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Device Profile

Transoral incisionless fundoplication for the treatment of gastroesophageal reflux disease Expert Rev. Med. Devices 11(4), 341–350 (2014)

Kevin M Reavis*1 and Kyle A Perry2 1 Esophageal and Foregut Surgery, Division of Gastrointestinal and Minimally Invasive Surgery, The Oregon Clinic, 4805 NE Glisan Street, Ste 6N60, Portland, OR 97213, USA 2 Division of General and Gastrointestinal Surgery, The Ohio State University, N729 Doan Hall 410 W. 10th Ave. Columbus, OH 43210, USA *Author for correspondence: Tel.: +1 503 281 0561 Fax: +1 503 281 0575 [email protected]

Gastroesophageal reflux disease (GERD) is a common and costly chronic medical condition affecting millions of patients. It is associated with substantial morbidity and negatively impacts quality of life. Reflux of gastric contents into the esophagus damages the esophageal mucosa and is associated with conditions including esophagitis and esophageal stricture. While GERD is most commonly seen in Western populations, changes in dietary patterns and the global increase in obesity have led to a pronounced increase in its prevalence worldwide. Medical and surgical GERD therapies are costly and pose considerable side effects, leading many to pursue effective endoscopic treatment options. Transoral incisionless fundoplication is an endoluminal procedure that offers patients a minimally invasive treatment option with the potential to eliminate the need for medical acid suppression with a low risk of side effects. KEYWORDS: endoluminal surgery • endoluminal therapy • esophagitis • EsophyXTM • gastroesophageal reflux disease • transoral incisionless fundoplication

Gastroesophageal reflux disease (GERD) is a progressive chronic condition that affects a substantial proportion of the world’s population. GERD develops when the antireflux barrier created by the lower esophageal sphincter (LES) between the stomach and esophagus is compromised. As a result, there is reflux of gastric contents into the esophagus causing typical symptoms of heartburn, dysphagia and regurgitation, and also atypical symptoms including chronic cough and laryngitis. GERD symptoms interfere with daily activities and have been associated with significantly increased work absenteeism, reduced productivity at work [1–5] and increased healthcare resource utilization [5]. The first clinical description of GERD appeared in 1935 as a case report of severe peptic esophagitis [6]. Clinical developments in the intervening decades, particularly flexible endoscopy, facilitated our understanding of the anatomy and physiology of the gastrointestinal tract, the ability to diagnose GI problems and a greater awareness of GERD informahealthcare.com

10.1586/17434440.2014.925394

and its consequences. Anatomically, the distal esophagus is composed of smooth muscle that contracts at rest and relaxes upon swallowing. At the gastroesophageal junction (GEJ), the musculature of the distal esophagus and gastric cardia in conjunction with the diaphragmatic hiatus forms the LES, a zone of increased pressure (10–30 mmHg) compared to intraluminal gastric pressure (5 mmHg). This pressure gradient and the anatomical structure of the stomach’s angle of His prevent the passage of gastric contents back into the esophagus (FIGURE 1). In GERD, disturbances in LES structure or function result in uncoordinated propulsion of food, regurgitation of gastric contents into the esophagus and inadequate clearance of acid and bile from the esophagus. If left untreated, this produces troublesome symptoms or complications in a significant proportion of patients [7,8]. In recent years, there has been a debate on whether GERD represents a continuum of

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ISSN 1743-4440

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Longitudinal esophageal muscle Esophageal mucosa

Circular esophageal muscle

Submucosa Gradual slight muscular thickening Phrenoesophageal ligament (ascending or upper limb)

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Supradiaphragmatic fascia Diaphragm

Diaphragm Infradiaphragmatic (transversalis) fascia Phrenoesophageal ligament (descending limb)

Subhiatal fat ring

Peritoneum

Zigzag (Z) line: juncture of esophageal and gastric mucosa

Cardiac notch

Cardiac part (cardia) of stomach

Longitudinal esophageal muscle (cut) Circular esophageal muscle (shown here as spiral)

Gastric folds (rugae)

