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Background
Gastroesophageal reflux disease (GERD), also known as reflux esophagitis, is probably the most prevalent clinical condition that arises from the gastrointestinal (GI) tract. There are 2 principal factors involved in esophageal reflux: (i) the GI contents and (ii) the anti-reflux mechanism, which is comprised of the lower esophageal sphincter (LES) and the anatomic configuration of the gastroesophageal junction. Reflux occurs when the gradient between the LES pressure and the intra-gastric pressure is compromised as a result of a transient or sustained reduction in the former, or an elevation in the latter. Most patients with GERD have decreased LES pressures. However, some patients have normal LES pressures, but their sphincters relax inappropriately, thus resulting in refluxes.
The initial treatment of GERD is geared toward reducing esophageal refluxes. Antacids, H2-receptor antagonists, as well as dietary and lifestyle modifications have been used for such purposes. For patients who fail initial treatment, proton pump inhibitors (e.g., lansoprazole and omeprazole) should be tried. When these standard medical therapies fail, surgery may be considered.
Anti-reflux surgery is required in only 1 to 2 % of all patients with GERD. These procedures are designed to raise the pressure within the LES by wrapping a portion or all of the cardia stomach around the esophagus. With the advent of laparoscopic anti-reflux surgery, the 2 most common procedures are the Nissen fundoplication and the Toupet partial fundoplication. Dependent on the skill and experience of the operating surgeon, anti-reflux surgery has been reported to have an efficacy rate of 90 %. These operations are usually performed on the day of hospital admission and take about 90 mins. In general, patients are discharged from the hospital on the second post-operative day and can return to work in 7 to 10 days. Other surgical options include Belsey partial fundoplication as well as Collis gastroplasty combined with Belsey partial fundoplication. However, anti-reflux surgery can be associated with complications. The most common complications are dysphagia and an inability to belch or vomit, occurring in 4 to 11 % of patients.
The Food and Drug Adminsitration (FDA) cleared for marketing via a 510 (k) application minimally invasive devices for the treatment of refractory GERD including: (i) the Bard EndoCinch Suturing System (BESS), and (ii) the Stretta System. The BESS entails insertion of a thin, flexible endoscopic tube into the patient's esophagus. The end of the scope holds a tiny device, much like a miniature sewing machine, which places stitches in 2 different locations near the LES. The suturing material is then tied to effectively tighten the valve and prevent reflux. The procedure requires no incisions and usually no general anesthesia. It is performed on an outpatient basis, and patients usually can return to work the next day.
In March 2007, the FDA granted 510(k) premarketing clearance to the StomaphyX (EndoGastric Solutions, Inc.), an endoluminal fastener and delivery system used to tighten esophageal tissue. The FDA clearance indicated that the StomaphyX is substantially equivalent to EndoCinch. In September 2007, the FDA granted 510(k) premarketing clearance to the EsophyX System with SerosaFuse Fastenter (Endogastric Solutions, Inc.) as being substantially equivalent to the StomaphyX and EndoCinch devices. The EsophyX System is designed to perform a transoral incisionless fundoplication procedure using to reconstruct a valve at the gastro-esophageal junction through transoral delivery of multiple fasteners. Cadiere et al (2008) reported on the outcome of a short-term, uncontrolled study of the EsophyX system for treating GERD. A total of 86 patients with chronic GERD treated with proton pump inhibitors (PPIs) were enrolled. Exclusion criteria included an irreducible hiatal hernia greater than 2 cm. At 12 months, 73 % of study subjects had 50 % or greater improvement in GERD health-related quality of life scores, and 81 % of study subjects discontinued PPI use. However, less than half (37 %) of study subjects had normalization of esophageal acid exposure. Serious adverse events consisted of 2 esophageal perforations upon device insertion and 1 case of post-operative intraluminal bleeding. The investigators reported that other adverse events were mild and transient.
In a retrospective study, Bergman and co-workers (2008) examined the safety and effectiveness of the EsophyX system in patients with GERD who had undergone endolumenal fundoplication with the device. At follow-up, PPI usage was elicited and 2 validated questionnaires were administered measuring GERD health-related quality of life (range of 0 to 50) and symptom severity (range of 0 to 72). In limited preliminary evaluation, the initial North American experience with endolumenal fundoplication using the EsophyX device is that it appears to be safe and provides moderate effectiveness in treating the symptoms of GERD. Moreover, the authors stated that further studies comparing this technique with conventional medical and surgical therapies are necessary.
The Stretta System uses radiofrequency (RF) energy to treat GERD. The procedure involves insertion of a flexible catheter with needle electrodes for energy delivery down the patient’s esophagus (patient is conscious but sedated). Precisely controlled RF energy is delivered to create lesions in the muscle of the LES and gastric cardia. The resorption of these lesions over the following weeks creates a tighter LES and a less compliant cardia. The tighter valve is thought to provide significantly increased resistance to gastric reflux. The procedure takes approximately 1 hour or less. Patients undergoing the procedure can get back to normal activities the next day.
These minimally invasive devices are marketed to provide a treatment option to patients who have failed standard medical therapies, or individuals who decide against or could not afford drug therapy. However, there is insufficient scientific data to support the effectiveness of these devices. Well-designed studies are needed to show that these procedures reduce or eliminate the use of anti-GERD medications. Comparative studies with standard drug therapy and traditional surgical procedures may shed some light on the role these devices play in the treatment of GERD. Some of the issues that have to be addressed are (i) what are the long-term outcomes of these procedures, and (ii) do patients need retreatment, and if so, how often?
Triadafilopoulos and Utley (2001) reported that temperature-controlled endoluminal radiofrequency energy delivery (the Stretta procedure) has been demonstrated in several studies to be safe and effective for the treatment of GERD and is a promising new technology for this chronic disorder. In a recent review, Katz (2002) noted that 2 endoscopic procedures were recently approved by the FDA for treatment of GERD: radiofrequency energy delivery to the gastro-esophageal junction, and transoral flexible endoscopic suturing. The author concluded that these techniques should be used selectively until more data are available and until results are compared to the safe and highly effective medical therapies. This is in agreement with Koop (2002) who stated that a number of new endoscopic techniques for the treatment of GERD have been developed, but the future for these is unclear.
Galmiche and des Varannes (2003) reviewed the literature on endoluminal therapies for GERD, and reached the following conclusions about the Stretta procedure:
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Although some surgeons propose use of the Stretta procedure for patients with severe, refractory, or complicated GERD, clinical studies of the Stretta procedure have excluded these patients. "Virtually all trials of these new therapeutic approaches have enrolled PPI-dependent patients without severe esophagitis. Patients refractory to PPIs, those with hiatus hernia larger than 2 cm, those with severe esophagitis, as well as obese individuals, have usually been excluded from these trials".
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No studies have involved direct comparisons with other established medical or surgical therapies.
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Some concern has also been expressed about the potential impact of these procedures on definitive management of GERD. For instance, it is possible that previous endoscopic therapy might complicate or reduce the effectiveness of subsequent procedures.
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Some severe, although very rare, complications (including perforations) have been observed, especially during early experience with the Stretta procedure.
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Studies have been short-term; the long-term effectiveness of the procedure is unknown.
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Studies of radiofrequency catheterization (Stretta) have largely been uncontrolled.
- The only controlled study (Corley, 2002) of the Stretta procedure has been published in abstract form only, and has failed to confirm that the results of uncontrolled studies regarding significant reductions in acid exposure and symptom relief.
Gamiche and des Varannes (2003) concluded: "In our opinion, endoscopic treatment for GERD needs to be done in reference centers with highly skilled staff, and not outside the framework of well-designed prospective, and appropriately controlled studies. Comparative studies of the cost-effectiveness of endoscopic therapy should include medical strategies such as intermittent or on-demand PPI therapy. Assessment of relevant outcome measures, including economic endpoints and long-term efficacy, are required before these novel approaches are used in routine practice."
Another published evidence review (Hochberger et al, 2003) reached similar conclusions about the Stretta procedure: "While many of these techniques have shown good results in preliminary studies, long-term results are not yet available and therefore all such procedures have to be considered experimental. Their effectiveness will need to be compared with that of established treatment forms."
A technology assessment of the Stretta procedure (Kahrilas, 2003), reached a similar conclusion: "Thus, within the framework of GERD subgroups discussed earlier, this author concludes that the current role of Stretta in clinical practice (circa January 2003) is as follows. Clear indications for Stretta treatment are nil because of the paucity of controlled data available, the limited follow-up currently available on treated patients, and the confusing nature of the data that are available. This opinion is in sharp disagreement with the FDA 510(k) summary statement on Stretta concluding that, "the risk-benefit profile (of Stretta) is substantially equivalent to that of fundoplication surgery." Because there are no clear indications for the procedure, it is the opinion of this author that all Stretta treatments rendered at this time should be done in the setting of clinical trials."
An assessment of endoluminal gastroplication for GERD by the National Institute for Clinical Excellence (2005) concluded that "[c]urrent evidence on the safety and efficacy of endoluminal gastroplication for gastro-oesophageal reflux disease (GORD) does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research." Specialist advisors to NICE expressed concerns about the long-term effectiveness of this procedure.
