Recent Advances in Endoscopic Antireflux Techniques




Heartburn is the most common symptom associated with gastroesophageal reflux disease, and life-long proton pump inhibitor therapy is often required to control symptoms. Antireflux surgery is an alternative, but there may be significant side effects and the duration of therapeutic effect is variable. Several endoscopic antireflux techniques (E-ARTs) have been developed to enhance the function of the lower esophageal sphincter or alter the structure of the angle of His with the goal of recreating or augmenting the reflux barrier. Many methods are no longer available, and some await regulatory approval. This article reviews available data for the most common E-ARTs.


Gastroesophageal reflux disease


Gastroesophageal reflux disease (GERD) has been defined as a condition that develops when reflux of stomach contents causes troublesome symptoms or complications. The physiologic antireflux barrier is dependent on many factors, including lower esophageal sphincter (LES) complex, anatomy of the angle of His, and gastric distension. Pathologic reflux is associated with a decrease in LES pressure or obliteration of the angle of His. The characteristic symptoms of GERD are retrosternal burning (pyrosis) and regurgitation. GERD is common, but its prevalence varies geographically. The prevalence of heartburn in a randomly selected adult population is approximately 10% to 20% in North America and Western Europe. Esophageal erosions (reflux esophagitis) are the most common structural manifestations of the esophageal exposure to gastric acid. In a large study, including 194,527 patients with GERD, 45.4% had erosive esophagitis. Other less common complications of GERD include ulceration (6.0%) or stricture formation (8.4%). Barrett’s esophagus can arise secondary to GERD, and esophageal intestinal metaplasia is the most important risk factor for esophageal adenocarcinoma. A study by Lagergren and colleagues demonstrated that risk of esophageal adenocarcinoma is increased for patients with GERD by an odds ratio of 7.7.




Medical therapy


Medical management of GERD using proton pump inhibitor (PPI) therapy is largely effective and considered standard therapy in treating symptoms and healing esophagitis. A recent meta-analysis included 134 trials involving 35,978 patients and evaluated outcomes for treatment of esophagitis. Five randomized controlled trials (RCTs) demonstrated a significant benefit from standard-dose PPI therapy compared with placebo. Ten RCTs reported a statistically significant benefit from H2-receptor antagonist (H2RA) compared with placebo. Three RCTs did not reveal any benefit from prokinetic therapy compared with placebo. Twenty six RCTs found PPIs superior to H2RA or H2RA plus prokinetics. These acid-suppressing medications, although effective in controlling common reflux symptoms in the majority of patients with GERD, are often required indefinitely and can occasionally be associated with intolerable side effects and persistence of nonacid regurgitation.




Medical therapy


Medical management of GERD using proton pump inhibitor (PPI) therapy is largely effective and considered standard therapy in treating symptoms and healing esophagitis. A recent meta-analysis included 134 trials involving 35,978 patients and evaluated outcomes for treatment of esophagitis. Five randomized controlled trials (RCTs) demonstrated a significant benefit from standard-dose PPI therapy compared with placebo. Ten RCTs reported a statistically significant benefit from H2-receptor antagonist (H2RA) compared with placebo. Three RCTs did not reveal any benefit from prokinetic therapy compared with placebo. Twenty six RCTs found PPIs superior to H2RA or H2RA plus prokinetics. These acid-suppressing medications, although effective in controlling common reflux symptoms in the majority of patients with GERD, are often required indefinitely and can occasionally be associated with intolerable side effects and persistence of nonacid regurgitation.




Interventional therapy


Interventional therapies for GERD include surgical or endoscopic techniques. All interventional therapies need to consider the pathophysiology of GERD and the anatomy of the gastroesophageal (GE) junction. Interventional therapy, therefore, should aim to alter the GE junction anatomy to prevent transient LES relaxation, increase baseline LES tone, or increase baseline LES length.




