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Review
Novel surgical options for gastroesophageal reflux disease Expert Rev. Gastroenterol. Hepatol. Early online, 1–9 (2015)
Jenny Chiu and Edy Soffer* Department of Medicine, Keck School of Medicine, University of Southern California, 1520 San Pablo Street, Los Angeles, CA 90033, USA *Author for correspondence: Fax: +1 323 442 5625 [email protected]
There are limited options to patients with gastroesophageal reflux disease (GERD) who are not satisfied with acid suppression therapy. Fundoplication, the standard surgical procedure for GERD, is effective but is associated with adverse side effects and has thus been performed less frequently, creating a need for alternative surgical interventions that are effective, yet less invasive and reversible. Lately, two such interventions were developed: the magnetic sphincter augmentation and electrical stimulation of the lower esophageal sphincter. Human studies describing safety and efficacy over a follow-up period of a number of years have been published, documenting efficacy and safety of these interventions. Future studies should clarify the role of these procedures in the spectrum of GERD therapy. KEYWORDS: electrical stimulation . gastroesophageal reflux disease . lower esophageal sphincter . magnetic sphincter augmentation . Nissen fundoplication
Gastroesophageal reflux disease (GERD) is among the most common gastrointestinal disorders. It affects up to 30% of the population in developed countries, with increased prevalence in other geographic areas [1,2]. GERD negatively impacts quality of life [3], particularly when it occurs at night [4]. GERD is one of the main risk factors for adenocarcinoma, which is nearly five- to seven-times as common in individuals with chronic GERD symptoms compared with those without GERD [5]. Intestinal metaplasia of the esophagus (Barrett’s esophagus) is a premalignant lesion and a precursor of esophageal adenocarcinoma. Barrett’s esophagus is most often diagnosed in people with long-term GERD. GERD remains a risk factor for the development of Barrett’s esophagus [6], and the incidence of Barrett’s esophagus is rising [7], along with the increased incidence of esophageal adenocarcinoma worldwide, but particularly in industrialized countries [8]. Lifestyle changes, such as avoiding triggerfoods, eating smaller meals, raising the head of the bed and acid suppression with H2 blocker agents were shown to have variable and minimal effectiveness in improving GERD symptoms [9]. Consequently, acid suppression therapy with proton pump inhibitors (PPIs) has been the mainstay of medical therapy for
informahealthcare.com
10.1586/17474124.2015.1039986
GERD. While such therapy has proven to be remarkably effective and safe, a substantial number of patients report continued symptoms despite adequate therapeutic regimens [10]. A number of reasons are thought to contribute to incomplete response, an important one being that acid suppression affects the acidic content of the refluxate but not reflux itself [11]. This is supported by the importance of regurgitation as a factor responsible for partial response to PPI therapy [12]. In fact, a substantial number of patients undergoing antireflux surgery report a lack of control of GERD symptoms with medications as the reason for choosing surgery [13,14]. PPI use has been reported to be associated with adverse effects such as decreased calcium absorption, osteoporosis, community acquired pneumonia, Clostridium difficile infection, small intestinal bacterial overgrowth, vitamin B12 deficiency and drug interactions [15]. However, conclusive data demonstrating clear causality between PPIs and such adverse effects are, for the most part, quite limited. Given their efficacy, current guidelines do not recommend discontinuing or avoiding PPIs in these settings [16]. However, these potential factors may influence the choice for alternative therapies. Fundoplication, the standard antireflux surgery, has
2015 Informa UK Ltd
ISSN 1747-4124
1
Review
Chiu & Soffer
A Diaphragm Esophagus Closed position
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 06/17/15 For personal use only.
Titanium case Magnetic device in closed position
Magnetic core
Stomach Titanium arm
B
Open position Bolus
Magnetic device in open position
Figure 1. Magnetic device for augmentation of the lower esophageal sphincter. Panel (A) shows the magnetic device in the closed position, which helps prevent opening of the lower esophageal sphincter and subsequent reflux. Each magnetic bead rests on adjacent beads to prevent esophageal compression. Panel (B) shows the device in the open position, which allows transport of food, belching and vomiting. Reprinted with permission from Massachusetts Medical Society [24].
failed due to lack of efficacy or complications [20]. Recently, two surgical interventions for GERD were developed as an alternative to the traditional fundoplication, the magnetic sphincter augmentation (MSA) and lower esophageal sphincter electrical stimulation therapy (LES-EST), and are the subject of this review. Laparoscopic MSA
Laparoscopic MSA or LINX Reflux Management System (Torax Medical, St. Paul, MN, USA) is composed of a series of titanium beads with magnetic cores within each bead. The beads are interlinked with titanium wires to form a flexible and expandable ring where each bead is able to move independently. This freemoving apparatus was designed to allow for a physiological mechanism to parallel the movements of the LES. Thus, the ring transiently opens to allow passage of a food bolus, permits belching and vomiting and approximates to its closed position at rest to prevent the upward migration of gastric contents. The beads range in number from 10 to 18 beads, so as to accommodate variations in size, and the device is placed laparoscopically under general anesthesia (FIGURE 1). The procedure is reported to take about half an hour, and most patients are discharged on a regular diet on the same day or the following day [21]. The US FDA approved the use of the device for the treatment of GERD in March 2012. Animal study
been the primary alternative to patients who are unsatisfied with pharmacological therapy because of poor symptoms control, cost or concerns about long-term safety of PPI. Antireflux surgery provides an effective control of GERD but is associated with adverse effects, such as gas-bloat, flatulence and dysphagia, and requires revision in a small percentage of subjects [17]. Perhaps as a result, the number of fundoplication procedures performed in the USA has been declining [18]. The resulting unmet need of patients, who are not satisfied with medical therapy and the traditional surgical approach, has prompted a search for alternative treatment modalities, both endoscopic and surgical. A desirable alternative should be effective yet: be less disruptive and have less adverse effects than that of a fundoplication and be truly reversible [19]. Various endoluminal procedures for GERD were developed over the years, but most doi: 10.1586/17474124.2015.1039986
Both ex vivo and chronic in vivo studies were conducted in a pig model to assess the function of the system. Studies on isolated pig stomachs were performed to determine gastric yield pressures, that is, the gastric pressure that can overcome and open the augmented lower esophageal sphincter. This was followed by a chronic, 20–44 weeks study in a pig model in which the function and competence of the implanted magnetic ring was tested during balloon distension and barium studies [22]. Upper endoscopy performed after the implantation revealed normal mucosa with no erosions or defects. Barium swallow test demonstrated separation of the beads with food and liquid boluses. Upon necropsy, all magnetic devices were encapsulated in fibrous tissue and confined to the adventitia without any migration or erosion into the lumen. On histology, there was minimal inflammation in the fibrous tissue and no inflammation was seen in the muscle Expert Rev. Gastroenterol. Hepatol.