In a prospective, randomized trial, Coron et al (2008) compared RF (Stretta procedure) and a PPI strategy in PPI-dependent patients. Patients with PPI-dependent typical reflux symptoms were randomly allocated to either RF or PPI regimen alone. The primary endpoint, evaluated at 6-month, was defined as the possibility for the patient to stop or to decrease PPI use to less than 50 % of the effective dose required at baseline. In the RF group, 18/20 patients stopped (n = 3) or decreased (n = 15) PPI use as compared to 8/16 in the PPI group (p = 0.01). None of the control patients could stop PPI. Health-related quality of life scores were not different between groups. No significant change in oesophageal acid exposure (OAE) was noted between baseline and 6-months after RF. No severe complication was reported. The authors concluded that RF energy delivery is a safe and effective therapeutic option, allowing reduction in or discontinuation of PPI therapy in patients with PPI-dependent symptoms, without loss of quality of life. However, in a majority of patients, PPI therapy can not be completely stopped. The effectiveness of RF does not seem to be related to a decrease in OAE. This was a small study with short-term follow-up. These findings need to be validated by well-designed studies with larger number of subjects and longer follow-up.
Aziz et al (2010) noted that GERD is a prevalent disorder that often requires long-term medical therapy or surgery. Radiofrequency energy delivery has been shown in several studies to improve GERD symptoms and quality of life for approximately 2/3 of patients. The authors proposed that increasing the dose of Stretta would further improve the response to this therapy. For this study, 36 patients were randomized into 3 groups: (i) group A; 12 patients underwent a single session Stretta procedure, (ii) group B; 12 patients under went a sham Stretta procedure (mirror of the active procedure in all aspects except there was no deployment of the electrodes), and (iii) group C; 12 patients underwent a single Stretta treatment followed by repeat Stretta if GERD health-related quality of life (HRQL) was not 75 % improved after 4 months. For each patient, 56 RF lesions were created per session. The principal outcome was GERD HRQL improvement. The secondary outcomes were medication use, LES basal pressure, endoscopic grade of esophagitis, and OAE by pH probe. The Stretta procedure was completed successfully for all the patients in both active treatment groups. At 12 months, the mean HRQL scores of those off medications, the LES basal pressure, the 24-hr pH scores, and the PPI daily dose consumption were significantly improved from baseline in both Stretta groups (p < 0.01). The double Stretta was numerically but not significantly better than the single Stretta for mean HRQL, mean 24-hr pH, mean LES pressure, and PPI use. Seven patients in the double Stretta treatment group had normalized their HRQL at 12 months compared with 2 patients in the single-treatment group (p = 0.035). The sham patients had a small but statistically significant decrease in their daily PPI dosages (p < 0.05) and mean HRQL scores (p < 0.05). No serious complications (bleeding, perforation, or death) occurred. However, 2 patients experienced significant delayed gastric emptying after the second Stretta treatment. The authors concluded that the Stretta procedure significantly reduced GERD HRQL, use of PPI drugs, OAE, LES pressure, and grade of esophagitis compared with the sham procedure. The double Stretta therapy had numerically superior outcomes for most parameters and a significantly more frequent normalization of HRQL scores compared with the single Stretta. These findings need to be validated by well-designed studies with larger number of subjects and longer follow-up.
An appraisal by the National Institute for Health and Clinical Excellence (NICE, 2009) concluded: "The evidence on safety and efficacy of endoscopic radiofrequency (RF) ablation for gastro-oesophageal reflux disease (GORD) is inadequate and there are inconsistencies in the evidence on efficacy." The Committee noted that improvements in subjective outcomes in the published series were not supported by objective outcomes (pH and pressure measurements). They also noted that symptomatic improvement may result from denervation caused by the procedure, making the lower esophagus insensitive to potentially harmful acid reflux, as opposed to true reflux control. More recently, updated NICE guidance (2013) concluded: “The evidence on the safety of endoscopic radiofrequency ablation for gastroesophageal reflux disease (GORD) is adequate in the short and medium term but there is uncertainty about longer-term outcomes. With regard to efficacy, there is evidence of symptomatic relief but objective evidence on reduction of reflux is inconclusive. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.”
In a review on endoscopic and laparoscopic treatment of GERD, Watson and Immanuel (2010) staetd that for selected patients, there is an established role for the surgical treatment of reflux, and possibly an emerging role for endoscopic anti-reflux procedures. Randomized trials have compared medical versus surgical management, laparoscopic versus open surgery and partial versus total fundoplications. However, the evidence base for endoscopic procedures is limited to some small sham-controlled studies, and cohort studies with short-term follow-up. Laparoscopic fundoplication has been shown to be an effective anti-reflux operation. It facilitates quicker convalescence and is associated with fewer complications, but has a similar longer term outcome compared with open anti-reflux surgery. In most randomized trials, anti-reflux surgery achieves at least as good control of reflux as medical therapy, and these studies support a wider application of surgery for the treatment of moderate-to-severe reflux. Laparoscopic partial fundoplication is an effective surgical procedure with fewer side effects, and it may achieve high rates of patient satisfaction at late follow-up. Many of the early endoscopic anti-reflux procedures have failed to achieve effective reflux control, and they have been withdrawn from the market. Newer procedures have the potential to fashion a surgical fundoplication. However, at present there is insufficient evidence to establish the safety and efficacy of endoscopic procedures for the treatment of GERD, and no endoscopic procedure has achieved equivalent reflux control to that achieved by surgical fundoplication.
Bredenoord (2010) stated that it is estimated that approximately 30 % of the GERD patients is not satisfied about the effect of PPI on their symptoms. Esophageal hyper-sensitivity, persistent non-acid reflux and incomplete acid suppression all can play a role in the pathogenesis of persistent GERD symptoms. More powerful PPIs are now being developed, resulting in a more prolonged and profound acid suppression. New prokinetics and inhibitors of transient lower esophageal sphincter relaxations (TLESRs) can potentially reduce both acid and non-acid reflux and drugs that reduce hyper-sensitivity are possibly helpful for the treatment of non-erosive reflux disease. Whether these drugs will make it to the markets will mainly depend on their side effect profile and their ability to have an additional beneficial effect over the current gold standard therapy as it likely that a new anti-reflux drug will be used in combination with PPIs. Over the last decade various endoscopic anti-reflux techniques have been introduced, most of them have been withdrawn soon after introduction due to lack of effect or after the occurrence of severe side-effects. Several endoluminal plication techniques and endoluminal RF ablation therapy are still available and being evaluated in research centers; but more data on safety and efficacy is needed before a more widespread use can be advised.
In addition to the EndoCinch and Stretta procedures, there are other endoscopic procedures being evaluated for the treatment of GERD. Enteryx (Boston Scientific Corp, Natick, MA) is a chemically inert, non-carcinogenic, hypoallergenic, non-antigenic, radio-opaque compound that is available in a liquid organic state but becomes solid on hydration (or placement in tissue). It has been used in the treatment of arterio-venous malformations, peripheral vascular disease, and hypervascular head and neck cancers. It can be injected into the LES under fluoroscopic and endoscopic guidance. The endoscopist can ensure that the injections are into the muscular layer because a ring appears at the LES on radiograph. This ring persists as long as the material is in the LES. On April 22, 2003, Enteryx was approved by the FDA for the treatment of patients with GERD who require and respond to PPIs. The pre-market approval (PMA) of Enteryx was recommended by the Gastroenterology and Urology Devices Advisory Panel of the FDA with 10 conditions including a post-market study to be performed as a placebo-sham controlled trial that also examine the effects of re-treatment.
In a pilot study of patients with GERD who required continuous therapy with a PPI (n = 15), Deviere et al (2002) examined the safety and effectiveness of Enteryx (ethylene-vinyl-alcohol polymer) in the management of these patients. Enteryx was injected into the muscle of the gastric cardia. Primary endpoints were the safety of the procedure, the effect on LES pressure and the stability of the injected material. A secondary endpoint was the effect on heartburn score after discontinuation of treatment with a PPI. The authors concluded that Enteryx implantation in the muscle of the cardia is feasible and safe. It leads to a sustained increase in resting LES pressure. This is associated with a sustained improvement in heartburn score for patients who previously required continuous therapy with a PPI. The authors stated that further studies are needed to delineate the potential clinical applications and long-term outcomes of this technique.
In a multi-center, single-arm study (n = 85), Johnson and associates (2003) evaluated the safety and effectiveness of Enteryx for the treatment of GERD. These patients had heartburn symptoms that were responsive to PPI therapy. At 6 months following Enteryx implantation, PPI use was eliminated in 74 % and reduced by greater than 50 % in 10 % of patients. Mean total esophageal acid exposure time was 9.5 % pre-therapy and 6.7 % at 6 months. Mean LES length increased from 2.0 cm at baseline to 3.0 cm post-therapy. There were no clinically serious adverse events. Transient mild-to-moderate chest pain commonly occurred after implantation. These investigators concluded that endoscopic implantation of Enteryx is a safe and effective therapy for eliminating or decreasing the need for PPI medications, improving GERD symptoms and patient quality of life, and decreasing esophageal acid exposure among patients suffering from GERD. The authors stated that studies evaluating the benefits of Enteryx implantation compared with sham procedures as well as those that examine the long-term effectiveness and durability of Enteryx are in progress.
