Endoluminal therapy for GERD: Where we stand
Fellow in Minimally Invasive Surgery, Vanderbilt University School of MedicineWilliam
Ingram Professor of Surgical Sciences, Director of Laparoendoscopic Surgery, Medical Director of the Center for Surgical Weight Loss, Vanderbilt University School of Medicine, Nashville, TN
Mastering the technology and tailoring the procedure to the pathology are keys to effective treatment.
Daily symptoms of gastroesophageal reflux disease (GERD) greatly disturb the quality of life for millions of patients—about 7% of the US population based on one estimate.1 Medical treatments have had wide success relieving the symptoms, but not curing the underlying disease. Laparoscopic fundoplication has been widely effective, but comes with its own set of drawbacks.
So one may logically think the perfect approach would be to replicate the curative effect of surgery without invading the abdominal or thoracic cavities. Thus, endoluminal treatments have emerged, but with mixed results. This article reviews each of the available therapies in terms of technique, safety, and efficacy.
Medical treatment with proton pump inhibitors (PPIs) successfully relieves heartburn and heals erosive esophagitis, but does not stop the actual reflux. In fact, once PPI therapy is discontinued, symptoms return in 75%–90% of patients. A few patients have developed intolerable side effects, and lifelong treatment can be costly. In 1999, more than 90 million prescriptions were written for antisecretive medications at a total cost of $8.5 billion.2171
FIGURE 1 When endoluminal treatment is best
The small hiatal hernia in the absence of Barrett’s esophagus or pulmonary complications may be the best indication for endoluminal treatment of GERD. (Illustration by Molly Borman)
MIS fundoplication: effective but with drawbacks
Laparoscopic fundoplication is an effective and durable treatment of GERD. It normalizes esophageal acid exposure and alleviates heartburn in more than 90% of patients in most large series. Surgery is effective because it reverses most of the mechanical defects that contribute to the underlying pathophysiology of GERD, including inadequate lower esophageal sphincter (LES) pressure, transient inappropriate LES relaxations, and the presence of a sliding hiatal hernia (FIGURE 1).
More significantly, fundoplication reduces refluxate, while PPI therapy only reduces the acid component of reflux while increasing nonacid refluxate.3 This is important because nonacid (bile) reflux is a key contributor in Barrett’s metaplasia.
Fundoplication, however, has its drawbacks. A minority of patients continue to require PPI therapy or develop disabling symptoms. In one study, 20% of patients undergoing fundoplication experienced abdominal bloating, 6% had persistent heartburn, and 7% developed dysphagia requiring esophageal instrumentation.4 Although the minimally invasive approach decreases incisional pain, hospital stay, and recovery time, its intrinsic surgical nature as an invasive treatment remains.
The natural orifice route
The logical approach to this problem may seem to accomplish repair of the mechanically incompetent LES without invading the abdominal or thoracic cavities. This leads to using the “natural orifice route” to reach the LES, and that is where endoluminal treatment takes place.
Three types of endoluminal approaches have emerged: suturing, radiofrequency therapy, and injection therapy. First, however, it is important to review the endoluminal procedures that have failed so that we avoid errors of the past (BOX).
Failed endoluminal treatments
The Enteryx (Boston Scientific Corporation, Natick, MA) procedure was withdrawn from the market by the manufacturer in 2005 due to safety concerns. It utilized a liquid polymer injected into the muscular wall of the GE junction, forming a semisolid mass once in the tissues to augment the antireflux barrier. Early clinical results suggested significant reduction in distal esophageal acid exposure and improvement in GERD symptoms.5
Soon after the procedure was released in 2003, the FDA started to receive reports of serious complications, including embolus of the polymers to the kidneys and development of aortoenteric fistulas resulting in several deaths. One potential explanation is that when initially tested, expert endoscopists used the device under rigorous clinical trials. Only after commercial introduction to endoscopists with less experience in this particular modality did these problems arise.
This situation has raised multiple questions about credentialing and specialized training for physicians using such novel procedures, the learning curve, and methods for teaching these techniques.
