Surg Endosc (2014) 28:3293–3301 DOI 10.1007/s00464-014-3603-x
and Other Interventional Techniques
Long-term results of electrical stimulation of the lower esophageal sphincter for treatment of proximal GERD Toshitaka Hoppo • Leonardo Rodrı´guez • Edy Soffer • Michael D. Crowell • Blair A. Jobe
Received: 29 January 2014 / Accepted: 3 May 2014 / Published online: 22 July 2014 Ó Springer Science+Business Media New York 2014
E. Soffer Department of Gastroenterology, University of Southern California, Los Angeles, CA, USA
pump inhibitors (PPI), hiatal hernia B3 cm, esophagitis BLA grade C underwent laparoscopic implantation of the LES stimulator. LES stimulation at 20 Hz, 215 ls, 5–8 m Amp sessions was delivered in 6–12, 30 min sessions each day. Esophageal pH at baseline and after 12-months of LES stimulation was measured 5 and 23 cm above the manometric upper border of LES. Results Total, upright and supine values of median (IQR) proximal esophageal pH at baseline were 0.4 (0.1–1.4), 0.6 (0.2–2.3), and 0 (0.0–0.2) %, respectively, and at 12 months on LES-EST were 0 (0–0) % (p = 0.001 total and upright; p = 0.043 supine comparisons). 24-hour distal esophageal acid exposure improved from 10.2 (7.6–11.7) to 3.4 (1.6–7.0) % (p = 0.001). Seven (37 %) patients had abnormal ([1.1 %) 24-hour proximal acid exposure at baseline; all normalized at 12 months (p = 0.008). In these 7 patients, total, upright, and supine median proximal acid exposure values at baseline were 1.7 (1.3–4.1), 2.9 (1.9–3.7), and 0.3 (0–4.9) %, respectively, and after 12 months of LESEST were 0 (0–0.0), 0 (0–0.1), and 0 (0–0) % (p = 0.018 total and upright; p = 0.043 supine comparisons). Distal esophageal pH for this group improved from 9.3 (7.8–17.2) at baseline to 3.2 (1.1–3.7) % at 12-months (p = 0.043). There were no GI side effects such as dysphagia, gas-bloat or diarrhea or device or procedure related serious adverse events with LES-EST. There was also a significant improvement in their GERD-HRQL scores. Conclusion LES-EST is associated with normalization of proximal esophageal pH in patients with GERD and may be useful in treating those with proximal GERD. The LESEST is safe without typical side effects associated with traditional antireflux surgery.
M. D. Crowell Department of Gastroenterology, Mayo Clinic in Arizona, Scottsdale, AZ, USA
Keywords GERD Electrical stimulation Surgical treatment Proximal GERD
Abstract Introduction Electrical stimulation of the lower esophageal sphincter (LES) in gastroesophageal reflux disease (GERD) patients, using EndoStimÒ LES stimulation system (EndoStim BV, the Hague, Netherlands), enhances LES pressure, decrease distal esophageal acid exposure, improves symptoms, and eliminates the need in many patients for daily GERD medications. Aim To evaluate, in a post hoc analysis, the effect of LES stimulation on proximal esophageal acid exposure in a subgroup of patients with abnormal proximal esophageal acid exposure. Methods Nineteen patients (median age 54 years; IQR 47–64; men-10) with GERD partially responsive to proton
Presented at the SAGES 2014 Annual Meeting, April 2–5, 2014, Salt Lake City, Utah.
Electronic supplementary material The online version of this article (doi:10.1007/s00464-014-3603-x) contains supplementary material, which is available to authorized users. T. Hoppo (&) B. A. Jobe Institute for the Treatment of Esophageal & Thoracic Disease, The Western Pennsylvania Hospital, Allegheny Health Network, Pittsburgh, PA, USA e-mail: [email protected] L. Rodrı´guez Department of Surgery, CCO Obesidad Y Diabetes, Santiago, Chile
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Gastroesophageal reflux disease (GERD) is the most common esophageal disorders in the United States and Western countries. Acid suppressive therapy using proton pump inhibitors (PPI) and H2 blocker has been the primary treatment option for patients with typical and/or atypical GERD symptoms; however, up to 45 % of patients with typical GERD symptoms have persistent or recurrent symptoms despite maximal dose of PPI [1], and no therapeutic benefit of PPI was observed in patients with atypical symptoms such as chronic cough in the recent meta-analysis [2, 3]. This may be reasonable because GERD is caused by a mechanically impaired antireflux barrier at the lower esophageal sphincter (LES), and none of antisecretory medications can address a mechanically impaired LES function. The recent systematic review to evaluate the role of acid, weakly acid, and weakly alkaline reflux in patients with GERD as measured by multichannel intraluminal impedance demonstrated that there was no significant difference in the total number of reflux events (both acid and non-acid) between on-PPI and off-PPI, and the number of non-acid reflux events became predominant in patients onPPI [4]. This data supports that PPI increases the pH of gastric contents but never stop reflux. Therefore, a structural restore of LES dysfunction by antireflux surgery such as fundoplication is a reasonable approach to effectively eliminate gastroesophageal reflux. Surgical fundoplication provides a significant increase in the LES pressure and length, thus normalizing abnormal acid exposure to the distal esophagus. However, surgical fundoplication is associated with post-operative side effects such as dysphagia and bloating despite extensive modifications of procedure [5, 6]. The majority of patients who are not satisfied with medical treatment are reluctant to undergo surgery because of fear of post-operative side effects, and hence, seek alternative treatments. Several less invasive antireflux procedures have been investigated; however, most of them could not achieve long-term sustained efficacy or impact objective measurements such as acid exposure time, and eventually disappeared from the market [7]. The EndoStimÒ LES stimulation system (EndoStim BV, the Hague, Netherlands) is an implantable electrical stimulator that delivers long-term electrical stimulation therapy to the LES. Previous studies have demonstrated that electrical stimulation of the LES provided an increase in resting LES pressure without interfering with physiological LES relaxation [8–11]. Based on these data, an open-label human trial has been conducted and has demonstrated the safety and efficacy of this device with a significant and sustained improvement in GERD symptoms, normalization of distal acid exposure, and reduction in PPI usage without any side effects at 6 and 12-month follow-up [12, 13]. This study is a post hoc analysis of the above open-label trial, to evaluate the effect
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of LES stimulation on proximal esophageal acid exposure in a subgroup of patients with abnormal proximal esophageal acid exposure.
Materials and methods Study design A prospective, open label, single center, treatment only trial was completed. The trial design and study inclusion and exclusion criteria have been previously published [14]. Patients meeting all the inclusion and exclusion criteria underwent laparoscopic implant of the LES stimulator. LESEST was initiated on day 1 post implantation, and PPI therapy was discontinued. The patients were followed perprotocol published earlier [14]. In brief, the patient underwent in-person post-op visit at week 2, and in-person study visits at month 1, 3, 6, and 12 and a phone visit at month 2, 4, 5, and 9. The trial was initially designed for 6 months followup, but has been extended to a 2-year follow-up to collect additional long-term data. A post hoc analysis of proximal acid exposure in all patients and those with abnormally high proximal pH defined as % 24 h acid exposure [1.1 % measure 23 cm proximal to the manometric upper border of LES was performed and is the basis for this manuscript. Subjects All patients enrolled in this study suffered from chronic GERD symptoms, were not satisfied with their medical therapy, and contemplated surgical therapy for GERD. They responded to a newspaper advertisement and chose this intervention because of its less invasive nature, compared to fundoplication. The study was approved by the Servicio de Salud Metropolitano Oriente, Santiago, Chile ethics committee, and all subjects signed informed consent. Symptoms’ assessment and physiologic tests Assessment of symptoms and esophageal tests were performed before and during electrical stimulation of the LES. Symptoms of GERD were assessed by a validated questionnaire, GERD-HRQL. It provides a composite score, as well as an assessment of individual symptoms [15]. Quality of life was also assessed by SF-12Ò Health Survey (SF-12). All the above variables were assessed at baseline while on PPI therapy, and after 2 weeks off-PPI therapy. These were evaluated again at follow-up while on LES stimulation therapy and data were collected at all in-person and phonevisits. GERD-HRQL does not include any laryngeal symptoms, and any additional assessment of laryngeal symptoms was not performed in this study.