Although many patients had improvements in their symptoms and medication requirements, objective evaluations of the esophagus performed during the clinical trial showed evidence of persistent acid reflux in 61 % of patients and low-grade inflammation in 37 % of patients at 12 months. The most common adverse event observed in patients undergoing Enteryx treatment was pain beneath the breastbone that usually diminished within 2 weeks. Other common side effects included temporary difficulty with swallowing (20 %), fever (12 %), sore throat (11 %), and gas/bloating/belching (7 %).
Current evidence for the use of Enteryx is limited to pilot studies as well as small trials that lack appropriate control groups and long-term follow-up data. Thus, the clinical value of Enteryx is uncertain at this time. It should be noted that the FDA has issued a warning to physicians to stop using Enteryx because it has been connected to serious health problems and, in at least 1 case, death. On September 23, 2005, Boston Scientific Corporation initiated a voluntary recall of all Enteryx procedure kits and Enteryx single pack injectors because of reports that improper injection procedures can lead to serious patient injury and death.
A consensus panel convened by the American Gastroenterological Association (AGA) has issued an evidence-based educational monograph to help physicians better manage patients with GERD (Peterson, 2002). It stated that "current endoscopic/intraluminal therapeutic procedures are FDA approved for safety, not efficacy. Use of these techniques is on the rise, despite the fact that there are little data on the procedures' efficacy. Endoscopic treatment is not recommended at present".
A review on surgical and endoscopic treatment of GERD by Waring (2002) stated that widespread use of endoscopic therapy for GERD is probably still several years away. The best endoscopic therapy is yet to be determined, but it will need to be safe, effective, and easy to use. This sentiment is echoed by Galmiche and des Varannes (2003) who stated that further studies are needed before an endoscopic approach can be adopted, as none of the published trials is well controlled. Longer follow-up is needed to ensure that relapses do not occur rapidly, complications do not occur more frequently with less skilled operators, or that endoscopic-induced changes do not complicate or compromise subsequent anti-reflux surgery.
An assessment by the Medical Services Advisory Committee (2002) stated that “[t]here is a paucity of data on the effectiveness of ELGP [endoluminal gastroplication] beyond six months of follow up. While it appears that medication use at six months is reduced, the duration of this effect is unknown due to the limited amount of data available on this procedure.” The assessment concluded that “there is currently insufficient evidence pertaining to endoluminal gastroplication for gastro-oesophageal reflux disease.”
An assessment conducted by the National Institute of Clinical Excellence (2004) concluded that current evidence on the safety and efficacy of endoscopic injection of bio-compatible polymer for GERD does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research. This is in agreement with that of 2004 Blue Cross Blue Shield Technology Evaluation Center (TEC)’s assessment on transesophageal endoscopic treatments for GERD, which stated that endoscopic suturing, radiofrequency energy delivery, or implantation of inert polymers for treatment of GERD do not meet the TEC criteria.
More recently, the National Institute for Health and Clinical Excellence (NICE, 2007) evaluated the Gatekeeper Reflux Repair System (Medtronic, Minneapolis, MN), a hydrogel prosthesis that is implanted endoscopically into the LES. The NICE guidance concluded that there is limited evidence of short-term efficacy on endoscopic augmentation of the LES using hydrogel implants for the treatment of GERD. This evidence also raises concerns about the procedure’s safety. "Therefore, this procedure should not be used without special arrangements for consent and for audit." The Gatekeeper Reflux Repair System clinical program was suspended in late 2005 before FDA approval due to concerns over efficacy.
The Plicator System (NDO Surgical Inc., Mansfield, MA) is another new treatment option for GERD. It consists of the reusable Plicator instrument, a single-use cartridge containing a suture-based implant, and a specially designed endoscopic tissue retractor. This system allows the physician to create a full-thickness plication at the gastro-esophageal junction, permitting serosa-to-serosa tissue healing and a re-structuring of the normal anti-reflux barrier. The Plicator procedure is an outpatient procedure performed using direct endoscopic visualization and under conscious sedation. The Plicator System was cleared by the FDA in April 2003 through a 510(k) application. The most common side effect associated with the Plicator procedure is pharyngitis (41 %), which resolved spontaneously within several days after the procedure.
There is only limited clinical data on the effectiveness of the Plicator System. In a pilot study, Chuttani et al (2003) reported that full-thickness plication (the Plicator procedure) was performed successfully in 6 of 7 patients, with 1 procedure aborted because of difficulty in sedating the patient. Mean procedure time was 21 mins. Mild epigastric pain was reported by 2 patients and difficulty with eructation by 1 patient; all symptoms resolved spontaneously within 7 days of the procedure. Endoscopy at 6 months revealed an intact plication in all patients. At 1 year after the procedure, patients reported sustained reduction in heartburn scores. One patient, who did not experience significant relief of symptoms, ultimately underwent successful laparoscopic Nissen fundoplication at 6 months after the procedure. At 1 year after the procedure, 3 of 5 patients were not taking anti-GERD medications. The authors concluded that endoscopic full-thickness plication is feasible, safe and, and appeared to reduce symptoms and medication use associated with GERD. Findings of this study need to be validated by prospective, randomized controlled studies.
A 2004 Canadian Coordinating Office for Health Technology Assessment (CCOHTA) assessment on endoscope-based treatments for GERD (such as EndoCinch, Stretta, Enteryx, Gatekeeper and Plicator) stated that these technologies are promising, but their place in health care is not established. The assessment noted that there is still little information on these products in comparison with other treatments, and there are no studies comparing different endoscope-based technologies. The assessment found that efficacy and safety have been mostly assessed over short periods. The assessment noted that promotion of the widespread introduction of such techniques in the absence of both controlled studies and long-term follow-up has been criticized. Most trials have excluded patients with esophagitis and other conditions. The assessment stated that reduced use of PPIs in a high proportion of patients is an important benefit, though acid exposure returns to normal in only 50 % of those treated.
In a review on non-pharmacological treatment strategies for patients with GERD, Sollano (2004) stated that several innovative endoluminal treatment modalities have been introduced such as endoscopic plicator/suturing devices, bulking injections, and radiofrequency treatment. These approaches focused on enhancing the performance of a malfunctioning LES. While results of several case series reflect substantial improvements in GERD-patients' quality of life scores, the lack of long-term durability data is a major concern when recommending these new techniques. It is evident that these therapies are still evolving and long-term outcomes of properly designed comparative efficacy trials are awaited.
An assessment prepared for the California Technology Assessment Forum (CTAF) concluded that the Stretta, Endocinch, and Enterx endoluminal treatments for GERD do not meet CTAF's assessment criteria (Feldman, 2004). The assessment explained that, in the case of Enterx and Bard EndoCinch, the current literature does not include any randomized trial data, so it is not possible to fully evaluate the safety and efficacy of these procedures. In addition, with the Bard EndoCinch, questions remain about the safety of the procedure and the training required to perform it under conditions of routine clinical practice. CTAF found that, although the Stretta procedure had been evaluated in a randomized, controlled clinical trial (Corley et al, 2003), the trial did not enroll patients who were refractory to medical therapy, so it is not possible to conclude from this trial if Stretta will be an acceptable alternative to surgery for patients with refractory symptoms on appropriate medical therapy. Although the study showed that the Stretta procedure was successful in returning patients back to a similar level of symptoms they had at baseline on medications, the procedure did not improve esophageal acid exposure, esophageal erosions or LES pressure, all presumably risk factors for developing later complications from GERD. The assessment found that it does not seem advisable to recommend that patients discontinue a safe and effective treatment that has been proven to reduce acid exposure (i.e., medications) in favor of one that does not (Stretta).
Ozawa et al (2005) stated that endoscopic treatments (e.g., the EndoCinch method, the NDO Plicator method, the Wilson-Cook Medical's Endoscopic Suturing Device, the Stretta System, the Enteryx procedure, and Medtronic's Gatekeeper Reflux Repair System) for GERD are still in the development phase. They further noted that the safety, effectiveness, durability, cost-effectiveness, indications of endoscopic treatments, and possible combination with other treatments must be thoroughly evaluated in randomized controlled trials. This is in agreement with the observations of Annese et al (2005) who stated that the use of endoscopic treatment for GERD should be limited to clinical trials, which should incorporate the provision of comprehensive and unbiased information to study patients as well as de Hoyos and Fernando (2005) who noted that endoscopic therapies for GERD are being rapidly introduced, despite lack of long-term follow-up and randomized trials.
