2025/07/01 by Sheraz R. Markar, Begüm Zeybek, Nainika Menon +12 · 1 voice · 1 citation
Medicine · #Esophageal Cancer Research and Treatment #Esophageal and GI Pathology #Gastroesophageal reflux and treatments
paper · pdf · doi:10.1093/bjs/znaf141
openalex publication_date 2025/07/01 · openalex created_date 2025/07/12 · openalex updated_date 2026/08/01
Gastro-oesophageal reflux disease (GORD) represents a significant burden on the Western healthcare system, affecting up to 20% of adults, with a rising prevalence1,2. GORD negatively impacts a patient’s health-related quality of life (HRQoL) and is associated with an increased risk of complications, including inflammation and strictures, Barrett’s oesophagus, and oesophageal adenocarcinoma3. Long-term use of proton pump inhibitors (PPIs) remains the mainstay of medical treatment for GORD; however, these may be associated with an increased risk of side effects, including dementia, renal pathology, infections, fractures, and gastric cancer4. A large UK RCT (REFLUX) showed that surgery (laparoscopic fundoplication) offers the most effective symptom control at 5-year follow-up, as well as being the most cost-effective treatment strategy when compared with medical therapy5,6. Laparoscopic fundoplication is currently the ‘gold standard’ surgical treatment for managing GORD, with an excellent safety profile and a 30-day mortality risk of 0.03%7. The side effects are mainly gas bloating and inability to belch (up to 85%), dysphagia (3–24%), diarrhoea (18–33%), and recurrence of reflux symptoms (10–62%)8,9. Approximately 5% of patients undergoing fundoplication in England may require secondary surgery and 60% of patients use antireflux medication within 12 months of primary antireflux surgery7. The introduction of the LINX device in 2007 provided a surgical alternative to fundoplication, requiring less extensive dissection and less disruption of the hiatal anatomy and natural antireflux mechanisms10,11. The LINX device is placed around the distal oesophagus and consists of titanium beads with a magnetic core that augments lower oesophageal tone and thus prevents reflux by mimicking normal anatomical antireflux mechanisms12. The LINX device, while augmenting the lower oesophageal sphincter, can accommodate the escape of elevated gastric pressure associated with belching or vomiting, which may reduce gas bloating. Complications of the LINX device include dysphagia, requiring dilatation at the site of the device in 5–11% of patients, and endoluminal erosions (0.1%) requiring device removal11,13. In non-randomized comparative studies patients have reported favourable outcomes with LINX compared with fundoplication13. Aside from its ease of insertion, the LINX device is appealing in terms of symptom control, shorter operating time, reduced hospital stay, and lower burden of postoperative care14. A systematic review and meta-analysis of the laparoscopic LINX procedure versus laparoscopic fundoplication (consisting of 6 cohort studies and 1099 patients) showed no statistically significant differences between the groups in the requirement of postoperative antireflux medication, GORD-HRQoL scores, dysphagia, or reoperation. However, LINX was associated with significantly less gas bloating (pooled OR 0.34 (95% c.i. 0.16 to 0.71)) and a greater ability to belch (pooled OR 12.34 (95% c.i. 6.43 to 23.7))13. A further systematic review evaluated the introduction of LINX in the context of the established Idea, Development, Exploration, Assessment, and Long-term follow-up (IDEAL) framework15. Several IDEAL phase IIb studies were identified, with a lack of standardized surgical quality assurance (SQA) regarding LINX implantation and lack of consensus regarding results that should be evaluated to meaningfully assess patient benefit. This review concluded that studies that are well designed and well conducted are needed to evaluate the LINX procedure. Although the National Institute for Health and Care Excellence (NICE) allows the use of the LINX device in clinical practice, it encourages research in this area, particularly trials that compare the LINX device with other forms of antireflux surgery16. The aim of this RCT is to test the hypothesis that the LINX procedure achieves similar reflux control and improves postoperative symptoms, specifically gas bloating and inability to belch, when compared with fundoplication at 24 months after surgery. The GOLF trial is an international, multicentre, pragmatic, two-arm, double-blind, phase III RCT. The study will recruit 460 patients (230 patients in each of the two arms) recommended for antireflux surgery from at least 16 centres in the UK and 7 other European high-volume upper gastrointestinal surgical centres. Patients will be randomized 1 : 1 to undergo either a laparoscopic/robotic LINX procedure or fundoplication. See Fig. 1 for the study summary flow chart, Fig. 2 for the data collection flow chart, and Fig. 3 for the post-study care and follow-up flow chart. Study summary flow chart GORD, gastro-oesophageal reflux disease; HRQoL, health-related quality of life. Data collection flow chart GI, gastrointestinal; GORD, gastro-oesophageal reflux disease; HRQoL, health-related quality of life. Post-study care and follow-up flow chart The GOLF trial will recruit adults aged ≥18 years being considered for antireflux surgery for GORD insufficiently controlled by or intolerant to medical therapy. The inclusion and exclusion criteria are presented in Table 1. Inclusion and exclusion criteria for the GOLF trial Age ≥18 years Willing and able to give informed consent GORD insufficiently controlled by medical therapy or intolerance to medical therapy and being considered for antireflux surgery Symptomatic and objectively defined GORD; endoscopy with appearances or biopsies consistent with reflux oesophagitis, or 24-h pH study or BRAVO test of the oesophagus