Other Treatment Modalities

Fig. 19.1

This procedure is typically performed under conscious sedation in the endoscopy suite. The recommended treatments for Stretta® are four treatment levels in and around the LES, 5 mm apart from each other, and two treatment levels in the gastric cardia [22] totaling six treatment levels. The squamocolumnar junction (Z line) serves as a reference level for the treatments using the Stretta® catheter. Initial endoscopy is used to identify and measure the distance to the squamocolumnar junction. The catheter is then positioned 1.0–1.5 cm proximal to the Z line, and the balloon is inflated. The system is then activated, and ablation occurs at the four needle tips that project out at 90° angles from the balloon. The balloon is then deflated, and the catheter is rotated 45°, and ablation is then performed in this orthogonal position at the same level. The ablations continue in a sequential fashion progressing distally until the gastric cardia is reached (Fig. 19.2) [21, 24]. The treatment has a small learning curve with reductions in time occurring after three procedures [26]. The first three procedures took approximately 76 min, while the subsequent procedures took approximately 50 min in one published series [26]. Patients can usually return home a few hours after the procedure and return to work and normal activities within 24 h [21]. The patient is placed on a liquid diet following the endoluminal treatment, and advanced to regular diet as tolerated.

../images/473262_1_En_19_Chapter/473262_1_En_19_Fig2_HTML.jpg — Fig. 19.2

Stretta procedure (Reused with permission © 2019 Restech | Mederi-RF)

The proposed mechanism of action of radiofrequency ablation of the esophageal musculature is multifactorial and includes decreased compliance and distensibility of the lower esophageal sphincter (LES) without fibrosis, lengthening of the LES, and restoration of a physiologic anti-reflux barrier [27–29]. A double-blind sham-controlled study of the effect of radiofrequency energy on symptoms and distensibility of the gastroesophageal junction (GEJ) by Arts et al. showed that Stretta® patients did not have any change in esophageal acid exposure or pressure at the LES. However, they did have significantly improved symptom scores and decreased GEJ compliance. The administration of sildenafil, a smooth muscle relaxant, showed normalization of GEJ compliance to a pre-Stretta® level, thus discerning that fibrosis is not the mechanism of decreased distensibility of the LES [28].

Furthermore, nerve alteration, decreased sensitivity to acid, increased wall thickness, and decreased relaxations of the LES result in symptomatic improvements for GERD patients [30–32]. Increased frequency of transient lower esophageal sphincter relaxations (TLESRs) has been demonstrated as a contributing factor to GERD, and the Stretta® procedure has been shown to decrease these transient LES relaxations. The therapy is believed to alter vagal efferent fibers thus inhibiting the motor component of TLESRs and decreasing this mechanism of reflux episodes [24, 33–35].

Results

Stretta® has been on the market since FDA approval in 2000 and has many published papers citing its safety and efficacy. Studies show that it is effective in reducing symptoms of GERD, improving quality-of-life scores, and decreasing compliance of the LES [13]. Safety data, short-term and long-term results from many studies including randomized trials, are available and show good outcomes in symptomatic improvement and medication reduction for GERD. The initial US open-label trial investigating the Stretta® procedure for the treatment of GERD showed 6- and 12-month data. At both 6 and 12 months, there were improvements in median heartburn score, GERD score, satisfaction, and mental and physical SF-36 quality-of-life scores. Additionally, PPI requirement went from 88% of patients to 30% of patients. This study showed a significant improvement in esophageal acid exposure and had a low complication rate of 8.6% [36]. An early randomized , sham-controlled trial by Corley et al. in 2003 showed 6-month data improvements in heartburn symptoms and quality of life but did not show decrease in esophageal acid exposure [32]. These initial studies along with a multitude of subsequent investigations emerged showing Stretta® as a new option for select symptomatic GERD patients and as an alternative to PPI therapy or surgical interventions.

