Study population
From October 2012 to December 2016, 835 individuals with symptoms of chronic GERD were assessed for eligibility at the Department of General and Visceral Surgery, Ordensklinikum Linz Sisters of Charity Hospital in Linz (Fig. 1). All patients were subjected to gastroscopy, barium esophagography, high-resolution esophageal manometry, and esophageal 24-h multichannel intraluminal impedance monitoring.
Inclusion criteria were as follows: at least one typical reflux symptom despite treatment with a PPI for at least 6 months and pathologic esophageal acid exposure as documented by a reflux-related DeMeester score of > 14.7, or symptom correlation (SI) > 50%, or > 73 reflux episodes per day. All subjects were candidates for LARS, according to the guidelines of the Society of American Gastrointestinal and Endoscopic Surgeons [6].
Exclusion criteria were as follows: age < 18 years, American Society of Anaesthesiologists physical status classification III-IV, evidence of a paraesophageal hernia or hiatal hernia measuring > 2 cm upon gastroscopy or barium esophagogram, gastroesophageal flap valve (GEFV) grade IV, previous esophageal or gastric surgery and pregnancy.
Study approval was obtained by the institution’s ethical committee, and all patients provided written informed consent.
The study was registered at ClinicalTrials.gov (Identifier: NCT 01798212).
Study design and follow-up
Prospective single-center one-arm trial on the clinical and functional outcomes of endoscopic plication with GERDx™. The GIQLI and symptom scores were calculated at baseline. Gastroscopy, high-resolution esophageal manometry, and 24-h pH-metry-impedance were performed before the intervention. The patients received a PPI treatment on daily basis for 2 weeks after plication. A gastroscopy was performed 6 weeks after the procedure and the GIQLI and symptom scores were calculated at 3-month follow-up, along with functional assessment through manometry and 24-h pH-metry-impedance.
The primary outcome measure was difference in the GIQLI after the intervention of at least 15 points. Secondary endpoints were difference in esophageal acid exposure, reflux-specific symptom scores, and perioperative morbidity.
Endoscopic full-thickness plication technique
Endoscopic full-thickness plication was performed using the GERDx™—system (G-SURG GmbH, Seeon-Seebruck, Germany). The GERDx™—device uses hydraulic elements for controlling and is the advanced single use product of a company that has taken over the Plicator technology, after the Plicator device (Ethicon Endosurgery, Sommerville, NJ) was taken off the market (Fig. 2). The design modifications of GERDx™ do not hinder clinical application and it shows similar safety in application compared to the NDO Plicator [5].
All procedures were performed under general anesthesia by the same surgical team with established experience in advanced endoscopic procedures. No peri-procedure antibiotics were given. A standard upper endoscopy was performed and a Savary-guidewire was placed upon gastroscope withdrawal. The GERDx™ device was introduced over the guidewire and into the stomach.
A 5.8-mm video endoscope (N-190 Olympus, Tokyo, Japan) was passed through the GERDx™ device. The distal end of the device was then retroflexed to the anterior gastric cardia approximately 1 cm below the gastroesophageal (GE) junction. The GERDx™ arms were opened, and an endoscopic tissue retractor was advanced deeply into the gastric cardia. The tissue retractor was drawn back to gather tissue between the open arms of the GERDx™ device. The arms were closed and a pre-tied transmural pledgeted suture was deployed. At the end of procedure, the GERDx™ device and the gastroscope were removed, and the gastroscope was re-inserted to evaluate the resulting plication.
According to study protocol, at least two pre-tied transmural pledgeted sutures were deployed. One or two additional sutures were placed, if necessary, until a tight closure of the gastroesophageal junction around the endoscope was achieved (Fig. 3).
Quality of life evaluation (QoL)
Quality of life was evaluated by means of the German gastrointestinal quality of life index (GIQLI) [7]. This questionnaire has been validated in the German language and has been recommended for use by the European Study Group for Antireflux Surgery [8]. The GIQLI is divided into 5 domains and 36 items: gastrointestinal symptoms (0–76 points), physical functions (0–28 points), emotional status (0–20 points), social functions (0–16 points), and a single item for stress of medical treatment (0–4 points), for a minimum of 0 and a maximum of 144 points. Higher scores indicate a better quality of life. Information on daily or on-demand use of PPI or other antacid medication was obtained.
Symptom evaluation
Symptom evaluation was carried out in a standardized way using a written questionnaire assessing the severity and intensity of 14 symptoms in a 4-point scale (SCL). This questionnaire has been used previously in the context of GERD [9]. Symptoms of heartburn, chest pain, regurgitation, hoarseness, cough, asthma, dysphagia, fullness, diarrhea, flatulence, constipation, belching, bloatedness, and distortion of taste are graded as none (0), once per week (1), several times per week (2), daily (3), and constantly (4). Intensity of the symptoms is graded as none (0), mild (1), moderate (2), severe (3), and extremely severe (4). In order to obtain the ultimate result, the frequency of each symptom is multiplied by its degree, resulting in scores from 0 to 16 for each symptom, for a total maximum score of 224 and a minimum score of 0 points. Additionally, four different scores were extracted to assess symptoms specific for reflux (heartburn, regurgitation, chest pain), gas-bloat (fullness, bloatedness), bowel-dysfunction (diarrhea, constipation, flatulence), and atypical reflux symptoms (cough, hoarseness, asthma, distortion of taste). Symptoms of dysphagia and belching are evaluated separately.
High-resolution esophageal manometry (HRM)
All patients were studied after an overnight fast in the supine position. A high-resolution manometry (HRM) using the Sierra system (Given Imaging, Duluth, GA, USA) was performed. A structurally defective lower esophageal sphincter (LES) was defined as an overall length below 2.4 cm, an intraabdominal length below 0.9 cm and/or the presence of a hiatal hernia. Pressure levels beyond the range of 29.8–180.2 mmHg were considered abnormal and any motility disorders were classified according to the Chicago Classification [10].
24-h ambulatory multichannel intraluminal impedance monitoring (MII)
Studies were performed after cessation of antisecretory therapy for at least 7 days. A catheter-based 24-h multichannel intraluminal impedance pH-metry (pH/MII, Dual-probe; Given Imaging, Duluth, GA, USA) was inserted. Further details have been published previously [9].
Symptom Index (SI) of > 50% was considered positive [11].
GERD was defined as an abnormal esophageal acid exposure, total number of reflux events within 24 h > 73, DeMeester score > 14.7, or positive SI for symptoms reported at least three times. In addition, elevated counts of acidic, weakly acidic, and non-acidic reflux episodes demonstrated by the impedance signal of the pH-catheter were considered abnormal [12, 13].
Statistical analysis
Statistical analysis was performed using SPSS-Statistical-Analysis Software (SPSS Inc., Chicago, IL, USA). Sample size considerations based on the assumption of a one-sided test (Wilcoxon signed-rank test) with α = 0.025 and power 1−β = 0.9 with respect to a medically relevant (absolute) effect size of 15 points in the change of the GIQLI-index suggested enrolment of at least 40 patients. All datasets were tested for normal distribution by Kolmogorov–Smirnow-Test. Data were compared using two-tailed paired-t test or Wilcoxon signed rank test, as applicable, on a per subject basis. Homogeneity of population was conducted using independent t test or Mann–Whitney U Test. Datasets were additionally presented as means and standard deviation (SD), if normally distributed. Previously published studies provided helpful information for variance estimation [5]. A p value below 0.05 was considered statistically significant.