Novel surgical options for GERD
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Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 06/17/15 For personal use only.
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Figure 2. Quality of life with gastroesophageal reflux disease. Panel (A) shows the median total score from the Gastroesophageal Reflux Disease-Health-Related Quality-of-Life Scale (the main component of the scale is heartburn) measured at baseline without and with proton pump inhibitors, as compared with 3 years after implantation, without proton pump inhibitors. Total scores range from 0 to 50, with higher scores indicating worse symptoms. There was significant improvement in the median score after implantation for all years, as compared with baseline assessments both without and with proton pump inhibitors (p < 0.005 for the three comparisons, by the Wilcoxon signed-rank test). Panel (B) shows the percentage of patients who reported being satisfied, neutral (neither satisfied nor dissatisfied), or dissatisfied with respect to their present condition, as assessed by means of the Gastroesophageal Reflux Disease-HealthRelated Quality-of-Life Scale at baseline with proton pump inhibitors and at 3 years after implantation and without proton pump inhibitors. There was significant improvement in the satisfaction level for all 3 years (p < 0.001 for the comparison of patients who were satisfied versus those who were not satisfied or who had a neutral response). Reprinted with permission from Massachusetts Medical Society [24].
layers. These animal results were followed by evaluation of the concept in humans. Human studies Feasibility study
The LINX device was laparoscopically implanted in 44 GERD patients, enrolled in a multicenter trial. All had heartburn as the main symptom, persisting while on acid suppression therapy and documented excessive esophageal acid exposure. Those with a hiatal hernia >3 cm, greater than Los Angeles Classification grade B esophagitis and abnormal esophageal contractile function were excluded [23]. At 2 years, there was a significant improvement in GERD-health-related quality-of-life questionnaire (HRQL) and esophageal acid exposure. Of the 20 patients who had a repeat esophageal pH test, 90% had a normal study, and 86% of the patients were completely off PPI therapy. Mild dysphagia was reported by 43% of patients and resolved by 3 months, except for one patient who underwent an explantation at 8 months because of persistent dysphagia. Chronic studies
The positive results from the feasibility study led to a multicenter, open-label, uncontrolled pivotal trial that included 100 patients and was conducted in 13 centers in the USA [24]. Inclusion and exclusion criteria were similar to those in the feasibility trial. Patients had a history of GERD of at least 6 months with a partial response to daily PPIs and increased esophageal informahealthcare.com
acid exposure confirmed by pH monitoring. Exclusion criteria included evidence of a large hiatal hernia, esophagitis of grade C or D by the Los Angeles classification, BMI > 35, Barrett’s esophagus and motility disorder of the esophagus. Primary and secondary outcomes were assessed at 1 year post-implant and follow-up data at 3 years were provided. There was a significant improvement in esophageal acid exposure and quality of life at 1 year that was sustained over the period of follow-up (FIGURE 2) and in other variables (FIGURE 3). Dysphagia was the most common adverse event, reported by 68% of patients (FIGURE 3), of whom 19 patients underwent esophageal dilation. Removal of the device was required in six patients; in three because of persistent dysphagia, and in the other three because of persistent nausea, reflux or chest pain each. Three of these six patients subsequently underwent Nissen fundoplication, with no complications. A longer follow-up was provided by Bonavina et al. [25]. One hundred patients with GERD were implanted in a single center, and were followed for a median of 3 years, with 30 patients completing 6 years of follow-up. There was a significant improvement in symptoms and in esophageal acid exposure. The device had to be explanted in three subjects because of persistent GERD, dysphagia or odynophagia. Nissen fundoplication compared with MSA
A comparison between the two interventions was evaluated in both single and multicenter studies. A single institution, retrospective study compared all LINX procedures performed in the doi: 10.1586/17474124.2015.1039986
Review
Chiu & Soffer
A Proton-pump-inhibitor use 100
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Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 06/17/15 For personal use only.