Rothstein et al (2006) examined the effectiveness of endoscopic full-thickness plication for the treatment of GERD in comparison with a sham procedure. Patients with symptomatic GERD requiring maintenance PPI therapy were entered into a randomized, single-blind, prospective, multi-center trial. A total of 78 patients were randomly assigned to undergo endoscopic full-thickness restructuring of the gastric cardia with transmural suture, while 81 patients underwent a sham procedure. Group assignments were revealed following the 3-month evaluation. The primary end point was greater than or equal to 50 % improvement in GERD HRQL score. Secondary end points included medication use and esophageal acid exposure. By intention-to-treat analysis, at 3 months, the proportion of patients achieving greater than or equal to 50 % improvement in GERD-HRQL score was significantly greater in the active group (56 %) compared with the sham group (18.5 %; p < 0.001). Complete cessation of PPI therapy was higher among patients in the active group than in the sham group by intention-to-treat analysis (50 % versus 24 %; p = 0.002). The percent reduction in median percent time pH less than 4 was significantly improved within the active group versus baseline (7 versus 10, 18 %, p < 0.001) but not in the sham group (10 versus 9, -3 %, p = 0.686). Between-group analysis revealed the active therapy to be superior to the sham in improving median percent time pH less than 4 (p = 0.010). There were no perforations or deaths. The authors concluded that endoscopic full-thickness plication more effectively reduces GERD symptoms, PPI use, and esophageal acid exposure than a sham procedure.
An editorial (Shaheen, 2006) accompanying the study by Rothstein and colleagues outlined the limitations of the study. It stated that the Plicator procedure shows promise as a treatment option for patients with mild GERD seeking an alternative to long-term acid-suppressive therapy. Furthermore, Shaheen stated there are issues to be dealt with concerning the acceptance of endoscopic anti-reflux devices such as safety, efficacy and durability. In regards to the study, Shaheen also stated that some head-to-head data with alternative treatment measure would be helpful. No study has truly compared the results of PPI therapy to endoscopic anti-reflux devices. Shaheen concluded that the study still leaves uncertainty as to where to position endoscopic anti-reflux procedures in the patient with GERD. Since there is a lack of data, there is no claim to superiority, or even equivalency, of these devices to the best medical or surgical therapy for GERD. Until the questions regarding safety, efficacy, and durability outlined above become clearer, the routine use of these devices in PPI responsive patients outside the realm of clinical studies can not be recommended.
In an open-label, prospective, multi-center study, von Renteln and colleagues (2008) evaluated the safety and effectiveness of placing multiple transmural sutures for the treatment of GERD. Subjects with symptomatic GERD who require daily maintenance PPI therapy. Study exclusions were hiatal hernia greater than 3 cm, grades III and IV esophagitis, Barrett's epithelium, and esophageal dysmotility. A total of 41 patients received 2 or more transmural sutures placed linearly in the anterior gastric cardia approximately 1 cm below the gastro-esophageal junction. Six months following the procedure, median GERD-health-related quality of life (HRQL) improved 76 % compared with off-medication baseline (6.0 versus 25.0, p < 0.001), with 75 % of patients (32/40) achieving over 50% improvement in their baseline GERD-HRQL score. Six months after the procedure, daily PPI therapy was eliminated in 70 % of patients (28/40). Heartburn symptoms improved 80 % compared with off-medication baseline (16.0 versus 84.0, p < 0.001). Median esophagitis grade improved 75 % compared with baseline (0.0 versus 1.0, p = 0.005). Esophageal pH assessed as median distal esophageal-acid exposure (percentage time pH less than 4.0) improved 38 % compared with baseline (9.0 versus 11.0, p < 0.020; nominal p value for a single statistical test: significance removed upon the Bonferroni adjustment for multiple testing of data) and manometric outcomes were also improved compared with baseline (median LES resting pressure improved 25 % [10.0 versus 6.0, p < 0.017; nominal p value for a single statistical test: significance removed upon the Bonferroni adjustment for multiple testing of data]) and median amplitude of contraction improved 11 % (70.0 versus 62.0, p < 0.037; nominal p value for a single statistical test: significance removed upon the Bonferroni adjustment for multiple testing of data). The authors concluded that endoscopic full-thickness plication with multiple serially placed implants was safe and effective in reducing GERD symptoms, medication use, esophageal-acid exposure, and esophagitis. The limitations of this study were small sample size, and a lack of randomized comparison with a single implant group.
The AGA's institute medical position statement on the use of endoscopic therapy for GERD (Falk et al, 2006) stated that "most studies of endoscopic therapy have only limited follow-up information of a relatively small number of patients. Thus, the durability of these technologies beyond 1 to 2 years remains unclear. Short-term and long-term safety issues are unresolved, but serious adverse events led to the voluntary withdrawal of Enteryx by the manufacturer in September 2005 and suspension of the Gatekeeper clinical program in late 2005. The economics of all techniques for the patient, practitioner, and society are unknown. While newer devices and improvements in endoscopic antireflux techniques may yield better and more durable treatment outcomes, current data suggest that there are no definite indications for endoscopic therapy for GERD at this time. Both practitioners and patients need to be aware of the limitations in the evidence that exist with these devices at present".
A systematic evidence review prepared for the Australian Safety and Efficacy Register of New Interventional Procedures - Surgical (ASERNIP-S) (McLoughlin et al, 2006) reached the following conclusions about endoscopic treatments of GERD: "The scope, applicability, efficacy and cost effectiveness of endoscopic anti-reflux therapies for the treatment of GORD have not been established. These procedures may provide an alternative treatment for selected patients with mild to moderate GORD who are dependent on medication and are reluctant or unable to undergo surgery. However, a substantial placebo effect has been demonstrated in sham controlled trials, and endoscopic results were generally inferior when compared with laparoscopic fundoplication. Doubts about the durability of the therapeutic effect remain since the follow-up period in most studies was short."
A systematic evidence review prepared for the Agency for Healthcare Research and Quality (Ip et al, 2005) reached similar conclusions about the need for reliable evidence about endoscopic treatments for GERD. The assessment found that data on comparative endoscopic treatments with continued (or intensified) use of PPIs are needed to better understand their efficacy compared to an established standard. The report also noted the need for more efficacy and safety data on new endoscopic approaches tested against a sham procedure with adequate follow-up.
Spicak (2007) stated that 3 types of endoscopic methods in several modifications have been developed for the treatment of GERD: (i) radiofrequency therapy (Stretta procedure) is available both in Europe and the United States and more than 5,000 patients have been treated to date; (ii) injection therapy requires the injection of bulking agents or implantation of bioprosthesis into the LES zone. Both Enteryx was withdrawn from the market in 2005, and Gatekeeper was suspended before FDA approval; (iii) suturing/plication therapy is based on the plication at the level of the LES, and most of all techniques resemble the principle of surgical treatment. Despite sophisticated technologies and promising short-term results, all these techniques are associated with inconsistencies, controversies, and relevant adverse affects. According to current practice, use of endoscopic methods is justifiable only as part of clinical trials.
Other reviews of the evidence have reached similar conclusions about the unproven status of endoscopic treatments for GERD, Schwarz and Smout (2007) reported that endotherapy has shown the potential to treat (uncomplicated) GERD, but that some procedures have failed or proven unsafe. The authors concluded: "Further developments and studies are necessary to determine what modifications to these techniques are required to produce optimal efficacy and durability. Until then, widespread clinical use of endotherapy for GORD should probably be avoided." Triadafilopoulos (2007) noted that future comparative studies with pre-determined clinically significant end points, validated outcome measures, prolonged follow-up, and complete complication registries will eventually determine the precise role of endoscopic therapies for patients with GERD.
In a review on endoscopic anti-reflux procedures, Pace et al (2008) concluded that none of the proposed anti-reflux therapies has fulfilled the criteria of efficacy, safety, cost, durability and, possibly, of reversibility. There is at present no definite indication for endoscopic therapy of GERD.
Jafri and colleagues (2009) analyzed existing endoscopy-based interventions for GERD. The focus is on the effectiveness of available procedures and to delineate goals for future research. These investigators noted that recent evaluations of the EndoCinch system reveal poor long-term results and no significant improvement over sham therapy due to poor apposition of mucosa with stitches. Recent studies with transoral incisionless fundoplication demonstrate improvement in GERD symptoms, quality of life, esophageal acid exposure, esophagitis, resting LES pressure and medication use. The SRS endoscopic stapling system creates a partial fundoplication wrap, and a preliminary study demonstrated improved symptoms and acid exposure. The Stretta system delivers RF energy to the gastro-esophageal junction. A large prospective series demonstrates sustained improvement in GERD symptoms, quality of life and PPI therapy elimination after RF ablation at the gastro-esophageal junction. A sham-controlled study showed improvement in symptoms at 6 months. The authors concluded that EndoCinch plication requires further study and modification of technique before it can be recommended for general clinical use. Transoral incisionless fundoplication is a very promising procedure in its early stages of development. They stated that further evaluation of procedure safety and durability is needed. Radiofrequency ablation therapy has been re-introduced and may have potential in patients with refractory GERD.
