before pursuing these therapies. AGSA did not recommend the use of these therapies, but suggested that endoscopic antireflux therapy be considered for selected individuals with uncomplicated GERD after careful discussion with the individual regarding potential adverse effects, benefits, and other available therapeutic options.
A 2013 report on emerging technology from the ASGE concluded that long-term data on the safety and efficacy of the LINX device are needed. The document indicated that the LINX band is currently being deployed laparoscopically; however, a natural orifice transluminal endoscopic surgery approach could be explored (ASGE, 2013).
American Society of General Surgeons (ASGS)
In 2014, the ASGS issued a position statement supporting the use of the LINX Reflux Management System. In their position statement, the ASGS stated that "[b]ased on currently available information and the experience of our members with the procedure we do support the LINX procedure as mechanism for controlling GERD when it is placed by properly trained laparoscopic surgeons with experience in foregut surgery and the management of GERD patients."
In 2011, the ASGS issued a position statement on transoral fundoplication stating that “the ASGS supports the use of transoral fundoplication by trained General Surgeons for the treatment of symptomatic chronic gastroesophageal reflux disease (GERD) in patients who fail to achieve satisfactory response to a standard dose of Proton Pump Inhibitor (PPI) therapy or for those who wish to avoid the need for a lifetime of medication dependence.”
Canadian Agency for Drugs and Technologies in Health (CADTH)
In 2013, CADTH issued a Health Technology Update that included the SRS Endoscopic Stapling System. In the review of the evidence section the authors stated that, “There are no published trials of SRS in peer-reviewed literature. Numerous abstracts of studies are posted on the manufacturer’s website. It should be noted that data contained in abstracts may not always accurately reflect data contained within the full article.”
National Institute for Health and Care Excellence (NICE)
In 2017, NICE issued an update to their 2012 interventional procedure guidance report on laparoscopic insertion of a magnetic titanium ring for the treatment of GERD. The authors stated that "there is limited evidence of short-term efficacy, but evidence of long-term efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research."
In 2013, NICE updated their interventional procedure guidance on endoscopic radiofrequency treatment for GERD, stating that although the evidence on the safety of this intervention is adequate in the short and medium term, there is uncertainty about longer term outcomes. They also noted that with regard to efficacy, there is evidence of symptomatic relief but objective evidence on reduction of reflux is inconclusive. They concluded that this procedure should only be used with special arrangements for clinical governance, consent and audit or research. They also noted that their reviewing committee expressed concern about the possibility that symptoms in individuals undergoing RF ablation may improve as a result of denervation caused by the procedure; if this were the case, then failure to recognize and treat reflux might lead to complications in the long term.
In 2012, NICE published a guidance report regarding laparoscopic insertion of a magnetic-bead band for GERD. In their report, NICE stated that "[t]he 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."
In 2011, NICE issued guidance on endoluminal gastroplication for GERD, stating that “The evidence on endoluminal gastroplication for gastro-oesophageal reflux disease (GORD) raises no major safety concerns. Evidence from a number of randomized 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.”
In 2007, NICE issued guidance on endoscopic augmentation of the LES using hydrogel implants for the treatment of GERD. 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." In June 2016 NICE updated their guidance with the following statement: "Please note that the device linked to this guidance has been withdrawn by the manufacturer."
In 2004, NICE issued guidance on endoscopic injection of bulking agents for GERD, stating that “Current evidence on the safety and efficacy of endoscopic injection of bulking agents for gastro-oesophageal reflux disease does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research.” In 2016, NICE removed guidance on endoscopic bulking agents/hydrogel implants from guidelines on treatment for "dyspepsia and gastro-esophageal reflux" because the product had been withdrawn by the manufacturer.
Society of American Gastrointestinal and Endoscopic Surgeons (SAGES)
In April 2021, guidelines for the surgical treatment of GERD were reviewed and approved by the Board of Governors of the SAGES based on a systematic review of the evidence. Key questions presented in these guidelines do not address the use of MSA.
In 2017, SAGES issued an update to their 2013 Technology and Value Assessment Committee (TAVAC) Safety and Effectiveness Analysis of the LINX Reflux Management System. SAGES concluded that the LINX Reflux Management System is a reasonable treatment option for appropriately selected individuals with GERD who meet indications for antireflux surgery. The LINX Reflux Management System is indicated for individuals diagnosed with GERD as defined by abnormal pH testing, and who continue to have chronic GERD symptoms despite medical therapy for the treatment of reflux. The LINX Reflux Management System should be performed by surgeons who are familiar with the workup and different management alternatives of GERD and should not be offered in isolation. SAGES noted that 3 to 5 years of experience with the LINX Reflux Management System confirms the initial safety profile that led to FDA approval, and that long-term GERD control based on symptomatic outcomes, PPI utilization and pH studies have been demonstrated. Data are from case series and retrospective reviews with generally small patient populations and short-term follow-ups. The Society noted that limitations of published data include:
- Individuals were used repeatedly in some publications
- Possible publication bias in favor of the LINX Reflux Management System, as several studies were either funded by the manufacturer or were performed by investigators affiliated with the manufacturer
- Most studies were performed in high-volume centers in highly selected individuals and may not reflect broader clinical practice, which may lead to underreporting of complications
- Current studies lack randomization and blinding
In 2017, SAGES issued an update to their 2013 Clinical Spotlight Review on Endoluminal Treatments for Gastroesophageal Reflux Disease (GERD) (Auyang et al., 2013). The review evaluated the evidence regarding Stretta and Esophyx. Recommendations are based on existing data or a consensus of expert opinion when little or no data are available. The quality of the evidence and the strength of the recommendation for the guidelines was assessed according to the GRADE system. A four-tiered system was used to rate the quality of evidence (very low [+], low [+ +], moderate [+ + +], or high [+ + + +]), and a two-tiered system was used to rate the strength of the recommendation (weak or strong). For EsophyX, SAGES made the following recommendation:
“Based on existing evidence, TIF can be performed with an acceptable safety risk in appropriately selected patients. The procedure leads to better control of GERD symptoms compared with PPI treatment in the short term (6 months), but appears to lose effectiveness during longer term follow-up and is associated with moderate patient satisfaction scores. Objective GERD measures improve similarly after TIF 2.0 compared with PPI. No comparative, controlled trials exist between TIF and surgical fundoplication, but preliminary evidence suggested that the latter can be used safely after TIF failure. (Level of evidence +++, strong recommendation)."
For Stretta, SAGES made the following recommendation:
“Based on existing evidence, Stretta significantly improves health related quality of life scores, heartburn scores, the incidence of esophagitis, and EAE 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 for 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. (Level of Evidence: +++; strong recommendation)".