Patient pretherapeutic assessment


Response rates of up to 50% have been reported for GERD with placebo therapy. As such, meticulous pre- and post-therapeutic assessment, which allows for objective measurement of GERD, is essential. An upper gastrointestinal endoscopy should be performed at baseline before endoscopic therapy for GERD to determine presence and size of a hiatal hernia, grade the degree of esophagitis, and determine if contraindications to endoscopic therapy are present. In patients with hiatal hernias greater than 3 cm, surgical treatment is recommended and preferred over endoscopic therapy. Most initial studies investigating endoscopic antireflux therapies excluded patients with grade IV esophagitis, Barrett’s epithelium, persistent dysphagia, or esophageal strictures.


Successful outcome of antireflux surgery can be predicted by an abnormal 24-hour pH test, the presence of typical reflux symptoms, and a favorable response to acid suppression therapy. Accordingly, patients being considered for endoscopic antireflux therapy should have symptomatic relief from PPI therapy and pathologic acid exposure defined as having distal esophageal pH less than 4.0 for at least 4.5% of a 24- or 48-hour monitoring period or a DeMeester score greater than or equal to 14.7. A limitation of traditional pH monitoring is that only reflux episodes with a pH drop below 4 are detected. Symptomatic nonacidic reflux or regurgitation of gastric contents neutralized by food or antisecretory therapy cannot be detected by this technique. Because the pH probe measures acid concentration regularly at a single pH sensor, it also cannot determine bolus volume, transit, or composition or localize the reflux within the esophagus. Multichannel intraluminal impedance monitoring (MII) is a relatively novel method, which addresses these limitations by reporting esophageal bolus transit in addition to pH data. Detection of nonacid or weakly acidic reflux events, aerophagia, and differentiation of true reflux events from nonreflux events (acidic or nonacidic swallows) is possible with MII monitoring. MII assessment before and after endoscopic antireflux therapy seems ideal to document objective changes in reflux events. Recent studies have shown MII a useful tool in selecting patients for antireflux surgery. Patients with a positive symptom index resistant to PPIs with nonacid or acid reflux demonstrated by MII monitoring proved good candidates for laparoscopic Nissen fundoplication.




Surgical therapy


As a therapeutic alternative to PPI treatment, laparoscopic Nissen fundoplication is considered safe and effective, especially for patients with significantly sized hiatal hernias. A recent meta-analysis, including 12 RCTs, compared laparoscopic and open antireflux surgery for the treatment of proved GERD. The meta-analysis demonstrated a significant reduction in the duration of hospital stay (2.68 days) and a significant reduction in time for return to normal activity (7.75 days), favoring the laparoscopic group. There was a statistically significant reduction of 65% in the relative odds of complication rates for the laparoscopic group. Treatment failure rates were comparable between both groups. On the basis of this meta-analysis, the investigators concluded that laparoscopic treatment is as effective but safer than open surgical treatment for GERD. Both surgical approaches are associated with significant complications and side effects, and a significant minority of patients undergoing fundoplication may need to return to medication use to control symptoms over time.




Endoscopic antireflux techniques


Several endoscopic antireflux procedures have been evaluated for the treatment of GERD. These techniques ( Table 1 ) include the injection or implantation of biopolymers, the application of radiofrequency energy to the LES, and endoluminal suturing/plication. Endoscopic treatment strategies currently target PPI-dependent GERD patients with small (<3 cm) or absent hiatal hernias who do not have severe esophagitis or Barrett’s esophagus. Thus far, EndoCinch (BARD, Billerica, Massachusetts), Enteryx (Boston Scientific, Natick, Massachusetts), Stretta (Curon Medical, Sunnyvale, California), and the Plicator (NDO Surgical, Mansfield, Massachusetts) have been studied in sham-controlled trials (see Table 1 ).