Cardiac notch Fundus of the stomach

Collar of helvetius

Window cut in middle circular muscle layer of stomach

Innermost oblique muscle layer of stomach (forms sling)

Outer longitudinal muscle layer of stomach (cut)

Figure 1. Gastroesophageal junction. The GEJ, located at the distal end of the esophagus, acts as an antireflux barrier. The distal end of the esophagus is composed of smooth muscle that contracts at rest and opens upon swallowing. At the junction of the lower esophageal sphincter and stomach (the GEJ or GEJ designated as the ‘Z’-line), a pressure zone is formed that has higher pressures (10–30 mmHg) than found in the gastric lumen (5 mmHg). This pressure difference and the anatomical structure of the stomach’s angle of His prevent the retrograde passage of gastric contents into the esophagus. GEJ: Gastroesophageal junction.

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TIF for the treatment of GERD

Device Profile

Table 1. Esophageal and extra-esophageal syndromes.

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Esophageal syndromes

Extra-esophageal syndromes

Symptomatic syndromes

Syndromes with esophageal injury

Established associations

Suggested associations

Typical reflux

Reflux esophagitis

Reflux-associated cough

Pharyngitis

Noncardiac chest pain

Reflux stricture

Reflux-associated laryngitis

Sinusitis

Barrett’s esophagus

Reflux-associated asthma

Idiopathic pulmonary fibrosis

Esophageal adenocarcinoma

Dental erosion

Recurrent otitis media

symptoms or a constellation of distinct syndromes [9,10]. The classification of GERD into esophageal and extra-esophageal syndromes underscores the diversity of symptoms experienced by patients, a large number of whom suffer from a broad range of symptoms other than heartburn (TABLE 1). Epidemiologic studies have established associations between GERD and chronic cough, chronic laryngitis, asthma and dental erosion [8,10,11]. Overview of the GERD marketplace

There are no definitive studies identifying the worldwide prevalence of GERD. In Western countries, 10–20% of the adult population report at least weekly heartburn or acid regurgitation [1]. This is significantly higher than the 5% prevalence commonly reported for Asian populations [1]. Epidemiological differences appear to be related to different lifestyles, eating habits and prevalence of Helicobacter pylori [7]. Epidemiologic studies have identified risk factors that help to explain the increasing prevalence of GERD worldwide. Obesity, diabetes mellitus and increasing age are all associated with GERD [1,7]. Smoking, coffee consumption and alcohol use have also been implicated as factors associated with GERD, but only the role of smoking has been clearly established [7]. An association between asthma and GERD has been found, but the nature of the association has not been established because either condition can induce the other [2]. Some prescription drugs including beta blockers, calcium channel blockers, antidepressants and nonsteroidal anti-inflammatory agents may interfere with gastric acid secretion, gastric mucus production, motility or LES pressure reduction, but their role in GERD has not been clearly established [4,7]. Changes in dietary patterns and the global increase in obesity have led to a pronounced increase in the prevalence of GERD. GERD can manifest in infancy, particularly in preterm infants, and is also increasingly seen in young children and adolescents [7]. Because GERD is one of the fastest growing diseases of the digestive tract, it is recognized and treated not only by gastroenterologists and surgeons but also by pulmonologists, family practitioners, internists, pediatricians and dentists [1,4]. The frequency of GERD visits in the USA increased consistently over a 12-year period, nearly doubling from 1995 (9.1 per 1000 visits) to 2006 (16.3 per 1000 visits), with the majority of these visits with primary care physicians [4]. The significant disease burden, reduction in patient quality of life, risk of serious complications, economic impact and market potential for new drugs and devices help explain the informahealthcare.com

intense interest in GERD and the development of cost–effective approaches for its diagnosis and management [12,13]. Treatment options for GERD