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Fig. 1 LES Stimulation System (EndoStim BV, the Netherlands) comprises an Implantable pulse generator (IPG 65 9 48 9 12 mm3, weighs 49 g) implanted in the subcutaneous pocket in the anterior abdomen and bipolar electrodes implanted in the lower esophageal sphincter and connected to the IPG. A Electrode position in the lower
esophageal sphincter. Bipolar stitch electrodes are placed in the abdominal esophagus inline 1 cm apart away from the anterior vagus nerve. B The lead is connected to the IPG that is implanted in the subcutaneous pocket in the anterior abdomen
Esophageal acid exposure was assessed using 24-hour esophageal pH-metry, with sensors (AL1 Sistema de pHMetria, Ver 1.26, Alacer Biomedica, Brazil), positioned in the esophageal body 5 and 23 cm proximal to the manometric upper border of the LES performed with patient offPPI for at least 5 days. Esophageal pH testing was conducted at month 3, 6, and 12. Normal values of proximal acid exposure of \1.1 % has been reported with a pH sensor 15 cm above the LES [16] and values of \ 0.9 % and 1.4 % have been reported with pH electrode placed 20 cm above the LES [17, 18]. For our analysis, we used a proximal 24 h pH value of [1.1 as abnormal. A reviewer (MDC) blinded to all identifying patient and visit data independently scored all pH data. High-resolution esophageal manometry was performed using either the Medical Measurement System (MMS, Dover, NH) or the Sierra Scientific Instruments system (Given Imaging, Los Angeles, California).
pulse is monophasic followed by a charge-balancing phase. The pulse is 215 ls wide and nominally 5 mA in amplitude (range 3–8 mA). The charge-balancing phase is 20 ms wide and typically less than 1 mA at the peak with a rapid drop off as charge dissipates. The stimulation pulse is delivered at a rate of 20 Hz and continues for a period of 30 min [14]. There are up to twelve 30 min treatment sessions/day delivered pre-meal and pre-reflux event based on patient symptoms and baseline 24-hr pH recordings. Electrical stimulation can be optimized to tailor delivery to individual needs as follows: the stimulation parameters can be adjusted using the external programmer, additional sessions can be added or timing of existing sessions changed at follow-up to address residual symptoms, or residual acid events on pH testing. Stimulation amplitude and electrode polarity can also be adjusted at follow-up to address suboptimal symptom or pH response. The device includes an accelerometer to detect upright and supine states, and the stimulation algorithm can be customized based on patient’s position to address supine/nocturnal reflux.
LES stimulation system The LES stimulation system 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 (Fig. 1). The IPG is connected to the stimulation leads and permanently implanted in a subcutaneous pocket in the left upper quadrant of the abdomen. Interrogation and programing of the IPG were provided via a wireless external programmer and computer software. The LES stimulation system delivers therapy that can be personalized to individual patient needs. The stimulation
LES stimulator implant procedure The detail of LES stimulator implant procedure was previously described [10]. Briefly, the procedure involved standard laparoscopic approach. The anterior aspect of intraabdominal esophagus was exposed while avoiding dissection of the phrenoesophageal attachment and damage to the anterior vagus nerve. The placement of electrodes was performed under endoscopic visualization to prevent perforation into the esophageal lumen. The first electrode
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was placed in the muscularis propria in the abdominal esophagus, and the second electrode was placed in an inline position, approximately 10 mm distal to the first electrode at the gastroesophageal junction. Subsequently, the lead electrical connector, which was pulled through the abdominal wall, was attached to the pulse generator placed in a subcutaneous packet. A functionality test was performed by the technical support personnel. None of patients in this study underwent repair of hiatal hernia. The patient was discharged home after an overnight stay and was recommended to wear an elastic compression bandage over the pulse generator implantation site for 10–14 days post-operatively in order to reduce the chances for a seroma formation. The implant site was inspected 10–14 days post-procedure. The battery life of the IPG with typical use is [10 years following which it can be replaced by simple outpatient procedure without the need for repeat laparoscopy.
Surg Endosc (2014) 28:3293–3301 Table 1 Baseline patient characteristics and relevant medical/GERD history of patients with abnormal proximal esophageal pH Characteristic
Mean (SD)
Age (years)
50.0 (12.3)
Body Mass Index (BMI)
26.9 (3.9)
Gender Male
5
Female
2
Patients using daily PPI
100 %
Duration of GERD symptoms Median (IQR)
Mean (SD)
Duration of PPI use
Mean (SD)
Median (IQR) GERD-HRQL total score
A total sample size of 22 provided a 90 % chance of detecting a mean (SD) difference C10 (10) on the GERDHRQL score from baseline to 12 months with 95 % confidence. Allowing for 10 % patient dropout, a sample size of 25 patients was chosen as the final enrollment target for the original trial. Safety evaluation was descriptive and included the incidence, severity, and type of AEs, and clinically significant changes or abnormalities in the patient’s physical examination, vital signs, clinical tests, and EKG results. All reported events were adjudicated by an independent Data Monitoring Committee for relatedness. Relatedness was adjudicated to the device and to the procedure independently. Extent of relatedness was categorized as definite, probable, possible, not related, or unknown. The effect of LES-EST on proximal esophageal acid exposure was assessed at 1 year follow-up and compared to their baseline proximal esophageal acid exposure. Patients’ symptoms on and 2 weeks off-PPI were measured using the GERD-HRQL, symptoms and medication use by measured using daily diary. All comparisons were made at the p \ 0.05 level using related-samples Wilcoxon Sign Rank test (SPSS v20.0, Chicago, IL).
Results
6.7 (2.8) years 5.0 (5–10) years
On-PPI
Off-PPI
Median (IQR)
9.0 (6–10)
21.0 (20–24)
% Not satisfied
71 %
71 %
Heartburn –Frequency/week Median (IQR)
Sample size calculation and data analysis
12.0 (6.5) years 11.0 (7–20) years
Regurgitation— Frequency/week Median (IQR) Nocturnal Heartburn— Frequency/week Median (IQR) Nocturnal regurgitation— Frequency/week Median (IQR) Total % pH time \4
Off-PPI 97 (88–100) % Off-PPI 93 (11–100) % Off-PPI 93 (16–100) % Off-PPI 43 (0–95) % 9.3 (7.8–17.2)
Median, (IQR) Hiatal Hernia (%) None/ \2 cm/C 2cm
71.4/0/28.6
SD standard deviation, IQR interquartile range
was available in 19 patients (median age 54 years; IQR 47–64; men-10). Seven patients had an abnormal proximal esophageal pH at baseline and their demographics and disease characteristics are provided in Table 1. Safety A total of 8 events in 3 subjects were reported. There was no Serious Adverse Events (SAE) reported for this subgroup of patients. All events were adjudicated and found to be not related to the device. Of the events, 1 of the 8 events (Nausea/Vomiting) was found as ‘‘Probable’’ in relation to the laparoscopic procedure.