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Figure 3. Proton pump inhibitor use, reflux symptoms, dysphagia and esophagitis over the 3-year period. Panel (A) shows the percentage of patients reporting any use of proton pump inhibitors before and after implantation. At 3 years, 87% of the patients reported complete cessation of proton pump inhibitors (p < 0.001 for all years, for the comparison of daily use with no use). Panel (B) shows the assessment of regurgitation symptoms, according to the Foregut Symptom Questionnaire. Patients rated the severity of regurgitation before and after treatment. Results are displayed as the percentage of patients reporting mild, moderate or severe regurgitation (p < 0.001 for improvement in all grades of severity, for all years). Panel (C) shows the percentage of patients reporting dysphagia at follow-up visits as well as the severity of the dysphagia. Any report of dysphagia after implantation was recorded as an adverse event. Panel (D) shows the percentage of patients with esophagitis, according to grade, before and after implantation (p < 0.001 for any esophagitis vs none at both 1 and 2 years). Grading on the Los Angeles classification for esophagitis is as follows: grade A indicates one or more mucosal breaks of 5 mm or less in length, grade B one or more mucosal breaks of more than 5 mm, grade C mucosal breaks that extend between two or more mucosal folds but involve less than 75% of the circumference of the esophagus, and grade D mucosal breaks of 75% or more of the circumference. Reprinted with permission from Massachusetts Medical Society [24].
course of 1 year (n = 12) with a matched group of patients who underwent a laparoscopic Nissen fundoplication (n = 12) [26]. The patients were matched for age, gender, hiatal hernia size and BMI. Perioperative outcomes, hospital length of stay, 30-day morbidity and mortality were similar in both groups. Operation time was shorter in the MSA device group (64 vs 90 min; p < 0.001). With an average follow-up time of 7 months, 75% of MSA and 83% of fundoplication patients reported resolution of their GERD symptoms post-surgery (p = 0.99). Symptoms were classified as heartburn, regurgitation or atypical, (which included laryngopharyngeal or doi: 10.1586/17474124.2015.1039986
pulmonary symptoms) and the primary presenting symptom was recorded, respectively. Improvement in the primary symptom (not defined) was comparable between the groups. More patients in the fundoplication group complained of bloating, flatulence and diarrhea (0 vs 33%). Dysphagia was common, with 83% of LINX and 58% of Nissen patients reporting some degree of dysphagia postoperatively. However, dysphagia following Nissen occurred within the first 30 days postoperatively, and resolved in all patients with expectant management. In contrast, dysphagia following the LINX procedure occurred after the first 7 days Expert Rev. Gastroenterol. Hepatol.
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Novel surgical options for GERD
Review
postoperatively, and once it occurred it Pre-stimulation Stimulation Post-stimulation was more persistent and severe. Endoscopic dilation was required in WS WS WS 50% of LINX patients versus 0% in the Nissen group (p = 0.01), and successfully resolved dysphagia in all but one patient. A prospective, multicenter trial evaluated 202 MSA and 47 laparoscopic fundoplication patients who had completed 1-year follow-up [27]. Most patients chose Sleeve surgery because of incomplete control of symptoms with PPI. Most outcome varia50 mm Hg bles showed comparable improvement, Gastric although the MAS group reported better 10 sec control of regurgitation and greater number of patients discontinuing PPIs. BloatFigure 4. The effect on esophageal and LES function of stimulation with pulses ing and inability to vomit were more of 200 ms, and 5 mA in one of the subjects. The three channels above the sleeve commonly reported by the fundoplicarepresent recording from the esophageal body, at 1, 6 and 11 cm above the sleeve. A stimulation-induced increase in resting LES pressure is observed at mid stimulation and tion group (31.9 vs 10.0 and 44.4 vs after the stimulus is stopped. 91.3, respectively), while dysphagia was LES: Lower esophageal sphincter; WS: Wet swallow. comparable between the two groups. The Reprinted with permission from John Wiley and Sons [31]. rate of reoperation was 4.0% in the MSA group and 6.4% in the fundoplication one, although the reasons differed. Reoperations in the MSA rise in pressure in both groups of animals. Pressure remained group were performed for device removal due to dysphagia, elevated for a number of hours when two pairs of electrodes pain or persistent GERD, while in the fundoplication group were used [29]. In an acute study in anesthetized dogs, were for persistent GERD and herniation of the fundic wrap. Clarke et al. used microstimulators implanted endoscopically in Importantly, pre-surgical hiatal hernia >3 cm were present in the LES, to deliver electrical current to the muscle. They 1.6% in the MSA group compared with 45.7% in the fundo- observed that constant stimulation with pulses of 200 ms at a plication group, and more patients in the fundoplication had frequency of 20 Hz increased LES pressure, but only at currents that exceeded 8 mA [30]. In a chronic canine model, Barrett’s esophagus (19.1 vs 1.0%, respectively). Sanmiguel et al. implanted a pair of electrodes in the LES and studies were done in awake animals. Using a variety of pulse Safety/adverse effects A recent study reviewed the overall safety profile of MSA devi- parameters, they found that stimulation with 375 ms pulses, of ces in the first 1000 patients to have them implanted [28]. Over 5 mA at 6 c.p.m. increased LES pressure [31]. The