Endoscopic Injection of Bulking Agents

EARTs of yesteryears include injection of bulking agents (Enteryx, Gatekeeper Reflux Repair System, Plexiglas, Durasphere) and endoscopic suturing (EndoCinch and NDO plicator) to boost the anti-reflux barrier.

The injectable bulking agents which have been used for sphincter augmentation are made of biocompatible non-resorbable co-polymers. These include ethylene-vinyl-alcohol copolymer (Enteryx), hydrogel cylinder-shaped prostheses (Gatekeeper System), and polymethyl methacrylate (Plexiglas). Initial studies evaluating sphincter augmentation with injectable bulking agents showed encouraging results [6, 10, 11, 14, 25, 44]. In a randomized sham controlled trial, implantation of Enteryx was more effective in reducing PPI dependency and symptoms of GERD [6]. In contrast, another multicenter randomized trial concluded that injectable prosthesis (Gatekeeper System) was no better than control group with respect to improvement in symptoms or objective parameters like esophageal acid exposure [12]. However, most of the other studies were non-randomized with small patient population and short follow-up periods. Besides, there was no significant improvement in objective parameters like esophageal acid exposure [20]. Nevertheless, the predominant reason for discontinuation of these agents was occurrence of serious AEs including several deaths. Serious AEs reported with the use of injectable implants include pneumothorax, pneumomediastinum, free perforation, esophageal abscess, atelectasis, pleural effusion, pericardial effusion requiring surgery, para-esophageal collection, visceral artery embolization, fatal haemorrhage, and sepsis [6, 12, 13, 19]. These AEs were attributed to uncontrolled depth of injection and migration of injected particles (embolization). Subsequently, some modifications were introduced like increasing the size of particles (40–125 microns) and modification of injection catheter [16, 27] to reduce embolization and accurately localize the depth of injection, respectively. However, despite these proposed improvisations, injectable techniques did not pick up again.

Endoscopic Suturing and Plication

Unwillingness for an invasive procedure and accompanying AEs associated with laparoscopic fundoplication have propelled the development of minimally invasive endoscopic options which mimic surgical fundoplication.

Various plication and suturing devices that have been evaluated for GERD include endoscopic suturing device (EndoCinch, Ethicon Endo-Surgery, Cincinnati, OH), endoscopic full thickness plication device (the Plicator, NDO Surgical, Inc., Mansfield, MA), transoral incisionless fundoplication device (EsophyX, EndoGastric Solutions, Redmond, WA), and ultrasonic surgical endostapler (MUSE, Medigus, Omer, Israel). All of these work on the same principle, i.e., enforcing the GEJ with sutures or plicators to reduce reflux events.

EndoCinch was the earliest of these devices to be evaluated (FDA approval in year 2000) with reasonable outcomes in short term. However, long-term results were disappointing and primarily attributable to suture loss. In addition, lack of significant improvement in objective parameters suggested that the device requires modifications for subsequent clinical use [33, 42, 43]. In a well-conducted prospective trial, more than 80% of patients had lost at least one suture at 18-month follow-up. Corresponding to the same, a short-term efficacy of 71% at 3 months could not be maintained at 18 months when efficacy was only 20% [43]. As of now EndoCinch device has been discontinued by the manufacturer and is no longer available for commercial use.

The Plicator device was next to be approved in 2003.The device soon underwent revision a few years later (2007) due to serious technical failure requiring surgical removal. Several studies confirmed the efficacy of the Plicator device in improving symptoms, esophageal acid exposure, and PPI dependence [36, 37, 40]. In the subsequent years, a key modification in the technique where multiple plicator implants were used instead of one was shown to improve the results with this device [28, 48, 49]. For unclear reasons, the manufacturers withdrew the device from market. More recently, the Plicator technology has been taken over by another manufacturer (GERDX, G-SURG, GmbH, Seeon-Seebruck, Germany) and is being further evaluated in clinical trials (NCT03322553).

Endoscopic Fundoplication

Transoral fundoplication using EsophyX device is among the well-studied anti-reflux devices. In randomized studies, improvement in GERD-HRQL and discontinuation of PPIs have been more or less uniform with this device [22]. However, improvement in objective pH parameters like normalization of esophageal acid exposure time and DeMeester score is less impressive. Like EndoCinch, the loss of sutures and deterioration of GEJ flap valve were found in one study and may be partly responsible for loss of response with this device as well [51].

The other endoscopic fundoplication devices including GERDx and MUSE are more recent and long-term results are awaited [18, 50].

Radiofrequency Energy Application (Stretta)

