Clinical Evidence
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Clinical Results

Long-term clinical results of EndoStim patients treated for up to five years shows that LES stimulation is safe and effective in controlling GERD symptoms and improving patient quality of life in most patients.

Most patients experience:

Resolution of regurgitation and heartburn
Significant improvement in sleep issues related to reflux
Elimination of dependency on PPI medication
Long-term normalization of acid exposure and sphincter function

International clinical results:

Meta-analysis of 2 published trials: Significant improvement in GERD symptoms and esophageal pH

Sustained improvement in GERD outcomes (GERD-HRQL)

Sustained improvement in esophageal acid exposure

Outcomes from ongoing multicenter commercial patient registry confirm results of the 2 long-term studies

Sustained improvement in GERD outcomes (GERD-HRQL)

Sustained improvement in esophageal acid exposure

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EndoStim LES Stimulation Therapy Improves GERD in Patients with Laparoscopic Sleeve Gastrectomy (LSG)

Alejandro Nieponice, Yves Borbély, Leonardo Rodriguez, Henning G Schulz, Camilo Ortiz, Michael Talbot, David Martin, Nicole Bouvy

Surg Endosc. 2016; 30:S263.

BACKGROUND: LSG is the most commonly performed bariatric procedure in the US/Canada and the Asia-Pacific region. However, LSG can result in new GERD and may worsen pre-existing GERD. LSG patients with GERD not well controlled with PPI do not have good treatment options except for more invasive, anatomy-altering gastric bypass surgery. LES electrical simulation therapy has shown to improve outcomes in GERD patients.

AIM: To evaluate the safety and efficacy of LES stimulation in LSG patients with GERD not controlled with maximum dose PPI therapy.

METHODS: Patients with LSG associated GERD with bothersome symptoms on maximum PPI dose underwent LES stimulator implant procedure and were enrolled in an international patient registry prospectively tracking outcomes in GERD patients treated with LES electrical stimulation. Electrical stimulation was delivered at 5mA, 220uSec pulse in 12, 30 minute sessions daily. GERD outcomes pre and post-stimulation were evaluated.

RESULTS: 12 patients, 66% (8/12) women at 8 centers have been treated. Median age was 46 (IQR=34-55) years. All (12/12) were on at least daily double-dose PPIs. At their last follow-up (median=12 months), 75% (6/8) were off-PPIs and one each was using PPIs on < 50% of days and standard dose once a day. The later was on daily PPI for GI prophylaxis for chronic steroid therapy for kidney transplants and not GERD symptoms. Median esophageal pH at baseline was 16.4% (IQR 8.5-22.4), which improved to 1.3% (IQR 0.4-2.2) % at last follow-up at least 6 month post-implant (n=6; p=0.01). All patients improved esophageal acid exposure, 83% (5/6) patients had normalized acid exposure and 1/6 patient had >40% improvement in distal esophageal acid exposure. Median GERD-HRQL scores at baseline was 25 (IQR 18-31) which improved to 4 (IQR 3-10) at last follow-up (n=6; p= 0.015). No SAEs related to the device or procedure were reported. No dysphagia or other GI side effects were reported.

CONCLUSION: Preliminary results on patients with LSG and GERD with bothersome symptoms despite maximal medical therapy, treated with LES electrical stimulation, revealed that LES stimulation is safe and results in a significant improvement in GERD symptoms and esophageal acid exposure. Most patients were off their PPI therapy with remaining taking PPI at a reduced dose. Data from a larger patient experience for this indication is being collected using the international registry trial.

Inadequate Symptom Control on Long-Term PPI Therapy in GERD – Fact or Fiction?

Joachim Labenz, Gisela Labenz, Dietmar Stephan, Frank Willeke

Gastroenterology , Volume 150 , Issue 4 , S279

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BACKGROUND: Randomized controlled trials report about 30% of GERD patients complain of bothersome remaining symptoms (heartburn, regurgitation) despite PPI. General practice physicians estimate this to be an over-representation.

METHODS: In a prospective, multicenter, observational study, which was conducted in 16 general practice clinics over 5 months, patients with GERD and taking PPI for over 1 year were asked to complete a questionnaire. Patients were asked the duration of their GERD, duration of PPI therapy, satisfaction with their condition on PPI, whether they have received diagnostic evaluation related to GERD (endoscopy, pH monitoring, manometry), whether they have received surgical consultation for GERD, and the frequency of any remaining complaints in the past week (i.e. heartburn, regurgitation, sleep disruption) as part of a validated questionnaire for the diagnosis of GERD (GerdQ). “Lost Patients” were defined as those likely to be suffering from true GERD as predicted by the GerdQ questionnaire, dissatisfied on their current PPI therapy, and had not previously received any specific GERD diagnostics (pH-metry or manometry). General practitioners participating in the study were surveyed for changes in the their perceptions toward reflux following the study.

RESULTS: 333 consecutive patient responses were collected. Patients suffered from GERD for an average of 8.6 years and prescribed PPI therapy for an average duration of 6.4 years. 39% of patients reported heartburn at least 2 days per week (20% 4-7 days per week), 30% complained of regurgitation at least 2 days per week (13% 4-7 days per week), and 22% reported symptoms disrupting sleep at least twice per week (6% 4-7 days per week). 20% of patients were dissatisfied on their current PPI therapy (score of 1 or 2 on a scale of 1-5, 1=very dissatisfied, 5=very satisfied), and 14% were both dissatisfied and had a high likelihood of complaints correlating to pathological pH based on the GerdQ questionnaire. A total of 86% of patients received an upper endoscopy in the past, but only 8% had a prior pH-metry and 2% manometry. Only 8% received prior surgical consult for GERD. The rate of “Lost Patients” was 10%. Following review of these results, 75% of GPs surveyed (n=8) agree that reflux patients with remaining symptoms on PPI is more of a problem than they previously thought.