studies also 1000 patients have been implanted with the MSA device at showed that the rise in LES pressure did not occur at the start 82 institutions from 2007 to 2013 with a median implant of stimulation, but showed a delayed onset and extended duration of 274 days; 0.1% intra- and perioperative complica- beyond the end of stimulation. The results of these studies sugtions, 1.3% hospital readmissions, 5.6% endoscopic dilations gested that electrical stimulation of the LES may be used to and 3.4% reoperations for device removal have been reported. treat GERD and paved the way to the application of such All removals were done through a laparoscopic approach, with- modality in humans. out conversion to laparotomy or described complications. One patient had erosion of the device into his esophagus (0.1%). Acute human studies of LES-EST Most common reason for removal was secondary to symptoms Two studies were conducted as a proof of concept, to evaluate the effect of EST on LES pressure. The first study included of dysphagia. 10 patients with GERD symptoms and documented abnormal esophageal acid exposure, scheduled to undergo an elective lapElectrical stimulation of the LES (LES-EST) aroscopic cholecystectomy. At the end of the procedure, two Animal models A number of studies in animals showed that electrical stimula- electrodes were implanted at each side of the LES and the lead tion of the LES can increase resting LES pressure. In an early was then exteriorized through the abdominal wall in the left study, Ellis et al. implanted one or two pairs of electrodes in upper quadrant. Following recovery, they underwent a series of the LES in normal dogs, and animals in which the gastroesoph- intermittent stimulation with various pulse parameters, lasting ageal junction was rendered incompetent by myotomy and cre- 30 min each, given while having concomitant esophageal ation of a hiatal hernia. Stimulation with square wave pulses of manometry [32]. There was a consistent and significant increase 3 ms, at 4 V and frequency of 20 Hz, induced a significant in LES pressure with both high frequency stimulation (pulse informahealthcare.com
doi: 10.1586/17474124.2015.1039986
Chiu & Soffer
width of 200 ms, frequency of 20 Hz and current of 5–15 mA, and low frequency stimulation (pulse width of 375 ms, frequency of 6 c.p.m. and current of 5 mA). The rise in pressure was observed after about 10 min following the start of stimulation, and was sustained beyond the end of stimulation (FIGURE 4). In most patients, the enhanced pressure was sustained for at least 2 h after cessation of stimulation, and up to a few hours in a few patients. There was no effect on LES relaxation in response to swallows, and none of the patients complained of dysphagia. In a second study, five patients with GERD were fitted with temporary electrodes placed endoscopically in the LES submucosa and stimulation was delivered 6–12 h post-implant. Comparable to the first study, high frequency electrical stimulation of the LES (20 Hz, duration of 200 ms or 3 ms) resulted in consistent and significant increase in LES pressure, with delayed onset of 5–10 min that was sustained after the end of stimulation. Stimulation had no effect on swallow-induced LES relaxation, and no patients complained of dysphagia [33]. The results of these studies prompted further assessment of this technology in GERD patients. Figure 5. Schematic of the EndoStim System implant in a patient. Electrode position and IPG implant location. Bipolar stitch electrodes are placed in the abdominal esophagus anteriorly in an inline configuration 1 cm apart. The lead is connected to the IPG that is implanted in the subcutaneous pocket in the anterior abdomen. Reprinted with permission from Elsevier [33].
Chronic human studies Single-center study
Twenty-five patients were implanted with the EndoStim LES Stimulation System (Endostim BV, The Hague, The Netherlands), in an open-label study performed in a single center. Data analysis was performed on 21 patients who completed the 2-year evaluation [34]. Inclusion/exclusion criteria in all studies of LES electrical stimulation were comparable to those described in the MSA studies. All patients had chronic GERD with only 30 23.5 partial response to PPI therapy, and 21.0–25.3 abnormal esophageal acid exposure. n = 24 25 Patients with a hiatal hernia >3 cm, and Los Angeles grade D esophagitis were excluded. Bipolar stitch electrodes were 20 implanted in the muscular layer of the LES, and connected to a pulse generator 15 implanted in a subcutaneous pocket in 9.0 the left upper quadrant of the 6.0–10.0 abdomen (FIGURE 5). No hiatal repair was n = 24 10 performed in any patient. The system delivers stimulation at a frequency of 2.0* 20 Hz, pulse width of 215 ms, 3–8 mA 5 0–3.0 0.0* at 30-min sessions, 6–12 sessions a day. n = 23 0–3.0 At 2 years, there was a significant n = 21 0 improvement in GERD-HRQL (FIGURE 6) Baseline Baseline Month 12 Month 24 and in esophageal acid exposure (FIGURE 7) on PPI off PPI on EST on EST with 71% demonstrating either normalization or at least 50% reduction in Figure 6. Change in median (IQR) GERD-HRQL composite scores on LES-EST comesophageal acid exposure. Seventy-six perpared with baseline on- and off-PPI GERD-HRQL composite scores (*p < 0.05). LES-EST: Lower esophageal sphincter electrical stimulation; GERD-HRQL: Gastroesophageal cent of patients reported complete cessareflux disease-health-related quality of life; PPI: Proton pump inhibitor. tion of PPI use (FIGURE 8). There was a Reprinted with permission from Elsevier [33]. significant improvement in sleep quality Median GERD-HRQL composite scores
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doi: 10.1586/17474124.2015.1039986
Expert Rev. Gastroenterol. Hepatol.