Table 1

Endoscopic antireflux techniques


























Injection or Implantation Thermal Energy Endoscopic Suturing, Plicating, or Stapling
Enteryx Stretta (radiofrequency ablation) Wilson-Cook ESD
Gatekeeper EndoCinch
Durasphere Plicator
EsophyX
Syntheon Anti-Reflux Device
His-Wiz antireflux device
Medigus SRS


Enteryx


Enteryx is a biocompatible polymer consisting of 8% ethylene vinyl alcohol mixed with tantalum powder that provided for radiographic opacification, in a solution of dimethyl sulfoxide. It is liquid before injection and becomes an inert spongy mass once injected into tissue. The procedure requires a special 4-mm, 23-gauge injector needle and the use of fluoroscopy. The standard procedure was placement of 1 mL or more of volume circumferentially around the GE junction until approximately 6 to 8 mL of Enteryx was implanted intramuscularly. The Enteryx procedure was repeatable if symptom control was inadequate but not reversible. Enteryx is no longer marketed or available for human clinical use.


An international multicenter study of 85 patients treated with Enteryx demonstrated cessation of PPI use in 74% of treated subjects at 6 months and, at 12-month follow-up, 70% of these subjects had significant improvements in objective measure of acid reflux (pH scores). pH normalization was encountered in 38.8% of patients at 12 months and the LES was approximately 1 cm longer after therapy. In the treated cohort, there was no effect on the incidence or severity of esophagitis after treatment. The GERD– health-related quality-of-life (HRQL) scores after Enteryx were comparable with those obtained on antisecretory medications. Complications included chest pain (92%) that resolved within l4 days in 83% of affected individuals and dysphagia (20%) that resolved within 2 to 12 weeks. There was one death related to Enteryx injection into the aortic wall that led to withdrawal of the device from the market.


Gatekeeper


The Gatekeeper Reflux Repair System (Medtronic, Minneapolis, Minnesota) restricts the diameter of the distal esophagus by submucosal implantation of a polyacrylonitrile-based hydrogel prosthesis. The device consists of a 16-mm overtube-type instrument through which a standard or pediatric-sized videogastroscope was passed, to monitor the procedure. Suction was used to draw mucosal tissue into multiple, shallow holes in the distal part of the Gatekeeper instrument and to place the hydrogel prostheses submucosally. A 1-mm diameter flexible endoscopic injector needle and a 1-mm trocar needle catheter were used through another channel in the overtube to prepare the submucosal region for implantation of the prosthesis. Usually, four to six implants were placed in a radial fashion during one treatment session. This implantation technique was repeatable and reversible.


A pilot study included 10 GERD patients and demonstrated successful implant placement in 97% of attempts. The procedures improved reflux symptom scores at 1 and 6 months’ follow-up. Four of 9 patients stopped their acid-suppressing medicines, whereas three reduced their PPI dosage by at least 50%. Pooled data from two prospective nonrandomized trials reported data for 68 patients treated with this method. At 6 months, time with pH less than 4 improved from 9.1% to 6.1% (n = 45, P <.05), LES pressure was slightly higher, and GERD-HRQL scores went from 24 to 5 ( P <.01). Two adverse events occurred: one patient suffered a pharyngeal perforation, and severe postprandial nausea was reported in another patient that resolved after endoscopic removal of the prostheses. An international, multicenter, sham-controlled trial was started for this device but was subsequently cancelled before completion, and the device is no longer available.


Durasphere


Durasphere (Carbon Medical Technologies, St Paul, Minnesota) is a Food and Drug Administration–approved injectable agent that has been used to treat urinary incontinence since 1999. It consists of carbon-coated beads ranging from 90 to 212 μm suspended in a water-based gel. The particles were specifically designed to prevent migration and are inert. This agent was recently used to treat 10 patients with objectively proved GERD on PPI therapy. The substance was injected submucosally at the Z-line in four quadrants using a standard endoscopic sclerotherapy needle. The patients were followed for 12 months and five of them were retreated within 90 days for poor symptom control. At the end of the study, the patients were found to have a significant reduction in DeMeester scores from 44.5 to 26.5. Four of the 9 patients followed had normal pH testing. The material and bulk effect was still in place at endoscopy 1 year later and adverse events, such as substernal pain and difficulty belching, were minor and transient. Further data are needed, including a randomized, controlled trial, but these initial results demonstrate a straightforward, safe technique with measurable symptom improvement.