The first published meta-analysis by Perry, Banerjee, and Melvin included a review of 18 publications and 2 RCTs with a total of 1441 patients who underwent Stretta® from 2001 to 2010. They were evaluated post-procedure and analysis compared symptoms, validated GERD-HQRS survey results , LES pressure, and esophageal acid exposure. Meta-analysis showed statistically significant GERD symptom improvement, GERD-HQRS score, and esophageal acid exposure, though it did not normalize. LES pressure improvement did not reach statistical significance [37, 38]. Long-term follow-up was then established with 8-year and 10-year follow-up data [39]. Noar et al. studied a group of 99 patients who were nonresponsive to PPIs and followed them for 10 years. Results showed that the GERD-HQRS normalized in 72% of patients , 41% of patients were able to stop PPI therapy, and 54% were satisfied at 10 years. There were 11 patients that required re-intervention with Stretta®, and 85% of patients who had Barrett’s esophagus on biopsy had regression of their disease, and there were no reported adverse events or side effects from the procedure [39]. These studies helped establish Stretta® as an effective, safe, and durable treatment option for select GERD patients. The most recent published meta-analysis by Fass et al. included 24 published observational studies and 4 RCTs with 2468 patients followed for over 2 years. Results showed a statistically significant improvement GERD-HRQL, heartburn standardized score, and esophageal acid exposure. Overall, 51% of patients were able to stop PPI use. The treatment reduced the incidence of erosive esophagitis by 24%, and LES basal pressure increased slightly but did not reach statistical significance [40]. Data since inception and availability of Stretta® in 2000 have consistently shown improvement in subjective symptoms but have not shown significant improvement in objective measures such as LES pressure and normalization of esophageal acid exposure. Treatment with Stretta has been shown to be safe, effective, durable, and feasible and may help fill the treatment gap between PPI therapy and surgical therapy for GERD.

The procedure has very low complication rates, however; they include perforation, bleeding, and recurrence of symptoms. Esophageal injury with mucosal injury requires close observation, whereas full-thickness injury and perforation require definitive repair. Endoluminal stenting of such injuries is a potential option. Endoluminal bleeding is caused by penetration of submucosal vessels and can usually be controlled endoscopically with pressure, injection, cautery, or clipping. Esophageal varices are a contraindication to Stretta® [13]. In patients who fail to have improvement in GERD after Stretta®, anti-reflux surgery can still be performed . [35]

Additional Considerations

The role of Stretta® in the treatment of GERD may be broad. There is an established use in patients with hiatal hernia <2 cm who are refractory to maximal PPI therapy, those who are concerned about long-term risk of PPI therapy, and those who are averse to surgery. Additionally, Stretta® can be used in the LES of patients with prior gastric bypass [41] or subtotal gastrectomy [13] or with prior Nissen [42]. The Stretta® procedure was shown to be safe and effective in improving satisfaction scores and quality of life and reducing PPI use in 18 patients with refractory GERD after laparoscopic NF [42]. Stretta® can therefore be used in patients with prior gastric surgery, but gastric surgery can also be done after Stretta®. Nissen or other laparoscopic anti-reflux operations can be safely performed after Stretta® [35, 43]. The therapy has also shown efficacy in reflux related childhood-to-adult persistent asthma [44] and is suggested as an initial anti-reflux procedure in children [45] and as treatment of recurrent reflux in pediatric patients [46].

Transoral Incisionless Fundoplication (TIF)

Transoral incisionless fundoplication (TIF) describes an endoluminal procedure that is another endoscopic option for the treatment of GERD. The procedure relies on restoring the angle of His to recreate and reinforce the gastroesophageal valve function, mimicking the anatomic principle of laparoscopic NF [5]. Incisionless fundoplication is performed using either the EsophyX™ device to create a 270° fundoplication or the Medigus Ultrasonic Surgical Endostapler (MUSE™) to create a partial anterior 180° fundoplication [6].

The EsophyX™ device, developed by Endogastric Solutions (Redwood City, WA), was initially approved by the FDA in 2007 [22] and is an endoscopic surgical stapling instrument that is single use and goes over the endoscope to create a partial fundoplication that is approximately 3-cm-long and 270° [47]. The TIF 2.0 technique is a plication formed by full-thickness apposition of the gastric fundus to the distal portion of the esophagus. The plication is fixed in place with H-shaped 3-0 polypropylene fasteners that measure 7.5 mm in length (Fig. 19.3) and are placed on the far anterior and far posterior sides of the lesser curve. The device is in its third iteration with the EsophyXZ® which was approved by the FDA in 2016 and boasts more efficient device use and stapler-style trigger device for fastener deployment and improved operative times. The procedure is performed under general anesthesia, requires less than 1 h to complete, and a surgeon operates the device while an assistant operates the gastroscope [22]. Patients can typically return to work within a few days of the procedure. Thus, the procedure may serve as an intermediate option to fill the treatment gap between PPI therapy and laparoscopic NF [22].

../images/473262_1_En_19_Chapter/473262_1_En_19_Fig3_HTML.jpg — Fig. 19.3

Transoral incisionless fundoplication with EsophyX® device. (a) GE junction with poor valve function. (b) Fastener delivery system. (c) Helical retractor for tissue grasping and repair. (d) Tissue approximation to recreate valve. (e) Repaired tissue with initial tissue approximation for wrap. (f) Fundoplication complete with H-shaped fasteners (Reused with permission © EndoGastric Solutions, Inc.)