The Gatekeeper System (Medtronic, Minneapolis, MN), which relies on the submucosal injection of a bulking polymer at the GE junction, also was withdrawn from the market. After implantation, the small cylinders enlarged with hydration. Although one prospective trial showed significant increases in LES pressure and decreases in esophageal acid exposure, subsequent studies failed to show efficacy.6
Some preliminary reports suggested that many of the implants were simply missing 6–12 months after the procedure. In the open label study of 67 patients, 2 had major complications: a pharyngeal perforation and a case of intractable postprandial nausea requiring removal of the implants.6
An important lesson from the failure of the Gatekeeper is the demonstration of a significant sham effect on GERD symptoms and subjective need for PPIs. It is sobering to realize that in one study, physicians were able to wean 39% of control patients off PPIs using a step-down algorithm.7 Because endoscopic GERD treatment appears to have a significant placebo effect, well-controlled studies with objective measurements of esophageal acid exposure are needed to scientifically gauge the effectiveness of endoluminal treatment for GERD.—DBW, WOR
FIGURE 2 Mucosa-to-mucosa plication
EndoCinch attaches to the end of an endoscope and applies a suture to the lower esophageal sphincter, then ties the suture mechanically.
The EndoCinch suturing device (CR Bard, Inc, Murray Hill, NY) is still available for endoluminal treatment of GERD, but long-term results have been disappointing. The device is fitted onto the end of a standard diagnostic endoscope and advanced to the level of the gastroesophageal (GE) junction, where it creates typically 2 to 4 plications of the gastric mucosa.172
Once the site is selected, the physician activates a suction mechanism that pulls the target tissue into the chamber and then deploys the suture. This suture is then pulled through the tissue, brought outside of the patient, and the device is reloaded with the same suture and redeployed to the target to obtain another bite of tissue.
The EndoCinch provides reasonable short-term results, but long-term outcome may be poor due to suture loss.
A mechanical crimping device then ties the suture to secure the plication (FIGURE 2). The proposed mechanism of action is that the EndoCinch improves the anti-reflux barrier at the gastroesophageal junction.
No study has definitively demonstrated improvements in LES pressure or length, or reductions in transient LES relaxations with the EndoCinch device. A randomized trial (n=60) showed similar levels of reduced acid exposure in the distal esophagus in patients who had EndoCinch plication or a sham procedure compared with observation.8 Interestingly, the treatment group had a significant reduction in PPI use compared with the sham and the observation groups.
Most other prospective clinical studies have failed to show any significant difference in distal esophageal acid exposure after the procedure.9,10 In a recent study, endoscopy showed persistence of all the sutures in only 12 of 70 patients (17%), while the sutures were completely gone in 18 of 70 (26%).10 The authors concluded that the EndoCinch provides reasonable short-term results, but that long-term outcome is poor probably due to suture loss. This illustrates the inherent flaw in a mucosa-to-mucosa plication.
FIGURE 3 Radiofrequency plication
The Stretta procedure delivers radiofrequency energy through 4 needles mounted on a balloon that is inflated to drive the needles into the tissue.
The Stretta procedure (Curon Medical, Sunnyvale, CA) may now also be considered a failed therapy, but more so from a business perspective. Due in part to poor insurance coverage, Stretta suffered financially and Curon declared bankruptcy and ceased operations in 2006.
Stretta delivers radiofrequency (RF) energy to the muscularis of the GE junction while cooling the mucosa with irrigation to prevent injury. It delivers RF energy through four needles mounted on a balloon that inflates to drive the needles into the tissue (FIGURE 3). The energy is delivered up to a target temperature and is applied at multiple locations in the distal esophagus and gastric cardia. Treatment aims to cause scar contraction and enhance the antireflux barrier of the LES.173
How Stretta works
The exact mechanism behind Stretta’s effect on GERD is uncertain, but it may improve LES function. An analysis of LES pressure 6 months after Stretta treatment showed a significant reduction in postprandial transient relaxations from 6.8 to 5.2 per hour. Also, mean basal LES pressure increased from 5.2 mm Hg to 8 mm Hg.11
Most prospective trials of Stretta provide evidence for the objective reduction in esophageal acid exposure.11,12 In the multicenter US prospective trial, Stretta produced a significant improvement in GERD-health-related quality of life (HRQL) scores and reduced distal esophageal percent acid exposure time (pH <4.0) from 10.2% to 6.4% in 118 patients. However, esophageal acid exposure failed to normalize in most patients.