Patient characteristics Esophageal pH and high-resolution manometry Successful LES-EST at one year was completed by 23 patients with GERD, who met all the inclusion and exclusion criteria. Proximal pH data at baseline and 1 year
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Dual-probe esophageal pH testing was completed in 19 patients at baseline and at the 12-month follow-up. Blinded
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Table 2 Baseline and 12 month post-LES-EST results
Baseline
Month 12
On-PPI (n = 7)
9.0 (6–10)
0.0 (0–3)
Off-PPI (n = 7)
21.0 (20–24)
p value
Median (IQR) GERD-HRQL \0.001 \0.001
Median (IQR) % 24-h distal esophageal pH \4.0 Total
9.3 (7.8–17.2)
3.2 (1.1–3.7)
Upright
10.8 (10.4–15.8)
4.7 (2.6–6.0)
0.018
Supine
1.7 (0.9–17.4)
0 (0–0.3)
0.248
DeMeester score
33.3 (25.6-68.9)
11.7 (5.2–13.7)
0.128
100 %
14 %
0.014
% Patients with abnormal distal esophageal pH (\4 for [4 %)
0.043
Median (IQR) % 24-h proximal esophageal pH \4.0 Total
1.7 (1.3–4.1)
0 (0–0)
0.018
Upright
2.9 (1.9–3.7)
0 (0–0.1)
0.018
Supine
0.3 (0–4.9)
0 (0–0)
0.043
100 %
0%
0.008
% Patients with abnormal proximal esophageal pH (\4 for [1.1 %)
Median (IQR) esophageal manometry parameters
Manometry at baseline and 12 months was performed using separate system hence a formal statistical analysis of the manometry data was not performed a
Each patient performed 20 wet swallows compared to 10 swallows performed traditionally
LES End expiratory pressure (mmHg)
8.8 (7.0–11.0)
16.0 (9.0–19.0)
LES Respiratory Mean Pressure (mm Hg)
17.4 (16.3–20.8)
26.0 (23.0–29.0)
LES Length (cm)
2.0 (1.8–2.6)
2.7 (2.3–3.1)
% Peristaltic swallows
100 (100–100)
100 (95–100)
Distal Esophageal contraction amplitude (mm Hg)
76.2 (50.0–111.0)
68.0 (47.0–75.0)
Number esophageal contraction [30 mm Hga
15.0 (12.0–15.0)
20.0 (17.0–20.0)
Residual LES pressure (mmHg)
8.4 (7.6–9.7)
9.3 (5.4–12.0)
pH analysis revealed that median (IQR) percent time with proximal and distal pH \4.0 in 24 h improved from 0.4 % and 10.2 % at baseline to 0.0 % and 3.4 % at 12 months, respectively (p = 0.001) (Table 2). Distal esophageal FAET was normalized (\4 % of 24-hour recording) in 58 %. An additional 5 % had[50 % improvement in distal esophageal FAET. Seven patients (37 %) had abnormal proximal esophageal pH at baseline. All these patients normalized the
proximal esophageal acid exposure at 12 month follow-up on LES-EST. Blinded pH analysis revealed that median (IQR) percent time with proximal and distal pH \4.0 in 24 h improved from 1.7 % and 9.3 % at baseline to 0.0 % and 3.2 % at 12 months, respectively (p = 0.018 and p = 0.043) (Table 2; Fig. 2A). None of the patients in this cohort developed new onset abnormal proximal acid exposure during the 1-year followup.
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GERD-HRQL and daily symptom diaries GERD symptoms improved soon after initiating LES-EST and improvement continued over the study period with individual optimization of LES-EST. GERD-HRQL composite and individual symptom scores were significantly better at 12 months compared with baseline both on and off-PPIs (Table 2) in the total cohort and in patients with abnormal proximal pH. In the subgroup of patients with abnormal proximal esophageal pH, improvement of 50 % or more from baseline GERD-HRQL score off-PPI was reported in 86 % of patients. Composite baseline GERDHRQL scores on-PPI improved at least 50 % in 71 % of patients. At baseline, 71 % of patients each reported that they were ‘‘unsatisfied’’ with their condition both off-PPI and on-PPI compared to 14 % ‘‘unsatisfied’’ at their 12-month evaluation on LES-EST off-PPI. Patient satisfaction at 12 months was significantly improved from baseline on-PPI (p = 0.046) and off-PPI (p = 0.046). Analysis of heartburn and regurgitation symptoms evaluated using the 14-day symptom diaries were completed in all 7 patients (Table 3). Frequency and severity of heartburn and regurgitation improved significantly over time with LES-EST. At baseline all patients were on-PPIs for GERD. At the 12-month diary evaluation, none of the patient was using any PPI.
Discussion This post hoc analysis of the first human open-label trial of LES-EST for the treatment of GERD demonstrated a significant, sustained improvement in typical GERD symptoms as measured by GERD-HRQL and daily-symptoms diaries, normalization of distal and proximal acid exposure as measured by pH testing and elimination of PPI usage at 1-year follow-up in patients with abnormal proximal acid exposure. LES-EST was associated with no adverse effects or sensations (dysphagia, gas-bloat, and diarrhea) typical of other antireflux procedures. Proximal reflux can cause typical symptoms of GERD such as heartburn and regurgitation and laryngeal (atypical) symptoms such as cough, hoarseness, throat clearing, and globus sensation. Laryngeal symptoms are commonly seen in general practice, and previous study has demonstrated that approximately 20 % of the adult population in the United States is affected [19]. Laryngeal symptoms appear to have a more significant impact on patients’ social functioning and vitality compared to typical GERD [20], which is associated with a worse quality of life than angina and congestive heart failure [21]. Accumulating evidence has suggested that proximal reflux is likely associated with aspiration, and can contribute to the development of
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Fig. 2 Improvement in GERD outcomes. A Significant improvement in median (IQR) GERD-HRQL composite score at months 12 compared to baseline ON-PPI and OFF-PPI median GERD-HRQL composite scores. B Change in median (IQR) proximal esophageal pH on LES-EST from baseline to 12 month (n = 7); p \ 0.001 (Related Sample Wilcoxon Signed Rank test). At 12 months, all patients had normalized their proximal esophageal acid exposure
pulmonary diseases such as adult-onset asthma [22, 23] and idiopathic pulmonary fibrosis [24, 25], and chronic allograft rejection in patients who underwent lung transplantation [14, 26]. Previous studies have shown that the proximal extent of the refluxate is an important determinant for reflux perception [27], and patients with non-erosive reflux disease (NERD) with normal pH testing have significantly higher number of proximal acid reflux and higher sensitivity to short-lasting reflux events compared to patients with typical GERD with esophagitis, which may explain why patients with NERD are less responsive to acid suppressive therapy compared to patients with esophagitis [28]. Furthermore, proximal extent of the refluxate is the most significant contributing factor for reflux perception in patients who are refractory to acid suppressive therapy [29, 30]. The management of laryngeal symptoms has been complicated due to a lack of definitive diagnostic or treatment strategy. Therefore, patients with laryngeal