consistent with GORD No hiatal hernia or hiatal hernia <5 cm in length Adequate lower oesophageal motility as defined by preoperative oesophageal manometry studies showing a mean contractile amplitude of >30 mmHg or distal contractile integral (DCI) of >450 mmHg per s per cm in 70% of swallows Unsuitable for surgical intervention due to medical conditions precluding general anaesthesia Suspected or known allergies to titanium, stainless steel, nickel, or ferrous materials Previous antireflux or gastric surgery Previous or planned neurosurgery Oesophageal manometry showing complete absence of lower oesophageal contractility Age ≥18 years Willing and able to give informed consent GORD insufficiently controlled by medical therapy or intolerance to medical therapy and being considered for antireflux surgery Symptomatic and objectively defined GORD; endoscopy with appearances or biopsies consistent with reflux oesophagitis, or 24-h pH study or BRAVO test of the oesophagus consistent with GORD No hiatal hernia or hiatal hernia <5 cm in length Adequate lower oesophageal motility as defined by preoperative oesophageal manometry studies showing a mean contractile amplitude of >30 mmHg or distal contractile integral (DCI) of >450 mmHg per s per cm in 70% of swallows Unsuitable for surgical intervention due to medical conditions precluding general anaesthesia Suspected or known allergies to titanium, stainless steel, nickel, or ferrous materials Previous antireflux or gastric surgery Previous or planned neurosurgery Oesophageal manometry showing complete absence of lower oesophageal contractility GORD, gastro-oesophageal reflux disease. Inclusion and exclusion criteria for the GOLF trial Age ≥18 years Willing and able to give informed consent GORD insufficiently controlled by medical therapy or intolerance to medical therapy and being considered for antireflux surgery Symptomatic and objectively defined GORD; endoscopy with appearances or biopsies consistent with reflux oesophagitis, or 24-h pH study or BRAVO test of the oesophagus consistent with GORD No hiatal hernia or hiatal hernia <5 cm in length Adequate lower oesophageal motility as defined by preoperative oesophageal manometry studies showing a mean contractile amplitude of >30 mmHg or distal contractile integral (DCI) of >450 mmHg per s per cm in 70% of swallows Unsuitable for surgical intervention due to medical conditions precluding general anaesthesia Suspected or known allergies to titanium, stainless steel, nickel, or ferrous materials Previous antireflux or gastric surgery Previous or planned neurosurgery Oesophageal manometry showing complete absence of lower oesophageal contractility Age ≥18 years Willing and able to give informed consent GORD insufficiently controlled by medical therapy or intolerance to medical therapy and being considered for antireflux surgery Symptomatic and objectively defined GORD; endoscopy with appearances or biopsies consistent with reflux oesophagitis, or 24-h pH study or BRAVO test of the oesophagus consistent with GORD No hiatal hernia or hiatal hernia <5 cm in length Adequate lower oesophageal motility as defined by preoperative oesophageal manometry studies showing a mean contractile amplitude of >30 mmHg or distal contractile integral (DCI) of >450 mmHg per s per cm in 70% of swallows Unsuitable for surgical intervention due to medical conditions precluding general anaesthesia Suspected or known allergies to titanium, stainless steel, nickel, or ferrous materials Previous antireflux or gastric surgery Previous or planned neurosurgery Oesophageal manometry showing complete absence of lower oesophageal contractility GORD, gastro-oesophageal reflux disease. Participants will be recruited from hospitals in the UK and other European countries that regularly perform antireflux surgery. Potential participants will be identified during routine clinic visits and informed about the study through posters and Participant Information Sheets (PISs). If their usual care clinician is not part of the study team, patients will be asked for permission to share their contact details with the study team for follow-up. The LINX procedure is not as well established as fundoplication. Recruitment is likely to be challenged by clinician and patient bias towards something new, potentially impacting eligibility decisions and how the treatments are presented. Furthermore, some centres may be less familiar explaining randomization to patients. A QRI has been included to understand and address recruitment challenges in real time17–19. The aim of the QRI is to assess the recruitment process at each recruiting site, to identify specific recruitment difficulties and tailor suggestions to change aspects of the design, conduct, or training that could lead to improvements in recruitment and informed consent. A multifaceted, flexible approach will be used to investigate site-specific or wider recruitment obstacles, consisting of: mapping of eligibility and recruitment pathways to collate basic data about the levels of eligibility and recruitment, and to identify bottlenecks in recruitment pathways; in-depth semi-structured interviews with study and centre staff (and eligible patients if needed) to explore perceptions of the study and equipoise, how recruitment is organized in individual centres, and local or national challenges anticipated or encountered; audio-recording study recruitment discussions with potential study participants to offer direct insights into how the study is presented and ways in which recruiters manage patients’ expectations and preferences; and attendance at study meetings to gain an overview of trial conduct and overarching challenges. The QRI team, with the Chief Investigator and Trial Management Group, will formulate action plans based on the findings to improve recruitment and information provision, with the format dependent on the