In a systematic review, Chen et al (2009) evaluated the safety and effectiveness of endoscopic procedures for GERD. Randomized controlled trials and non-randomized comparative studies with at least 10 patients in each study arm, and case series studies of at least 10 patients, were included. A total of 33 studies examining 7 endoscopic procedures (Stretta procedure, Bard EndoCinch, Wilson-Cook Endoscopic Suturing Device, NDO Plicator, Enteryx, Gatekeeper Reflux Repair System and Plexiglas) were included in the review. Of the 3 procedures that were tested against sham controls (Stretta procedure, Bard EndoCinch and Enteryx), patient outcomes in the treatment group were either as good as, or significantly better than, those of control patients in terms of heartburn symptoms, quality of life and medication usage. However, for the 2 procedures that were tested against laparoscopic fundoplication (Stretta procedure and Bard EndoCinch), outcomes for patients in the endoscopic group were either as good as, or inferior to, those for the laparoscopic group. The authors concluded that currently there is insufficient evidence to determine the safety and effectiveness of endoscopic procedures for GERD, especially in the long-term.
The Angelchik anti-reflux prosthesis was approved (PMA) by the FDA in 1979. It is a soft, collar-shaped, silicone elastomer shell filled with silicone gel, with an internal diameter of 3.1 cm. It is placed around the esophagus under the diaphragm and above the stomach, and is secured by 2 reinforced Teflon straps around the gastro-esophageal junction. The alleged advantage of the Angelchik device is the simplicity of the procedure -- its placement requires only limited dissection, thus decreasing the operating time. Since its introduction, more than 25,000 prostheses have been inserted into patients worldwide. Early faulty design had caused breakage of the circumferential strap, and led to migration of the device. Modification of the original strap to 2 re-inforced, non-circumferential straps by the manufacturer appears to have minimized the migration problem. However, complications as a consequence of implantation of the Angelchik prosthesis have been reported in as many as 10 to 20 % of patients. An American Medical Association's DATTA evaluation of the Angelchik prosthesis found that this device has not been established as safe and effective for routine use in the treatment of GERD. Long-term studies concluded that the Angelchik device causes long-term dysphagia in many patients, severe enough to require its removal in 25 % of these patients. Thus, its continual use can not be recommended.
In a feasibility study, Bonavina et al (2010) evaluated the safety and efficacy of the LINX Reflux Management System (Torax Medical, Shoreview, MN), a laparoscopically implanted sphincter augmentation device, for the treatment of GERD. The device, designed to prevent reflux due to abnormal opening of the LES, was laparoscopically implanted at the gastro-esophageal junction in 44 patients. At baseline, all patients had abnormal esophageal acid exposure on 24-hr pH monitoring and improved, but persistent, typical GERD symptoms while on acid suppression therapy with PPIs. The device comprises a miniature string of inter-linked titanium beads, with magnetic cores, placed around the gastro-esophageal junction. The magnetic bond between adjacent beads augments sphincter competence. The beads temporarily separate to accommodate a swallowed bolus, allow belching or vomiting, and re-approximate to augment the LES in the closed position. Patients were evaluated after surgery by GERD Health-Related Quality of Life symptom score, PPI usage, endoscopy, esophageal manometry, and 24-hr esophageal pH monitoring. The total mean GERD Health-Related Quality of Life symptom scores improved from a mean baseline value of 25.7 to 3.8 and 2.4 at 1- and 2-year follow-up, representing an 85 % and 90 % reduction, respectively (p < 0.0001). Complete cessation of PPI use was reported by 90 % of patients at 1 year and by 86 % of patients at 2 years. Early dysphagia occurred in 43 % of the patients and self-resolved by 90 days. One device was laparoscopically explanted for persistent dysphagia without disruption of the anatomy or function of the cardia. There were no device migrations, erosions, or induced mucosal injuries. At 1 and 2 years, 77 % and 90 % of patients had a normal esophageal acid exposure. The mean percentage time pH was less than 4 decreased from a baseline of 11.9 % to 3.1 % (p < 0.0001) at 1 year and to 2.4 % (p < 0.0001) at 2 years. Patient satisfaction was 87 % at 1 year and 86 % at 2 years. The authors concluded that the new laparoscopically implanted sphincter augmentation device eliminates GERD symptoms without creating undue side effects and is effective at 1 and 2 years of follow-up. The findings of this small feasibility study need to be validated by well-designed studies.
Ganz and colleagues (2013) evaluated the safety and effectiveness of a new magnetic device to augment the LES. These investigators prospectively assessed 100 patients with GERD before and after sphincter augmentation. The study did not include a concurrent control group. The primary outcome measure was normalization of esophageal acid exposure or a 50 % or greater reduction in exposure at 1 year. Secondary outcomes were 50 % or greater improvement in quality-of-life related to GERD and a 50 % or greater reduction in the use of PPIs at 1 year. For each outcome, the pre-specified definition of successful treatment was achievement of the outcome in at least 60 % of the patients. The 3-year results of a 5-year study were reported. The primary outcome was achieved in 64 % of patients (95 % confidence interval [CI]: 54 to 73). For the secondary outcomes, a reduction of 50 % or more in the use of PPIs occurred in 93 % of patients, and there was improvement of 50 % or more in quality-of-life scores in 92 %, as compared with scores for patients assessed at baseline while they were not taking PPIs. The most frequent adverse event was dysphagia (in 68 % of patients post-operatively, in 11 % at 1 year, and in 4 % at 3 years). Serious adverse events occurred in 6 patients, and in 6 patients the device was removed. The authors concluded that in this single-group evaluation of 100 patients before and after sphincter augmentation with a magnetic device, exposure to esophageal acid decreased, reflux symptoms improved, and use of PPIs decreased. Moreover, they stated that follow-up studies (prospective, randomized trials with appropriate controls) are needed to confirm these preliminary findings and evaluate longer-term safety.
In a prospective, randomized, sham-controlled, single-blinded, international multi-center study, Fockens et al (2010) evaluated if endoscopic implantation of an injectable esophageal prosthesis, the Gatekeeper Reflux Repair System (GK), is safe and effective for controlling GERD. A total of of 204 patients were assigned to 3 groups: (i) 60 lead-in, (ii) 96 GK, and (iii) 48 sham patients. The sham patients were allowed to cross-over to the GK treatment arm or exit the study at 6 months. The primary end points were (i) reduction in serious device- and procedure-related adverse device effects compared with a surgical composite complication rate, and (ii) reduction in heartburn symptoms 6 months after the GK procedure compared with the sham procedure. The secondary end point was improved esophageal pH (total time pH was less than 4) 6 months after the GK procedure compared with baseline. A planned interim analysis was performed after 143 patients were enrolled (25 lead-in, 75 GK, and 43 sham patients), and the GK study was terminated early due to lack of compelling efficacy data. Four reported serious adverse events had occurred (2 perforations, 1 pulmonary infiltrate related to a perforation, and 1 severe chest pain) at termination of the study with no mortality or long-term sequelae. Heartburn symptoms had improved significantly at 6 months compared with baseline in the GK group (p < 0.0001) and the sham group (p < 0.0001), but no significant between-group difference in improvement was observed (p = 0.146). Esophageal acid exposure had improved significantly at 6 months compared with baseline in the GK group (p = 0.021) and the sham group (p = 0.003), but no significant between-group difference in improvement was observed (p = 0.27). The authors concluded that the GK procedure was associated with some serious but infrequent complications. No statistically significant difference in outcomes was observed between the treatment and control groups at 6 months compared with baseline.
The American Society of General Surgeons' position statement on "Natural orifice surgery and transoral incisionless fundoplication" (ASGS, 2009) stated that "ASGS supports the continued development and refinement of this procedure as well as other appropriate natural orifice procedures performed by adequately trained general surgeon specialists". While the ASGS Board of Trustees issued a favorable position statement regarding transoral incisionless fundoplication (TIF); its recommendation does not appeared to be based from a full-fledged technology assessment of the procedure.
Zagol and Mikami (2011) evaluated transoral fundoplication devices for GERD that have been commercially available within the last 5 years. Literature databases including Medline and PubMed were searched from January 2005 to November 2010. Both blinded and unblinded randomized studies were evaluated. These investigators reviewed the literature for evaluations of primary transoral endoluminal fundoplication devices which included EndoCinch, NDO Plicator, Esophyx, and Stretta. Reviews of all studies with greater than 20 patients were evaluated to assess the efficacy and safety of transoral fundoplication devices. These endoluminal devices were primary matched against sham procedures. The EndoCinch and Stretta procedures were the only devices compared to laparoscopic fundoplication, the current standard for surgical management of GERD. The authors concluded that the field of endoluminal treatment of GERD has gained popularity over the last several years. Endoluminal treatment of GERD has been shown to be safe and effective in recent studies. The authors still believe more randomized prospective studies need to be carried out to determine if endoluminal therapies will be a durable option for patients with GERD. Continuing research will further the advancement of endoluminal GERD procedures in the future. Also, Frazzoni et al (2011) concluded that in patients with refractory GERD, EsophyX fundoplication is significantly less effective than laparoscopic fundoplication in improving reflux parameters and accordingly, in inducing symptom remission.