CONCLUSION: Inadequate control of symptoms is common in GERD patients prescribed PPI therapy, and is often overlooked in daily practice. These patients with insufficient symptom control should be methodically identified and considered for further diagnostics and/or treatment modification, for example with a screening questionnaire.

Electrical Stimulation Therapy (EST) of the Lower Esophageal Sphincter (LES) for Refractory GERD – One Year Results of an International Multicenter Trial

Peter D. Siersema, Albert J. Bredenoord, José M. Conchillo, Albis C. Hani, Michael Booth, Alex Escalona, Abraham Botha, Justin C. Wu, Nageshwar D. Reddy, Gonzalo Torres Villalobos, Philip W. Chiu, Nicole D. Bouvy, Mark I. van Berge Henegouwen, Jelle P. Ruurda, Nicolas Quezada, Miguel A. Valdovinos

Gastroenterology. 2016; 150(4):S216.

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BACKGROUND: A long-term single-center trial showed that LES-EST significantly improves esophageal acid exposure and symptoms in GERD patients (Surg Endosc. 2015;DOI10.1007/s00464-015-4539-5).

AIM: To establish safety and efficacy of LES-EST in GERD patients partially responsive to PPI in an international multi-center trial.

METHODS: We studied GERD patients partially responsive to proton pump inhibitors (PPI) with off PPI GERD-HRQL >20 and ?5 point improvement on-PPI, LES end-expiratory pressure ?5mmHg, % 24 hour esophageal pH<4 for ?5%, hiatal hernia <3cm and esophagitis ?LA Grade C. Bipolar stitch electrodes and a pulse generator (EndoStim BV) were implanted laparoscopically. EST at 20Hz, 220usec, 4-6mAmp in 12 30-minute sessions was initiated post-implant. GERD related outcomes were evaluated at regular intervals.

RESULTS: Forty-two patients (median 51 yr; 24 men) were enrolled and implanted with an LES stimulator; 37 completed 12-month follow-up. Median(IQR) GERD-HRQL improved from 31(26-37) off-PPI and 17(9-23) on-PPI at baseline to 5(2-9) at 12 mo. (p<0.001 vs. BL on and offPPI). Median esophageal acid exposure (pH<4.0) improved from 10.0(7.6-12.9)% at baseline to 4.4(2.5-6.4)% at 12 mo. (p<0.001). At 12 mo. 81% were completely off PPI, 8% used PPI intermittently (<50% days) and 11% used PPI regularly (>50% days). Median SF-12 mental health score improved from 48 on-PPI and 45 off-PPI at baseline to 53 at 12 mo. (p=0.096 vs. BL on-PPI; p<0.01 vs. off-PPI). Median SF-12 physical health score improved from 45 on-PPI and 39 off-PPI at baseline to 50 at 12 mo. (p<0.001 vs. BL on and off-PPI). Median activity impairment, measured by the WPAI:GERD questionnaire, improved from 20% at baseline on-PPI and 60% off-PPI to 0% at 12-mo. (p<0.001 vs. BL on and off-PPI). Four SAEs were reported. Two were asymptomatic electrode erosions related to the device and/or procedure; both patients reported loss of therapy efficacy and underwent uneventful fundoplication surgery during which the device was explanted. One was a procedure-related laparoscopic trocar perforation of the small bowel during the implant procedure, successfully repaired laparoscopically. One was an AV nodal reentrant tachycardia, not related to the device or therapy, successfully treated with AV nodal ablation. Five instances of dysphagia were reported in 4 patients with a hiatal closure procedure at the time of implant, all resolved without intervention. Other device and/or procedure related events were typical of surgical implant procedures, e.g. nausea and pocket pain.

CONCLUSION: One-year results of this multicenter trial show that LES-EST is safe and effective for treating PPI partially responsive GERD, validating previous reports. LES-EST resulted in significant improvement in esophageal acid exposure, GERD symptoms, PPI usage and quality of life, with excellent safety and tolerability.

Preliminary Results of a Prospective Multi-Center Observational Registry of Lower Esophageal Sphincter Stimulation for GERD: The Less-GERD Registry

Joachim Labenz, Henning G. Schulz, Andreas Leodolter, Jan B. Pedersen, Ernst Eypasch, Alejandro Nieponice, Ralf Weise, Nicole D. Bouvy

Gastroenterology. 2016; 150(4):S478.

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BACKGROUND: Electrical stimulation of the lower esophageal sphincter (LES-ES) using the EndoStim® LES Stimulation System (The Hague, The Netherlands) was shown to be effective and safe in clinical trials. Data from routine clinical practice has not yet been reported.

METHODS: An ongoing, prospective multicenter web-based registry is collecting data at baseline and at routine follow-ups for 5-year in patients with disruptive GERD symptoms treated with LES-ES in routine clinical practice. Demographics, adverse events, GERD symptoms recorded in daily diaries, GERD health related quality of life scores (GERD-HRQL), structured GI symptom questionnaires for extra-esophageal symptoms, use of proton pump inhibitors (PPIs) and objective endoscopic and physiological data (esophageal pH / manometry) are collected when available.