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Novel surgical options for GERD
In an open-label trial, 37 GERD patients with partial response to PPI were implanted with a similar system. Stimulation was initiated at 20 Hz, 220 ms, 5 mA in 12 30-min 12 sessions. Data from 29 patients who completed their 6-month visit, and 19 their 12-month visit, were analyzed [35]. There was a significant improvement in both GERDHRQL and esophageal acid exposure at both 6 and 12 months. There was also a significant improvement in sleep quality and work productivity. At 12 months, 79% of patients were completely off PPI. There was one serious adverse event, a trocar perforation of the small bowel during laparoscopy. Four subjects, all of whom underwent a hiatal hernia closure, reported transient dysphagia that resolved without intervention. While a larger number of implanted patients, and longer follow-up are needed to determine long-term safety, data from gastric electrical stimulation for gastroparesis, an intervention that uses comparable technique, indicate that such intervention has a very good safety profile [36]. The mechanisms of action of LESEST are not fully elucidated, and enhancement of LES tone, observed primarily in acute and short-term studies, may only partially explain the beneficial effect of this intervention. Other mechanisms, affecting such pathophysiological aspects of GERD as transient LES relaxation or gastroesophageal compliance remain to be explored. Expert commentary
The increased prevalence of GERD, and the concomitant decline in the number of fundoplication procedures have resulted in an unmet therapeutic need, driving a search for alternative intervention for GERD. Both the MSA device and LES-EST were developed to fill such need. Short to medium follow-up of treated patients shows both interventions informahealthcare.com
Median % 24-h distal esophageal PH
Review
Novel surgical options for gastroesophageal reflux disease Expert Rev. Gastroenterol. Hepatol. Early online, 1–9 (2015)
Jenny Chiu and Edy Soffer* Department of Medicine, Keck School of Medicine, University of Southern California, 1520 San Pablo Street, Los Angeles, CA 90033, USA *Author for correspondence: Fax: +1 323 442 5625 [email protected]
There are limited options to patients with gastroesophageal reflux disease (GERD) who are not satisfied with acid suppression therapy. Fundoplication, the standard surgical procedure for GERD, is effective but is associated with adverse side effects and has thus been performed less frequently, creating a need for alternative surgical interventions that are effective, yet less invasive and reversible. Lately, two such interventions were developed: the magnetic sphincter augmentation and electrical stimulation of the lower esophageal sphincter. Human studies describing safety and efficacy over a follow-up period of a number of years have been published, documenting efficacy and safety of these interventions. Future studies should clarify the role of these procedures in the spectrum of GERD therapy. KEYWORDS: electrical stimulation . gastroesophageal reflux disease . lower esophageal sphincter . magnetic sphincter augmentation . Nissen fundoplication
Gastroesophageal reflux disease (GERD) is among the most common gastrointestinal disorders. It affects up to 30% of the population in developed countries, with increased prevalence in other geographic areas [1,2]. GERD negatively impacts quality of life [3], particularly when it occurs at night [4]. GERD is one of the main risk factors for adenocarcinoma, which is nearly five- to seven-times as common in individuals with chronic GERD symptoms compared with those without GERD [5]. Intestinal metaplasia of the esophagus (Barrett’s esophagus) is a premalignant lesion and a precursor of esophageal adenocarcinoma. Barrett’s esophagus is most often diagnosed in people with long-term GERD. GERD remains a risk factor for the development of Barrett’s esophagus [6], and the incidence of Barrett’s esophagus is rising [7], along with the increased incidence of esophageal adenocarcinoma worldwide, but particularly in industrialized countries [8]. Lifestyle changes, such as avoiding triggerfoods, eating smaller meals, raising the head of the bed and acid suppression with H2 blocker agents were shown to have variable and minimal effectiveness in improving GERD symptoms [9]. Consequently, acid suppression therapy with proton pump inhibitors (PPIs) has been the mainstay of medical therapy for
informahealthcare.com
10.1586/17474124.2015.1039986
GERD. While such therapy has proven to be remarkably effective and safe, a substantial number of patients report continued symptoms despite adequate therapeutic regimens [10]. A number of reasons are thought to contribute to incomplete response, an important one being that acid suppression affects the acidic content of the refluxate but not reflux itself [11]. This is supported by the importance of regurgitation as a factor responsible for partial response to PPI therapy [12]. In fact, a substantial number of patients undergoing antireflux surgery report a lack of control of GERD symptoms with medications as the reason for choosing surgery [13,14]. PPI use has been reported to be associated with adverse effects such as decreased calcium absorption, osteoporosis, community acquired pneumonia, Clostridium difficile infection, small intestinal bacterial overgrowth, vitamin B12 deficiency and drug interactions [15]. However, conclusive data demonstrating clear causality between PPIs and such adverse effects are, for the most part, quite limited. Given their efficacy, current guidelines do not recommend discontinuing or avoiding PPIs in these settings [16]. However, these potential factors may influence the choice for alternative therapies. Fundoplication, the standard antireflux surgery, has
2015 Informa UK Ltd
ISSN 1747-4124
1
Review
Chiu & Soffer
A Diaphragm Esophagus Closed position
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 06/17/15 For personal use only.
Titanium case Magnetic device in closed position
Magnetic core
Stomach Titanium arm
B
Open position Bolus
Magnetic device in open position
Figure 1. Magnetic device for augmentation of the lower esophageal sphincter. Panel (A) shows the magnetic device in the closed position, which helps prevent opening of the lower esophageal sphincter and subsequent reflux. Each magnetic bead rests on adjacent beads to prevent esophageal compression. Panel (B) shows the device in the open position, which allows transport of food, belching and vomiting. Reprinted with permission from Massachusetts Medical Society [24].
failed due to lack of efficacy or complications [20]. Recently, two surgical interventions for GERD were developed as an alternative to the traditional fundoplication, the magnetic sphincter augmentation (MSA) and lower esophageal sphincter electrical stimulation therapy (LES-EST), and are the subject of this review. Laparoscopic MSA
Laparoscopic MSA or LINX Reflux Management System (Torax Medical, St. Paul, MN, USA) is composed of a series of titanium beads with magnetic cores within each bead. The beads are interlinked with titanium wires to form a flexible and expandable ring where each bead is able to move independently. This freemoving apparatus was designed to allow for a physiological mechanism to parallel the movements of the LES. Thus, the ring transiently opens to allow passage of a food bolus, permits belching and vomiting and approximates to its closed position at rest to prevent the upward migration of gastric contents. The beads range in number from 10 to 18 beads, so as to accommodate variations in size, and the device is placed laparoscopically under general anesthesia (FIGURE 1). The procedure is reported to take about half an hour, and most patients are discharged on a regular diet on the same day or the following day [21]. The US FDA approved the use of the device for the treatment of GERD in March 2012. Animal study
been the primary alternative to patients who are unsatisfied with pharmacological therapy because of poor symptoms control, cost or concerns about long-term safety of PPI. Antireflux surgery provides an effective control of GERD but is associated with adverse effects, such as gas-bloat, flatulence and dysphagia, and requires revision in a small percentage of subjects [17]. Perhaps as a result, the number of fundoplication procedures performed in the USA has been declining [18]. The resulting unmet need of patients, who are not satisfied with medical therapy and the traditional surgical approach, has prompted a search for alternative treatment modalities, both endoscopic and surgical. A desirable alternative should be effective yet: be less disruptive and have less adverse effects than that of a fundoplication and be truly reversible [19]. Various endoluminal procedures for GERD were developed over the years, but most doi: 10.1586/17474124.2015.1039986
Both ex vivo and chronic in vivo studies were conducted in a pig model to assess the function of the system. Studies on isolated pig stomachs were performed to determine gastric yield pressures, that is, the gastric pressure that can overcome and open the augmented lower esophageal sphincter. This was followed by a chronic, 20–44 weeks study in a pig model in which the function and competence of the implanted magnetic ring was tested during balloon distension and barium studies [22]. Upper endoscopy performed after the implantation revealed normal mucosa with no erosions or defects. Barium swallow test demonstrated separation of the beads with food and liquid boluses. Upon necropsy, all magnetic devices were encapsulated in fibrous tissue and confined to the adventitia without any migration or erosion into the lumen. On histology, there was minimal inflammation in the fibrous tissue and no inflammation was seen in the muscle Expert Rev. Gastroenterol. Hepatol.