Radiofrequency ablation


The Stretta System delivers low-power, temperature-controlled radiofrequency energy to the GE junction. The system consists of a special 20-French, balloon-basket, single-use catheter with four radially distributed, curved, 25-gauge, 5.5-mm long, nickel-titanium needles. Each needle is equipped with dual thermocouple temperature sensors to maintain consistent energy delivery to the muscular layer. Ports in the catheter provide cold-water irrigation during the procedure to reduce mucosal heating and prevent surface tissue injury. The radiofrequency generator is a computerized control module unit that delivers the radiofrequency energy to the needle electrodes. The target temperature for tissue thermal treatment was 85 °C. The full Stretta procedure involves applying thermal radiofrequency treatment in four antegrade rings that straddle the GE junction from 1 cm above to just beneath the squamocolumnar junction in 0.5 cm increments. The irreversible procedure takes approximately 45 minutes.


A sham-controlled study of 64 GERD patients demonstrated Stretta treatment (performed in 35 patients) as superior to sham (in 29 patients) for control of heartburn symptoms and improvement in quality of life at 6 months after the intervention. Although there were more Stretta-treated than sham subjects who responded to the intervention (defined as >50% improvement in GERD quality-of-life score) at 6 months (61% vs 30%), and more treated than sham who were without daily heartburn symptoms at this follow-up interval (61% vs 33%), no differences in reduction of daily medication use were evident between the groups. There were also no differences in esophageal acid exposure times between the two groups at 6 months. The Stretta System is no longer marketed or available for human clinical use.




Suturing, plicating, or stapling devices


Wilson-Cook Endoscopic Suturing Device


The Endoscopic Suturing Device (ESD) (Cook Medical, Bloomington, Indiana) consists of an external accessory channel, a flexible Sew-Right device, and a flexible Ti-Knot device. The external accessory channel is attached to a flexible endoscope and provides the pathway for the Sew-Right and Ti-Knot devices. The flexible Sew-Right device is a dual-needle system that uses a single suture loop to create the tissue plication. The target tissue is aspirated into a suction chamber. A needle with suture is then passed through the tissue collected within the chamber. A continuous single suture loop is used to stitch two adjacent areas in the proximal stomach to form the plication. With the ESD, no repeated endoscope withdrawals are required to create the gastric plication. Typically, two or three plications are placed during a single treatment. The ESD is no longer marketed or available for human clinical use.


Studies revealed early loss of the sutures. At 6 months, only 5% of the sutures were found in situ. No significant changes in reflux esophagitis or 24-hour pH monitoring were observed at 6 months (median pH <4/24 h, 9.9% vs 12.3% [therapy vs baseline]; P = .60). LES sphincter pressure was unchanged (median LES pressure 7.2 mm Hg vs 9.9 mm Hg; P = .22). PPI use was not improved either. A second uncontrolled study confirmed the same poor outcomes mainly related to early loss of the sutures.


BARD EndoCinch


The EndoCinch suturing device is inserted via an overtube. A sewing capsule is attached to the distal tip of a standard videogastroscope and has a cavity into which a tissue fold can be suctioned. A handle is attached to the biopsy port of the endoscope and controls the advance of a hollow-core suturing needle. A treasury-tag (t-tag) is back-loaded into the hollow-bore needle and is captured into the tip of the capsule after being driven forward by a stiff wire pushed through the hollow needle. It can be reloaded and a second area of tissue can be captured. The two captured areas are drawn together to create a tissue plication. A catheter cuts the suture ends as it cinches together the tag components at the luminal surface. Stitches to form plications can be placed in a linear, circumferential, or helical fashion. Typically two or three plications are created at a treatment session.