RESULTS: Eighty-nine patients are enrolled in the LESSGERD Registry, of whom 39 have available data at baseline and 6 months post-op. All but three (36/39; 92%) patients showed an improvement in their GERD-HRQL score on LESES compared to baseline. Overall, the median (IQR) composite GERD-HRQL score improved from 22 (18-27) preoperatively to 8.0 (3.5-12.5) at 6-month follow-up (p <0.0001). Median distal esophageal acid exposure improved from 11.7 (5.0-24.0)% at baseline to 5.1(2.0- 12.6)% at 6 months (n=17; p=0.59). Proportion of patients with moderate to severe regurgitation decreased from 70% while on medication therapy preoperatively to 27% after 6 months of LES-ES (p<0.04). Proportion of patients with bothersome reflux symptoms during sleep improved from 71% pre-op to 20% at 6 months (p<0.004). Proportion of patients with recurrent cough improved from 40% (6 patients) preoperatively to 10% after 6 months (1 patient). One patient reported severe dysphagia pre-op that was resolved post-op. There was no change in the rate of occasional dysphagia reported. All patients were on long-term PPI at baseline. At 6 months, 17 (80%) patients were completely free of PPI use, 3 patients (8%) used PPI occasionally and only 5 patients (13%) were still taking daily PPI. Final safety data being analyzed and adjudicated by independent DSMB and will be reported at the meeting.

CONCLUSION: In routine clinical practice, LES-ES is safe and effective in treating GERD patients with disruptive GERD symptoms despite PPI with improvement across all reported outcomes. LES-ES may be considered a viable treatment option for this indication.

Effect of Electrical Stimulation Therapy of the Lower Esophageal Sphincter on Postprandial Reflux Mechanisms in GERD Patients

Nicolaas F. Rinsma, Boudewijn F. Kessing, Nicole D. Bouvy, Mark I. van Berge Henegouwen, Andreas J. Smout, Albert J. Bredenoord, Ad Masclee, José M. Conchillo

Gastroenterology. 2016; 150(4):S478.

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BACKGROUND: Two open-label trials have shown that Electrical stimulation therapy (EST) of the lower esophageal sphincter (LES) (LES-EST) significantly improves esophageal acid exposure and symptoms in GERD patients. However, the underlying antireflux mechanism(s) of LES-EST remain(s) unclear.

AIM: The aim of this study is to evaluate the effect of EST on postprandial reflux mechanisms, especially on transient LES relaxations (TLESRs).

METHODS: We studied 10 chronic GERD patients with abnormal acid exposure (pH<4.0 during > 6% of time) and hiatal hernia <3 cm (3 males; mean age 53, range 32-66 yrs). Bipolar stitch electrodes and a pulse generator (EndoStim BV, The Hague, Netherlands) were implanted during laparoscopic surgery. LES-EST was delivered at 20 Hz, 220 µs, 5 mA in 12 30- minute sessions. Postprandial reflux mechanisms were studied before and 3 months after EST-implantation, using a combined stationary high-resolution manometry (HRM) and impedance-pH monitoring. Patients consumed a standardized high caloric (500 kCal) meal (cheeseburger, crisps and 200 ml orange juice), followed immediately by a 90-minute measurement. Patients remained in a semi-recumbent position during the measurement and were not allowed to sleep.

RESULTS: The majority of postprandial reflux episodes occurred during TLESRs, both before (77%) and after (63%) EST-implantation. After LES-EST, a significant reduction in the total number of TLESRs (from 9.1 (4.0) to 5.6 (3.2), p<0.01) and in the number of TLESRs associated with reflux episodes (from 6.7 (4.1) to 3.8 (3.6), p=0.04) was observed. Total postprandial reflux episodes were not significantly altered by LES-EST (from 9.0 (5.1) to 6.8 (6.1), p=0.14); however, the number of reflux episodes facilitated by TLESRs was significantly reduced (7.0 (3.6) to 3.9 (3.4), p=0.03). The number of reflux episodes induced by other mechanisms (such as abdominal straining or swallow induced) were unaffected by the treatment. EST showed no effect on the duration of TLESRs (from 17.5 4.3) s to 14.4 (5.7) s, p=0.14) nor on LES resting pressure (from 19.2 (11.3) mmHg to 21.1 (14.9) mmHg, p=NS).

CONCLUSION: Electrical stimulation therapy of the LES reduced the total number of postprandial TLESRs as well as the number of TLESR-associated reflux episodes in GERD patients. These results suggest that the effect of LES-EST on acid exposure and GERD symptoms is primarily TLESR-mediated.

Electrical Stimulation Therapy (EST) of the Lower Esophageal Sphincter(LES) is Successful in Treating GERD – Long-term 4 Year Results

Leonardo Rodriguez, Patricia Rodriguez, Beatrice Gómez, Manoel Galvao Neto, Michael Crowell, Edy Soffer

BACKGROUND: We have previously reported that LES-EST has improved in outcomes in patients with GERD at 3 year follow-up (Surg Endosc. 2015; DOI 10.1007/s00464-015-4539-5).

AIM: The aim of this open-label human pilot trial registry was to study the safety and efficacy of LES-EST in the cohort of GERD patients over longer 5-year follow-up. We report the results at 4 year.

METHODS: GERD patients at least partially responsive to proton pump inhibitors (PPI) and had off-PPI GERD HRQL>20, % 24 hour esophageal pH5%, hiatal hernia < 3cm and esophagitis < LA Grade C have been treated with LES-EST (EndoStim BV, the Hague, the Netherlands). Patients were evaluated using GERD-HRQL, symptom diaries, and esophageal pH testing at their 4 year follow-up.