Data from Vanderbilt have suggested a durable treatment effect at a mean of 27 months after the procedure.13 While no 24-hour pH studies were performed, long-term patient satisfaction, GERD-specific symptom scores, and PPI use were similar to those obtained shortly after the procedure. Fifty-eight percent of patients discontinued PPIs at short-term follow-up compared with 56% at long-term follow-up.
Safety of Stretta
The Stretta procedure appears to be safe. Published reports have indicated mild complications such as minor GI bleeding, transient dysphagia, and fever.11 Prolonged gastroparesis has also been reported.13
Review of the FDA web site for serious post-marketing adverse events reveals two deaths attributed to cardiac arrhythmia and aspiration pneumonia. Esophageal perforations reported during the early experience were virtually eliminated with vigorous physician training, and patient education emphasizing a soft diet, and avoidance of nasogastric tube placement in the early postoperative period.
Most prospective trials have suggested a significant reduction in acid exposure after Stretta, and all presented evidence for improvement in GERD-specific symptom scores. However, the only randomized trial showed no significant change in esophageal acid exposure in the Stretta-treated group. Moreover, as previously mentioned, Stretta is no longer available.
FIGURE 4 Serosa-to-serosa plication
The NDO Full-thickness Plicator deploys a pre-tied implant to create a full-thickness plication under direct vision via a slim gastroscope.
Full-thickness suture plicator
The NDO Full-thickness Plicator (NDO Surgical, Mansfield, MA) is a promising endoluminal therapy. As opposed to the EndoCinch, the NDO plicator takes full-thickness bites, achieving a serosa-to-serosa plication that restores the valvular mechanism of the GE junction. The FDA approved the system in 2003.
The only randomized trial showed no significant change in esophageal acid exposure in the Stretta-treated group.
The device creates a full-thickness plication under direct vision provided by retroflexion of a slim gastroscope placed through a side channel (FIGURE 4). Once the physician identifies the GE junction, the tissue retractor advances through the layers of the gastric wall at the chosen site until it reaches the serosal layer. This full-thickness gastric fold is pulled toward the instrument. Next, the user deploys a pre-tied suture with bolsters and retention bridges to create a full-thickness plication.
Mechanism of action
The randomized sham-controlled trial failed to demonstrate significant changes in LES pressure after plication.13 Other possible salutary mechanisms include alteration of the angle of His and reduction of the compliance in the cardia and fundus, which might reduce the incidence of transient LES relaxations.174
In a recent study, 56% of the patients in the treatment group experienced improved symptoms compared with 18.5% in the sham group.14 Twenty-four hour pH studies showed plication decreased percent acid exposure time in the distal esophagus from 10% to 7%. However, the majority of patients failed to achieve a normal (<4.5% as defined within this study) esophageal acid exposure time.
NDO Surgical recommends prophylactic antibiotics with the use of the Full-thickness Plicator.
Intact plication was seen on endoscopy in all pilot study patients at 12 months. In a 3-year follow-up of patients undergoing plication in the open-label trial, median GERD-HRQL scores improved from 19 preoperatively to 8 at 36 months.15 Preoperatively, 28 of the 29 patients utilized daily PPIs, while at 3 years only 14 did so. These data suggest that the full-thickness plication may be durable for up to 3 years.
Safety and efficacy
Preliminary clinical studies have suggested the procedure in expert hands is safe. Patients have developed pneumothorax and pneumoperitoneum that resolved without any operation. One patient developed a gastric perforation seen at the time of endoscopy that was successfully closed with endoluminal clips.14,16
Several patients who did not receive prophylactic antibiotics developed fever and leukocytosis in the early postoperative period. From this experience, the manufacturer recommends prophylactic antibiotics because the plication may cause some contamination of the peritoneum.