The Agency for Healthcare Research and Quality's updated evidence report on "Treatment options for GERD or acid reflux disease" (AHRQ, 2011) compared the risks and benefits of treatments for GERD. The report stated that "[t]hree types of endoscopic treatments are EndoCinch™, Stretta®, and EsophyX™. These treatments are very new and are not as common as medicines or surgery to treat GERD. People receiving one of these treatments may be in a study to see how well it works. There are not enough studies to say how well endoscopic treatments (EndoCinch™, Stretta®, and EsophyX™) work to control the symptoms of GERD". Regarding the EndoCinch procedure, the AHRQ assessment (Ip, et al., 2011) concluded that the quality of evidence was "low", consisting of two sham-controlled studies and 6 noncomparative cohort studies. The AHRQ report found that no consistent differences between EndoCinch and sham were reported, and that significant improvements in heartburn, qualtiy of life, and esophagitis healing were found in some but not all cohort studies. The AHRQ assessment (Ip, et al., 2011) found the strength of evidence for the EsophyX procedure was "insufficient," consisting of five small cohort studies. The reported proportion of patients who were off PPIs at the end of the followup period ranged from 47 to 71%. Significant improvement of quality as measured by the GERD-HRQL scale was reported by 2 of 5 studies. The AHRQ assessment (Ip, et al., 2011) found "insufficient" evidence for the.Stretta procedure, consisting of one sham-controlled study and 7 noncomparative cohort studies. In the randomized controlled trial, the proportion of patients who stopped or decreased PPI use was significantly greater in the Stretta group than the control group at 6 months (but it was not significant at 1 year). No significant differences in heartburn symptoms, quality of life, acid exposure, and esophagitis outcomes were found. The majority of cohort studies found significant improvements in GERD symptoms, quality of life, and medication use.
In a retrospective study, Barnes et al (2011) evaluated the clinical outcomes in 124 consecutive gastro-esophageal reflux disease (GERD) patients who underwent transoral incisionless fundoplication (TIF) at 2 community hospitals. Out of 123 patients treated successfully, 110 gave consent (74 % females, median age 60 [range of 21 to 87] years, BMI 27.5 [19.0 to 47.9]). At a median 7-month follow-up (range of 5 to 17), typical and atypical symptom scores were normalized in 75 % to 80 % of patients, PPIs were completely discontinued by 93 %, and 83 % were satisfied with their current health condition. Endoscopy in 53 patients revealed Hill grade I tight valves in 89 % of the cases, reduced hiatal hernia in 33/34 (97 %), and healed reflux esophagitis in 25/30 (83 %). Based on global analysis, 72 % of the patients were in remission, 20 % improved symptomatically, and only 8 % had ongoing GERD. These results supported the safety and efficacy of TIF as well as encouraged its application as an alternative treatment of GERD refractory to PPIs. The drawbacks of this study were its retrospective nature (symptom data at baseline were based on retrospective recall) and short-term follow-up. Furthermore, the lack of pH measuring systems at the authors' institutions prevented these researchers from measuring esophageal acid exposure before and after TIF.
Bell and Freeman (2011) retrospectively evaluated the safety and effectiveness of a rotational/longitudinal esophagogastric TIF using subjective and objective outcomes. A total of 37 consecutive patients on anti-secretory medication and with proven GERD and limited hiatal hernia underwent TIF for persistent GERD symptoms. Five patients were re-operated for failed laparoscopic fundoplication. Of the 37 treated patients, 57 % were female. The median age was 58 (range of 20 to 81) years and body mass index (BMI) was 25.5 (range of 15.9 to 36.1) kg/m(2). Sixty-eight percent indicated GERD-associated cough, asthma, or aspiration as a primary complaint and 32 % complained of heartburn or regurgitation. The TIF procedures created tight wraps of 230° to 330° extending 3-4 cm above the Z-line. Two complications occurred: 1 mediastinal abscess treated laparoscopically and 1 post-operative bleeding requiring transfusion. At 6 (range of 3 to 14) months median follow-up, TIF resulted in a significant improvement of both atypical and typical symptoms in 64 % and 70 to 80 % of patients, respectively, as indicated by the corresponding GERD health-related quality of life (HRQL) and reflux symptom index (RSI) score reduction by 50 % or more compared to baseline on proton pump inhibitors (PPIs). No patient reported problems with dysphagia, bloating, or excess flatulence, and 82 % were not taking any PPIs. Reflux characteristics were significantly improved and normalized in 61, 89, and 56 % of patients in terms of acid exposure, number of refluxates, and DeMeester scores, respectively. TIF was effective in treating GERD in 75 % of patients among whom 54 % were in a complete "remission" and 21 % were "improved". The remaining 25 % were considered failures, and 5 (13.5 %) patients underwent revision. The authors concluded that rotational/longitudinal esophagogastric fundoplication using the EsophyX device significantly improved symptomatic and objective outcomes in over 70 % of patients at median 6-month follow-up. Post-fundoplication side effects were not reported after TIF. This was a small, retrospective study with short-term follow-up; its findings need to be validated by well-designed studies.
Testoni et al (2012) assessed the long-term effect of TIF in patients with symptomatic GERD. TIF 2.0 fundoplication was done in 42 consecutive patients. All were studied with GERD-HRQL and GERD-QUAL questionnaires, upper gastrointestinal (GI) endoscopy, esophageal manometry, and 24-hr pH impedance before and at 6, 12, and 24 months after TIF. In all, 35 patients completed 6-month follow-up; 21 (60.0 %) completely stopped proton pump inhibitor (PPI) therapy, 6 (17.1 %) more than halved it, and 8 (22.9 %) continued with the same dose as before the procedure. There were 26 patients with complete 24-month follow-up; 11 (42.3 %) completely stopped PPI therapy, 7 (26.9 %) more than halved it, and 8 (30.8 %) were taking the same dose as before the procedure. Hiatal hernia and ineffective esophageal motility seemed to raise the risk of recurrence of symptoms (p = 0.02 and p < 0.001, respectively). The number of fasteners deployed during TIF was the only factor predictive of successful outcome (p = 0.018). The authors concluded that TIF using the EsophyX device allowed withdrawal or reduction of PPI in about 77 % of patients at 6-month follow-up and about 69 % at 24 months. Larger number of fasteners deployed during TIF was predictive of positive outcome; pre-TIF ineffective esophageal motility and hiatal hernia raised the risk of recurrence of GERD symptoms, but were not significant from a prospective point of view. The major drawback of this small study was its uncontrolled design. Also, while 77 % of patients stopped or at least halved PPI use at 6-month follow-up; this proportion dropped to about 69 % at 24-month evaluation, raising concerns regarding how long fundoplication lasts with the current technique. The authors stated that "[i]n light of these results and awaiting randomized controlled studies on larger series, the TIF procedure can at present be offered as a complement to medical therapy or an alternative to surgery only in selected patients with small or no hiatal hernia, who refuse surgery or do not want long-term PPI therapy, or are intolerant or partial responders to PPI".
In a retrospective study, Trad et al (2012) evaluated safety, symptom resolution, patient satisfaction, and medication use 1 to 2 years after TIF in patients with GERD and/or laryngopharyngeal reflux (LPR) symptoms. A total of 34 patients with a confirmed diagnosis of GERD symptoms that were inadequately controlled by anti-secretory medications, and who where either dissatisfied with their current therapy or not willing to continue taking medication, underwent TIF using EsophyX at the authors' community-based hospital. Follow-up assessments were completed in 28 patients. Median age of the study group was 57 years (range of 23 to 77), BMI was 25.7 (18.3 to 36.4) kg/m(2), and 50 % were female. All patients had documented chronic GERD for a median 5 years (1 to 20) and refractory symptoms to PPIs. Hiatal hernia was present in 75 % (21/28) of patients, and 21 % (6/28) had erosive esophagitis (LA grade A or B). Transoral incisionless fundoplication was performed following a standardized TIF-2 protocol and resulted in reducing hiatal hernia and restoring the natural anatomy of the gastroesophageal (GE) junction (Hill grade I). There were no post-operative complications. At a median 14-months follow-up, 82 % (23/28) of patients were off daily PPIs (64 % completely off PPIs), and 68 % (19/28) were satisfied with their current health condition compared to 4 % before TIF. Median GERD-HRQL scores were significantly reduced to 4 (0 to 25) from 26 (0 to 45) before TIF (p < 0.001). Heartburn was eliminated in 65 % (17/26) and improved by greater than 50 % in 86 % (24/28) of patients. Regurgitation was eliminated in 80 % (16/20) of patients. Atypical LPR symptoms such as hoarseness, coughing, and throat clearing were eliminated in 63 % (17/27) of patients as measured by Reflux Symptom Index scores. The authors concluded that these findings in 28 patients confirmed the safety and effectiveness of TIF, documenting symptomatic improvement of GERD and LPR symptoms and clinically significant discontinuation of daily PPIs in 82 % of patients. Limitations of this study included its retrospective, single-center design, small sample size and a lack of follow-up comparative pH/impedance monitoring data. The authors are currently enrolling patients in a prospective, multi-center TIF Registry.