If left untreated, GERD may lead to esophagitis, esophageal stricture, Barrett’s esophagus, laryngeal injury, pneumonia and other potentially serious esophageal conditions [7,14]. The diagnosis is complicated by the fact that some GERD symptoms can be indicators of other functional gastrointestinal disorders including functional dyspepsia and irritable bowel syndrome [9]. Disease manifestations vary greatly between individuals and patients may present to physicians of various disciplines with symptoms that may or may not provide clues to the underlying cause of the symptoms. To differentiate GERD from other potential conditions and to assess its severity, a standard work-up of the GERD patient should be followed, whether the patient seeks medical, surgical or endoluminal treatment [15,16]. Patient evaluation should include: • Contrast esophagram to evaluate the overall anatomy of the foregut and identify hiatal hernias. • Upper endoscopy to evaluate the esophagogastric mucosa and tissue diagnosis of suspect lesions such as Barrett’s esophagus. • pH and/or impedance testing to objectively characterize the severity of disease. Impedance testing provides an option for patients who are unable to tolerate pH testing while off of antisecretory medication and for patients presenting with atypical symptoms that are not adequately characterized with standard pH testing. • Esophageal manometry to characterize esophageal motility and customize treatment for patients with severe esophageal dysmotility. The common medical approach is the use of antisecretory drugs, most commonly proton pump inhibitors (PPIs). PPIs are considered the first-line treatment for patients with GERD due to their demonstrated efficacy and general safety profiles [17]. PPIs successfully relieve heartburn in 60–80% of patients and heal erosive esophagitis in 50–90%, but they do not stop the regurgitation. A recent systematic literature review indicates that 17–32% of those included in interventional studies in primary care have persistent reflux symptoms despite PPI therapy [18]. Other studies estimate that 20–30% of patients with GERD continue to experience persistent and intense reflux symptoms while receiving standard-dose PPI therapy [19]. 343

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initial results, safety concerns and failure to control GERD symptoms at longer follow-up intervals resulted in the withdrawal of several of them from the market [30,31]. Three endoluminal treatment approaches are currently available [32]:

• Helix – Anchors tissue for radial manipulation – Engages and retracts tissue close to the z-line • Tissue mold and chassis

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– Compresses tissue – Wraps tissue around the esophagus • Invaginator – Enables retraction of distal esophagus – Reduce hiatal hernia and prepare construct for fastener delivery • Stylets and fasteners – Transect apposed tissues – Plicate apposed tissues

Figure 2. EsophyXTM transoral incisionless fundoplication device.

• Transoral incisionless fundoplication (TIF); • Radiofrequency (RF) ablation (Stretta procedure), which utilizes the delivery of RF energy to the LES to decrease compliance of the LES and create a physiologic antireflux barrier; • Endoluminal gastroesophageal plication (endoscopic stapling) that allows plication of the gastric fundus from within the lumen to recreate the LES or repair a patulous antireflux barrier. TM

In addition, people with atypical GERD symptoms have unpredictable responses to PPIs [2]. Once PPI therapy is discontinued, reflux symptoms return in 75–90% of patients. As a result, many patients are confronted with the prospect of costly lifelong medical treatment to avoid recurrent symptoms. Occasionally, patients may develop intolerable side effects. Emerging data have also suggested potential risks associated with long-term PPI therapy including variations in bioavailability of common medications, vitamin B12 deficiency, Clostridium difficile-associated diarrhea, community-acquired pneumonia, mineral and electrolyte imbalances and hip fracture [20–22]. GERD patients who receive little or no symptomatic relief, those who cannot adhere to long-term PPI use and patients with atypical symptoms or regurgitation are candidates for a surgical fundoplication to potentially improve their quality of life. Fundoplication was previously performed via thoracotomy or laparotomy; however, the laparoscopic approach is now considered the standard surgical treatment for GERD [23]. Overall patient satisfaction during long-term follow-up has been reported between 90 and 96% [2,24,25]. The main objective of fundoplication is to restore the antireflux barrier by reconstructing the LES. The result of a fundoplication, however, is often a supercompetent valve that limits the ability to vent air, leading to surgically associated morbidity and side effects of dysphagia, bloating, flatulence and difficulty belching [26–28]. These side effects may persist for more than 6 months following surgery and can be difficult to treat [29]. The potential for these side effects is considered intolerable by many patients who are reluctant to consider surgery [27]. Particularly in the elderly, concerns regarding morbidity and mortality can result in delayed referral for potentially beneficial surgical procedures [12,27]. Over the past two decades, progress has been made in the development of endoscopic treatment of GERD. Several early endoluminal techniques showed promise, but inadequate 344