Novel surgical options for GERD
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Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 06/17/15 For personal use only.
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Figure 2. Quality of life with gastroesophageal reflux disease. Panel (A) shows the median total score from the Gastroesophageal Reflux Disease-Health-Related Quality-of-Life Scale (the main component of the scale is heartburn) measured at baseline without and with proton pump inhibitors, as compared with 3 years after implantation, without proton pump inhibitors. Total scores range from 0 to 50, with higher scores indicating worse symptoms. There was significant improvement in the median score after implantation for all years, as compared with baseline assessments both without and with proton pump inhibitors (p < 0.005 for the three comparisons, by the Wilcoxon signed-rank test). Panel (B) shows the percentage of patients who reported being satisfied, neutral (neither satisfied nor dissatisfied), or dissatisfied with respect to their present condition, as assessed by means of the Gastroesophageal Reflux Disease-HealthRelated Quality-of-Life Scale at baseline with proton pump inhibitors and at 3 years after implantation and without proton pump inhibitors. There was significant improvement in the satisfaction level for all 3 years (p < 0.001 for the comparison of patients who were satisfied versus those who were not satisfied or who had a neutral response). Reprinted with permission from Massachusetts Medical Society [24].
layers. These animal results were followed by evaluation of the concept in humans. Human studies Feasibility study
The LINX device was laparoscopically implanted in 44 GERD patients, enrolled in a multicenter trial. All had heartburn as the main symptom, persisting while on acid suppression therapy and documented excessive esophageal acid exposure. Those with a hiatal hernia >3 cm, greater than Los Angeles Classification grade B esophagitis and abnormal esophageal contractile function were excluded [23]. At 2 years, there was a significant improvement in GERD-health-related quality-of-life questionnaire (HRQL) and esophageal acid exposure. Of the 20 patients who had a repeat esophageal pH test, 90% had a normal study, and 86% of the patients were completely off PPI therapy. Mild dysphagia was reported by 43% of patients and resolved by 3 months, except for one patient who underwent an explantation at 8 months because of persistent dysphagia. Chronic studies
The positive results from the feasibility study led to a multicenter, open-label, uncontrolled pivotal trial that included 100 patients and was conducted in 13 centers in the USA [24]. Inclusion and exclusion criteria were similar to those in the feasibility trial. Patients had a history of GERD of at least 6 months with a partial response to daily PPIs and increased esophageal informahealthcare.com
acid exposure confirmed by pH monitoring. Exclusion criteria included evidence of a large hiatal hernia, esophagitis of grade C or D by the Los Angeles classification, BMI > 35, Barrett’s esophagus and motility disorder of the esophagus. Primary and secondary outcomes were assessed at 1 year post-implant and follow-up data at 3 years were provided. There was a significant improvement in esophageal acid exposure and quality of life at 1 year that was sustained over the period of follow-up (FIGURE 2) and in other variables (FIGURE 3). Dysphagia was the most common adverse event, reported by 68% of patients (FIGURE 3), of whom 19 patients underwent esophageal dilation. Removal of the device was required in six patients; in three because of persistent dysphagia, and in the other three because of persistent nausea, reflux or chest pain each. Three of these six patients subsequently underwent Nissen fundoplication, with no complications. A longer follow-up was provided by Bonavina et al. [25]. One hundred patients with GERD were implanted in a single center, and were followed for a median of 3 years, with 30 patients completing 6 years of follow-up. There was a significant improvement in symptoms and in esophageal acid exposure. The device had to be explanted in three subjects because of persistent GERD, dysphagia or odynophagia. Nissen fundoplication compared with MSA
A comparison between the two interventions was evaluated in both single and multicenter studies. A single institution, retrospective study compared all LINX procedures performed in the doi: 10.1586/17474124.2015.1039986
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A Proton-pump-inhibitor use 100
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Figure 3. Proton pump inhibitor use, reflux symptoms, dysphagia and esophagitis over the 3-year period. Panel (A) shows the percentage of patients reporting any use of proton pump inhibitors before and after implantation. At 3 years, 87% of the patients reported complete cessation of proton pump inhibitors (p < 0.001 for all years, for the comparison of daily use with no use). Panel (B) shows the assessment of regurgitation symptoms, according to the Foregut Symptom Questionnaire. Patients rated the severity of regurgitation before and after treatment. Results are displayed as the percentage of patients reporting mild, moderate or severe regurgitation (p < 0.001 for improvement in all grades of severity, for all years). Panel (C) shows the percentage of patients reporting dysphagia at follow-up visits as well as the severity of the dysphagia. Any report of dysphagia after implantation was recorded as an adverse event. Panel (D) shows the percentage of patients with esophagitis, according to grade, before and after implantation (p < 0.001 for any esophagitis vs none at both 1 and 2 years). Grading on the Los Angeles classification for esophagitis is as follows: grade A indicates one or more mucosal breaks of 5 mm or less in length, grade B one or more mucosal breaks of more than 5 mm, grade C mucosal breaks that extend between two or more mucosal folds but involve less than 75% of the circumference of the esophagus, and grade D mucosal breaks of 75% or more of the circumference. Reprinted with permission from Massachusetts Medical Society [24].