The early results from this novel technique do show some benefit in the treatment of GERD, with subjective indicators of improvement (quality-of-life scales and medication requirements) supported by objective data (improved endoluminal findings and reduced esophageal acid exposure). However, the improvements fall short of those achieved by laparoscopic Nissen fundoplication.
FIGURE 5 Newest suture plication
A suction device allows the EsophyX endoluminal fundoplicator to invaginate the esophagus, advancing the z-line to the level of the diaphragm. (Courtesy Endogastric Solutions)
Endoluminal suture plication
The EsophyX device (Endogastric Solutions, Redmond, WA) also employs serosa-to-serosa suture plication. It received FDA approval in 2007.
Like the NDO Plicator, the EsophyX creates a plication under direct vision provided by retroflexion of a gastroscope placed through the instrument (FIGURE 5). After locating the GE junction, a suction device allows invagination of the esophagus, advancing the z-line to the level of the diaphragm.
A retractor then pulls down a flap of fundus and allows placement of polypropylene H-fasteners through the tissue flap. Multiple fasteners can be placed circumferentially without removing the device.175
EsophyX mechanism of action
EsophyX reduces reflux by accentuating the angle of His, reducing small hiatal hernias, and creating a 3–5 cm 200–310° tissue valve at the GE junction.17
Clinical studies and efficacy
A multicenter European trial of 17 patients showed mean GERD-HRQL scores had improved from 21.6 to 10.1 at 3 months, and 80% of patients had discontinued PPI use at 6 months.15 Esophageal pH was normalized in 67% at 6 months. No long-term results have been published.
Reported adverse events have included throat irritation and epigastric pain, all of which resolved spontaneously. Objective pH-based trials, including randomized sham versus EsophyX treatment and long-term follow-up, will clarify its role in the treatment of GERD.
The current paradigm of endoluminal treatment of GERD is to replicate surgical fundoplication, as the treatments based on this model have achieved the best results. We have learned that this plication must achieve a serosa-to-serosa apposition for durability.
We have also learned that these new technologies must be introduced carefully into general use, possibly involving a specialized credentialing and proctoring process. A potentially effective new treatment may be doomed by adverse events from inexperienced users. Also, release of an effective new treatment must be accompanied by strong advocacy to ensure insurance coverage and financial success.
Patients with small hiatal hernias, who do not have Barrett’s esophogus or pulmonary complications, may be better served by endoluminal therapy.
The promise of endoluminal therapy
Endoluminal therapy has a promise of reversing the underlying pathophysiology of GERD while reducing the invasiveness and side effects of surgery. Indeed, patients with small hiatal hernias, who do not have Barrett’s esophagus or pulmonary complications, may be better served by endoluminal therapy.
Thus, the physician can tailor the invasiveness of the procedure according to the degree of pathology. According to the literature and our personal experience, many patients have a high degree of satisfaction with endoluminal therapy.
Evidence-based practice recommendations
Endoluminal therapy has not yet achieved the same high success rate as surgery in the treatment of GERD. However, certain devices have shown promising results. The best candidates for endoluminal therapy are patients with small hiatal hernias, adequate LES pressure, absence of GERD-related pulmonary symptoms, and absence of Barrett’s esophagus. Level of evidence: 2b—based on individual cohort study.
The poor long-term results with EndoCinch illustrate the inherent flaw in a mucosa-to-mucosa plication. Level of evidence: 2b
The Stretta effectively reduces GERD symptoms at short- and mid-term follow-up, but does not significantly reduce acid exposure to the distal esophagus. Level of evidence: 1b—individual randomized clinical trial with narrow confidence interval; and 2b. (Stretta is not currently available due to bankruptcy of the company.)
The NDO Full-Thickness Plicator effectively reduces GERD symptoms and acid exposure to the distal esophagus at short-term follow up. Level of evidence: 1b. These improvements seem to be durable at 3-year follow-up. Level of evidence: 3b—individual case-control study.
The EsophyX improves GERD symptoms and esophageal acid exposure in small short-term studies. Level of evidence: 3b.—DBW, WOR
Dr Richards is on the Scientific Advisory Board of NDO Surgical.
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