TIF using the EsophyX device (EndoGastric Solutions Inc., Redmond, WA, USA) is the subject of this device profile. The EsophyX device & TIF technique

The EsophyX device is an endoluminal surgery device designed to create a transoral esophagogastric fundoplication for the treatment of GERD (FIGURE 2). TIF is facilitated by elements of the device, which allow suction, retraction, clamping and transmural fastening of tissue at the GEJ from within the gastric and esophageal lumen. The procedure creates an anterior partial fundoplication by attaching the fundus of the stomach to the anterior and left lateral wall of the distal esophagus [31–33]. General anesthesia with nasotracheal or orotracheal intubation is induced and the patient is prepared and positioned in the left lateral decubitus position for a standard upper endoscopy. A diagnostic upper endoscopy is performed to assess the anatomic characteristics of the diaphragmatic crus, to evaluate for the presence of a hiatal hernia and to confirm that no obvious evidence of malignancy or other mucosal abnormalities are present. The EsophyX device and endoscope are introduced as a unit transorally into the stomach under direct visualization. The dilation of the cricopharyngeus muscle with a 56 French Maloney dilator and the lubrication of the endoscope and EsophyX device with medical grade olive oil or similar lubricant allow for easier passage of the device. Under direct visualization and in the retroflexed position, the EsophyX device manipulates the gastric fundus up to and around the lower esophagus. ‘H’-shaped polypropylene fasteners are delivered through the folded tissue approximately 1–2 cm above the GEJ. Fourteen to twenty fasteners are placed using the device to develop a 2–3 cm, 200–270˚ esophagogastric plication. A final upper endoscopy is performed to confirm that an adequate fundoplication has been created and that no evidence of perforation or bleeding is present.

Expert Rev. Med. Devices 11(4), (2014)

TIF for the treatment of GERD

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Indications for TIF

Patients with objective evidence of moderate GERD without significant anatomic distortion at the GEJ (i.e., hiatal hernia less than 2 cm) are candidates for endoluminal treatment. Contraindications to TIF include a body mass index greater than 35 kg/m2, Barrett’s esophagus, prior esophageal myotomy, esophageal varices, major connective tissue disorders and hiatal hernia greater than 2 cm. Because esophageal motility disorders have been associated with early recurrence of GERD symptoms following TIF [34,35], alternative treatment approaches should be used in these patients. The indications for TIF are based on descriptions of those patients who have mild-to-moderate disease or are unresponsive or partially responsive to PPIs. This is defined as patients who are on at least daily PPI therapy and are still experiencing breakthrough heartburn and/or regurgitation. Although anecdotal clinical indications have been known to vary, the experience reflected in the cited papers is reported here. The results of hypothesis-driven prospective clinical research are needed to more accurately identify the patient population(s) who will most benefit from TIF. TIF procedure & postprocedure care

When performed as described above, the mean operating time reported for TIF averages 45–80 min with a postoperative stay of 1 day [27,36–38]. Postoperatively, a 2-week thickened liquid diet is commonly utilized to minimize gastric distension and stress on the fundoplication. The diet is then advanced to a soft diet for another 2 weeks and transitioned to regular food as the patient tolerates. Liberal use of antiemetic medications may also avoid stress to the treated area. PPI therapy may be prescribed for 14 days postoperatively to reduce the risk of gastric bleed and patients are asked to refrain from vigorous physical activities during the immediate postoperative period [39]. Standard post-antireflux surgery follow-up clinic appointments are recommended, and patients who report recurrent symptoms should be considered for additional evaluation with upper endoscopy or pH testing. Adverse events