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Table 3 Symptoms of nocturnal and daytime heartburn and regurgitation and their severity at baseline and 12 months compared to baseline as reported on daily diary Median (IRQ) % diary days
None
Mild
Moderate
Severe
Nocturnal
Daytime
Antacid/day
Regurgitation
Baseline off-PPI
7 (0–89)
11 (5–68)
29 (0–48)
0 (0–13)
43 (0–95)
93 (11–95)
0.8 (0–1.6)
Month 12
100 (90–100)
4 (0–11)
0 (0–0)
0 (0–0)
0 (0–2)
0 (0–10)
0 (0–0.1)
Baseline off-PPI
4 (0–13)
25 (14–39)
54 (21–75)
0 (0–34)
93 (16–100)
93 (82–95)
Month 12
100 (40–100)
0 (0–60)
0 (0–0)
0 (0–0)
0 (0–4)
0 (0–60)
Heartburn
Data presented as median and interquartile range (IQR). All comparisons were statistically significant except mild heartburn at baseline and 12 month
symptoms require multiple specialty consultations, diagnostic/therapeutic procedures and medications, resulting in 5.6 times higher direct cost than that for typical GERD [31]. A 3-month empiric trial of high-dose proton pump inhibitors (PPI) has been recommended as an initial diagnostic measure [32]; however, PPIs have a significant placebo effect and a recent meta-analysis has demonstrated no therapeutic benefit of PPIs in this setting [2, 3]. Furthermore, the outcomes of surgical fundoplication in patients with laryngeal symptoms have been less favorable than those with typical GERD symptoms [33–36]. The recent retrospective studies of patients with laryngeal symptoms, who had abnormal proximal exposure as measured by hypopharyngeal multichannel intraluminal impedance, have suggested a direct measurement of proximal reflux events such as LPR increase the sensitivity of diagnosis, thus improving the outcome of antireflux surgery on patients with laryngeal symptoms [23, 37]. Antireflux surgery such as laparoscopic Nissen fundoplication effectively eliminates any types of reflux events including non-acid reflux and proximal reflux [38–40]. However, antireflux surgery may be associated with side effects such as dysphagia and bloating, which make patients and health care providers reluctant to undergo surgery or refer patients for surgery. Recently, two promising, less invasive approaches have been introduced; LESEST and the magnetic device (LINX). Both procedures attempt to augment the LES to eliminate gastroesophageal reflux. Recently, the outcome at 3-year follow-up after LINX procedure was published, demonstrating that a sustained efficacy of symptom control, normalization of distal acid exposure, and reduction in PPI use; distal acid exposure time of pH \4 at 1-year follow-up after LINX procedure was significantly reduced (median, total 3.3; upright 4.3; supine 0.4) compared to baseline (median, total 10.9; upright 12.7; supine 6.0), which is quite similar with our results; however, there was no data of impact of LINX procedure on proximal acid exposure. Furthermore, the LINX procedure was associated with dysphagia, which occurred in 68 % of patients, although dysphagia improved over time (11 % at 1-year, 5 % at 2-year, 4 % at 3-year)
[41]. In the present study, we demonstrated an equivalent subjective and objective efficacy of LES-EST without any side effects or adverse events. Furthermore, we demonstrated that abnormal proximal acid exposure was completely normalized after LES-EST in all patients with preprocedure abnormal proximal acid exposure. Although no objective assessment of atypical symptoms was performed in this study, patient satisfaction at 1-year was significantly improved compared to baseline on-PPI and off-PPI, suggesting LES-EST may positively impact laryngeal symptoms via normalization of proximal acid exposure. There are some limitations to this study. Although there was an elimination of abnormal proximal acid exposure, objective assessment of laryngeal symptoms pre- and postprocedure using validated questionnaires was not performed. GERD-HRQL and patient satisfaction were significantly improved after LES-EST, suggesting that patients’ symptoms including laryngeal symptoms if existed, significantly improved after LES-EST. However, this is totally expectation, and objective assessment of laryngeal symptoms will be included in the future study. The sample size is small, and data establishes the proof of concept. A large-scale, randomized controlled study comparing LESEST to sham stimulation with longer follow-up is required to evaluate the true benefit of LES-EST to treat GERD with typical and/or atypical symptoms. Additional comparative effectiveness trials comparing LES-EST to PPI medications and surgery are desirable.
Conclusion In patients with abnormal proximal esophageal acid exposure, LES-EST provides a sustained efficacy to improve clinical symptoms and quality of life, and normalize objective measures such as distal and proximal acid exposure without any side effects or adverse events at 1-year follow-up. LES-EST is a safe, less invasive procedure to treat GERD; however, a large-scale, randomized controlled study with longer follow-up is required to evaluate the true benefit of LES-EST for the treatment of GERD.
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3300 Disclosures Study Sponsor—EndoStim BV, The Hague, Netherlands provided funding for the trial. Prof. Michael D Crowell and Blair Jobe are consultant for EndoStim Inc. Prof. Edy Soffer is a stock holder in EndoStim Inc. Remaining study authors or their immediate family has no financial relationship with the sponsor that would constitute a conflict of interest.
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Surg Endosc (2014) 28:3293–3301 16. Vaezi MF, Schroeder PL, Richter JE (1997) Reproducibility of proximal probe pH parameters in 24-hour ambulatory esophageal pH monitoring. Am J Gastroenterol 92(5):825–829 17. Cool M, Poelmans J, Feenstra L, Tack J (2004) Characteristics and clinical relevance of proximal esophageal pH monitoring. Am J Gastroenterol 99(12):2317–2323 18. Dobhan R, Castell DO (1993) Normal and abnormal proximal esophageal acid exposure: results of ambulatory dual-probe pH monitoring. Am J Gastroenterol 88(1):25–29 19. Koufman JA, Amin MR, Panetti M (2000) Prevalence of reflux in 113 consecutive patients with laryngeal and voice disorders. Otolaryngol Head Neck Surg 123(4):385–388 20. Carrau RL, Khidr A, Crawley JA, Hillson EM, Davis JK, Pashos CL (2004) The impact of laryngopharyngeal reflux on patientreported quality of life. Laryngoscope. 