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Lower esophageal electrical stimulation therapy targets GERD

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A promising start to clinical use

Gastroesophageal reflux disease is one of the most common chronic gastrointestinal disorders. The mainstay of medical therapy is to suppress gastric acid secretion with medications such as PPIs. An alternative approach to acid suppression is modulation of the antireflux barrier, composed of the lower esophageal sphincter (LES) and the crural diaphragm. Surgical fundoplication is a well-established method to augment the function of the antireflux barrier. Fundoplication has proven effective in high-quality trials, but it also has well-documented side effects such as dysphagia, bloating, and diarrhea in a subset of patients.

Additional means of enhancing the function of the antireflux barrier include pharmacological inhibition of transient LES relaxations (TLESR) with various agents and several endoscopic antireflux procedures. Unfortunately, the use of TLESR inhibitors and endoscopic procedures for GERD is very limited due to side effects and adverse events, along with insufficient efficacy.

Electrical stimulation of the LES has been previously shown to increase LES resting tone in an animal model (Am. J. Physiol. Gastrointest. Liver Physiol. 2008;295:G389-94). More recently, in a 6-month, open-label trial, electrical stimulation of the LES was found to reduce or eliminate PPI use and to improve symptoms and 24-hour esophageal pH parameters in GERD patients who were at least partially responsive to PPIs (Surg. Endosc. 2012 Oct. 17 [doi: 10.1007/s00464-012-2561-4]).

During the recent American College of Gastroenterology meeting, 1-year data for the open-label trial mentioned above was presented by Dr. Soffer, Dr. Crowell, and their collaborators, showing that improvement in symptoms, PPI use, and distal esophageal acid exposure persisted at 12 months with minimal side effects or adverse events.

Preliminary results of an international multicenter trial of LES electrical stimulation for refractory GERD were also presented at the meeting by Dr. Bredenoord and his colleagues. They found that LES electrical stimulation improved symptoms, PPI use, and esophageal acid exposure in this group of patients, but the preliminary number of patients was small and follow-up was mostly limited to 3 months. Importantly, they did report some adverse events.

These studies provide additional information to suggest that electrical stimulation of the LES may be an effective treatment for GERD. While the available data is compelling, more work will be required to evaluate the durability of the procedure, assess long-term safety and side effects, study the effects of stimulation on esophageal sensation, and define which GERD patients are best suited for this treatment. This will be ideally accomplished by randomized controlled trials that will compare electrical stimulation of the LES to the well-established pharmacological and surgical approaches currently used to treat GERD.

Marcelo F. Vela, M.D., is an associate professor of medicine and director of gastrointestinal motility at Baylor College of Medicine and the Michael E. DeBakey VA Medical Center, both in Houston. He is a member of an advisory panel for Given Imaging.


 

FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF GASTROENTEROLOGY

Electrical stimulation of the lower esophageal sphincter using an implanted device shows promise for the treatment of gastroesophageal reflux, according to findings from three recent studies.

In one open-label pilot extension study, 77% of 23 patients treated with EndoStim’s Lower Esophageal Sphincter (LES) stimulation system reported normalization of (or at least a 50% reduction in) distal esophageal acid exposure at 12 months’ follow-up, Dr. Edy Soffer reported in October at the annual meeting of the American College of Gastroenterology.

Courtesy Dr. Mark I. van Berge Henegouwen

Long-term safety and side effects will be studied next in trials of the EndoStim device, here shown with its electrodes (near center) placed at the gastroesophageal junction to stimulate the lower esophageal sphincter.

The patients also experienced significant improvement in their median GERD-Health Related Quality of Life (GERD-HRQL) score while implanted with the LES stimulation system (LES-EST), compared with their score while on proton pump inhibitor (PPI) therapy (increase of 9 vs. 2 points) and while off PPI therapy (increase of 23.5 vs. 2), said Dr. Soffer, professor of clinical medicine and director of the GI motility program at the University of Southern California, Los Angeles.

All but one patient reported cessation of regular PPI use, and no implantation- or stimulation-related unanticipated adverse events or "untoward sensation" due to stimulation occurred during follow-up; nor was swallowing function as assessed by manometry affected.

Patients included in the study were GERD patients with a mean age of 53 years who were at least partially responsive to PPI therapy, and who had off-PPI GERD-HRQL scores of at least 20, as well as hiatal hernia.

The findings indicate that LES-EST, which uses low-energy electrical pulses to strengthen a weak or dysfunctional lower esophageal sphincter, is safe and effective for long-term use, he said.

In an interview, Dr. Soffer said that the findings have held up at 18 months of follow-up.

"The results are comparable to those observed at 12 months with regard to control of symptoms, and with near elimination of the use of PPIs," he said, noting that the safety profile remains excellent, with no new adverse event reported beyond those seen at 12 months’ follow-up.

Physiological studies such as esophageal pH will be conducted at 24 months, he said.

In a related study presented in a poster at the meeting, Michael Crowell, Ph.D., looked more closely at the effects of LES-EST on both distal and proximal esophageal acid exposure in a post hoc analysis.

In 19 patients with a median age of 54 years, LES-EST was associated with normalization of total and upright proximal esophageal acid exposure, which improved from 0.4% and 0.6%, respectively, at baseline to 0% at 12 months’ follow-up. Supine esophageal acid exposure was unchanged from 0% at baseline, said Dr. Crowell of the Mayo Clinic, Scottsdale, Ariz.

This was true even among seven patients with abnormal proximal esophageal pH, whose total, upright, and supine proximal esophageal acid exposure values at baseline were 1.7%, 2.9%, and 0.3%, respectively. Distal esophageal pH improved from 10.2% to 3.6% for the entire cohort, and from 9.3% to 3.4% in those seven patients.

Patients in this study had GERD that was at least partially responsive to PPIs, a hiatal hernia of less than 3 cm, and esophagitis of less than Los Angeles Classification grade D. Electrical stimulation was administered for 220 microseconds at 20 Hz and 5-8 mA in 6-12 30-minute sessions starting on day 1 after implantation.

No gastrointestinal side effects occurred in the patients, nor were there any device- or procedure-related adverse events.

LES-EST may be effective in treating proximal GERD, Dr. Crowell concluded.

In an interview, he added that the findings are important, particularly for the one-third of patients who remain symptomatic on PPIs.

"LES dysfunction is the root cause of GERD. Medications such as PPIs block stomach acid production, but do not address the pathophysiology of GERD. Hence, more than a third of patients continue to suffer from symptoms despite maximal medical therapy," he said.

Additionally, there are significant safety concerns with long-term acid suppression, he noted.

LES-EST, on the other hand, addresses the root cause of GERD by improving LES pressure and function, thereby restoring the LES physiology and its barrier function, preventing reflux of gastric acid into the esophagus.

"LES stimulation does not affect normal LES relaxation, allowing for the patient to swallow normally, and has no side effects," he said.

In a third, unrelated study also reported in a poster at the meeting, LES-EST was similarly effective.

Of 11 patients treated with EndoStim’s LES stimulation system as part of an international multicenter study, 10 were able to discontinue PPI therapy at 3-6 months of follow-up, according to Dr. Arjan J. Bredenoord of Academic Medical Center Utrecht, Rotterdam.

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