In the past 2 decades, acid suppressive medications such as proton pump inhibitors have remained the first-line therapy for patients with GERD. According to experts interviewed by Healio Gastroenterology, however, a substantial population of GERD patients assigned proton pump inhibitors are refractory or unsatisfied with long-term proton pump inhibitor therapy.
Refractory patients, which may account for up to one-quarter of all patients with GERD, experts said, are typically considered for surgery with the current gold standard laparoscopic Nissen fundoplication, especially if their symptoms include regurgitation, which is notoriously difficult to treat medically. Many of these patients, however, are unable or unwilling to undergo this invasive surgery despite its high efficacy.
Thus, an unmet need for a “middle therapy” to fill the treatment gap between medication and surgery persists. Despite a range of efforts to develop nonmedical and minimally invasive alternative treatments over the years, experts agreed that mounting data demonstrate that the only two endoluminal therapies for GERD currently approved by the FDA — the Stretta procedure (Mederi Therapeutics) and the EsophyX device (EndoGastric Solutions) — finally provide viable middle-ground options for patients seeking alternatives to long-term PPIs or surgery.
Stretta and EsophyX are quick, noninvasive outpatient procedures with demonstrated safety, efficacy and durability, which represent “a new day” for endoscopic GERD treatments, according to Kenneth Chang, MD, executive director of the H.H. Chao Comprehensive Digestive Disease Center at University of California, Irvine. “The desire to have effective endoscopic treatments for GERD has been around for years,” Chang said. “I have been doing GI for 26 years, and almost since my fellowship, there have been devices that have come and gone. The device graveyard for endoscopic GERD treatments is significant — and I’ve been involved with nearly all of them.”
Some of them “really tanked,” he said. The Enteryx procedure, for example, was approved by the FDA in 2003 but was recalled by Boston Scientific shortly after because of a fatal complication. Many devices have similarly come to a dead end, “not necessarily due to lack of clinical efficacy,” Chang said, but more often because of safety concerns, fundraising and business development challenges, or the increasing rigor required by the FDA to approve new devices. “It has been a long history of trying to get to the finish line, with hopes and expectations rising and falling as these products come and go.”
What has fueled the enduring effort to develop viable endoscopic GERD therapies are the limitations of PPI therapy and surgical options, experts agreed. Although PPI therapy is highly effective in treating acid-related symptoms in about 80% of patients with GERD, this leaves 20% to 25% who are refractory to medical therapy, according to Chang. Furthermore, there is “an even larger, expanding population of patients who respond to medical therapy but want to get off the medications, and with good reason considering all of the studies coming out showing the possible risks of long-term PPI, especially in postmenopausal women who may be at risk for osteoporosis-related hip fractures.”
The gastroenterology community is increasingly recognizing the inadequacies of PPI therapy, according to Reginald C.W. Bell, MD, FACS, founder of the SurgOne Foregut Institute. It is primarily patients with symptoms of heartburn and regurgitation who fail PPI therapy, but there are some patients with laryngeal symptoms who also do not respond well to medical therapy, he said. “Of those patients, many don’t have the degree of anatomic compromise or distortion that requires a laparoscopic Nissen procedure to correct, so we have been looking for ways to treat the problem of reflux that aren’t as supraphysiologic as Nissen fundoplication is, or are more designed for mild anatomic deterioration.”
Although Nissen fundoplication has efficacy exceeding 90%, the main drawbacks include its adverse effects (dysphagia, bloating, inability to vomit, and diarrhea, according to a recent editorial), its durability where studies have shown up to 65% of patients may be back on PPI therapy 10 years after surgery and its irreversibility, Chang said. “Undoing this procedure is impossible, and redoing it is difficult. So if you’ve got a 35- to 50-year-old patient with GERD and you send them for a lap Nissen, 10 years later your options may be limited. Around 60 to 70 years old may be the sweet spot to do this. However, for symptomatic patients with a hiatal hernia larger than 2 cm, middle therapies are not available and the Nissen fundoplication is the best solution.”