RESULTS: Twenty five patients (mean (SD) age= 53 (12) years; men=14) were successfully implanted, 21 agreed to participate in the long-term registry trial and 15 completed their 4-year evaluation. At 4 years on LES-EST, median (IQR) GERD-HRQL was 3 (1-3), significantly improved from 9 (8-10) at baseline on-PPI (p=0.004) and 24 (21-25) at baseline off-PPI (p<0.001). Median 24-hour distal esophageal acid exposure significantly improved from 10.2 (7.9- 11.5)% at baseline to 3.6 (2.8-6.6)% at 4 year (p<0.02). Seventy-nine % (11/14) of patients who received continuous therapy for 48 months experienced normalization or at least 50% improvement of their distal esophageal acid exposure. All but 2 patients reported cessation of regular PPI use (>50% of days with PPI use). There were no unanticipated device- or stimulation-related adverse events, or untoward sensation reported between 3 and 4 year follow-up. There was one procedure related SAE – “hiatal hernia mesh related coronary artery erosion and resulting cardiac tamponade” requiring laparoscopic exploration and repair of the coronary erosion. Patient had a prolonged hospital stay and recovered uneventfully from the complication.

CONCLUSION: LES-EST is safe and effective for treating patients with GERD over a long-term 4-year duration. There was a significant and sustained improvement in symptoms, esophageal acid exposure and reduction in PPI use. Further, LES-EST is not associated with any GI side-effects or adverse events.

Electrical stimulation therapy of the lower esophageal sphincter is successful in treating GERD: long-term 3-year results

Leonardo Rodríguez, Patricia A. Rodriguez, Beatrice Gómez, Manoel Galvao Netto, Michael D. Crowell, Edy Soffer

Surg Endosc. 2015. doi:10.1007/s00464-015-4539-5

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BACKGROUND: Electrical stimulation of the lower esophageal sphincter (LES) has been shown to improve outcomes in patients with gastroesophageal reflux disease (GERD) at 2 years.

AIM: The aim of the study was to evaluate the safety and efficacy of LES stimulation in the same cohort at 3 years.

METHODS: GERD patients with partial response to PPI, with % 24-h esophageal pH < 4.0 for >5 %, with hiatal hernia <3 cm and with esophagitis =LA grade C were treated with LES stimulation in an open-label 2-year trial. All patients were on fixed stimulation parameter of 20 Hz, 220 µs, 5 mA delivered in twelve, 30-min sessions. After completing the 2-year open-label study, they were offered enrollment into a multicenter registry trial and were evaluated using GERD-HRQL, symptom diaries and pH testing at their 3-year follow-up.

RESULTS: Fifteen patients completed their 3-year evaluation [mean (SD) age = 56.1 (9.7) years; men = 8] on LES stimulation. At 3 years, there was a significant improvement in their median (IQR) GERD-HRQL on electrical stimulation compared to both their on PPI [9 (6–10) vs. 1 (0–2), p = 0.001] and off PPI [22 (21–24) vs. 1 (0–2), p < 0.001]. Median 24-h distal esophageal acid exposure was significantly reduced from [10.3 (7.5–11.6) % at baseline vs. 3 (1.9–4.5) %, p < 0.001] at 3 years. Seventy-three % (11/15) patients had normalized their distal esophageal acid exposure at 3 years. Remaining four patients had improved their distal esophageal acid exposure by 39–48 % from baseline. All but four patients reported cessation of regular PPI use (>50 % of days with PPI use); three had normal esophageal pH at 3 years. There were no unanticipated device- or stimulation-related adverse events or untoward sensation reported during the 2- to 3-year follow-up.

CONCLUSION: LES-EST is safe and effective for treating patients with GERD over long-term, 3-year duration. There was a significant and sustained improvement in esophageal acid exposure and reduction in GERD symptoms and PPI use. Further, no new GI side effects or adverse events were reported.

Electrical Stimulation Therapy (EST) of the Lower Esophageal Sphincter (LES) – An Effective Therapy for Refractory GERD – Interim Results of an International Multi-center Trial

Kappelle WFW, Bredenoord AJ, Conchillo JM, Ruurda JP, Bouvy ND, van Berge Henegouwen MI, Chiu PW, Booth M, Hani A, Reddy DN, Bogte A, Smout AJPM, Wu JC, Escalona A, Valdovinos MA, Torres-Villalobos G, Siersema PD

Aliment Pharmacol Ther. 2015. doi:10.1111/apt.13306

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BACKGROUND: A previous single-centre study showed that lower oesophageal sphincter electrical stimulation therapy (LES-EST) in gastro-oesophageal reflux disease (GERD) patients improves reflux symptoms and decreases oesophageal acid exposure.

AIM: To evaluate safety and efficacy of LES-EST in GERD patients with incomplete response to proton pump inhibitors (PPIs) in a prospective, international, multicentre, open-label study.

METHODS: GERD patients, partially responsive to PPIs, received LES-EST. GERD health-related quality of life (GERD-HRQL), daily symptom diaries, quality of life scores, oesophageal acid exposure, and LES resting and residual pressure were measured before and after initiation of LES-EST. Stimulation sessions were optimised based on residual symptoms and oesophageal acid exposure.

RESULTS: Forty-four patients were enrolled and 6-month data from 41 patients are available. Hiatal repair was performed in 16 patients. One device-related, one procedure-related and one unrelated severe adverse event were reported. GERD-HRQL improved from 31.0 (IQR 26.2-36.8) off-PPI and 16.5 (IQR 9.0-22.8) on-PPI to 4 (IQR 1-8) at 3-month and 5 (IQR 3-9) at 6-month follow-up (P < 0.0001 vs. on- and off-PPI). Oesophageal acid exposure (pH < 4.0) improved from 10.0% (IQR 7.5-12.9) to 3.8% (IQR 1.9-12.3) at 3 months (P = 0.0027) and 4.4% (IQR 2.2-7.2) at 6 months (P < 0.0001).

CONCLUSION: These interim results show an acceptable safety record of LES-EST to date, combined with good short-term efficacy in GERD patients who are partially responsive to PPI therapy. A remarkable reduction in regurgitation symptoms, without the risk of intervention-requiring dysphagia may prove to be an advantage compared with other anti-reflux procedures.