Feretis et al (2001) noted that a gelatinous implant containing polymethylmethacrylate (PMMA) beads is successfully used to augment the diminished thickness of the chorium in patients with skin defects and wrinkles. These investigators examined if submucosal injection of PMMA microspheres into the lower esophageal folds decreases the severity of symptoms and acid reflux in patients with GERD. Endoscopic submucosal implantation of PMMA was carried out in 10 patients with GERD who were either refractory to or dependent on PPIs. Symptom severity score, 24-hour pH monitoring, upper GI endoscopy, and endoscopic ultrasonography were performed to evaluate the efficacy of implantation. A significant decrease in the symptom severity score and mean total time with esophageal pH less than 4 was noted after the implantation of PMMA (p < 0.05); 7 of 10 patients were taking no medication after PMMA implantation. There were no serious procedure-related complications. The authors concluded that endoscopic implantation of PMMA into the submucosa of the lower esophageal folds may be a new method for treating GERD. Moreover, they stated that further studies are needed to determine the long-term effectiveness of the procedure.
Neuhauser et al (2003) stated that therapeutic options for GERD include lifestyle modifications, medical therapy, laparoscopic anti-reflux surgery, and 3 more recent options: (i) injection therapy to the LES, (ii) endoscopic sewing procedures, and (iii) radio frequency ablation therapy. Medical therapy is effective in most patients but not always successful with advanced disease. Up to 70 % of subjects do not have adequate nocturnal control of gastric acid secretion with 20 mg of omeprazole given twice-daily. Patients who do not tolerate medical therapy, who respond inadequately, or who want to avoid life-long drug therapy are candidates for alternate treatments. Studies on endoscopic procedures such as PMMA injection, the Stretta procedure, and endoscopic suturing techniques all suffer from having small study groups for each procedure, unknown durability, short follow-up, and the absence of randomized, controlled trilas. Limitations on endoscopic techniques are esophageal motility disorders, severe esophagitis, and larger hiatal hernias. Laparoscopic anti-reflux surgery remains a well-established, durable alternative to long-term medical therapy. It has the benefits of convenience, safety, minimal complications, improved quality of life, and low cost. Alternative methods will have to earn their place against this gold standard.
In a pilot study, Ganz et al (2009) evaluated the long-term safety and effectiveness of Durasphere (Carbon Medical Technologies, St Paul, MN), a new injectable bulking agent, in the treatment of mild-moderate GERD. A total of 10 GERD subjects, confirmed by pH monitoring, on daily PPI therapy, hiatal hernia less than 3 cm, and no or mild erosive esophagitis were enrolled in this study. Subjects received endoscopic injection with Durasphere at the gastro-esophageal junction. Outcome measures included change in symptom scores, PPI use, pH scores, and endoscopic findings; safety profile was monitored. Nine of 10 patients completed the 12-month trial. There were no adverse events. The procedure was well-tolerated with minimal patient discomfort and no dysphagia. At 12 months 70 % of patients discontinued all antacid medication completely; 90 % of patients reduced PPI use by greater than 50 %. DeMeester scores improved from a mean of 44.5 at baseline to 26.5 at 12 months; 4 patients achieved normal pH scores. There was no esophagitis at 12 months, and no erosion, ulceration or sloughing of material was noted at any injection site. The Durasphere material did not appear to migrate. The authors concluded that Durasphere appears to be a promising new injectable bulking agent for the treatment of mild-moderate GERD, with demonstrable efficacy and no significant adverse events in a small cohort. Drawbacks of this study were its non-randomized study design without a control group and small number of subjects.
Svoboda et al (2011) stated that natural orifice transluminal surgery (NOTES) has been introduced in endoscopic surgery as a new system offering the advantage of a less invasive procedure. Gastro-esophageal reflux disease appears to be the most promising application of NOTES treatment. The aims of our study were to evaluate the safety and efficacy of this procedure and length of hospital stay. Patients indicated for surgery of GERD were randomly assigned (ratio 2:1) to TIF (n = 34) and control group, where gold standard Nissen laparoscopic fundoplication was performed (NLF group, n = 18). For TIF, the Plicator method was initially used for 18 patients, but the company terminated production in 2008 without a follower. During the last 2 years the EsophyX method was used for 16 patients. After the evaluation of 34 TIF patients and 18 NLF patients we observed similar efficacy of TIF procedures compared with NLF after 3 and 12 months. The hospital stay was significantly shorter (p < 0.0001) in TIF group (average of 2.9 +/- 0.8 days) than in NLF group (6.4 +/ - 0.7). The TIF procedure was safe; 1 serious adverse event in the TIF group and 3 in the NLF group were observed. The authors concluded that both NOTES TIF procedures were, after the initial learning curve, safe and effective methods for treatment of GERD, allowing substantial shortening of hospital stay. The effect of both procedures was sustained over 12 months. Moreover, they noted that longer follow-up is necessary to verify efficacy for more years.
In a prospective, open-label, multi-center, single-arm study, Bell et al (2012) attempted to (i) validate previously reported safety and symptomatic outcomes of TIF, (ii) evaluate the relative benefit of TIF within different GERD subgroups, and (iii) determine predictors of success in community settings. Between January 2010 and February 2011, a total of 100 consecutive patients who underwent TIF procedures at 10 centers were enrolled in this study. Symptom improvement and objective outcomes of TIF were analyzed at 6-month follow-up. One hundred TIF procedures were performed. No complications were reported. Median GERD symptom duration was 9 years (range of 1 to 35 years) and median duration of PPI use was 7 years (1 to 20 years). Maximal medical therapy resulted in incomplete symptom control for 92 % of patients; GERD-HRQL total score was normalized in 73 %. Median heartburn and regurgitation scores improved significantly, from 18 (range of 0 to 30) and 15 (range of 0 to 30) on PPIs before TIF to 3 (range of 0 to 25) and 0 (range of 0 to 25), respectively; p < 0.001. Median Reflux Symptom Index scores were reduced after TIF from 24 (range of 14 to 41) to 7 (range of 0 to 44); p < 0.001. Eighty percent of patients were completely off PPIs after TIF versus 92 % of patients on PPIs before TIF. Pre-operative factors associated with clinical outcomes were less severe heartburn (total GERD-HRQL less than or equal to 30, p = 0.02) and the presence of esophagitis (p < 0.02). The authors concluded that TIF is safe and effective in multiple community-based settings in the treatment of medically refractory GERD, as demonstrated by an absence of complications, excellent symptom relief, and complete cessation of PPIs at 6-month follow-up. The main drawbacks of this study were its non-randomized nature and short-term follow-up. Furthermore, TIF is not as effective in primary symptom response as traditional laparoscopic fundoplication.
Muls et al (2013) prospectively evaluated the long-term safety and durability of TIF in a multi-center setting. A longitudinal per protocol (PP) and a modified intention-to-treat (mITT) analysis at 1 and 3 years consisted of symptom evaluation using the GERD-HRQL questionnaire, medication use, upper GI endoscopy, and pH-metry. Of 79 patients previously reported at 1 year, 12 were lost to follow-up, and 1 died from an unrelated cause. The remaining 66 patients were followed-up and analyzed (mITT). Of 66 patients, 12 underwent revisional procedures, leaving 54 patients for PP analysis at a median of 3.1 years (range of 2.9 to 3.6). No adverse events related to TIF were reported at 2- or 3-year follow-up. On PP analysis, median GERD-HRQL score off PPIs improved significantly to 4 (range of 0 to 32) from both off (25 [13 to 38], p < 0.0001) and on (9 [0 to 22], p < 0.0001) PPIs. Discontinuation of daily PPIs was sustained in 61 % (mITT) and 74 % (PP) of patients. Of 11 patients with pH data at 3 years (PP), 9 (82 %) remained normal. Based on mITT analysis, 9/23 (39 %) remained normal at 3 years. The authors concluded that the clinical outcomes at 3 years following TIF, patient satisfaction, healing of erosive esophagitis, and cessation of PPI medication support long-term safety and durability of the TIF procedure for those with initial treatment success. Moreover, they noted that although complete normalization of pH studies occurred in a minority of patients, successful cases showed long-term durability. Furthermore, they stated that “the steep learning curve with the EsophyX device may negatively influence the results of this study. Perhaps, multi-center studies with surgeons who are through their learning curve with a focus primarily on physiological outcomes may further define the role of TIF in the management of chronic GERD in the future”.
In a multi-center, prospective, single-arm study, Lipham et al (2012) examined the long-term safety and effectiveness of the LINX reflux management system. A total of 44 patients underwent a laparoscopic surgical procedure for placement of the LINX System around the gastro-esophageal junction (GEJ). Each patient's baseline GERD status served as the control for evaluations post-implant. Long-term efficacy measures included esophageal acid exposure, GERD quality-of-life measures, and use of PPIs. Adverse events and long-term complications were closely monitored. For esophageal acid exposure, the mean total % time pH less than 4 was reduced from 11.9 % at baseline to 3.8 % at 3 years (p < 0.001), with 80 % (18/20) of patients achieving pH normalization (less than or equal to 5.3 %). At greater than or equal to 4 years, 100 % (23/23) of the patients had improved quality-of-life measures for GERD, and 80 % (20/25) had complete cessation of the use of PPIs. There have been no reports of death or long-term device-related complications such as migration or erosion. The authors concluded that sphincter augmentation with the LINX Reflux Management System provided long-term clinical benefits with no safety issues, as demonstrated by reduced esophageal acid exposure, improved GERD-related quality of life, and cessation of dependence on PPIs, with minimal side effects and no safety issues. Patients with inadequate symptom control with acid suppression therapy may benefit from treatment with sphincter augmentation. The major drawbacks of this study were its small sample size (only 23 patients were available at 4 years) and the lack of a comparison group.