A sham-controlled, randomized study available published as an abstract demonstrated improved heartburn frequency at 3 months’ post treatment for the EndoCinch group (69% vs 31%, P = .03). There was no significant difference in heartburn severity (81% vs 50%), regurgitation (53% vs 56%), or bothersome scores (75% vs 50%). More subjects in the gastric plication group discontinued their daily acid-suppressing medications compared with sham treatment (75% vs 25%; P = .01). No difference was found comparing use of acid-suppressive medications (56% vs 25%), however. Acid exposure significantly improved in the EndoCinch versus sham groups (pH difference: -4.0 vs +1.0; P = .03) but normalized only in two (12.5%) treated patients. The study did not detect a difference between treated and sham patients on LES pressure or quality-of-life measures.


An uncontrolled, single-center study, including 70 patients, demonstrated long-term treatment failure mainly due to suture loss. Eighteen months after treatment, 56 of 70 patients (80%) did not improve their heartburn symptoms or PPI medication use by greater than 50%. Endoscopy exhibited all sutures in situ in 12 of 70 (17%) patients and no remaining sutures in 18 of 70 (26%). In 54 and 50 patients examined, no significant changes in 24-hour pH monitoring (median pH <4/24 h, 9.1% vs 8.5%; P = .82) or LES pressure (7.7 vs 10.3 mm Hg; P = .051) were observed respectively, whereas median LES length increased slightly (3.0 to 3.2 cm; P <.05).


A second sham-controlled study demonstrated reduced acid-inhibitory drug use and improved GERD symptoms and improved the quality of life at 3 months compared with a sham procedure. No difference in reduction of esophageal acid exposure was seen after endoscopic treatment compared with sham procedure. Due to suture loss, the effects only persisted up to 12 months.


NDO Plicator


The NDO Plicator was designed to create a transmural full-thickness placation at the angle of His. The plication is formed with a pretied, suture-based implant. The Plicator can be advanced into the stomach over a Savary guide wire and is retroflexed for placement of the full-thickness sutures at the GE junction. Visualization is accomplished using a 5.9-mm flexible endoscope inserted through a dedicated channel in the instrument. This plicating device remodels the antireflux barrier at the angle of His by fashioning a pleat of full-thickness tissue and permitting serosa-to-serosa apposition. The components of the system include the plicator instrument, a tissue retracting helical catheter, and pretied pledgeted suture implants. The plicator has a handle with wheels for opening/closing the arms and sliding/locking the pretied suture implant. The total procedure time is approximately 10 to 20 minutes to form a single plication. Newer data suggest that placement of 2 to 3 implants may be preferable to optimally restructure the GE junction.


A sham-controlled trial randomly assigned 159 patients to plication (n = 78) or a sham procedure (n = 81). The percentage reduction in esophageal pH time less than 4 was significantly improved in the plication group (7% vs 10% compared with baseline) but not in the sham group (10% vs 9%). There were no perforations or deaths. Four patients required hospitalization for postprocedure pain and one required exploratory laparoscopy 3 months after the procedure for persistent abdominal pain. Recent studies have used serial implants to improve restructuring of the angle of His and demonstrated significant reductions in esophageal acid exposure, esophagitis, and PPI use at 6 and 12 months. The NDO device is no longer available on for commercial use.


EsophyX


EsophyX (EndoGastric Solutions, Redmond, Washington) is a large overtube device with an insertion channel for a videogastroscope. It also includes a bending section, or elbow, which can articulate and retroflex to reach and manipulate tissue at the angle of His. The system is designed to create a 270° circumferential endoscopic plication at the angle of His. The technique uses a helical retractor to engage and manipulate tissue at the fundus and to create the correct angle. After tissue grasping and fixation, double-sided t-tags can be passed through a double layer full-thickness plication. The method involves the placement of approximately 6 to 14 sutures to create a near circumferential gastroplication of 180° to 260°. The device can be used to reduce small hiatal hernias. EsophyX is Conformite Europeenne marked and available in Europe and recently received Food and Drug Administration clearance in the United States.