114(4):670–674 21. Wiklund I (2004) Review of the quality of life and burden of illness in gastroesophageal reflux disease. Dig Dis 22(2): 108–114 22. DiMango E, Holbrook JT, Simpson E et al (2009) Effects of asymptomatic proximal and distal gastroesophageal reflux on asthma severity. Am J Respir Crit Care Med 180(9):809–816 23. Komatsu Y, Hoppo T, Jobe BA (2013) Proximal reflux as a cause of adult-onset asthma: the case for hypopharyngeal impedance testing to improve the sensitivity of diagnosis. JAMA Surg 148(1):50–58 24. Hoppo T, Komatsu Y, Jobe BA (2012) Gastroesophageal reflux disease and patterns of reflux in patients with idiopathic pulmonary fibrosis using hypopharyngeal multichannel intraluminal impedance. Dis Esophagus. doi:10.1111/j.1442-2050.2012.01446.x 25. Raghu G, Freudenberger TD, Yang S et al (2006) High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 27(1):136–142 26. Sweet MP, Herbella FA, Leard L et al (2006) The prevalence of distal and proximal gastroesophageal reflux in patients awaiting lung transplantation. Ann Surg 244(4):491–497 27. Weusten BL, Akkermans LM, vanBerge-Henegouwen GP, Smout AJ (1995) Symptom perception in gastroesophageal reflux disease is dependent on spatiotemporal reflux characteristics. Gastroenterology 108(6):1739–1744 28. Cicala M, Emerenziani S, Caviglia R et al (2003) Intra-oesophageal distribution and perception of acid reflux in patients with non-erosive gastro-oesophageal reflux disease. Aliment Pharmacol Ther 18(6):605–613 29. Fass R, Sifrim D (2009) Management of heartburn not responding to proton pump inhibitors. Gut 58(2):295–309 30. Zerbib F, Duriez A, Roman S, Capdepont M, Mion F (2008) Determinants of gastro-oesophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors. Gut 57(2):156–160 31. Francis DO, Rymer JA, Slaughter JC et al (2013) High economic burden of caring for patients with suspected extraesophageal reflux. Am J Gastroenterol 108(6):905–911 32. Ford CN (2005) Evaluation and management of laryngopharyngeal reflux. JAMA 294(12):1534–1540 33. Lindstrom DR, Wallace J, Loehrl TA, Merati AL, Toohill RJ (2002) Nissen fundoplication surgery for extraesophageal manifestations of gastroesophageal reflux (EER). Laryngoscope. 112(10):1762–1765 34. So JB, Zeitels SM, Rattner DW (1998) Outcomes of atypical symptoms attributed to gastroesophageal reflux treated by laparoscopic fundoplication. Surgery 124(1):28–32 35. Swoger J, Ponsky J, Hicks DM et al (2006) Surgical fundoplication in laryngopharyngeal reflux unresponsive to aggressive acid suppression: a controlled study. Clin Gastroenterol Hepatol 4(4):433–441
Surg Endosc (2014) 28:3293–3301 36. Westcott CJ, Hopkins MB, Bach K, Postma GN, Belafsky PC, Koufman JA (2004) Fundoplication for laryngopharyngeal reflux disease. J Am Coll Surg 199(1):23–30 37. Hoppo T, Komatsu Y, Jobe BA (2013) Antireflux surgery in patients with chronic cough and abnormal proximal exposure as measured by hypopharyngeal multichannel intraluminal impedance. JAMA Surg 148(7):608–615 38. Frazzoni M, Piccoli M, Conigliaro R, Manta R, Frazzoni L, Melotti G (2013) Refractory gastroesophageal reflux disease as diagnosed by impedance-pH monitoring can be cured by laparoscopic fundoplication. Surg Endosc 27(8):2940–2946
3301 39. Roman S, Poncet G, Serraj I, Zerbib F, Boulez J, Mion F (2007) Characterization of reflux events after fundoplication using combined impedance-pH recording. Br J Surg 94(1):48–52 40. Frazzoni M, Conigliaro R, Manta R, Melotti G (2011) Reflux parameters as modified by EsophyX or laparoscopic fundoplication in refractory GERD. Aliment Pharmacol Ther 34(1):67–75 41. Ganz RA, Peters JH, Horgan S et al (2013) Esophageal sphincter device for gastroesophageal reflux disease. N Engl J Med 368(8):719–727
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and Other Interventional Techniques
Long-term results of electrical stimulation of the lower esophageal sphincter for treatment of proximal GERD Toshitaka Hoppo • Leonardo Rodrı´guez • Edy Soffer • Michael D. Crowell • Blair A. Jobe
Received: 29 January 2014 / Accepted: 3 May 2014 / Published online: 22 July 2014 Ó Springer Science+Business Media New York 2014
E. Soffer Department of Gastroenterology, University of Southern California, Los Angeles, CA, USA
pump inhibitors (PPI), hiatal hernia B3 cm, esophagitis BLA grade C underwent laparoscopic implantation of the LES stimulator. LES stimulation at 20 Hz, 215 ls, 5–8 m Amp sessions was delivered in 6–12, 30 min sessions each day. Esophageal pH at baseline and after 12-months of LES stimulation was measured 5 and 23 cm above the manometric upper border of LES. Results Total, upright and supine values of median (IQR) proximal esophageal pH at baseline were 0.4 (0.1–1.4), 0.6 (0.2–2.3), and 0 (0.0–0.2) %, respectively, and at 12 months on LES-EST were 0 (0–0) % (p = 0.001 total and upright; p = 0.043 supine comparisons). 24-hour distal esophageal acid exposure improved from 10.2 (7.6–11.7) to 3.4 (1.6–7.0) % (p = 0.001). Seven (37 %) patients had abnormal ([1.1 %) 24-hour proximal acid exposure at baseline; all normalized at 12 months (p = 0.008). In these 7 patients, total, upright, and supine median proximal acid exposure values at baseline were 1.7 (1.3–4.1), 2.9 (1.9–3.7), and 0.3 (0–4.9) %, respectively, and after 12 months of LESEST were 0 (0–0.0), 0 (0–0.1), and 0 (0–0) % (p = 0.018 total and upright; p = 0.043 supine comparisons). Distal esophageal pH for this group improved from 9.3 (7.8–17.2) at baseline to 3.2 (1.1–3.7) % at 12-months (p = 0.043). There were no GI side effects such as dysphagia, gas-bloat or diarrhea or device or procedure related serious adverse events with LES-EST. There was also a significant improvement in their GERD-HRQL scores. Conclusion LES-EST is associated with normalization of proximal esophageal pH in patients with GERD and may be useful in treating those with proximal GERD. The LESEST is safe without typical side effects associated with traditional antireflux surgery.
M. D. Crowell Department of Gastroenterology, Mayo Clinic in Arizona, Scottsdale, AZ, USA
Keywords GERD Electrical stimulation Surgical treatment Proximal GERD
Abstract Introduction Electrical stimulation of the lower esophageal sphincter (LES) in gastroesophageal reflux disease (GERD) patients, using EndoStimÒ LES stimulation system (EndoStim BV, the Hague, Netherlands), enhances LES pressure, decrease distal esophageal acid exposure, improves symptoms, and eliminates the need in many patients for daily GERD medications. Aim To evaluate, in a post hoc analysis, the effect of LES stimulation on proximal esophageal acid exposure in a subgroup of patients with abnormal proximal esophageal acid exposure. Methods Nineteen patients (median age 54 years; IQR 47–64; men-10) with GERD partially responsive to proton
Presented at the SAGES 2014 Annual Meeting, April 2–5, 2014, Salt Lake City, Utah.