The initial phase I trial examined the histology of the procedure and demonstrated serosal fusion of full-thickness tissue plications. The procedure was shown to reduce the circumference of the gastric cardia and improve the Hill classification grade. The phase II trial showed normalization of distal esophageal acid exposure, increased LES pressure and length, and a valve appearance and location that appeared similar to the laparoscopic NF [48]. The procedure not only recreates the flap valve at the angle of His but also reduces the number of postprandial TLESRs, reduces EGJ distensibility, reduces the proximal extent of acid exposure, and reduces the number of reflux episodes [49].

Results

The randomized control trial by Hunter et al. in 2015 included patients with regurgitation and daily PPI use and evaluated the efficacy of transoral fundoplication versus omeprazole for treatment of regurgitation. Initially 696 patients were screened, and patients with troublesome regurgitation/GERD and hiatal hernias <2 cm were assigned to TIF followed by 6 months of placebo or sham surgery and 6 months of PPI (either once or twice daily). Results showed TIF eliminated troublesome regurgitation in 67% of patients, while PPIs did so in 45% of patients. There were 36% of patients who had no response at 3 months in the control group versus only 11% in the TIF group. Esophageal acid exposure improved, but did normalize, after TIF but not after sham surgery. Subjects in both groups reported similar improvements in GERD symptom scores. The complication rate was low with 3/87 in TIF group and 1/42 in the control group. This study showed that TIF was an effective treatment for GERD at 6 months and had a low complication rate [49].

The TEMPO RCT in 2015 compared TIF versus PPIs in 63 randomized patients with regurgitation and atypical symptoms and found at 6-month follow-up troublesome GERD was eliminated in 97% of TIF patients versus 50% of PPI patients . Regurgitation and extraesophageal symptoms were eliminated in 62% of TIF patients versus 5% of PPI patients. Esophageal acid exposure normalized in 54% of TIF patients and 52% of PPI patients, while 90% of TIF patients were off PPIs at 6-month follow-up [50]. The 3 and 5 year data from the TEMPO trial provide data on the long-term results of TIF. Of 63 patients who underwent TIF, 60 were available for 1-year follow-up, 52 for 3 years, and 44 patients at 5-year follow-up. At 3 years 90% of TIF patients had absence of regurgitation, while 88% had absence of atypical symptoms. Additionally, 71% of TIF patients no longer used PPIs, and 86% of patients had a full recovery of esophagitis [51]. This 3-year data showed that TIF offers durable symptom control for chronic GERD. At 5 years, the TEMPO trial showed that TIF is safe, durable, and cost-effective [52]. Troublesome regurgitation was eliminated in 86% of patients at 5 years, while resolution of troublesome atypical symptoms occurred in 80% of patients. No serious adverse events occurred, and only 34% of patients were on daily PPIs at 5 years compared to 100% of these patients prior to intervention. The GERD-HRQL score improved from 22.2 to 6.8 at 5 years showing sustained symptom improvement at 5 years.

Further long-term data at 6 and 8 years were published. The 6-year data by Testoni et al. showed elimination of daily dependence on PPIs in over 75% of patients, while 30% of patients were off PPIs altogether at 6 years [53]. Symptom scores off PPI were lower at 6, 12, 24, and 36 months. Factors predicting good outcome included absence of hiatal hernia or hernia <2 cm, effective esophageal motility, and increased number of fasteners deployed [53]. A retrospective cohort study by Chimakangara et al. provided 8-year data regarding reflux symptoms and quality of life after TIF in a patient group who were all taking PPI at least daily. At median follow-up of 97 months, 12 of 57 patients underwent subsequent laparoscopic anti-reflux surgery, and of the remaining patients who did not, 23 patients completed long-term follow-up. Of these patients, 73% reported daily acid-reducing medication use. The Median GERD-HRQL scores improved from 24 at baseline to 10 at long-term follow-up. Of these patients available for long-term follow-up, 78% were either satisfied or neutral regarding their GERD management. The majority of patients in this study resumed daily PPI therapy; however, they did demonstrate significantly improve GERD-HRQL scores compared to baseline and increased satisfaction regarding their GERD management [54].

