Implanted electrical devices and gastroesophageal reflux disease: an effective approach to treatment

Keywords::

• electrical stimulation
• gastroesophageal reflux disease
• gastroesophageal reflux disease treatment
• implantable stimulator
• lower esophageal sphincter
• lower esophageal sphincter stimulation
• medical devices
• stimulator

Gastroesophageal reflux disease (GERD) is the leading diagnoses for gastrointestinal disorders in outpatient clinic visits in the USA and has a rising worldwide prevalence [1–3]. It has significant impact on patients’ quality of life, resulting in significant healthcare resource utilization [4]. Acid suppression, particularly with proton pump inhibitors (PPIs), is highly effective in controlling the symptoms and complications of GERD [5]. However, current pharmacologic therapy targets acid secretion rather than the underlying pathophysiology of GERD, which may result in persisting symptoms and reduced quality of life, despite pharmacologic therapy [6]. Inadequate control of symptoms and rising concerns about the long-term safety and cost of medications have been the main reasons for choosing surgical therapy for GERD [7]. Fundoplication is effective, but is associated with adverse effects [7]. This unmet medical need has led to multiple attempts at development of less-invasive endoscopic and surgical therapies for the treatment of GERD [8].

EndoStim™ lower esophageal sphincter (LES) stimulation system (EndoStim, The Hague, The Netherlands) is an implantable electrical stimulator that delivers electrical stimulation therapy to the LES. It is similar to traditional neurostimulators with three components; a bipolar stimulation lead with two stitch electrodes, an implantable pulse generator (IPG) and an external programmer. The IPG and stimulation leads are implanted by conventional laparoscopy into the muscle of the lower esophageal body. The lead is delivered through the abdominal wall and secured to the IPG located in a subcutaneous pocket in the left upper quadrant. Following implantation, a wireless programmer is used to interrogate and program the IPG.

Electrical stimulation of the LES in animal models has been shown to increase resting LES pressure [9–11]. Short-term LES electrical stimulation, using temporary leads implanted in the LES in subjects with GERD, has supported observations from animal studies. Importantly, LES stimulation did not interfere with normal swallow functions, such as LES relaxation, and was not associated with any sensation or side effects. These observations suggest that electrical stimulation of the LES may be an effective method of restoring the antireflux of the LES in GERD patients [12,13].

Rodriguez et al. conducted an open-label trial of LES stimulation in 24 chronic GERD patients seeking alternative therapy for their GERD [14]. All patients were at least partially responsive to acid suppression therapy with PPI. The trial included patients with GERD symptoms for a median of 8 years and chronic PPI medication use for more than 6 years. Gastroesophageal reflux was documented using esophageal pH testing. Patients with hiatal hernia greater than 3 cm or long segment Barrett’s were excluded. At 1 year, their median GERD–Health-Related Quality of Life (GERD–HRQL) scores improved significantly with LES electrical stimulation compared to baseline GERD–HRQL scores on‑PPI (9 vs 2; p = 0.002) and off-PPI (23.5 vs 2; p < 0.001). GERD–HRQL sleep and dysphagia scores also improved significantly. Frequency and severity of heartburn and regurgitation and of nocturnal symptoms improved significantly over time with LES electrical stimulation. At baseline, 33% of on-PPI and 88% of off-PPI patients reported that reflux impacted their sleep. Bothersome dysphagia due to reflux was reported by 13% of on-PPI and 58% of off-PPI patients. At the 12-month follow-up, only 4% of the patients reported bothersome impact of GERD on sleep (p = 0.001 vs on-PPI; p < 0.001 vs off-PPI) and bothersome dysphagia/odynophagia (p = 0.3 vs on-PPI; p = 0.001 vs off-PPI). All but one patient (96%) reported complete cessation of their PPI use. There was significant and sustained improvement in patients’ median 24-h distal esophageal acid exposure at 1 year (10.1 vs 3.3; p < 0.001) compared with their baseline. Normalization, or at least a 50% reduction in distal esophageal acid exposure, was observed in 77% of the patients on therapy. The high-resolution esophageal manometry showed that end-expiratory LES pressures improved and were sustained at 12-month follow-up [14].

In a post‑hoc analysis of patients that were incomplete responders to PPI therapy, Rodriguez et al. reported significant improvement in outcomes of GERD–HRQL (9 vs 2; p < 0.01) and distal esophageal pH (9.1 vs 3.5%; p < 0.01) [15]. In another post‑hoc analysis of a subgroup of patients with abnormal proximal esophageal acid exposure, a hallmark of proximal reflux, Crowell et al. showed normalization of abnormal proximal esophageal acid exposure in all patients (p = 0.01) [16]. The median (interquartile range [IQR]) GERD–HRQL in these patients improved from 9 (6–10) on-PPI and 21 (20–24) off-PPI to 0 (0–3) at their 1-year follow-up (p < 0.05) [16].

In an ongoing, prospective, open-label multicenter trial in symptomatic GERD patients, Bredenoord et al. reported similar preliminary results with LES electrical stimulation [17]. The median (IQR) GERD–HRQL scores at baseline off-PPI were 30 (24–37), which improved to 6 (4–11) on LES electrical stimulation at 3 months (p < 0.001), and 9 (7–13) at 6 months (p < 0.01). There was also a significant improvement compared with the GERD–HRQL scores on-PPI of 19 (8–22) at baseline. Patients’ median (IQR) esophageal pH at baseline was 12.4% (8.8–15%) and improved to 3.6% (2–10%; p = 0.07) at 3 months and 4.2% (2.7–6.7%; p = 0.01) at 6 months. GERD–HRQL scores off-PPI improved by greater than 50% in 92% (11 out of 12) of the patients that were able to discontinue PPI use. Esophageal acid exposure either normalized or improved by more than 50% in 83% (ten out of 12) of patients [17].

There have been no device or stimulation-related unanticipated adverse events, or untoward sensation due to stimulation in any of these studies. Swallowing function assessed by manometry was shown to be unaffected and no dysphagia symptoms have been reported.

These are encouraging results supporting the use of LES stimulation for the treatment of GERD, but there are limitations. The open-label design of these trials cannot control for placebo or ‘regression to mean’ effects, which can be addressed by well designed randomized controlled trials. However, improvement in objective measures, such as esophageal pH sustained for 1 year, suggests a true therapeutic effect. Patients with >3 cm hiatal hernia were excluded from the trial, which constituted of a significant proportion of refractory GERD patients. Future trials should evaluate patients with moderate 3–5 cm hiatal hernias that may be treated by a combination of restoration of abdominal esophagus, repair of the diaphragmatic hiatus and implant of the LES stimulator. Finally, the generalizability of these results will be established after the final results of a multicenter trial with a larger number of patients are available.

In conclusion, early results suggest that the electrical stimulation of the LES using a laparoscopically implanted LES stimulation system is safe and effective in the treatment of GERD and results in significant improvement of GERD symptoms of heartburn and regurgitation, reduction in GERD medication use and improvement in esophageal acid exposure and LES pressures without causing adverse sensation or symptoms. The improvement in patient outcomes is sustained over the long term. Furthermore, LES electrical stimulation can be noninvasively optimized to individual patient’s disease profile and changing needs over time to achieve sustained improvement in patient outcomes.

Financial & competing interests disclosure

MD Crowell has been a consultant with EndoStim Inc. and the Chair of its data monitoring committee. The author has 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.