Electronic supplementary material The online version of this article (doi:10.1007/s00464-014-3603-x) contains supplementary material, which is available to authorized users. T. Hoppo (&) B. A. Jobe Institute for the Treatment of Esophageal & Thoracic Disease, The Western Pennsylvania Hospital, Allegheny Health Network, Pittsburgh, PA, USA e-mail: [email protected] L. Rodrı´guez Department of Surgery, CCO Obesidad Y Diabetes, Santiago, Chile
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Gastroesophageal reflux disease (GERD) is the most common esophageal disorders in the United States and Western countries. Acid suppressive therapy using proton pump inhibitors (PPI) and H2 blocker has been the primary treatment option for patients with typical and/or atypical GERD symptoms; however, up to 45 % of patients with typical GERD symptoms have persistent or recurrent symptoms despite maximal dose of PPI [1], and no therapeutic benefit of PPI was observed in patients with atypical symptoms such as chronic cough in the recent meta-analysis [2, 3]. This may be reasonable because GERD is caused by a mechanically impaired antireflux barrier at the lower esophageal sphincter (LES), and none of antisecretory medications can address a mechanically impaired LES function. The recent systematic review to evaluate the role of acid, weakly acid, and weakly alkaline reflux in patients with GERD as measured by multichannel intraluminal impedance demonstrated that there was no significant difference in the total number of reflux events (both acid and non-acid) between on-PPI and off-PPI, and the number of non-acid reflux events became predominant in patients onPPI [4]. This data supports that PPI increases the pH of gastric contents but never stop reflux. Therefore, a structural restore of LES dysfunction by antireflux surgery such as fundoplication is a reasonable approach to effectively eliminate gastroesophageal reflux. Surgical fundoplication provides a significant increase in the LES pressure and length, thus normalizing abnormal acid exposure to the distal esophagus. However, surgical fundoplication is associated with post-operative side effects such as dysphagia and bloating despite extensive modifications of procedure [5, 6]. The majority of patients who are not satisfied with medical treatment are reluctant to undergo surgery because of fear of post-operative side effects, and hence, seek alternative treatments. Several less invasive antireflux procedures have been investigated; however, most of them could not achieve long-term sustained efficacy or impact objective measurements such as acid exposure time, and eventually disappeared from the market [7]. The EndoStimÒ LES stimulation system (EndoStim BV, the Hague, Netherlands) is an implantable electrical stimulator that delivers long-term electrical stimulation therapy to the LES. Previous studies have demonstrated that electrical stimulation of the LES provided an increase in resting LES pressure without interfering with physiological LES relaxation [8–11]. Based on these data, an open-label human trial has been conducted and has demonstrated the safety and efficacy of this device with a significant and sustained improvement in GERD symptoms, normalization of distal acid exposure, and reduction in PPI usage without any side effects at 6 and 12-month follow-up [12, 13]. This study is a post hoc analysis of the above open-label trial, to evaluate the effect
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of LES stimulation on proximal esophageal acid exposure in a subgroup of patients with abnormal proximal esophageal acid exposure.
Materials and methods Study design A prospective, open label, single center, treatment only trial was completed. The trial design and study inclusion and exclusion criteria have been previously published [14]. Patients meeting all the inclusion and exclusion criteria underwent laparoscopic implant of the LES stimulator. LESEST was initiated on day 1 post implantation, and PPI therapy was discontinued. The patients were followed perprotocol published earlier [14]. In brief, the patient underwent in-person post-op visit at week 2, and in-person study visits at month 1, 3, 6, and 12 and a phone visit at month 2, 4, 5, and 9. The trial was initially designed for 6 months followup, but has been extended to a 2-year follow-up to collect additional long-term data. A post hoc analysis of proximal acid exposure in all patients and those with abnormally high proximal pH defined as % 24 h acid exposure [1.1 % measure 23 cm proximal to the manometric upper border of LES was performed and is the basis for this manuscript. Subjects All patients enrolled in this study suffered from chronic GERD symptoms, were not satisfied with their medical therapy, and contemplated surgical therapy for GERD. They responded to a newspaper advertisement and chose this intervention because of its less invasive nature, compared to fundoplication. The study was approved by the Servicio de Salud Metropolitano Oriente, Santiago, Chile ethics committee, and all subjects signed informed consent. Symptoms’ assessment and physiologic tests Assessment of symptoms and esophageal tests were performed before and during electrical stimulation of the LES. Symptoms of GERD were assessed by a validated questionnaire, GERD-HRQL. It provides a composite score, as well as an assessment of individual symptoms [15]. Quality of life was also assessed by SF-12Ò Health Survey (SF-12). All the above variables were assessed at baseline while on PPI therapy, and after 2 weeks off-PPI therapy. These were evaluated again at follow-up while on LES stimulation therapy and data were collected at all in-person and phonevisits. GERD-HRQL does not include any laryngeal symptoms, and any additional assessment of laryngeal symptoms was not performed in this study.
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Fig. 1 LES Stimulation System (EndoStim BV, the Netherlands) comprises an Implantable pulse generator (IPG 65 9 48 9 12 mm3, weighs 49 g) implanted in the subcutaneous pocket in the anterior abdomen and bipolar electrodes implanted in the lower esophageal sphincter and connected to the IPG. A Electrode position in the lower
esophageal sphincter. Bipolar stitch electrodes are placed in the abdominal esophagus inline 1 cm apart away from the anterior vagus nerve. B The lead is connected to the IPG that is implanted in the subcutaneous pocket in the anterior abdomen
Esophageal acid exposure was assessed using 24-hour esophageal pH-metry, with sensors (AL1 Sistema de pHMetria, Ver 1.26, Alacer Biomedica, Brazil), positioned in the esophageal body 5 and 23 cm proximal to the manometric upper border of the LES performed with patient offPPI for at least 5 days. Esophageal pH testing was conducted at month 3, 6, and 12. Normal values of proximal acid exposure of \1.1 % has been reported with a pH sensor 15 cm above the LES [16] and values of \ 0.9 % and 1.4 % have been reported with pH electrode placed 20 cm above the LES [17, 18]. For our analysis, we used a proximal 24 h pH value of [1.1 as abnormal. A reviewer (MDC) blinded to all identifying patient and visit data independently scored all pH data. High-resolution esophageal manometry was performed using either the Medical Measurement System (MMS, Dover, NH) or the Sierra Scientific Instruments system (Given Imaging, Los Angeles, California).
pulse is monophasic followed by a charge-balancing phase. The pulse is 215 ls wide and nominally 5 mA in amplitude (range 3–8 mA). The charge-balancing phase is 20 ms wide and typically less than 1 mA at the peak with a rapid drop off as charge dissipates. The stimulation pulse is delivered at a rate of 20 Hz and continues for a period of 30 min [14]. There are up to twelve 30 min treatment sessions/day delivered pre-meal and pre-reflux event based on patient symptoms and baseline 24-hr pH recordings. Electrical stimulation can be optimized to tailor delivery to individual needs as follows: the stimulation parameters can be adjusted using the external programmer, additional sessions can be added or timing of existing sessions changed at follow-up to address residual symptoms, or residual acid events on pH testing. Stimulation amplitude and electrode polarity can also be adjusted at follow-up to address suboptimal symptom or pH response. The device includes an accelerometer to detect upright and supine states, and the stimulation algorithm can be customized based on patient’s position to address supine/nocturnal reflux.
LES stimulation system The LES stimulation system 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 (Fig. 1). The IPG is connected to the stimulation leads and permanently implanted in a subcutaneous pocket in the left upper quadrant of the abdomen. Interrogation and programing of the IPG were provided via a wireless external programmer and computer software. The LES stimulation system delivers therapy that can be personalized to individual patient needs. The stimulation
LES stimulator implant procedure The detail of LES stimulator implant procedure was previously described [10]. Briefly, the procedure involved standard laparoscopic approach. The anterior aspect of intraabdominal esophagus was exposed while avoiding dissection of the phrenoesophageal attachment and damage to the anterior vagus nerve. The placement of electrodes was performed under endoscopic visualization to prevent perforation into the esophageal lumen. The first electrode
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was placed in the muscularis propria in the abdominal esophagus, and the second electrode was placed in an inline position, approximately 10 mm distal to the first electrode at the gastroesophageal junction. Subsequently, the lead electrical connector, which was pulled through the abdominal wall, was attached to the pulse generator placed in a subcutaneous packet. A functionality test was performed by the technical support personnel. None of patients in this study underwent repair of hiatal hernia. The patient was discharged home after an overnight stay and was recommended to wear an elastic compression bandage over the pulse generator implantation site for 10–14 days post-operatively in order to reduce the chances for a seroma formation. The implant site was inspected 10–14 days post-procedure. The battery life of the IPG with typical use is [10 years following which it can be replaced by simple outpatient procedure without the need for repeat laparoscopy.