There have been two recent meta-analyses examining the efficacy of TIF. The first by Huang et al. in 2017 analyzed 18 studies comprised of 5 RCTs and 13 prospective observational studies totaling 963 patients. An intention-to-treat analysis of the pooled data of 5 RCTs showed that the relative risk of response rate to TIF versus PPI or sham was 2.44 and the total number of reflux events was decreased after TIF compared to the PPI or sham groups. The studies showed an improvement in typical and atypical GERD symptoms and a trend toward reduction of esophageal acid exposure that did not reach statistical significance. The majority of patients decreased PPI dose compared to pre-procedure, but PPI use increased with time following the TIF procedure. After TIF, the total satisfaction rate at 6 months was about 69%. This meta-analysis showed that TIF is an alternative intervention to control GERD-related symptoms and that short-term patient satisfaction is good but long-term results showed decreased efficacy with time [55]. Additional meta-analysis by Gerson et al. in 2018 analyzed RCTs of the TIF 2.0 procedure versus controls in patients with long-term chronic, refractory GERD on maximal PPI therapy. Data from 233 patients was included at 3-year follow-up and showed statistically significant improvement in esophageal pH, a decrease in PPI utilization, and improvement in quality of life [56]. Overall, TIF with the EsophyX™ device has been shown to be effective in improving GERD-related symptoms, PPI use, and quality of life and received a strong recommendation from the SAGES guidelines committee in 2017; however, the effectiveness of laparoscopic NF on GERD outcomes remained superior to PPIs and TIF [22].

Complications and Additional Considerations

The complication rate for the Esophyx™ device is low; however, severe adverse events occurred at a rate of 2.4% and consisted of gastrointestinal perforation and bleeding [55]. A total of 781 patients were evaluated in a meta-analysis including 4 RCTs and 12 prospective observational trials, and severe adverse events occurred in 19 patients. There were seven perforations, five complications of bleeding, four patients with pneumothorax and one patient, with severe post-procedure epigastric pain. There was one death reported which was 20 months after the procedure; however, the relationship to the prior TIF procedure was unknown.

The use of Esophyx as salvage for recurrent GERD after failed fundoplication has been described by Bell et al. and was shown in this study to be safe and effective [57, 58]. Additionally, Perry et al. showed that prior TIF does not significantly increase the morbidity of a subsequent laparoscopic NF [59]. Upon laparoscopic evaluation after TIF, reasons for failure were fundoplication breakdown or presence of hiatal hernia [58, 59].

Another proposed use of TIF described in one small retrospective cohort study is neurologically impaired children with GERD. In this small study, TIF was shown to resolve GERD in 10 out of 11 of these children [60]; however, TIF is not FDA approved in children, and the use of a 54Fr diameter delivery system limits its application in pediatrics. Areas for future investigation include comparisons of TIF to laparoscopic NF and evaluation of TIF effects on long-term GERD complications such as Barrett’s esophagus, esophageal cancer, and stricture formation [20].

Medigus Ultrasonic Surgical Endostapler (MUSE™)

The Medigus Ultrasonic Surgical Endostapler (MUSE™ Medigus Ltd, Omer, Israel) is an endoscope that has an ultrasound transducer, a video camera, and an endostapler that deploys five 4.8-mm titanium surgical staples proximal to the Z line to create a partial anterior fundoplication (Fig. 19.4) [6]. The patient is placed under general anesthesia with endotracheal (ET) intubation, and the endoscope is inserted through an overtube, advanced and retroflexed in the stomach. The ideal site above the EGJ to create the partial fundoplication is detected using ultrasound and video images, and then the tissue is clamped and stapled endoscopically. The procedure is repeated to form a flap, creating a partial anterior 180° fundoplication [19, 61].

../images/473262_1_En_19_Chapter/473262_1_En_19_Fig4_HTML.jpg — Fig. 19.4

Transoral incisionless fundoplication with MUSE™ endostapler. (a) MUSE™ endoscopic stapler. (b) Ultrasound guidance, device in retroflexion, and ready to begin creation of partial fundoplication. (c) Flap valve after endoscopic stapling (Reused with permission © Medigus)

The MUSE™ device and procedure are the newest (FDA approval 2014) for the endoscopic treatment of GERD and, as a result, has the least amount of data supporting its use. The first preclinical trial was completed in 2008 on 12 study animals. All animals had a successful partial fundoplication with no short-term post-procedure complications [62]. An international multicenter, prospective trial evaluated 69 patients who underwent endoscopic anterior fundoplication and 6-month follow-up data for 66 patients showed GERD-HRQL score improved by >50% while patients were off PPIs in 73% of patients. Additionally, 64.6% of patients were no longer using daily PPIs at 6 months. The remaining patients who continued PPIs post-procedure reported ≥50% reduction in dose, and the mean percent of time with esophageal pH <4.0 decreased from baseline at 6 months. Adverse effects were periprocedural chest discomfort and sore throat, fever, and one patient with pneumomediastinum and pneumothorax. There were 2 severely adverse events that occurred in the first 24 patients (1patient with pneumothorax, pleural effusion, and esophageal leak; 1 patient with GI bleed), which prompted protocol and device changes. Subsequently, there were no further severe events that occurred in the remaining 48 enrolled patients [61].