course of 1 year (n = 12) with a matched group of patients who underwent a laparoscopic Nissen fundoplication (n = 12) [26]. The patients were matched for age, gender, hiatal hernia size and BMI. Perioperative outcomes, hospital length of stay, 30-day morbidity and mortality were similar in both groups. Operation time was shorter in the MSA device group (64 vs 90 min; p < 0.001). With an average follow-up time of 7 months, 75% of MSA and 83% of fundoplication patients reported resolution of their GERD symptoms post-surgery (p = 0.99). Symptoms were classified as heartburn, regurgitation or atypical, (which included laryngopharyngeal or doi: 10.1586/17474124.2015.1039986
pulmonary symptoms) and the primary presenting symptom was recorded, respectively. Improvement in the primary symptom (not defined) was comparable between the groups. More patients in the fundoplication group complained of bloating, flatulence and diarrhea (0 vs 33%). Dysphagia was common, with 83% of LINX and 58% of Nissen patients reporting some degree of dysphagia postoperatively. However, dysphagia following Nissen occurred within the first 30 days postoperatively, and resolved in all patients with expectant management. In contrast, dysphagia following the LINX procedure occurred after the first 7 days Expert Rev. Gastroenterol. Hepatol.
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Novel surgical options for GERD
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postoperatively, and once it occurred it Pre-stimulation Stimulation Post-stimulation was more persistent and severe. Endoscopic dilation was required in WS WS WS 50% of LINX patients versus 0% in the Nissen group (p = 0.01), and successfully resolved dysphagia in all but one patient. A prospective, multicenter trial evaluated 202 MSA and 47 laparoscopic fundoplication patients who had completed 1-year follow-up [27]. Most patients chose Sleeve surgery because of incomplete control of symptoms with PPI. Most outcome varia50 mm Hg bles showed comparable improvement, Gastric although the MAS group reported better 10 sec control of regurgitation and greater number of patients discontinuing PPIs. BloatFigure 4. The effect on esophageal and LES function of stimulation with pulses ing and inability to vomit were more of 200 ms, and 5 mA in one of the subjects. The three channels above the sleeve commonly reported by the fundoplicarepresent recording from the esophageal body, at 1, 6 and 11 cm above the sleeve. A stimulation-induced increase in resting LES pressure is observed at mid stimulation and tion group (31.9 vs 10.0 and 44.4 vs after the stimulus is stopped. 91.3, respectively), while dysphagia was LES: Lower esophageal sphincter; WS: Wet swallow. comparable between the two groups. The Reprinted with permission from John Wiley and Sons [31]. rate of reoperation was 4.0% in the MSA group and 6.4% in the fundoplication one, although the reasons differed. Reoperations in the MSA rise in pressure in both groups of animals. Pressure remained group were performed for device removal due to dysphagia, elevated for a number of hours when two pairs of electrodes pain or persistent GERD, while in the fundoplication group were used [29]. In an acute study in anesthetized dogs, were for persistent GERD and herniation of the fundic wrap. Clarke et al. used microstimulators implanted endoscopically in Importantly, pre-surgical hiatal hernia >3 cm were present in the LES, to deliver electrical current to the muscle. They 1.6% in the MSA group compared with 45.7% in the fundo- observed that constant stimulation with pulses of 200 ms at a plication group, and more patients in the fundoplication had frequency of 20 Hz increased LES pressure, but only at currents that exceeded 8 mA [30]. In a chronic canine model, Barrett’s esophagus (19.1 vs 1.0%, respectively). Sanmiguel et al. implanted a pair of electrodes in the LES and studies were done in awake animals. Using a variety of pulse Safety/adverse effects A recent study reviewed the overall safety profile of MSA devi- parameters, they found that stimulation with 375 ms pulses, of ces in the first 1000 patients to have them implanted [28]. Over 5 mA at 6 c.p.m. increased LES pressure [31]. The studies also 1000 patients have been implanted with the MSA device at showed that the rise in LES pressure did not occur at the start 82 institutions from 2007 to 2013 with a median implant of stimulation, but showed a delayed onset and extended duration of 274 days; 0.1% intra- and perioperative complica- beyond the end of stimulation. The results of these studies sugtions, 1.3% hospital readmissions, 5.6% endoscopic dilations gested that electrical stimulation of the LES may be used to and 3.4% reoperations for device removal have been reported. treat GERD and paved the way to the application of such All removals were done through a laparoscopic approach, with- modality in humans. out conversion to laparotomy or described complications. One patient had erosion of the device into his esophagus (0.1%). Acute human studies of LES-EST Most common reason for removal was secondary to symptoms Two studies were conducted as a proof of concept, to evaluate the effect of EST on LES pressure. The first study included of dysphagia. 10 patients with GERD symptoms and documented abnormal esophageal acid exposure, scheduled to undergo an elective lapElectrical stimulation of the LES (LES-EST) aroscopic cholecystectomy. At the end of the procedure, two Animal models A number of studies in animals showed that electrical stimula- electrodes were implanted at each side of the LES and the lead tion of the LES can increase resting LES pressure. In an early was then exteriorized through the abdominal wall in the left study, Ellis et al. implanted one or two pairs of electrodes in upper quadrant. Following recovery, they underwent a series of the LES in normal dogs, and animals in which the gastroesoph- intermittent stimulation with various pulse parameters, lasting ageal junction was rendered incompetent by myotomy and cre- 30 min each, given while having concomitant esophageal ation of a hiatal hernia. Stimulation with square wave pulses of manometry [32]. There was a consistent and significant increase 3 ms, at 4 V and frequency of 20 Hz, induced a significant in LES pressure with both high frequency stimulation (pulse informahealthcare.com