Surg Endosc (2014) 28:3293–3301 Table 1 Baseline patient characteristics and relevant medical/GERD history of patients with abnormal proximal esophageal pH Characteristic
Mean (SD)
Age (years)
50.0 (12.3)
Body Mass Index (BMI)
26.9 (3.9)
Gender Male
5
Female
2
Patients using daily PPI
100 %
Duration of GERD symptoms Median (IQR)
Mean (SD)
Duration of PPI use
Mean (SD)
Median (IQR) GERD-HRQL total score
A total sample size of 22 provided a 90 % chance of detecting a mean (SD) difference C10 (10) on the GERDHRQL score from baseline to 12 months with 95 % confidence. Allowing for 10 % patient dropout, a sample size of 25 patients was chosen as the final enrollment target for the original trial. Safety evaluation was descriptive and included the incidence, severity, and type of AEs, and clinically significant changes or abnormalities in the patient’s physical examination, vital signs, clinical tests, and EKG results. All reported events were adjudicated by an independent Data Monitoring Committee for relatedness. Relatedness was adjudicated to the device and to the procedure independently. Extent of relatedness was categorized as definite, probable, possible, not related, or unknown. The effect of LES-EST on proximal esophageal acid exposure was assessed at 1 year follow-up and compared to their baseline proximal esophageal acid exposure. Patients’ symptoms on and 2 weeks off-PPI were measured using the GERD-HRQL, symptoms and medication use by measured using daily diary. All comparisons were made at the p \ 0.05 level using related-samples Wilcoxon Sign Rank test (SPSS v20.0, Chicago, IL).
Results
6.7 (2.8) years 5.0 (5–10) years
On-PPI
Off-PPI
Median (IQR)
9.0 (6–10)
21.0 (20–24)
% Not satisfied
71 %
71 %
Heartburn –Frequency/week Median (IQR)
Sample size calculation and data analysis
12.0 (6.5) years 11.0 (7–20) years
Regurgitation— Frequency/week Median (IQR) Nocturnal Heartburn— Frequency/week Median (IQR) Nocturnal regurgitation— Frequency/week Median (IQR) Total % pH time \4
Off-PPI 97 (88–100) % Off-PPI 93 (11–100) % Off-PPI 93 (16–100) % Off-PPI 43 (0–95) % 9.3 (7.8–17.2)
Median, (IQR) Hiatal Hernia (%) None/ \2 cm/C 2cm
71.4/0/28.6
SD standard deviation, IQR interquartile range
was available in 19 patients (median age 54 years; IQR 47–64; men-10). Seven patients had an abnormal proximal esophageal pH at baseline and their demographics and disease characteristics are provided in Table 1. Safety A total of 8 events in 3 subjects were reported. There was no Serious Adverse Events (SAE) reported for this subgroup of patients. All events were adjudicated and found to be not related to the device. Of the events, 1 of the 8 events (Nausea/Vomiting) was found as ‘‘Probable’’ in relation to the laparoscopic procedure.
Patient characteristics Esophageal pH and high-resolution manometry Successful LES-EST at one year was completed by 23 patients with GERD, who met all the inclusion and exclusion criteria. Proximal pH data at baseline and 1 year
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Dual-probe esophageal pH testing was completed in 19 patients at baseline and at the 12-month follow-up. Blinded
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Table 2 Baseline and 12 month post-LES-EST results
Baseline
Month 12
On-PPI (n = 7)
9.0 (6–10)
0.0 (0–3)
Off-PPI (n = 7)
21.0 (20–24)
p value
Median (IQR) GERD-HRQL \0.001 \0.001
Median (IQR) % 24-h distal esophageal pH \4.0 Total
9.3 (7.8–17.2)
3.2 (1.1–3.7)
Upright
10.8 (10.4–15.8)
4.7 (2.6–6.0)
0.018
Supine
1.7 (0.9–17.4)
0 (0–0.3)
0.248
DeMeester score
33.3 (25.6-68.9)
11.7 (5.2–13.7)
0.128
100 %
14 %
0.014
% Patients with abnormal distal esophageal pH (\4 for [4 %)
0.043
Median (IQR) % 24-h proximal esophageal pH \4.0 Total
1.7 (1.3–4.1)
0 (0–0)
0.018
Upright
2.9 (1.9–3.7)
0 (0–0.1)
0.018
Supine
0.3 (0–4.9)
0 (0–0)
0.043
100 %
0%
0.008
% Patients with abnormal proximal esophageal pH (\4 for [1.1 %)
Median (IQR) esophageal manometry parameters
Manometry at baseline and 12 months was performed using separate system hence a formal statistical analysis of the manometry data was not performed a
Each patient performed 20 wet swallows compared to 10 swallows performed traditionally
LES End expiratory pressure (mmHg)
8.8 (7.0–11.0)
16.0 (9.0–19.0)
LES Respiratory Mean Pressure (mm Hg)
17.4 (16.3–20.8)
26.0 (23.0–29.0)
LES Length (cm)
2.0 (1.8–2.6)
2.7 (2.3–3.1)
% Peristaltic swallows
100 (100–100)
100 (95–100)
Distal Esophageal contraction amplitude (mm Hg)
76.2 (50.0–111.0)
68.0 (47.0–75.0)
Number esophageal contraction [30 mm Hga
15.0 (12.0–15.0)
20.0 (17.0–20.0)
Residual LES pressure (mmHg)
8.4 (7.6–9.7)
9.3 (5.4–12.0)
pH analysis revealed that median (IQR) percent time with proximal and distal pH \4.0 in 24 h improved from 0.4 % and 10.2 % at baseline to 0.0 % and 3.4 % at 12 months, respectively (p = 0.001) (Table 2). Distal esophageal FAET was normalized (\4 % of 24-hour recording) in 58 %. An additional 5 % had[50 % improvement in distal esophageal FAET. Seven patients (37 %) had abnormal proximal esophageal pH at baseline. All these patients normalized the
proximal esophageal acid exposure at 12 month follow-up on LES-EST. Blinded pH analysis revealed that median (IQR) percent time with proximal and distal pH \4.0 in 24 h improved from 1.7 % and 9.3 % at baseline to 0.0 % and 3.2 % at 12 months, respectively (p = 0.018 and p = 0.043) (Table 2; Fig. 2A). None of the patients in this cohort developed new onset abnormal proximal acid exposure during the 1-year followup.
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GERD-HRQL and daily symptom diaries GERD symptoms improved soon after initiating LES-EST and improvement continued over the study period with individual optimization of LES-EST. GERD-HRQL composite and individual symptom scores were significantly better at 12 months compared with baseline both on and off-PPIs (Table 2) in the total cohort and in patients with abnormal proximal pH. In the subgroup of patients with abnormal proximal esophageal pH, improvement of 50 % or more from baseline GERD-HRQL score off-PPI was reported in 86 % of patients. Composite baseline GERDHRQL scores on-PPI improved at least 50 % in 71 % of patients. At baseline, 71 % of patients each reported that they were ‘‘unsatisfied’’ with their condition both off-PPI and on-PPI compared to 14 % ‘‘unsatisfied’’ at their 12-month evaluation on LES-EST off-PPI. Patient satisfaction at 12 months was significantly improved from baseline on-PPI (p = 0.046) and off-PPI (p = 0.046). Analysis of heartburn and regurgitation symptoms evaluated using the 14-day symptom diaries were completed in all 7 patients (Table 3). Frequency and severity of heartburn and regurgitation improved significantly over time with LES-EST. At baseline all patients were on-PPIs for GERD. At the 12-month diary evaluation, none of the patient was using any PPI.