Immediate postsurgical complaints and symptoms experienced within the first 2 weeks are generally mild and limited. Epigastric pain is reported in approximately 50% of cases and a small proportion (15%) complain of left shoulder pain. Sore throat occurs in 4–5% of patients and a small proportion (1%) complain of nausea [27]. Pain symptoms may require narcotic pain medication for 3–4 days following surgery, but pain beyond 4 days is unusual [36]. As with any endoscopic procedure, careful insertion and manipulation of the EsophyX device is required, as hypopharyngeal perforation has occurred. Because transmural fasteners are placed above the Z-line, there is a potential for esophageal laceration, esophageal leak, mediastinal infection or subdiaphragmatic abscess. Finally, care should be taken during device manipulation as the tissue mold can cause trauma to the spleen during retroflexion and opening, and informahealthcare.com

Device Profile

incorrect advancement of the stylets carries the potential to injure the liver, diaphragm or heart [36]. Clinical profile & postmarketing findings

TIF has evolved since its introduction in 2006. Initially, the procedure was called endoluminal fundoplication that enhanced the LES by creating a gastro–gastric plication (TIF 1). The procedure was later modified to gastroesophageal plication that envelopes a segment of distal esophagus within the gastric fundus (TIF 2) [27,40]. Anatomic studies of the two procedures in canine models demonstrated that the gastroesophageal plication generated a physiologic flap valve that closed more consistently with increasing intragastric pressure [41]. To date, the literature consists of mostly singleinstitution retrospective cohort studies, and the clinical studies presented here include those assessing outcomes of the currently utilized TIF 2 technique. One study included a population of 19 patients with typical GERD symptoms who had failed management with PPIs, a positive esophageal pH test with symptom correlation and no hiatal hernia larger than 2 cm [42]. Three patients experienced major complications (esophageal perforation, hemorrhage requiring transfusion and permanent numbness of the tongue) that were treated nonoperatively. Five patients completely discontinued and three decreased the use of PPIs at a mean follow-up of 10.8 months. However, 10 patients were converted to laparoscopic fundoplication for recurrent reflux symptoms. Another clinical report of the experience of 110 patients has demonstrated clinical effectiveness for the general population. In this community-based study, 72% of patients were considered in remission (satisfied with TIF 2 therapy, reported no symptoms and did not require any GERD medications) at a median follow-up of 7 months [27]. Another community-based study of 34 patients with 14-month follow-up demonstrated discontinuation of PPI use in 64% of patients, elimination of heartburn in 65% and control of regurgitation in 80% [43]. The procedure was successfully performed in all patients with no postoperative complications. Narsule et al. [38] reported their initial clinical experience with 46 patients and reported subset analyses of patients with typical (n = 35) and atypical (n = 11) GERD symptoms. Among patients with typical symptoms, significant improvements were seen in mean GERD-health related quality of life (GERD-HRQL) scores (p < 0.001), whereas patients with atypical symptoms did not show significant improvements in GERD-HRQL. Among the 46 patients, there were three who experienced recurrent symptoms due to wrap disruption. Three underlying mechanisms were identified: suboptimal placement of the polypropylene H-fasteners, suboptimal patient selection (a type 4 Hill gastroesophageal valve), and poor postsurgical patient compliance with recommended activity levels. A small clinical study reported on the results of 24-h pH monitoring and esophageal manometry at 6-month follow-up for 14 patients [44]. Compared with preprocedure testing, TIF 345