A study with 5-year follow-up data , published in 2015, followed 13 patients initially in a MUSE™ pilot study for 6 weeks and then to 5 years. At 6 weeks the mean total acid exposure was significantly reduced, and 12/13 patients had reduced GERD-HRQL severity scores by ≥50% and were able to stop daily GERD medications. At 5 years, 11 of 13 patients were available for follow-up. GERD-HRQL scores were normal in 10/11 patients, and all patients would agree to do the procedure again with a median satisfaction score of 8/10. At 4–5 years no patients had dysphagia, 54% (7/13) patients eliminated PPI use, while another 23% (3/13) reduced PPI use by ≥50% [63]. Additional long-term data with 4-year follow-up was reported by Kim et al. in 2016. A multicenter, prospective study using the MUSE™ endoscopic stapling device evaluated 37 patients at baseline, 6 months, and annually up to 4 years post-procedure. At 6 months 83.8% of patients remained off daily PPIs, and at 4 years 69.4% were off of daily PPIs. The GERD-HRQL scores off PPIs were significantly decreased from baseline at both 6 months and 4 years post-procedure, and for those who were on GERD medications , the daily dose decreased at both time points [64, 65]. Overall, initial data for the MUSE™ endoscopic stapling device is promising for symptom relief and decreased PPI use with an acceptable safety profile; however, further study is needed. Future investigations with larger randomized groups of patients, longer follow-up, presence of sham or control, and comparison to other endoscopic treatments for GERD along with ongoing safety and efficacy studies are warranted prior to widespread use of the device.

The endoscopic treatments for GERD discussed above represent new options to potentially fill the treatment gap between medications and traditional surgical techniques of fundoplication; however, patient selection remains paramount. In addition to endoscopic treatments for GERD, emerging laparoscopic therapies aside from NF pose additional options and these include LINX® magnetic LES augmentation, EndoStim® LES stimulation, and laparoscopic RYGB, particularly in patients with BMI >35 kg/m². These laparoscopic operations still allow for repair of hiatal hernias but eliminate fundoplication, and its side effects, and attempt to improve inefficient LES function [6].

Laparoscopic Modalities for Treatment of GERD

Magnetic Sphincter Augmentation (MSA) Using the LINX® Device

Magnetic sphincter augmentation (MSA) using the LINX® reflux management system (Torax Medical, Shoreview, MN) was approved in the USA in 2012 and is now an established laparoscopic procedure for reflux with published efficacy [6]. The device consists of a string of titanium beads (MRI safe to 1.5 T) with a magnetized core that are connected with independent titanium wires to form a ring that is placed circumferentially around the EGJ (Fig. 19.5) [66]. The beads are attracted to each other by magnetic forces and increase the pressure of the LES circumferentially to help restore the anti-reflux barrier and eliminate transient esophageal relaxations thought to contribute to reflux. The beads rest on each other when the device is in the closed position to prevent esophageal compression. The wire connecting the beads allows adjacent beads to be displaced relative to each other to reach a maximal fixed diameter of 3.6 mm [67]. The mechanism of action is dynamic augmentation; the magnets help keep the LES closed to minimize reflux yet temporarily open to allow a food bolus and liquid to pass through during swallowing. When adequate pressure is reached, 27 mm Hg, the magnetic attraction is overcome and the LES is allowed to open, allowing patients to eat, drink, belch, or vomit [6, 19, 67]. Peristaltic contractions of the esophagus produce pressure of 40–100 mmHg which is sufficient for the food bolus to overcome the force of the device and pass through the esophagogastric junction normally. Gastric contents will not generate enough pressure to overcome the barrier, hence, minimizing reflux. Emesis will generate enough force to allow patients to vomit if needed [66].

../images/473262_1_En_19_Chapter/473262_1_En_19_Fig5_HTML.jpg — Fig. 19.5

LINX® Magnetic Sphincter Augmentation device placement and function. (a) Sizing tool for LINX® device measurement. (b) Positioning of LINX® around LES. (c) Closure and fastening of LINX® device using pre-attached sutures. (d) Device positioned at LES to resist opening gastric pressure and reflux. (e) Device opening during swallowing of food bolus. (f) Device returned to closed position to augment LES. © Ethicon Endosurgery

Pre-procedure workup includes EGD, GERD-HRQL score, pH study, and esophageal manometry. Selection criteria include patients 18–75 years of age, >6 months of reflux, a partial response to daily PPIs, and increased esophageal acid confirmed with esophageal pH study. Exclusion criteria are LA grade C or D esophagitis, Barrett’s esophagus, esophageal motility disorder, dysphagia >3 times per week, BMI >35, allergy to components of the device (titanium, stainless steel, nickel, or ferrous materials), and traditionally, large hiatal hernia (≥3 cm) [68].