Another relatively new and minimally invasive surgical option is laparoscopic magnetic sphincter augmentation with the LINX (Torax Medical) device, which the FDA approved in March 2012. Data from a recent prospective 3-year follow-up study involving 100 patients demonstrated the safety and efficacy of LINX, with reduced esophageal acid exposure (64% of patients; 95% CI, 54-73), reduced PPI use (93%), improved quality of life scores (92%) and a low rate of long-term adverse effects.
“The LINX procedure provides an alternative to the traditional antireflux surgery in a selected patient population,” Ronnie Fass, MD, FACG, director of the division of gastroenterology and hepatology and head of the Esophageal and Swallowing Center at the MetroHealth Medical Center in Cleveland, and professor of medicine at Case Western Reserve University, and colleagues wrote in a clinical review published in the Journal of Clinical Gastroenterology. “Although the results of the studies show great promise, concerns remain high about potential long-term adverse events, in particular the possibility of the ring eroding into the esophagus or migrating from its original anatomic placement. More long-term studies are needed.”
Chang also shared some concerns. “One of the major limitations for the LINX procedure is that these patients cannot have an MRI scan because it may demagnetize the LINX. Right now, MRIs are one of the most commonly used imaging modalities, and basically everyone who strains their back or blows out their knee will get an MRI,” he said. “So in my practice when I talk about LINX and mention that, patients usually say, ‘Let’s look at something else.’
“So for all the reasons stated above, there is a need for endoscopic treatment alternatives,” Chang said. “There are essentially two FDA-approved devices.”
Stretta Radiofrequency Energy Treatment
According to Fass, Stretta is the only endoscopic therapy for GERD “that has lasted since the introduction of these types of devices to the market more than a decade ago.” In addition, he and colleagues wrote in the aforementioned clinical review, “It is also one of the few endoscopic techniques for GERD that has been tested in a sham-controlled trial.”
A widely cited sham-controlled trial published in 2003 demonstrated that “patients who underwent Stretta had significantly improved heartburn scores at 6 months, but no significant improvement in esophageal acid exposure times,” Prateek Sharma, MD, from the Veterans Affairs Medical Center and University of Kansas School of Medicine in Kansas City, Missouri, and Philip Katz, MD, from Albert Einstein Medical Center in Philadelphia, wrote in a recent editorial. “Although the study showed promising results, [it] also had strict inclusion/exclusion criteria, enrolling only a select subpopulation of GERD patients. Open-label, long-term studies have shown promising results and there is a recommendation from [the Society of American Gastrointestinal and Endoscopic Surgeons] that it be considered in patients unwilling or unable to undergo fundoplication,” they wrote.
Although some reduction of esophageal acid exposure has been observed with Stretta, Fass and Chang said controlling symptoms should be the primary outcome goal of any GERD treatment.
“The outcome of normalizing 24-hour pH, in a sense, is not as clinically meaningful because even PPIs don’t normalize 24-hour pH; with PPIs, your goal is to control symptoms.” Chang said. “Stretta has been shown in studies to improve symptomatic control compared to placebo, but while pH does improve it may not normalize, although I’m not sure that’s a necessary outcome for clinical application.”
Fass agreed, referencing the recent systematic review and meta-analysis published in Clinical Gastroenterology and Hepatology, which found that Stretta was not superior to sham. “Even though, for example, it’s been shown in the meta-analysis Stretta was not able to normalize esophageal acid exposure, at the same time it improved symptoms,” he said. “Patients may not have normalization of esophageal acid exposure but still have resolution of symptoms.
“Large phase 3 therapeutic trials of PPIs, for example, have not used pH monitoring to verify that patients who demonstrated complete symptom resolution also had complete normalization of esophageal acid exposure, so we don’t know if that’s the case — maybe a lot of patients who did have complete resolution of symptoms did not normalize their esophageal acid exposure,” Fass said. “Endoscopic therapies have to meet a high bar when it comes to clinical endpoints for their trials, and the consequence of that may have influenced the results of the meta-analysis.”