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Reavis & Perry

demonstrated significant reductions in distal acid exposure time and DeMeester score. No significant difference was identified in mean LES pressure. Six patients had a normal pH study at 6 months. Three patients experienced minor side effects (dysphagia, bloating and nausea) that are also associated with laparoscopic fundoplication and one experienced a minor mucosal tear above the GEJ. Recently, initial follow-up of 100 consecutively enrolled patients in the TIF registry and a prospective, open-label, multicenter, postmarketing study in 15 US centers with experienced TIF surgeons was reported [39]. In addition to PPI usage, typical and atypical GERD symptoms were assessed and pH testing was completed when available. At 6-month follow-up, GERDHRQL scores were normal in 73% of patients, median heartburn and regurgitation scores improved significantly (p < 0.001), median reflux symptoms were significantly reduced (p < 0.001) and 80% of patients discontinued PPI therapy. There were no minor or major adverse events reported. A recent systematic review and meta-analysis of the published literature examined the effects of TIF on subjective symptom scores and objective reflux measures [45]. This review found significant improvements in GERD-HRQL (21.9 vs 5.9) and reflux symptom index (24.5 vs 5.4) following TIF with an overall patient satisfaction rate of 72%. PPI therapy was successfully discontinued in two-thirds of patients with a median follow-up interval of 8.3 months. While improvements in DeMeester score and esophageal acid exposure time were demonstrated in some studies, TIF did not consistently normalize esophageal acid exposure. Overall, the major complication rate was 3.2% and the procedure failed in 7.2% of patients. In summary, the clinical studies reported in literature have demonstrated improved subjective outcomes in over 70% of patients with GERD symptoms resistant to PPI therapy; over 60% of patients discontinued the use of PPIs. The modifications to the procedure (TIF 2) and the EsophyX device have resulted in lower incidence of major complications (1.5%) and a lower reoperation rate (3.9%). Minor adverse events have been of limited duration and readily resolved with conservative clinical intervention. Early failures are generally attributed to patients coughing, retching or vomiting after the procedure, disrupting the wrap and preventing adhesion and scarring to keep the walls of the fundoplication together [46]. Alternative devices

Several endoscopic therapies for GERD have been introduced, but most have not demonstrated long-term efficacy. These include silicone injection into the LES and endoscopic suturing of the LES. It has been suggested that early approaches were less successful because they resulted in a narrowing of the GEJ, which is inadequate to mitigate acid reflux, and they did not restore the competency of the reflux valve [31,38]. In addition to TIF, two endoscopic treatments are currently available to treat GERD: RF energy delivery [StrettaÒ Therapy (Mederi Therapeutics, Inc., Greenwich, CT, USA)] and 346

an endoscopic stapling system [SRS System (Medigus, Ltd., Tel Aviv, Israel)]. Radiofrequency energy delivery system

The Stretta procedure delivers RF energy to the musculature of the LES and gastric cardia. The delivery system consists of an 8-Fr catheter and a distal balloon with four externally attached needle electrodes. The electrodes deliver computerregulated, low-power, temperature-controlled RF energy to the GEJ zone at 56 separate sites. The thermal lesions are believed to decrease the frequency of gastric reflux and transient LES relaxation due to shrinkage and cellular response in the submucosal tissue that surrounds each puncture site [31]. The procedure is performed as an outpatient (same day) procedure without general anesthesia. Clinical studies have shown improvement in clinical parameters and durability of effect [32,33,46]. The exact mechanism leading to improvement is not known, but may involve a combination of factors: increased wall thickness, increased LES pressure, decreased transient LES relaxation, decreased tissue compliance, decreased acid sensitivity or decreased acid exposure [46]. The Stretta RF energy delivery system was initially launched in 1998 by the former Curon Medical and was acquired by Mederi Therapeutics in 2008. A CE mark was awarded in 2010; the US FDA originally cleared the device in 2000 and provided an updated clearance for a secondgeneration RF generator and catheter in 2011 [40,46]. A single-center, randomized, double-blind, sham-controlled crossover trial evaluated the effect of RF energy on GERD symptoms, esophageal acid exposure, distensibility of the GEJ and quality of life in 22 consecutive patients [47]. The primary outcome variable was the change in compliance of the GEJ before and after the Stretta procedure; secondary outcomes included change in GERD symptom scores, esophageal acid exposure, esophageal motility characteristics, resting LES pressure and PPI use. Changes in quality of life were measured using the SF-36. There was a significant improvement in GERD symptoms in the Stretta group in the absence of significant change in acid exposure. The Stretta procedure decreased the distensibility of the GEJ that was reversed following administration of a smooth muscle relaxant. Long-term safety and efficacy of the Stretta procedure was demonstrated in several studies with follow-up assessments at 48 months [48–50]. In all three studies, heartburn scores decreased, quality of life scores improved and the use of PPI medications declined significantly. Only one major adverse event (prolonged transient gastroparesis) occurred in the 248 patients enrolled in the studies; minor adverse events included dyspepsia, chest discomfort and minor gastric bleeding. A recent meta-analysis that included 1441 patients from studies published over 10 years confirmed an improved DeMeester score (from 44.4 to 28.5) and significant improvements in quality of life measured by the GERD-HRQL scale and quality of life in reflux and dyspepsia. RF treatment significantly reduced heartburn scores from 3.55 to 1.19 in pooled analysis [51]. Expert Rev. Med. Devices 11(4), (2014)