Lower Esophageal Sphincter (LES) Electrical Stimulation Improves Sleep Quality, Work Productivity, And Quality of Life in Patients with Refractory GERD

Bouvy N, Rinsma NF, Escalona A, Ruurda JP, Conchillo J, Bredenoord A, van Berge Henegouwen M, Chiu P, Booth M, Hani A, Reddy D, Smout A, Wu J, Siersema P. Rodriguez L, Rodriguez P, Gomez B, Soffer E, Crowell MD, Netto MG.

UEG Journal. 2014; 2(1S):A577.

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INTRODUCTION: Sleep-Quality and Work-Productivity are commonly affected in refractory GERD patients which in-turn negatively affects patients’ quality of life.

AIM: Evaluate Sleep-Quality, Work-Productivity and QoL in refractory GORD patients undergoing long-term electrical stimulation therapy (EST) using the LOS Stimulation System (EndoStim BV, the Hague, Netherlands).

METHODS: We evaluated GORD patients (n=37) partially responsive to PPI with Off-PPI GERD HRQL ≥20 and at least 5 point improvement on PPI, % 24 hour esophageal pH <4 for ≥5%, hiatal hernia ≤ 3cm and esophagitis ≤ LA Grade-C. The LOS stimulation system was implanted laparoscopically and EST was initiated at 20Hz, 220usec, 5 mAmp in 12, 30-min sessions. Patients completed the Pittsburgh Sleep Quality Index (PSQI), WorkProductivity and Activity-Impairment Questionnaire: Specific Health Problem V2.0 (WPAI:SHP) and SF-12 QoL instrument both On-PPI and Off-PPI at baseline, and at 6 and 12-mo on LOS-EST

RESULTS: Sleep scores [median (IQR)] at baseline On-PPI were 6.5 (5.2-9.5) and 8 (6.2-10.5) when Off-PPI. At 6mo, sleep scores significantly improved to 5 (3.2-6; p =0.02 vs. On-PPI and p =0.02 vs. Off-PPI scores) and was sustained at 12months [5 (3.2-7) p = 0.057 vs On-PPI, p = 0.075 vs. Off-PPI) on LOS-EST. Patients’ median %time missed from work due to GORD at baseline was 0 (0- 6.9)% On-PPI and 3.8 (0-11.2)% Off-PPI. At 6mo, this improved to 0 (0-0)% (n=15; p=0.04 vs. off-PPI) and was sustained at 12mo 0 (0-0)% (n=8; p=0.10 vs. off-PPI). Median percent impairment while working due to GERD at baseline was 15 (0-45)% on-PPI and 60 (30-80)% off-PPI. At 6mo, this improved to 0 (0- 10) (n=16; p=0.07 vs. On-PPI and p=0.002 vs. Off-PPI) and was 0 (0-10) at 12mo (n=9; p=0.21 vs. On-PPI, p=0.15 vs. Off-PPI) on LOS-EST. Median % overall impairment due to GERD at baseline was 20 (0-55.5)% On-PPI and 63 (33.3-81.8)% Off-PPI. At 6mo, this improved to 0 (0-10)% (n=16; p=0.05 vs. baseline On-PPI and p=0.003 vs. Off-PPI) and was sustained at 0 (0-2.5)%; n=8; p=0.02 vs. On-PPI, p=0.06 vs. Off-PPI] at 12mo on LOS-EST. Subjects reported a median % activity impairment due to GERD of 25 (10-50)% On-PPI and 60 (30-80)% Off-PPI at baseline. This improved to 0 (0-20)% at 6mo, (n=27; p=0.04 vs. On-PPI, p<0.001 vs. Off-PPI) and remained improved at 5 (0-30)% at 12mo (n=18; p=0.03 vs. On-PPI, p=0.02 vs. Off-PPI) on LOSEST. Median SF-12 physical health score was 44 on-PPI, 37 off-PPI at baseline, 52 at 6mo (p<0.0001), and 50.5 at 12mo (p<0.0001). Median SF-12 mental health score was 49 on-PPI, 46 off-PPI at baseline, 52 at 6mo, and 55 at 12mo (p = NS) on LOS-EST. There was improvement in all other GORD specific outcomes.

CONCLUSION: In refractory GERD patients, LES-EST significantly improves sleep-quality, work-productivity and overall impairment in activity resulting in improvement in patient QoL. These results were significantly better than baseline PPI therapy in many of the parameters evaluated.

Two-year results of intermittent electrical stimulation of the lower esophageal sphincter treatment of gastroesophageal reflux disease

Rodriguez L, Rodriguez P, Gómez B, Ayala JC, Oxenberg D, Perez-Castilla A, Netto MG, Soffer E, Boscardin WJ, Crowell MD.

Surgery. 2015; 157(3):556-567.

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BACKGROUND: Lower esophageal sphincter (LES) electrical stimulation therapy (EST) has been shown to improve outcome in gastroesophageal reflux disease (GERD) patients at 1 year. The aim of this open label extension trial (NCT01578642) was to study the 2-year safety and efficacy of LES-EST in GERD patients.

METHODS: GERD patients responsive partially to proton pump inhibitors (PPI) with off-PPI GERD health-related quality of life (HRQL) of >20, 24-hour esophageal pH <4.0 for >5% of the time, hiatal hernia <3 cm, and esophagitis LA grade C or lower participated in this trial. Bipolar stitch electrodes and a pulse generator (EndoStim BV, The Hague, The Netherlands) were implanted laparoscopically. LES-EST at 20 Hz, 215 ms, 3-8 mAmp was delivered over 30-minute sessions, 6-12 sessions per day, starting on day 1 after implantation. Patients were evaluated using GERD-HRQL, symptom diaries, Short Form-12, and esophageal pH testing at regular intervals. Stimulation sessions were optimized based on residual symptoms and esophageal pH at follow-up.