Application of RFA to GEJ or Stretta (Mederi Therapeutics, Greenwich, Connecticut) is the oldest (FDA approval in year 2000) of currently available EARTs. Over 15,000 patients have been treated with this device. Ease of application, no requirement of general anesthesia, minimal impact on future anti-reflux therapies, and excellent safety profile (<1% AE) have enabled it to sustain among the various disappearing endoscopic therapies for GERD. Multiple studies have revealed the safety and efficacy of RFA for the management of GERD [7, 29, 35, 46, 52]. In addition, several non-randomized studies have reported reasonable (although inferior) outcomes of RFA when compared to surgical fundoplication for the management of typical and atypical symptoms of GERD [5, 21, 30, 31, 54, 55]. Despite excellent outcomes in multiple short- and long-term studies, RFA has not gained a worldwide acceptance as expected. The skepticism regarding the efficacy of Stretta is not absolutely unreasonable. Among the vast number of studies published on Stretta, there are only five randomized trials with maximum follow-up duration of 12 months [1–4, 26]. Moreover, important outcome parameters like HRQL, PPI use, and heartburn were not measured in all of them. Consequently, a meta-analysis comprising of these four RCTs (n = 92) concluded that RFA is no better than placebo or sham therapy [32]. This is in contrast with the results from another recent systematic review and meta-analysis which encompassed 23 cohort studies in addition to the four RCTs (n = 2468) included in the previous meta-analysis. This review concluded the efficacy of RFA with significant reduction in the use of PPIs and improvement in esophageal acid exposure time, heartburn symptoms, and HRQL [9]. The long-term maintenance of efficacy with Stretta was confirmed in two single-arm studies with follow-up duration of 8 and 10 years, respectively [7, 35]. In the prospective study by Noar and colleagues, GERD-HRQL was normalized in 72% at 10-years follow-up [35]. PPI discontinuation was achieved in 41% at 10 years and 79% at 8 years in these studies [7, 35].

In conclusion, RFA treatment leads to improvement in symptoms and HRQL and allows elimination or reduction in doses of PPIs. However, the improvement in objective parameters like esophageal acid exposure, basal lower esophageal sphincter pressure, and erosive esophagitis is not impressive. Large, randomized, and sham controlled studies with long-term follow-up are required to establish the role of RFA in the management algorithm of GERD. Also, the impact of second session of RFA on treatment outcomes needs to be studied. One study did report improved results with a second session of RFA in initial non-responders [2].

Endoscopic Anti-reflux mucosectomy (ARMS )

ARMS is an endoscopic technique in which mucosal resection is performed along the lesser curvature side of gastric cardia to reshape the mucosal flap valve. Initial results published by Inoue and colleagues demonstrated the feasibility and safety of ARMS [23]. More recently, the same group has demonstrated reasonable outcomes in a relatively large cohort of patients with refractory GERD (DDW 2017). There was significant improvement in QOL, esophageal acid exposure time, and endoscopic appearance of gastric flap valve, and PPIs could be discontinued in 61% of patients at one-year follow-up. Certain important questions need to be addressed before wider clinical adoption of ARMS. The technique is not standardized and the extent of mucosectomy is mainly based on the subjective judgment of the operator. Too much resection may lead to stricture, whereas too less will be unrewarding. Second, the impact of mucosectomy on the feasibility of subsequent EARTs is not known. As of now, the available data is limited and ongoing randomized trials (NCT03259191) may clarify the role of ARMS in the management of GERD.

Goals and Patient Selection

The objective benefit from EARTs is not unequivocal. The results are not absolutely concordant between randomized trials and cohort studies as discussed above. Moreover, there is discrepancy in the response rates between symptoms and 24-hour pH metrics. Improved patient outcomes (GERD-HRQL) have been reported despite a lack of improvement in esophageal acid exposure times in many of the studies. This discrepancy can be attributed to either high placebo or sham response rates or poor correlation between symptom response and esophageal acid exposure in these patients. This brings us back to the argument – what should be the goal of anti-reflux therapies: normalization of esophageal acid exposure or symptom relief? The proponents of EART would argue that normalization of esophageal acid exposure may not be required to relieve troublesome symptoms of GERD or healing of esophagitis. Moreover, the improvement in GERD-HRQL and reduction in use of PPI are more relevant goals from a patient’s perspective. On the other hand, normalization of esophageal acid exposure is an important objective parameter and cannot be ignored altogether. Lack of normalization in the majority would raise concerns regarding the mode of action as well as long-term durability of these procedures. This in turn implies that further modifications in technique or anti-reflux devices or both may be required. In conclusion, a reasonable goal would be improvement in quality of life with elimination of troublesome regurgitation and heartburn, abolition or reduction in requirement of PPI, and a reasonable improvement in esophageal acid exposure.

Appropriate patient selection is paramount for achieving optimal outcomes with EARTs in patients with GERD. An important question is that which patients qualify for EARTs. Broadly speaking two categories of patients appear to be appropriate candidates for EARTs. These include patients in whom symptoms of GERD are adequately controlled on PPIs but unwilling to continue them for long term. The second group is patients in whom symptoms are inadequately controlled on PPIs, i.e., refractory GERD, but are reluctant to undergo a surgical procedure. These patients should be subsequently investigated so that they can gain optimum benefits from EARTs. In addition, the cause of refractoriness to PPIs should be actively sought. A proportion of these patients are non-compliant to lifestyle modifications and adequate PPI dosage and, therefore, are not refractory in true sense.

The currently available EARTs are better avoided in those with large hiatal hernia (>2 cm), Hill’s grade III/IV flap valve, severe esophagitis (Los Angeles grade C and D), poor symptom correlation on pH-impedance, psychological comorbidity, functional heartburn, ineffective esophageal peristalsis analysis, and high BMI [34].

Endoscopic Anti-Reflux Therapies – Wait or Ready for Prime Time

The emergence and persistence of some of the EARTs is partly due to unwillingness of the patients to undergo surgery and adverse events related to total fundoplication procedure. However, this argument may not hold absolutely if emerging surgical options like magnetic sphincter augmentation and electrical stimulation therapy are considered [15, 39]. These procedures, though invasive, have been shown to be associated with reduced rate of typical AEs associated with total fundoplication procedure like dysphagia and gas bloat. Therefore, EARTs are likely to face wider range of competitors in the near future (Fig. 22.1).

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