“We want to hold these treatments to the same standard,” Chang said. “If normalization of pH is the primary indicator for effectiveness, then PPIs would not be around. The goal is symptomatic improvement.”
The international panel at DDW 2014 also agreed that Stretta has “an excellent safety record,” and of all the available procedures for GERD, Chang said he considered Stretta to be the safest.
“Stretta has evolved over time with many improvements made to the technique that markedly improved its side effect profile, and at this point it is unmatched,” Fass said, adding that many of the cited adverse effects associated with Stretta are often “from the first year that Stretta came out, and not necessarily the experience that we currently have after the technique has been improved by the manufacturers.”
Besides multiple randomized controlled trials demonstrating efficacy for controlling esophageal and extraesophageal symptoms, Chang said, Stretta has the longest follow-up of all the available endoscopic treatments for GERD. “We now have the long-term 10 year data showing that its durability may be as good as surgical fundoplication.”
The 10-year prospective follow-up study evaluated long-term safety, efficacy and durability of response to Stretta therapy in 217 patients with medical refractory GERD. Noar and colleagues found that 72% (95% CI, 65-79) maintained normalized GERD-related quality of life, and 41% were able to eliminate PPI therapy entirely. These findings “clearly show that 10 years down the line patients were able to maintain the same level of symptom control and health-related quality of life as they had immediately after the procedure, which was also significantly better than before the procedure. This provides the longest follow-up documented and published on the Stretta procedure,” Fass said.
“Stretta’s effectiveness is about 80% to 85%, so it’s not as high as the 90% with surgery,” Chang said, “but the durability looks good, it’s a minimally invasive, outpatient procedure with no surgical wounds that takes less than an hour, so it has a real advantage, as does the EsophyX TIF procedure,” although reimbursement has been more difficult with that procedure due to its lack of a CPT code. However, the manufacturer announced on March 10 that the procedure was granted a unique CPT code by the American Medical Association.
The EsophyX transoral incisionless fundoplication (TIF) procedure has recently joined Stretta as being among the few endoscopic techniques that have been tested in a sham-controlled trial, after the publication of data from the RESPECT trial.
“We are proud of our achievements in the first ever randomized blinded trial that focused exclusively on regurgitation symptoms, and our ability to meet the most rigorous standards with regards to conducting the trials involving the sham procedure and optimized PPI therapy,” said Emir Deljkich, MD, senior director of clinical and medical affairs and medical science liaison for EndoGastric Solutions.
Conducting a sham-controlled trial is difficult, Deljkich said, but the importance of this effort is highlighted in a perspective written by Rita F. Redberg, MD, MSc, from the University of California, San Francisco Medical Center, recently published in The New England Journal of Medicine, which “challenges the medical device community to conduct more sham-controlled trials to get to a level comparable to the rigorous studies that pharmaceutical companies are doing,” Deljkich said.
“Blinded, randomized, controlled trials (RCTs), in which the proposed therapy is compared with a placebo or a ‘sham’ (nontherapeutic) intervention, are common for drugs but rare for medical devices,” Redberg wrote. “In light of mounting evidence that medical procedures can produce a strong placebo effect that can be mistaken for actual effectiveness, I believe it is time for more frequent use of interventional trials in which patients are unaware of their randomized assignment.”
Bell, who co-wrote the RESPECT paper, said a major strength of this study is that it was structured as “the surgical equivalent of a placebo-controlled trial. The reason for that is we know that patients often symptomatically improve even with a placebo effect or a sham surgery, so we wanted to make sure that the responses we had been seeing in other studies were not just due to a sham effect or a placebo effect.”
Of more than 20 other published studies on TIF, by Bell’s estimates, he was involved with one of the larger U.S. prospective studies involving 100 patients who underwent the procedure. “We showed that they symptomatically responded very well and that response seemed to be fairly stable up to 3 years of follow-up. So we had a background of observing a response and some improvement in pH, but we needed to be able to demonstrate that symptomatic response is not just a placebo effect.”