doi: 10.1586/17474124.2015.1039986
Chiu & Soffer
width of 200 ms, frequency of 20 Hz and current of 5–15 mA, and low frequency stimulation (pulse width of 375 ms, frequency of 6 c.p.m. and current of 5 mA). The rise in pressure was observed after about 10 min following the start of stimulation, and was sustained beyond the end of stimulation (FIGURE 4). In most patients, the enhanced pressure was sustained for at least 2 h after cessation of stimulation, and up to a few hours in a few patients. There was no effect on LES relaxation in response to swallows, and none of the patients complained of dysphagia. In a second study, five patients with GERD were fitted with temporary electrodes placed endoscopically in the LES submucosa and stimulation was delivered 6–12 h post-implant. Comparable to the first study, high frequency electrical stimulation of the LES (20 Hz, duration of 200 ms or 3 ms) resulted in consistent and significant increase in LES pressure, with delayed onset of 5–10 min that was sustained after the end of stimulation. Stimulation had no effect on swallow-induced LES relaxation, and no patients complained of dysphagia [33]. The results of these studies prompted further assessment of this technology in GERD patients. Figure 5. Schematic of the EndoStim System implant in a patient. Electrode position and IPG implant location. Bipolar stitch electrodes are placed in the abdominal esophagus anteriorly in an inline configuration 1 cm apart. The lead is connected to the IPG that is implanted in the subcutaneous pocket in the anterior abdomen. Reprinted with permission from Elsevier [33].
Chronic human studies Single-center study
Twenty-five patients were implanted with the EndoStim LES Stimulation System (Endostim BV, The Hague, The Netherlands), in an open-label study performed in a single center. Data analysis was performed on 21 patients who completed the 2-year evaluation [34]. Inclusion/exclusion criteria in all studies of LES electrical stimulation were comparable to those described in the MSA studies. All patients had chronic GERD with only 30 23.5 partial response to PPI therapy, and 21.0–25.3 abnormal esophageal acid exposure. n = 24 25 Patients with a hiatal hernia >3 cm, and Los Angeles grade D esophagitis were excluded. Bipolar stitch electrodes were 20 implanted in the muscular layer of the LES, and connected to a pulse generator 15 implanted in a subcutaneous pocket in 9.0 the left upper quadrant of the 6.0–10.0 abdomen (FIGURE 5). No hiatal repair was n = 24 10 performed in any patient. The system delivers stimulation at a frequency of 2.0* 20 Hz, pulse width of 215 ms, 3–8 mA 5 0–3.0 0.0* at 30-min sessions, 6–12 sessions a day. n = 23 0–3.0 At 2 years, there was a significant n = 21 0 improvement in GERD-HRQL (FIGURE 6) Baseline Baseline Month 12 Month 24 and in esophageal acid exposure (FIGURE 7) on PPI off PPI on EST on EST with 71% demonstrating either normalization or at least 50% reduction in Figure 6. Change in median (IQR) GERD-HRQL composite scores on LES-EST comesophageal acid exposure. Seventy-six perpared with baseline on- and off-PPI GERD-HRQL composite scores (*p < 0.05). LES-EST: Lower esophageal sphincter electrical stimulation; GERD-HRQL: Gastroesophageal cent of patients reported complete cessareflux disease-health-related quality of life; PPI: Proton pump inhibitor. tion of PPI use (FIGURE 8). There was a Reprinted with permission from Elsevier [33]. significant improvement in sleep quality Median GERD-HRQL composite scores
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Novel surgical options for GERD
In an open-label trial, 37 GERD patients with partial response to PPI were implanted with a similar system. Stimulation was initiated at 20 Hz, 220 ms, 5 mA in 12 30-min 12 sessions. Data from 29 patients who completed their 6-month visit, and 19 their 12-month visit, were analyzed [35]. There was a significant improvement in both GERDHRQL and esophageal acid exposure at both 6 and 12 months. There was also a significant improvement in sleep quality and work productivity. At 12 months, 79% of patients were completely off PPI. There was one serious adverse event, a trocar perforation of the small bowel during laparoscopy. Four subjects, all of whom underwent a hiatal hernia closure, reported transient dysphagia that resolved without intervention. While a larger number of implanted patients, and longer follow-up are needed to determine long-term safety, data from gastric electrical stimulation for gastroparesis, an intervention that uses comparable technique, indicate that such intervention has a very good safety profile [36]. The mechanisms of action of LESEST are not fully elucidated, and enhancement of LES tone, observed primarily in acute and short-term studies, may only partially explain the beneficial effect of this intervention. Other mechanisms, affecting such pathophysiological aspects of GERD as transient LES relaxation or gastroesophageal compliance remain to be explored. Expert commentary
The increased prevalence of GERD, and the concomitant decline in the number of fundoplication procedures have resulted in an unmet therapeutic need, driving a search for alternative intervention for GERD. Both the MSA device and LES-EST were developed to fill such need. Short to medium follow-up of treated patients shows both interventions informahealthcare.com
Median % 24-h distal esophageal PH