The procedure is a minimally invasive laparoscopic procedure during which the device is placed around the LES to augment its function [19]. The median time required to place the device, in the initial multicenter FDA trial, from time of last port insertion to first port removal was 36 min (range 7–125 min) [68]. The operation includes careful dissection of the GE junction fat pad away from the GE junction, opening the phrenoesophageal ligament along the anterior border of the left crus, and then dissection on the right side of the hiatus. The gastrohepatic ligament is incised, hepatic branch of the vagus nerve preserved, and the gastroesophageal junction is identified. The peritoneum along the anterior border of the right crus is opened above the crural decussation, and the posterior vagus nerve is identified. A retroesophageal window between the vagus nerve and the esophagus is created bluntly and then a Penrose or vessel loop is placed around the esophagus, excluding the posterior vagus nerve. The esophageal sizing tool is placed circumferentially, assuring that the underlying esophagus and musculature are not indented or compressed, to determine the appropriately sized device. The device is then placed encircling the esophagus, excluding the posterior vagus nerve, and the two ends of the device are approximated anteriorly and fastened into place using the pre-attached traction sutures. If there is a hiatal hernia present, it should be formally repaired prior to device measurement and placement. Patients can typically go home within 24 h on a solid diet [67–70].

Additional discussion exists around minimal versus obligatory dissection of the diaphragmatic hiatus during MSA surgery. At the inception of the device, minimal hiatal dissection (MHD) was recommended as the best surgical approach for MSA placement due to concern for device migration into the hiatus. However, in late 2015 the recommendation changed to obligatory dissection (OD) of the hiatus with concurrent hiatal hernia repair, if identified. A study published in 2018 showed that there was no difference in early dysphagia between the two groups. Delayed-onset dysphagia, recurrent GERD, recurrent hiatal hernia, and repeat surgery for hiatal hernia repair were less frequent in the OD group; hence obligatory hiatal dissection is now recommended [71].

Results

Results of the LINX® magnetic sphincter augmentation (MSA) device have been published starting with the feasibility trial in 2010 to establish safety and efficacy of the treatment. The pilot study included 44 patients with abnormal acid exposure on 24-hour pH monitoring and persistent GERD symptoms despite PPIs. The study showed improvement in GERD-HRQL scores from baseline of 25.7 to 3.8 at 1 year (80% reduction) and 2.4 (90% reduction) at 2-year follow-up. At 1- and 2-year follow-up, 90 and 86% of patients were able to stop PPI use, respectively. The most common side effect was early dysphagia, occurring in 43% of patients, which resolved without intervention within 90 days in all but one patient, who had the device explanted due to persistent dysphagia. There were no reported device migrations or erosions. At 1 and 2 years, 77 and 90% of patients had normal esophageal acid exposure, respectively, and the mean percentage of time the pH was <4 decreased from 11.9 to 3.1% at 1 year and 2.4% at 2 years. Patient satisfaction was ≥86% at both follow-up periods. This initial study showed efficacy and safety at 1- and 2-year follow-up [70]. The 5-year results of this pilot study were subsequently published in 2015, and 33 of the 44 initial patients were available for follow-up. At 5 years esophageal acid exposure was 4.6% from 11.9%, 85% of patients had ≥50% reduction in esophageal pH, and 93.9% of patients had ≥50% reduction in total GERD-HRQL score with a mean score of 2.9 from 25.7 at baseline. Additionally, 87.8% of patients were able to stop PPIs, and no erosions or device migrations were observed [72].

A multicenter FDA trial involving 100 patients was published including 1-year, 3-year, and 5-year follow-up. The 1- and 3-year follow-up was published first, and the primary outcome of normalization or ≥50% acid reduction was achieved in 64% of patients with success of the device defined as achievement of the primary endpoint in ≥60% of patients. For the secondary outcomes, 93% of patients had ≥50% reduction in PPIs, and 92% of patients had ≥50% reduction in GERD-HRQL scores. Esophagitis was decreased from 40% at baseline to 12% at follow-up. Satisfaction with the reflux condition improved to 95% at 1 year, 90% at 2 years, and 93% at 3 years follow-up compared to 12% at baseline on PPI therapy. The most common adverse event was dysphagia in 68% of patients postoperatively, 11% of patients at 1-year follow-up, and 4% of patients at 3-year follow-up. Esophageal dilation for dysphagia was done on 19 patients, 16 of which reported improvement in symptoms. Of note, cruroplasty was performed in 34% of patients who underwent the procedure, thus confounding dysphagia analysis based on device or cruroplasty [66, 68].