KEY RESULTS: Twenty-five patients (mean age [SD] = 52 [12] years; 14 men) were implanted successfully; 23 patients participated in the 2-year extension trial, and 21 completed their 2-year evaluation. At 2 years, there was improvement in their median GERD-HRQL on LES-EST compared with both their on-PPI (9 vs 0; P = .001) and off-PPI (23.5 vs 0; P < .001) baseline scores. Median 24-hour distal esophageal acid exposure improved from 10% at baseline to 4% (per-protocol analysis; P < .001) at 2 years with 71% demonstrating either normalization or a >50% decrease in their distal esophageal acid exposure. All except 5 patients (16/21) reported complete cessation of PPI use; only 2 patients were using a PPI regularly (>50% of days). There was significant improvement in sleep quality and daily symptoms of heartburn and regurgitation on LES-EST. At baseline, 92% of the subjects (22/24) reported that they were ‘‘unsatisfied’’ with their condition off-PPI and 71% (17/24) on-PPI compared with 0% (0/21) ‘‘unsatisfied’’ at the 24-month visits on LES-EST. There were no device- or therapy-related serious adverse events and no untoward sensation or dysphagia reported with LES-EST.

CONCLUSION: LES-EST is safe and effective for treating patients with GERD over a period of 2 years. LESEST resulted in a significant and sustained improvement in GERD symptoms, and esophageal acid exposure and eliminated PPI use in majority of patients (16 of 21). Further, LES-EST was not associated with any gastrointestinal side effects or adverse events. (Surgery 2015;157:556-67.)

Electrical stimulation to increase lower esophageal sphincter pressure after POEM.

Ciotola F, Ditaranto A, Bilder C, Badaloni A, Lowenstein D, Riganti JM, Hoppo T, Jobe B, Nachman F, Nieponice A.

Surg Endosc. 2015. Volume 29, Issue 1, pp230-235

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INTRODUCTION: Postoperative reflux remains to be a challenge for patients with achalasia undergoing Heller myotomy. Similarly, per-oral endoscopic myotomy (POEM) is gaining rapid acceptance but the impossibility of adding a fundoplication is questioned as the main pitfall to control reflux. Electrical stimulation of the lower esophageal sphincter (LES) has emerged as a new alternative for the treatment of reflux disease. The objective of this study was to evaluate the potential benefits of combining electrical stimulation with endoscopic esophageal myotomy to prevent post procedural reflux.

METHODS: Five pigs were subjected to POEM. After myotomy was completed, two electrical leads were implanted at the LES level and electrical stimulation was applied with the Endostim system with a regimen of 215 µs (5 mA amplitude), at 20 Hz for 25 min. LES pressures were recorded with manometry at pre and post-myotomy and after LES stimulation.

RESULTS: TMyotomy was completed successfully in all cases. Mean pre-myotomy LES pressure was 35.99 ± 8.08 mmHg. After myotomy, the LES pressure significantly dropped to 10.60 ± 3.24 mmHg (p = 0.03). Subsequent to LES-EST, LES pressure significantly increased to 21.74 ± 4.65 mmHg (p = 0.01).

CONCLUSION: The findings of this study show that LES-EST in healthy animals increases LES pressure after POEM procedure, and could be useful tool to minimize gastroesophageal reflux.

Long-term results of electrical stimulation of the lower esophageal sphincter for treatment of proximal GERD.

Hoppo T, Rodríguez L, Soffer E, Crowell MD, Jobe BA.

Surg Endosc. 2014. Volume 28, Issue 12, pp3293-3301

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INTRODUCTION: Electrical stimulation of the lower esophageal sphincter (LES) in gastroesophageal reflux disease (GERD) patients, using EndoStim® 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 pump inhibitors (PPI), hiatal hernia <3 cm, esophagitis <LA grade C underwent laparoscopic implantation of the LES stimulator. LES stimulation at 20 Hz, 215 µs, 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 LES-EST 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 LES-EST is safe without typical side effects associated with traditional antireflux surgery.

Electrical stimulation therapy for gastroesophageal reflux disease.

Rinsma NF, Bouvy ND, Masclee AA, Conchillo JM.

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Electrical stimulation therapy (EST) of the lower esophageal sphincter is a relatively new technique for the treatment of gastroesophageal reflux disease (GERD) that may address the need of GERD patients, unsatisfied with acid suppressive medication and concerned with the potential risks of surgical fundoplication. In this paper we review available data about EST for GERD, including the development of the technique, implant procedure, safety and results from open-label trials. Two short-term temporary stimulation and long-term open-label human trials each were initiated to investigate the safety and efficacy of EST for the treatment of GERD and currently up to 2 years follow-up results are available. The results of EST are promising as the open-label studies have shown that EST is a safe technique with a significant improvement in both subjective outcomes of symptoms and objective outcomes of esophageal acid exposure in patients with GERD. However, long-term data from larger number of patients and a sham-controlled trial are required before EST can be conclusively advised as a viable treatment option for GERD patients.

Electrical stimulation of the lower oesophageal sphincter: an emerging therapy for treatment of GORD

Prof. Dr. med. E. Eypasch MD

European Surgery. April 2014, Volume 46, Issue 2, pp 57-64

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BACKGROUND: A significant proportion of gastro-oesophageal reflux patients remain unsatisfied with medical treatment and suffer from residual symptoms or quality-of-life issues. Anti-reflux surgery demonstrates excellent results in clinical trials, but is not widely utilized due to concerns of side effects, long-term failures and suboptimal results from low-volume centres. Hence, the search for a less invasive treatment has been an active area of clinical development. Electrical stimulation is increasingly utilized for various neuromuscular disorders and has recently emerged as a new minimally invasive treatment option for gastro-oesophageal reflux disease (GORD) by modulating the dysfunctional lower oesophageal sphincter.