No randomized controlled data are reported to date. Early clinical experience assessed the degree of postprocedural valve tightness relative to the gastroscope and reported the valves as tightly adherent in 14 and moderately adherent in 3 of 17 cases. The hiatal hernias present in 13 of 17 patients were all reduced. Adverse events reported include mild-to-moderate pharyngeal irritation and epigastric pain, which all resolved spontaneously. At 12-month follow-up (n = 16), the valve length had a mean of 3 cm (range 1 to 4 cm) and circumference of 200° (150° to 210°). Eighty-one percent of the valves retained their tightness. The hiatal hernias, present in 76% of subjects initially, were now found in 38%. The median GERD-HRQL scores improved by 67% and 9 of 17 patients (82%) were still off their PPI medications, whereas normalization of the pH was seen in 63%. Recent 2-year data were published by the same group, which included 14 of the initial 19 patients. The long-term safety profile of the device is good, and it seems as though the restructured anatomy is durable when examined endoscopically. Among the patients treated, 29% were completely relieved of GERD, 60% of hiatal hernias were reduced, and esophagitis was eliminated in 55% of individuals. This data must be interpreted with caution because they are essentially all from a single center, and a single, small cohort of patients. The only North American study using this device is a retrospective report of eight patients who underwent the procedure. Half of the patients did not benefit from the procedure, and one patient had clear disruption of the sutures. Two patients were off PPIs and the other two were on reduced doses of the medication. Much further study is needed, including a prospective RCT.


Syntheon Anti-Reflux Device


Using this device, a titanium implant is delivered into the cardia to create a serosa-to-serosa apposition similar to the Plicator. The Anti-Reflux Device (Syntheon, Miami, FL) instrument differs from the Plicator in that the device can be passed alongside the endoscope and controlled independently. A catheter-based tissue retractor through the endoscope biopsy channel is used to pull the gastric wall into the jaws of the Anti-Reflux Device. The titanium implant is deployed as the jaws close, to create a full-thickness pleat. Results of a multicenter clinical trial have been published in abstract form. Seventy GERD patients were treated, and 57 had been followed for a minimum of 6 months at the time of abstract publication. GERD-HRQL improved by 50% or more in 79% of the subjects. At 6 months, 33 of 52 individuals (63%) stopped all antisecretory therapy. The implants were all found in place on follow-up endoscopy and one gastric perforation occurred requiring surgical repair. Despite superior engineering, the Anti-Reflux Device was not brought forward to commercialization.


The His-Wiz Antireflux Procedure


Another overtube-based endoscopic suturing machine, coined the His-Wiz (Apollo Group/Olympus Optical, Tokyo, Japan), allows for full-thickness suturing and cutting in a single step. Two plications are performed, one anterior and the other posterior, just below the Z-line. A small clinical trial of seven patients with 1-year follow-up is available in abstract form. Subjective (heartburn scores) and objective (pH testing) improvements were observed, but the effect seemed to deteriorate slowly over time. Based on these preliminary data, the durability and effectiveness of this procedure are still unknown, and the device has not been brought forward to commercialization.


The Medigus Endoscopy System


Few data are available regarding this novel device (Medigus SRS, Omer, Israel), which consists of an ultrasonic video endoscope and an integrated surgical stapler. The cartridge is mounted onto the shaft of the scope and the anvil is at the tip. B-shaped, 4.8-mm staples are fired under ultrasound guidance to create an anterior, full-thickness, 180° fundoplication. One Medigus-sponsored survival porcine study has been published to date using this device. Twelve animals successfully underwent the procedure and survived for 6 weeks. The mean procedure time was 12 minutes, and all of the fundoplications seemed to be in place at the end of the study. More data will be available from a recently initiated international human clinical trial using this highly refined technology.

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Sep 12, 2017 | Posted by in GASTOINESTINAL SURGERY | Comments Off on Recent Advances in Endoscopic Antireflux Techniques
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