Serious adverse events occurred in six patients, requiring device removal in four of the six (three patients for persistent dysphagia, one patient due to intermittent vomiting of unknown etiology with no relief after removal). The remaining two patients had rehospitalization for nausea and vomiting 2 days after surgery with resolution of symptoms without reoperation. Two additional devices were removed, one for persistent reflux symptoms and one for persistent chest pain. Three of the six patients who underwent device removal underwent subsequent NF with no complications. At 3-year follow-up only two patients complained of inability to belch or vomit. Based on chest radiography and endoscopy at 1-year and 2-year follow-up, there was no evidence of device migration or erosion [68].

The 5-year results of the FDA trial study were published in 2016, and the GERD-HRQL scores decreased to 4, from 27 at baseline (off PPIs) and 11 (on PPIs). At baseline, all study patients required PPIs, while only 15.3% of patients required them at 5 years post-LINX® and 89.4% of patients had ≥50% reduction in dose at 5 years versus 93% at 1 year. At baseline, 57% of study patients had moderate to severe regurgitation, while only 1.2% of patients experienced this at 5 years. At baseline, 40 patients had esophagitis, and of these patients 34 underwent follow-up endoscopy at 5 years, and 8 were shown to have esophagitis versus 12 at the 1-year mark, while 5 patients developed new esophagitis (grade A or B) during this period. All patients were able to belch and vomit. Troublesome dysphagia occurred in 5% of patients at baseline and 6% of patients at 5 years. Troublesome gas bloat was reported in 52% of patients at baseline and was decreased to 8.3% of patients at 5 years. There were no device erosions, malfunctions, or migrations reported [73].

The continued assessment of safety and efficacy post-FDA approval has been studied and published in 2018. A multicenter prospective study included 200 patients treated with MSA. At 1 year the mean total acid exposure time decreased from 10% to 3.6% and 74.4% of patients had normal esophageal acid exposure time. Additionally, GERD-HRQL scores improved from 26 to 4 (lower is better). The device removal rate was 2.5% with one erosion and no serious adverse events [74], thus confirming LINX® MSA as a safe and effective therapy for GERD outside of the initial investigational setting.

The most feared complication of implanting a device around the mobile LES remains to be erosion. A safety analysis of the first 1000 patients (from 82 institutions across the USA and Europe) treated with LINX® MSA over a 6-year period was performed and results published in 2015. The median implant duration at the time of analysis was 274 days. Various safety parameters were analyzed, and for intra- or peri-\operative complications, the event rate was 0.1% (one patient with respiratory arrest postop, considered unrelated to device, successfully resuscitated), 1.3% for hospital readmissions (dysphagia, pain, nausea, vomiting), 5.6% for endoscopic dilations due to dysphagia, and 3.4% for reoperations for device removal. Dysphagia rate of 5.6% of patients is similar to the reported rate of 6.4% after NF, both of which typically improved after dilation. Notably, many patients are able to overcome the early post-LINX® dysphagia by persistent swallowing of food boluses forcing the device to open and close to minimize constriction by the scar tissue around the device. All reoperations were nonemergent, primarily for dysphagia, and none had complications or required conversion to an open operation. Following removal, 10 of the 36 patients had subsequent NF, though this rate is likely underestimated as not all post-removal data was available. Erosion rate was 0.1% as it occurred in one patient, and no migrations or malfunctions were reported [75].

A similar study assessing 3283 patients undergoing MSA at 191 institutions with a median implant duration of 1.4 years and >1000 patients with the device in place >2 years showed an overall device removal rate of 2.7% (89/3283) with 57% removed within 1 year after implantation. The reasons for removal included dysphagia (52/89), persistent reflux symptoms (19/89), and erosion in 0.15% (5/3283), and no migrations or perforations were noted [76]. Worldwide experience with erosion was published in 2018 using manufacturer and user databases, and from 2007 to 2017, a total of 9453 devices were placed worldwide, and there were 29 reported cases of erosions. The median time to presentation was 26 months, and the risk of erosion at 4 years was 0.3% with the most commonly presenting symptom of new-onset dysphagia. The devices were successfully removed in all patients. The most commonly employed technique for removal was endoscopic removal of the eroded portion of the device followed by delayed laparoscopic removal of the remaining beads. At a median follow-up of 58 days, no long-term complications were reported after device removal [77]. A noted limitation of these studies is the reliance on providers for reporting of events outside of the clinical study to the FDA and manufacturer, which is likely not complete, raising the concern of underreporting of complications in the post-FDA approval period [75]. An additional study focusing on device removal had a high follow-up rate and evaluated 164 patients for 4 years during which 6.7% (11 devices) required removal and 1.2% (2 patients) had esophageal erosion (at 12 and 19 months post-placement) requiring removal [78]. The data supports the conclusion that MSA with the LINX® device is highly effective and safe for the treatment of GERD that should be considered as a tool to help fill the GERD treatment gap.