Moreover, the NICE’s guidance on “Laparoscopic insertion of a magnetic bead band for gastro-oesophageal reflux disease” (2012) considered insertion of a magnetic bead band for the treatment of GERD to be an innovative concept which, if shown to be safe and effective in further studies, could be a useful addition to the treatment options. The report stated that “The evidence on the safety and efficacy of laparoscopic insertion of a magnetic bead band for gastro-oesophageal reflux disease (GORD) is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research …. NICE encourages further research and collaborative data collection on laparoscopic insertion of a magnetic bead band for GORD”.
A technology brief on the LINX device for the Australian Safety and Efficacy of New Interventional Procedures - Surgical (ASENIP-S, 2013) concluded: "The findings of the two clinical trials reported in this Technology Brief illustrate promising results for the use of the LINX® Reflux Management System in treating patients with GORD. In particular, the device’s ability to be removed if required and the lower rate of side effects, compared with conventional surgical intervention, make the device a favourable treatment alternative (provided its utility in patients with significant oesophagitis and hiatal hernia can be determined). However, the evidence base for this technology is in its infancy and it is not currently possible to determine the safety and effectiveness of the LINX® device. Future studies should be comparative (ideally randomised), with broader patient populations and without industry sponsorship. Particular outcomes of interest for future studies should include the durability of the device (i.e. the lifespan of the magnets), its ability to reduce the likelihood of complications of GORD (i.e., Barrett’s oesophagus and cancer) and patient QoL. In addition, regulatory approval of the LINX® Reflux Management System in Australia does not appear to be imminent, and the cost of the device is likely to be a barrier to its uptake in clinical practice at this time."
On October 2, 2012, EndoGastric Solutions Inc. (Redwood City, CA) announced the completion of enrollment in its Transoral Incisionless Fundoplication (TIF) versus Medical Proton Pump Inhibitor (PPI) Management of Refractory GERD Symptoms (TEMPO) clinical trial, which will generate U.S. Level I evidence for TIF. The trial is designed to assess the safety and effectiveness of the TIF procedure as compared to PPI therapy to treat bothersome symptoms associated with chronic GERD. The TEMPO trial is a prospective, controlled, multi-center, randomized, open-label comparative clinical study. A total of 51 patients have been enrolled in the trial. Patients were randomized in a 2:1 ratio, in which 34 patients were treated with TIF and 17 remained on PPI therapy. The primary endpoint is symptom elimination or improvement. Secondary endpoints are esophageal acid exposure time, PPI usage, healing of esophagitis and patient satisfaction. Eligible patients were those who have objective evidence of GERD, a history of daily PPI therapy for over 6 months, and a hiatal hernia less than 2 centimeters. Additional information about the TEMPO trial can be found at http://www.clinicaltrials.gov/ and http://www.acidrefluxtrial.com/.
Ganz et al (2013) prospectively assessed 100 patients with GERD before and after sphincter augmentation. The study did not include a concurrent control group. The primary outcome measure was normalization of esophageal acid exposure or a 50 % or greater reduction in exposure at 1 year. Secondary outcomes were 50 % or greater improvement in quality of life related to GERD and a 50 % or greater reduction in the use of PPIs at 1 year. For each outcome, the pre-specified definition of successful treatment was achievement of the outcome in at least 60 % of the patients. The 3-year results of a 5-year study were reported. The primary outcome was achieved in 64 % of patients (95 % CI: 54 to 73). For the secondary outcomes, a reduction of 50 % or more in the use of PPIs occurred in 93 % of patients, and there was improvement of 50 % or more in quality-of-life scores in 92 %, as compared with scores for patients assessed at baseline while they were not taking PPIs. The most frequent adverse event was dysphagia (in 68 % of patients post-operatively, in 11 % at 1 year, and in 4 % at 3 years). Serious adverse events occurred in 6 patients, and in 6 patients the device was removed. The authors concluded that the current study was designed so that the direct effects of the sphincter augmentation device on each patient's exposure to esophageal acid, use of PPIs, and symptom control could be measured before and after the implantation. This design was limited in that it did not allow direct comparisons with other forms of therapy. These researchers stated that prospective, randomized trials with larger samples and longer-term follow-up are needed to confirm these early results and assess longer-term safety.
Bonavina et al (2013) stated that the LINX Reflux Management System is designed to provide a permanent solution to GERD by augmenting the sphincter barrier with a standardized, reproducible laparoscopic procedure that does not alter gastric anatomy and is easily reversible. Two single-group trials confirmed that a magnetic device designed to augment the LES can be safely and effectively implanted using a standard laparoscopic approach. The device decreased esophageal acid exposure, improved reflux symptoms and quality of life, and allowed cessation of PPIs in the majority of patients.
Yew and Chuah (2013) discussed the past and present status of anti-reflux endoluminal therapy. Currently, there are 3 commonly employed anti-reflux endoluminal procedures: (i) fundoplication or suturing techniques (EndoCinch, NDO, and EsophyX), (ii) intramural injection or implant techniques enhancing LES volume and/or strengthening compliance of the LES-Enteryx and Gatekeeper), and (iii) RF ablation of LES and cardia. EndoCinch plication requires further study and modification of technique before it can be recommended because of durability issues. Esophyx, the TIF, may reduce hiatal hernias and increase LES length. Preliminary studies have shown promising reduction in symptoms and medication use but evidence concerning safety and long-term durability is still pending. The safety issue with injection technique is the main concern as evident from the incidences of implant withdrawals after reported major adverse events. Future research with cautious monitoring is required before any new implant material can be recommended for commercial application. Radiofrequency ablation therapy is regaining popularity in treating refractory symptoms despite PPI use due to improved efficacy, durability, and safety after years of refinement of protocol.
Kim and colleagues (2013) noted that while acid suppression with PPIs remains the mainstay of treatment of GERD, some patients showed refractory response to PPIs, necessitating further intervention. After increasing dosage of PPIs and other kinds of pharmacological intervention adopting prokinetics or others, variable endoscopic treatments were introduced for the treatment of these refractory cases. Implantation of reabsorbable or synthetic materials in the distal esophagus was tried in vain and is expelled from the market due to limited efficacy and serious complication. The authors stated that RF energy delivery (Stretta) and TIF (EsophyX) are actively tried currently.
The expert panel convened by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Technology and Value Assessment Committee (2013) concluded the following:
- The incidence of initial dysphagia following LINX implantation is high. Difficulty swallowing was more commonly reported at 12 and 24 months following LINX implantation than at baseline. Patients should be advised about the possibility that it may be more difficult to swallow following surgery, and that this symptom may persist.
- The LINX device may provide an option currently lacking in clinical practice for patients with medically refractory GERD who have not yet progressed to end-stage reflux disease with associated complications.
- Direct comparative studies between the LINX procedure and Nissen fundoplication will be needed
- On the basis of the available evidence, the LINX device should be an option available to patients and providers for the management of medically refractory GERD.
On the other hand, the American College of Gastroenterology (ACG)’s guidelines on “Diagnosis and management of gastroesophageal reflux disease” (Katz et al, 2013) did not agree with the expert opinion rendered by the SAGES Technology and Value Assessment Committee. The ACG guidelines stated that “Endoscopic therapies for GERD have been developed but have not demonstrated long-term efficacy. These therapies included radiofrequency augmentation to the lower esophageal sphincter, silicone injection into the lower esophageal sphincter, and endoscopic suturing of the LES. None of these therapies demonstrated long-term improvement in esophageal pH levels or the ability for patients to stop antireflux therapy and were subsequently removed from the US marketplace. Recent alternative approaches have included transoral incisionless fundoplication, a suturing device designed to create a full thickness gastroesophageal valve from inside the stomach. Unfortunately long-term data regarding efficacy of this device are limited to a small number of subjects and short duration of follow-up. A recent study suggested that at 36 months of follow-up, the majority of patients had required additional medical therapy or a revisional fundoplication. Sphincter augmentation using the LINX Reflux system constructed of titanium beads has shown efficacy up to 4 years in the reduction of the amount of pathologic esophageal acid exposure in a small number of subjects. This device has been approved by the FDA based on a clinical study in 100 GERD patients. This study found that performance of LINX resulted in consistent symptom relief and pH control with markedly fewer side effects than traditional laparoscopic fundoplication in well-selected patients. More data are required before widespread usage can be recommended. The usage of current endoscopic therapy or transoral incisionless fundoplication cannot be recommended as an alternative to medical or traditional surgical therapy”.
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