Discussion This post hoc analysis of the first human open-label trial of LES-EST for the treatment of GERD demonstrated a significant, sustained improvement in typical GERD symptoms as measured by GERD-HRQL and daily-symptoms diaries, normalization of distal and proximal acid exposure as measured by pH testing and elimination of PPI usage at 1-year follow-up in patients with abnormal proximal acid exposure. LES-EST was associated with no adverse effects or sensations (dysphagia, gas-bloat, and diarrhea) typical of other antireflux procedures. Proximal reflux can cause typical symptoms of GERD such as heartburn and regurgitation and laryngeal (atypical) symptoms such as cough, hoarseness, throat clearing, and globus sensation. Laryngeal symptoms are commonly seen in general practice, and previous study has demonstrated that approximately 20 % of the adult population in the United States is affected [19]. Laryngeal symptoms appear to have a more significant impact on patients’ social functioning and vitality compared to typical GERD [20], which is associated with a worse quality of life than angina and congestive heart failure [21]. Accumulating evidence has suggested that proximal reflux is likely associated with aspiration, and can contribute to the development of
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Fig. 2 Improvement in GERD outcomes. A Significant improvement in median (IQR) GERD-HRQL composite score at months 12 compared to baseline ON-PPI and OFF-PPI median GERD-HRQL composite scores. B Change in median (IQR) proximal esophageal pH on LES-EST from baseline to 12 month (n = 7); p \ 0.001 (Related Sample Wilcoxon Signed Rank test). At 12 months, all patients had normalized their proximal esophageal acid exposure
pulmonary diseases such as adult-onset asthma [22, 23] and idiopathic pulmonary fibrosis [24, 25], and chronic allograft rejection in patients who underwent lung transplantation [14, 26]. Previous studies have shown that the proximal extent of the refluxate is an important determinant for reflux perception [27], and patients with non-erosive reflux disease (NERD) with normal pH testing have significantly higher number of proximal acid reflux and higher sensitivity to short-lasting reflux events compared to patients with typical GERD with esophagitis, which may explain why patients with NERD are less responsive to acid suppressive therapy compared to patients with esophagitis [28]. Furthermore, proximal extent of the refluxate is the most significant contributing factor for reflux perception in patients who are refractory to acid suppressive therapy [29, 30]. The management of laryngeal symptoms has been complicated due to a lack of definitive diagnostic or treatment strategy. Therefore, patients with laryngeal
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Table 3 Symptoms of nocturnal and daytime heartburn and regurgitation and their severity at baseline and 12 months compared to baseline as reported on daily diary Median (IRQ) % diary days
None
Mild
Moderate
Severe
Nocturnal
Daytime
Antacid/day
Regurgitation
Baseline off-PPI
7 (0–89)
11 (5–68)
29 (0–48)
0 (0–13)
43 (0–95)
93 (11–95)
0.8 (0–1.6)
Month 12
100 (90–100)
4 (0–11)
0 (0–0)
0 (0–0)
0 (0–2)
0 (0–10)
0 (0–0.1)
Baseline off-PPI
4 (0–13)
25 (14–39)
54 (21–75)
0 (0–34)
93 (16–100)
93 (82–95)
Month 12
100 (40–100)
0 (0–60)
0 (0–0)
0 (0–0)
0 (0–4)
0 (0–60)
Heartburn
Data presented as median and interquartile range (IQR). All comparisons were statistically significant except mild heartburn at baseline and 12 month
symptoms require multiple specialty consultations, diagnostic/therapeutic procedures and medications, resulting in 5.6 times higher direct cost than that for typical GERD [31]. A 3-month empiric trial of high-dose proton pump inhibitors (PPI) has been recommended as an initial diagnostic measure [32]; however, PPIs have a significant placebo effect and a recent meta-analysis has demonstrated no therapeutic benefit of PPIs in this setting [2, 3]. Furthermore, the outcomes of surgical fundoplication in patients with laryngeal symptoms have been less favorable than those with typical GERD symptoms [33–36]. The recent retrospective studies of patients with laryngeal symptoms, who had abnormal proximal exposure as measured by hypopharyngeal multichannel intraluminal impedance, have suggested a direct measurement of proximal reflux events such as LPR increase the sensitivity of diagnosis, thus improving the outcome of antireflux surgery on patients with laryngeal symptoms [23, 37]. Antireflux surgery such as laparoscopic Nissen fundoplication effectively eliminates any types of reflux events including non-acid reflux and proximal reflux [38–40]. However, antireflux surgery may be associated with side effects such as dysphagia and bloating, which make patients and health care providers reluctant to undergo surgery or refer patients for surgery. Recently, two promising, less invasive approaches have been introduced; LESEST and the magnetic device (LINX). Both procedures attempt to augment the LES to eliminate gastroesophageal reflux. Recently, the outcome at 3-year follow-up after LINX procedure was published, demonstrating that a sustained efficacy of symptom control, normalization of distal acid exposure, and reduction in PPI use; distal acid exposure time of pH \4 at 1-year follow-up after LINX procedure was significantly reduced (median, total 3.3; upright 4.3; supine 0.4) compared to baseline (median, total 10.9; upright 12.7; supine 6.0), which is quite similar with our results; however, there was no data of impact of LINX procedure on proximal acid exposure. Furthermore, the LINX procedure was associated with dysphagia, which occurred in 68 % of patients, although dysphagia improved over time (11 % at 1-year, 5 % at 2-year, 4 % at 3-year)
[41]. In the present study, we demonstrated an equivalent subjective and objective efficacy of LES-EST without any side effects or adverse events. Furthermore, we demonstrated that abnormal proximal acid exposure was completely normalized after LES-EST in all patients with preprocedure abnormal proximal acid exposure. Although no objective assessment of atypical symptoms was performed in this study, patient satisfaction at 1-year was significantly improved compared to baseline on-PPI and off-PPI, suggesting LES-EST may positively impact laryngeal symptoms via normalization of proximal acid exposure. There are some limitations to this study. Although there was an elimination of abnormal proximal acid exposure, objective assessment of laryngeal symptoms pre- and postprocedure using validated questionnaires was not performed. GERD-HRQL and patient satisfaction were significantly improved after LES-EST, suggesting that patients’ symptoms including laryngeal symptoms if existed, significantly improved after LES-EST. However, this is totally expectation, and objective assessment of laryngeal symptoms will be included in the future study. The sample size is small, and data establishes the proof of concept. A large-scale, randomized controlled study comparing LESEST to sham stimulation with longer follow-up is required to evaluate the true benefit of LES-EST to treat GERD with typical and/or atypical symptoms. Additional comparative effectiveness trials comparing LES-EST to PPI medications and surgery are desirable.
Conclusion In patients with abnormal proximal esophageal acid exposure, LES-EST provides a sustained efficacy to improve clinical symptoms and quality of life, and normalize objective measures such as distal and proximal acid exposure without any side effects or adverse events at 1-year follow-up. LES-EST is a safe, less invasive procedure to treat GERD; however, a large-scale, randomized controlled study with longer follow-up is required to evaluate the true benefit of LES-EST for the treatment of GERD.
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3300 Disclosures Study Sponsor—EndoStim BV, The Hague, Netherlands provided funding for the trial. Prof. Michael D Crowell and Blair Jobe are consultant for EndoStim Inc. Prof. Edy Soffer is a stock holder in EndoStim Inc. Remaining study authors or their immediate family has no financial relationship with the sponsor that would constitute a conflict of interest.
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