Additional Considerations

The efficacy of MSA in patients with GERD has been evaluated; however, the outcomes in comparison to NF remain unclear. A meta-analysis published in 2017 pooled results of 4 trials including 624 patients. MSA had shorter operative time than NF and length of stay. Rates of PPI use, GERD-HRQL scores, symptoms, complications, and severe dysphagia requiring dilation were similar among the groups. The number of adverse events was similar between groups; however, there was statistically significant increased gas bloating in the NF group while there was not a statistically significant difference in the ability to belch or vomit [79]. Another meta-analysis compared MSA to NF and evaluated 688 patients with approximately 1-year follow-up and found that MSA was statistically superior to NF in preserving ability to belch and vomit, while there was no difference between the two operations in gas, bloating, postoperative dysphagia, or PPI elimination [80]. The data comparing MSA to NF is short term and inconsistent in its findings; hence further investigation is required, including long-term studies and RCTs to further elucidate these differences.

A multicenter, randomized trial comparing MSA to double-dose PPI for the management of GERD despite once-daily PPI therapy evaluated 152 patients from 21 institutions followed for 6 months. Patients were randomized 2:1 to treatment with twice-daily PPOs versus laparoscopic MSA. Relief of regurgitation symptoms was achieved in 89% of patients who underwent MSA versus 10% of patients in the twice-daily PPI group, while 81% of MSA patients had ≥50% improvement in GERD-HRQL scores versus 8% in the twice-daily PPI group. Of MSA patients, 91% were off PPI therapy, 91% had normal number of reflux episodes (versus 58% in PPI group), and 89% of MSA patients had normal number of acid exposures (versus 75% in PPI group). No significant safety events were observed; however, 28% of MSA patients reported transient dysphagia, and 4% reported ongoing dysphagia. The results of this study suggest that MSA is more effective than increasing PPI dose for controlling GERD in patients with moderate to severe regurgitation despite once-daily PPI [81].

Laparoscopic MSA has efficacy in the aforementioned populations; however, its use is being explored in additional patient populations. Reflux after sleeve gastrectomy is typically managed by conversion to RYGB; however, the LINX® device may have a potential use in these patients. In a recent case report, the device was placed for severe reflux after sleeve gastrectomy after which the postoperative UGI showed no reflux, the 10-day postop and the quality of life score improved, and at 1 year postop, the patient remained off antacid medication with no report of reflux [82].

The efficacy of the device in patients with large hiatal hernias, defined as ≥3 cm, was studied retrospectively and results published in 2017. There were 52 patients identified with large hiatal hernias, and they showed that mean GERD-HRQL score decreased from 20.5 to 3.6 and had decreased postop PPI requirement when compared to those with smaller hiatal hernias. The percentage of patients needing intervention for dysphagia was similar to those with small hiatal hernias at 13.5 versus 17.9% (p = 0.52), respectively, and the symptom improvement and resolution rates were similar in both groups at 98.1 and 91.3% (p = 0.118), respectively [83]. An additional study published in 2018 prospectively reviewed 200 patients treated with MSA with the LINX® device along with repair of hiatal hernias >3 cm, 78% of which had hiatal hernia ≥5 cm. Of note, nonpermanent mesh reinforcement of the hiatal repair was performed in 83% of patients. There were 156 patients available for follow-up with a median of 8.6 months and shown to have improvement in GERD-HRQL scores from 26 to 2, no explants, erosions or migrations; however, 19 patients did require dilation for dysphagia, showing overall favorable outcomes at 9-month follow-up [84]. This opens another potential door for the use of LINX® in GERD patients with large hiatal hernias .

Electrical Stimulation of the Lower Esophageal Sphincter (EndoStim®)

Electrical stimulation of the lower esophageal sphincter with the EndoStim® device (EndoStim, St. Louis, MO, USA) is an implantable electrical stimulator that delivers energy to the LES [6, 66]. The device has three components including a bipolar stimulation lead with two stitch electrodes, a pulse generator, and an external programmer [6]. The device received CE mark in Europe in 2012, and multiple FDA trials are ongoing in the USA. The device is placed laparoscopically during which the two electrodes are implanted anteriorly along the esophagus spanning the LES in a staggered position (Fig. 19.6) with approximately 1-cm distance between the two electrodes. The Z line is identified endoscopically, and transillumination is used to guide placement of the electrodes. A superficial longitudinal seromuscular bite measuring 15 mm along the axis of the esophagus is performed, with care taken not to incorporate esophageal mucosa. The second electrode is placed in the same fashion. The generator is implanted in a subcutaneous pocket in the abdominal wall [66, 69]. The device settings can be modified with a wireless programmer; the battery lasts 7–10 years, and it can be exchanged as an outpatient surgical procedure [85].