TIF for the treatment of GERD

Endoscopic stapling system

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TM

Lifestyle

Device Profile Conventional

surgery The Medigus SRS Endoscopic Stapling Pharmaceuticals TIF procedure changes System is a modified endoscope that fires three rows of staples (five staples per row) plicating the fundus onto the esophagus approximately 2.5–3 cm above the Early disease, no anatomic Anatomic correction GEJ and separated by at least 90˚ [52]. correction required warranted The stapling procedure results in a gastroesophageal plication intended to create Mild Severe GERD a flap valve and restore the angle of His. The procedure may be used to treat Figure 3. Gastroesophageal reflux disease symptom and treatment continuum. patients with hiatal hernia as large as GERD: Gastroesophageal reflux disease; TIF: Transoral incisionless fundoplication. 3 cm as long as the hernia can be reduced below the diaphragm [46]. The SRS system is CE marked and was FDA cleared in May 2012. of epidemiologic and clinical evidence indicates that classifying To date, there has been little published data from clinical tri- patients with GERD as a homogeneous group is inappropriate. als. A summary of unpublished data from 14 patients indicated A treatment algorithm that recognizes the clinical heterogeneity that 93% of the patients with grade I gastroesophageal flap of GERD and the patient preferences that emerge during the valve had improved quality of life scores. Twenty-four-hour discussion of treatment options should include endoscopic proacid exposure decreased from a median of 15% at baseline to cedures for well-selected patients (FIGURE 3). Additional evidence comparing the TIF procedure to other 6% [31]. A preliminary report of 19 patients with 6 months of treatment options will help to achieve better patient selection follow-up reported improved quality of life scores in 79%, four and outcomes. Available literature has reported on observapatients with normal acid exposure and 12 with improved acid tional studies with brief follow-up periods. Sham-controlled triexposure. All patients had reduced or stopped acid reflux medications at 6 months. Preliminary results from an open-ended als and studies directly comparing TIF to other antireflux prospective study of 13 patients in India followed for up to therapies have been lacking, although two forthcoming ran24 weeks reported improved quality of life and 83% reported domized, controlled clinical studies begin to address this need. The first study, TIF versus Medical PPI Management of significant relief of symptoms [53]. A recently published nonrandomized study assessed the Refractory GERD Symptoms trial, compares the 24-month safety and efficacy of the SRS system compared to laparoscopic experience of TIF to PPI therapy in patients with objective eviantireflux surgery (LARS) [54]. Eleven patients self-selected SRS dence of chronic GERD experiencing continued symptoms and 16 self-selected LARS (nine with Nissen fundoplication while on PPI therapy. The second study, Randomized EsophyX and seven with Toupet fundoplication). The SRS procedure versus Sham/Placebo Controlled TIF Trial, evaluates the relawas significantly longer than LARS (89 vs 47 min, respectively; tive merits, safety and effectiveness of the TIF procedure in p < 0.05). Over 6 months of follow-up, there were decreases in patients experiencing ‘troublesome symptoms,’ as defined by GERD-HRQL scores in both groups (87% of patients in the the Montreal consensus definition while on PPI therapy comLARS group; 64% of patients in the SRS groups); PPI use did pared with sham and placebo controls. not differ between the two groups. Topuz and colleagues have also described anesthetic management for the procedure and Five-year view Endoluminal therapies like the TIF procedure are technically the clinical experience on 12 patients [55]. safe in well-selected patients, including those with prior esophageal and gastric surgeries, and the long-term effectiveness of Conclusion TIF represents an important step in the evolution of endolumi- these treatments is being evaluated. As each of these approaches nal GERD therapy. Clinical studies conducted to date have evolve, careful evaluation of symptom resolution and esophshown that TIF is an effective and safe treatment for mild-to- ageal acid exposure will remain an important clinical research moderate GERD symptoms in carefully selected patients. The focus. Ultimately, high-quality clinical studies directly comparmajor and minor adverse event experience compares favorably ing TIF with other GERD therapies, more studies that include with that reported for laparoscopic fundoplication. Controlled postoperative pH evaluations and studies assessing long-term studies regarding the comparative efficacy and long-term dura- durability and cost-effectiveness are required. Widespread use of TIF for patients with mild-to-moderate bility of TIF are ongoing. GERD will depend on continued improvements in the device and refinement of the procedure that will create a robust valve Expert commentary The continued refinement of the TIF procedure has resulted in that is consistent and durable. Also, device modifications that an effective and, for many patients, acceptable treatment option simplify the location, deployment and placement of the for the management of symptomatic GERD. A growing body H-fasteners are needed.