The RESPECT trial randomly assigned patients with confirmed GERD and hiatal hernias less than or equal to 2 cm to groups that either underwent TIF and then received placebo pills for 6 months (n = 87) or underwent a sham procedure and then received an optimized dose of omeprazole for 6 months. Based on intention-to-treat analysis, the investigators’ findings included:
- TIF was superior to PPIs in eliminating troublesome regurgitation (in 67% vs. 45% of patients; P = .23);
- Thirty-six percent of sham/PPI controls compared with 11% of TIF patients had no response at 3 months (P = .004);
- Control of esophageal pH improved with TIF (mean 9.3% before and 6.3% after procedure; P < .001), but did not with sham (mean 8.6% before and 8.9% after); and
- Severe complications were rare.
“The major impact of these data is that we saw improvement in regurgitation scores, which was the primary symptom that we looked at for enrolling patients,” Bell said. “We showed, compared to sham, that the TIF procedure produced a significantly better response with regurgitation than did continued medical therapy. We also saw heartburn improving as well and it associated with an improvement in pH. Other procedures have shown an improvement in symptoms but not correlated with an improvement in pH and we were able to demonstrate both — that pH goes down and symptoms improve after the TIF procedure.”
In the editorial by Sharma and Katz, which accompanied the publication of the RESPECT trial in Gastroenterology, they concluded that these data seem to make TIF “a viable option for treatment in carefully selected, well-informed patients, and puts endoscopic therapy ‘back in the game.’ How it compares with other endoscopic and minimally invasive therapies remains a question for subsequent studies.”
“This a significant turnaround from editorials I’ve seen in the past about the endoscopic and endoluminal therapies,” Bell said. “There is now recognition that this is a genuine procedure that should be made available to patients, not only in just a study setting.”
According to Deljkich, the RESPECT trial’s 12-month follow-up is currently ongoing, with plans for publication sometime this year. Additionally, 3-year data will be collected from a second randomized trial, TEMPO, which aims to compare TIF with optimized PPI therapy for treatment of atypical symptoms and regurgitation, whereas initial data from a third randomized trial in Europe also is expected this year.
Furthermore, EndoGastric Solutions recently partnered with the American Gastroenterological Association Center for GI Innovation and Technology to develop the STAR registry, “a large U.S. registry developed for a community-based prospective trial being conducted at 14 centers and involving 500 patients. This trial will for the first time present real-world data for the TIF procedure compared with laparoscopic Nissen fundoplication,” Deljkich said.
According to Chang, although the data on TIF is not as mature as the data on Stretta, “it certainly looks promising so far. So, finally, we’ve got two devices that have made it through the rigor of FDA approval, and more will come because if you have none in the space, then it’s hard to get into, whereas if you have one or two established, then it will be easier to piggyback on success,” he said. “The potential is huge for these devices to change gastroenterology practice, in terms of now routinely treating GERD with safe, quick and durable outpatient procedures as opposed to just throwing PPIs at patients.” – by Adam Leitenberger
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For more information:
Reginald C.W. Bell, MD, FACS, can be reached at firstname.lastname@example.org.
Kenneth Chang, MD, FACS, can be reached at email@example.com.
Emir Deljkich, MD, can be reached at firstname.lastname@example.org.
Ronnie Fass, MD, FACG, can be reached at email@example.com.
Disclosures: Bell reports he received research grant support from EndoGastric Solutions. Chang reports he is a consultant for Cook Medical and is on the Medical Advisory Board of Mauna Kea Technologies. Deljkich is an employee of EndoGastric Solutions. Fass reports he received research grant support from Evoke Pharmaceuticals and Ironwood, is a consultant/advisor to GlaxoSmithKline, Mederi Therapeutics, Reckitt Benckiser, Tulip and Vecta, and is a speaker for Takeda.