METHODS: This review article includes available data from five peer-reviewed publications summarizing three human trials. Abstracts from major international conferences provided additional long-term results and interim data on an ongoing international trial. Four published trials with animal data are also reported.

RESULTS: Published in vivo animal studies showed that electrical stimulation can be safely used to enhance lower oesophageal sphincter pressure. Feasibility clinical trials with temporary stimulation reproduced this effect in GORD patients and demonstrated preservation of swallow function. Two long-term trials showed improvement in oesophageal acid exposure, GORD symptoms and proton pump inhibitor (PPI) medications use with minimal side effects.

CONCLUSION: Enhancement of the anti-reflux function of the lower oesophageal sphincter using electrical stimulation is a safe and effective GORD treatment and can potentially address the unmet need of patients who are unsatisfied with PPIs. Additional data will help in a wider adoption of this technology.

Effect of electrical stimulation of the lower esophageal sphincter using endoscopically implanted temporary stimulation leads in patients with reflux disease.

Banerjee R, Pratap N, Kalpala R, Reddy DN.

Surg Endosc. 2014 Mar;28(3):1003-9.

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BACKGROUND: Electrical stimulation therapy (EST) has been shown to increase lower esophageal sphincter (LES) pressure in animals; however, data on the effect of EST on LES pressure in patients with gastroesophageal reflux disease (GERD) are lacking.

OBJECTIVE: The aim of our study was to investigate the effect of EST on LES pressure and esophageal function in patients with GERD

METHODS: Patients with a diagnosis of GERD responsive to proton pump inhibitors (PPIs), increased esophageal acid on 24-h pH monitoring off GERD medications, basal LES pressure >5 mmHg, hernia <2 cm and esophagitis <LA grade B were included. A temporary pacemaker lead was placed endoscopically in the LES by creating a 3 cm submucosal tunnel, secured to the esophagus using endoscopic clips along the body of the lead and exteriorized nasally. EST was delivered 6-12 h post-implant per protocol using (i) short-pulse 200 us, 20 Hz, and (ii) intermediate-pulse 3 ms, 20 Hz, each for 20 min at varying amplitudes. High-resolution manometry was performed pre-, during and post-EST. Symptoms of heartburn, chest or abdominal pain and dysphagia pre-, during and post-stimulation and 7 days post-procedure were recorded. Continuous cardiac monitoring was performed during and after the EST to evaluate any effect of EST on cardiac rhythm.

RESULTS: Six male patients (mean age 34.6 years) underwent successful endoscopic lead implantation; the first patient had premature lead dislodgement and did not undergo EST. The remaining five patients underwent successful EST. All patients had a significant increase in LES pressure with all sessions of EST. There was no effect on swallow-induced LES relaxation, And there were no EST-related adverse symptoms or any cardiac rhythm abnormalities.

CONCLUSION: In patients with GERD, short-term EST delivered using electrodes endoscopically implanted in the LES results in a significant increase in LES pressure without affecting patients’ swallow function or causing any adverse symptoms or cardiac rhythm disturbances. EST may offer a novel therapy to patients with GERD.

Long-term results of electrical stimulation of the lower esophageal sphincter for the treatment of gastroesophageal reflux disease

L. Rodriguez, P. Rodriguez, B. Gomez, J.C. Ayala, D. Oksenberg, A. Perez-Castilla, M.G. Netto, E. Soffer, M.D. Crowell

Endoscopy 2013; 45: 595-604

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BACKGROUND AND STUDY AIMS: In patients with gastroesophageal reflux disease (GERD), temporary electrical stimulation of the lower esophageal sphincter (LES) increases LES pressure without interference with LES relaxation. The aim of the current study was to investigate the safety and efficacy of long term LES electrical stimulation therapy (LES–EST), using a permanently implanted stimulator for the treatment of GERD.

PATIENTS AND METHODS: Patients with GERD who were at least partially responsive to proton pump inhibitors (PPIs) and who had hiatal hernia of à 3 cm and esophagitis of Los Angeles Grade A, B, or C were included in the study. Stimulation electrodes were placed in the LES and a pulse generator (EndoStim LES Stimulation System; EndoStim BV, The Hague, The Netherlands) was implanted laparoscopically. LES stimulation was delivered at 20 Hz, 215 µs, 3 – 8 mA in multiple 30-minute sessions. Patients were evaluated at follow-up using the GERD Health-Related Quality of Life (HRQL) questionnaire, daily symptom and medication diaries, the SF-12 Health Survey, esophageal pH testing, and high resolution manometry.

RESULTS: A total of 24 patients (mean age 53 +/- 12 years; 14 men) were implanted and 23 completed the 12-month evaluation. No serious implantation or stimulation-related adverse affects or sensations were reported. Median composite GERD–HRQL score at 12 months was 2.0 (interquartile range [IQR] 0 – 3.0), which was significantly better than baseline scores both on PPI therapy (median 9.0, IQR 6.0 – 10.0; P = 0.002) and off PPIs (median 23.5, IQR 21 – 25.75; P < 0.001). The median percentage of the 24-hour period with esophageal pH < 4.0 at baseline was 10.1 % (IQR 7.7 – 15.5), which was reduced to 3.3 % (1.8 – 6.9) at 12 months (P < 0.001), with 69 % of patients showing either normalization or > 50 % improvement in their distal esophageal pH. At 12 months, 96 % of patients (22/23) were completely off PPI medication.