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Information resources

Financial & competing interests disclosure

For further information on TIF and the TIF device, please see resources. Available from: www.endogastricsolutions.com [Last accessed 6 October 2013]. For further information on the RF energy delivery system, please see resources. Available from: www.mederitherapeutics. com [Last accessed 4 December 2013]. For further information on the endoscopic stapling system, please see resources. Available from: www.medigus.com/ [Last accessed 4 December 2013].

K Reavis and K Perry are consultants for EndoGastric Solutions Inc. Angeline Carlson from Data Intelligence Consultants LLC provided content support. Data Intelligence Consultants, LLC, Eden Prairie, MN, USA provided editorial assistance with this manuscript, which has been supported by funding from EndoGastric Solutions Inc., Redmond, WA, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Gastroesophageal reflux disease is a common and costly chronic condition affecting a substantial proportion of the world’s population. • Until recently, available treatment options offered limited choices for patients with inadequately controlled gastroesophageal reflux disease symptoms – potentially lifelong, high-dose proton pump inhibitors therapy or laparoscopic surgery with significant sequelae. • Transoral incisionless fundoplication offers an endoscopic alternative to laparoscopic fundoplication for patients with minimal anatomic changes in the gastroesophageal junction. • Transoral incisionless fundoplication surgery is a safe, well-tolerated and effective treatment that has yielded significant symptomatic improvement in patients with medically refractory gastroesophageal reflux disease symptoms. • Studies in the USA using the transoral incisionless fundoplication procedure have demonstrated significantly improved objective and subjective outcomes in up to 70% of patients with proton pump inhibitor-resistant symptoms.

Papers of special note have been highlighted as: • of interest •• of considerable interest 1.

2.

3.

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5.

Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastroesophageal reflux disease: a systematic review. Gut 2005;54: 710-17 Heidelbaugh JJ, Gill AS, Van Harrison R, Nostrant TT. Atypical presentations of gastroesophageal reflux disease. Am Fam Physician 2008;78(4):483-8 Fass R. Effect of gastroesophageal reflux disease on sleep. J Gastroenterol Hepatol 2010;25(Suppl 1):S41-4 Friedenberg FK, Hanlon A, Vanar V, et al. Trends in gastroesophageal reflux disease as measured by the National Ambulatory Medical Care Survey. Dig Dis Sci 2010;55: 1911-17 Toghanian S, Wahlqvist P, Johnson DA, et al. The burden of disrupting gastro-oesophageal reflux disease: a database study in US and European cohorts. Clin Drug Investig 2010;30(3):167-78

6.

Dent J. Landmarks in the understanding and treatment of reflux disease. J Gastroenterol Hepatol 2009;24(Suppl 3): S5-14

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