CONCLUSION: During the long term follow-up of 12 months, LES – EST was safe and effective for the treatment of GERD. There was a significant and sustained improvement in GERD symptoms, reduction in esophageal acid exposure with elimination of daily PPI usage, and no stimulation- related adverse effects.

Electrical stimulation therapy of the lower esophageal sphincter is successful in treating GERD: final results of open-label prospective trial

L. Rodriguez, P. Rodriguez, B. Gomez, J.C. Ayala, D. Oksenberg, J. Saba, A. Perez-Castilla, M.G. Netto, M.D. Crowell

Surg Endosc (2013) 27: 1083-1092

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BACKGROUND: Electrical stimulation of the lower esophageal sphincter (LES) improves LES pressure without interfering with LES relaxation. The aim of this open-label pilot trial was to evaluate the safety and efficacy of long-term LES stimulation using a permanently implanted LES stimulator in patients with gastroesophageal reflux disease (GERD).

METHODS: GERD patients who were at least partially responsive to proton pump inhibitors (PPI) with abnormal esophageal pH, hiatal hernia </= 3 cm, and esophagitis </= LA grade C were included. Bipolar stitch electrodes were placed in the LES and an IPG was placed in a subcutaneous pocket. Electrical stimulation was delivered at 20 Hz, 215 ls, 3–8 mA in 30 min sessions. The number and timing of sessions was tailored to each patient’s GERD profile. Patients were evaluated using GERD-HRQL, daily symptom and medication diaries, SF-12, esophageal pH, and high-resolution manometry.

RESULTS: 24 patients (mean age = 53 years, SD = 12 years; 14 men) were implanted; 23 completed their 6-month evaluation. Median GERD-HRQL scores at 6 months was 2.0 (IQR = 0–5.5) and was significantly better than both baseline on-PPI [9.0 (range = 6.0–10.0); p< 0.001] and off-PPI [23 (21–25); p< 0.001] GERD- HRQL. Median% 24-h esophageal pH < 4.0 at baseline was 10.1 and improved to 5.1 at 6 months (p< 0.001). At their 6-month follow-up, 91 % (21/23) of the patients were off PPI and had significantly better median GERD-HRQL on LES stimulation compared to their on-PPI GERD- HRQL at baseline (9.0 vs. 2.0; p< 0.001). There were no unanticipated implantation- or stimulation-related adverse events or untoward sensation due to stimulation. There were no reports of treatment-related dysphagia, and man- ometric swallow was also unaffected.

CONCLUSION: During the long term follow-up of 12 months, LES – EST was safe and effective for the treatment of GERD. There was a significant and sustained improvement in GERD symptoms, reduction in esophageal acid exposure with elimination of daily PPI usage, and no stimulation- related adverse effects.

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

Michael D Crowell

Expert Rev. Gastroenterol. Hepatol. 7(3), 189-191 (2013)

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Short-term electrical stimulation of the lower esophageal sphincter increases sphincter pressure in patients with gastroesophageal reflux disease

L. Rodriguez, P. Rodriguez, M.G. Neto, J.C. Ayala, J. Saba, D. Berel, J. Conklin, E. Soffer

Neurogastroenterol Motil (2012) 24: 446-450

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BACKGROUND: Electrical stimulation (ES) of the lower esophageal sphincter (LES) increases resting LES pressure (LESP) in animal models. Our aims were to evaluate the safety of such stimulation in humans, and test the hypothesis that ES increases resting LESP in patients with gastroesophageal reflux disease (GERD).

METHODS: A total of 10 subjects (nine female patients, mean age 52.6 years), with symptoms of GERD responsive to PPIs, low resting LES pressure, and abnormal 24-h intraesophageal pH test were enrolled. Those with hiatal hernia >2 cm and/or esophagitis >Los Angeles Grade B were excluded. Bipolar stitch electrodes were placed longitudinally in the LES during an elective laparoscopic cholecystectomy, secured by a clip and exteriorized through the abdominal wall. Following recovery, an external pulse generator delivered two types of stimulation for periods of 30 min: (i) low energy stimulation; pulse width of 200 ls, frequency of 20 Hz and current of 5–15 mA (current was increased up to 15 mA if LESP was less than 15 mmHg), and (ii) high energy stimulation; pulse width of 375 ms, frequency of 6 cpm, and current 5 mA. Resting LESP, amplitude of esophageal contractions and residual LESP in response to swallows were assessed before and after stimulation. Symptoms of chest pain, abdominal pain, and dysphagia were recorded before, during, and after stimulation and 7-days after stimulation. Continuous cardiac monitoring was performed during and after stimulation.

KEY RESULTS: All patients were successfully implanted nine subjects received high frequency, low energy, and four subjects received low frequency, high energy stimulation. Both types of stimulation significantly increased resting LESP: from 8.6 mmHg (95% CI 4.1–13.1) to 16.6 mmHg (95% CI 10.8–19.2), P < 0.001 with low energy stimulation and from 9.2 mmHg (95% CI 2.0–16.3) to 16.5 mmHg (95% CI 2.7–30.1), P = 0.03 with high energy stimulation. Neither type of stimulation affected the amplitude of esophageal peristalsis or residual LESP. No subject complained of dysphagia. One subject had retrosternal discomfort with stimulation at15 mA that was not experienced with stimulation at 13 mA. There were no adverse events or any cardiac rhythm abnormalities with either type of stimulation.

CONCLUSIONS AND INFERENCES: Short-term stimulation of the LES in patients with GERD significantly increases resting LESP without affecting esophageal peristalsis or LES relaxation. Electrical stimulation of the LES may offer a novel therapy for patients with GERD.

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