nature of the recruitment barriers identified. Supportive and responsive group or individual feedback and training is likely to be a core component of the plan of action, including written recruitment ‘tips’ documents and suggested modifications to study pathways and patient-facing study material. The QRI work will be undertaken in an iterative and cyclical manner, continuing throughout the recruitment interval with close monitoring of changes in screening log data and recruiter practice to optimize recruitment and informed consent, all in close collaboration with the Chief Investigator and wider study team. The laparoscopic insertion of a magnetic ring, such as the LINX device, has been part of the NICE guidelines for treating GORD and therefore standard of care in the National Health Service (NHS) since 2017. Participants randomized to laparoscopic or robotic magnetic sphincter augmentation (LINX procedure) will undergo surgical treatment under general anaesthesia, with placement of the LINX device around the distal oesophagus. The LINX device consists of titanium beads with magnets in the centre. Participants randomized to laparoscopic or robotic fundoplication will undergo surgical treatment for managing GORD, including a total or partial fundic wrap behind or in front of the distal oesophagus and gastro-oesophageal junction. According to several international guidelines, there is no convincing evidence at present to suggest a total or partial wrap to be superior to the other. As this is a pragmatic trial, all types of fundoplication will be recorded and form part of the subgroup analysis8,20,21. SQA is an important component of this trial because LINX is a newer surgical procedure and because there is (inter)national variation in fundoplication techniques. This is the first trial of its kind to embed an SQA programme based on video analysis. The SQA will help to ensure the procedures are also completed to a good surgical standard, to maximize internal and external validity and facilitate accurate interpretation of trial results and replication of the successful intervention across wider clinical practice. Every operation performed within the trial will be video recorded and reviewed as part of the SQA programme. The SQA programme will consist of five phases: Surgeon training: Surgeons who have not previously undertaken the LINX procedure will attend a hands-on training day with Johnson and Johnson, followed by two proctored cases. A ‘gold standard’ demonstrative video will be circulated to all participating surgeons along with the competency assessment tools for the LINX procedure and fundoplication to ensure consistency. Credentialling of centres and surgeons: All surgeons who have performed <20 LINX procedures will be required to submit two videos each of them performing the LINX procedure and fundoplication, which will be assessed using a competency assessment tool (described below in phase 3). Standardization of surgical techniques: A competency assessment tool for the LINX procedure will be developed after a virtual Delphi consensus process and robust testing for inter- and intra-assessor reliability for video assessment. The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) has developed and validated a competency assessment tool for fundoplication, which will be used in the GOLF trial22. Mechanistic work: Video assessment will be undertaken for all operations performed within the trial to monitor learning curves and maintain surgical quality. Ongoing monitoring of adherence to the intervention protocols: This will be associated with correlating surgical quality with clinical and patient-reported outcomes. Symptomatic reflux and HRQoL assessed using the GORD-HRQoL questionnaire23 at 24 months after surgery (Table 2). GERD-HRQoL questionnaire How bad is your heartburn? Heartburn when lying down? Heartburn when standing up? Heartburn after meals? Does heartburn change your diet? Does heartburn wake you from sleep? Do you have difficulty swallowing? Do you have bloating or gassy feelings? Do you have pain with swallowing? If you take medication, does this affect your daily life? How satisfied are you with your present condition? How bad is your heartburn? Heartburn when lying down? Heartburn when standing up? Heartburn after meals? Does heartburn change your diet? Does heartburn wake you from sleep? Do you have difficulty swallowing? Do you have bloating or gassy feelings? Do you have pain with swallowing? If you take medication, does this affect your daily life? How satisfied are you with your present condition? GORD, gastro-oesophageal reflux disease; HRQoL, health-related quality of life. GERD-HRQoL questionnaire How bad is your heartburn? Heartburn when lying down? Heartburn when standing up? Heartburn after meals? Does heartburn change your diet? Does heartburn wake you from sleep? Do you have difficulty swallowing? Do you have bloating or gassy feelings? Do you have pain with swallowing? If you take medication, does this affect your daily life? How satisfied are you with your present condition? How bad is your heartburn? Heartburn when lying down? Heartburn when standing up? Heartburn after meals? Does heartburn change your diet? Does heartburn wake you from sleep? Do you have difficulty swallowing? Do you have bloating or gassy feelings? Do you have pain with swallowing? If you take medication, does this affect your daily life? How satisfied are you with your present condition? GORD, gastro-oesophageal reflux disease; HRQoL, health-related quality of life. Prevalence of gas bloating measured using participant-reported outcomes/GORD-HRQoL and foregut symptom questionnaire24 at 24 months after surgery. Prevalence of inability to belch measured using participant-reported outcomes/GORD-HRQoL and foregut symptom questionnaire at 24 months after surgery. Prevalence of reflux symptoms, inability to belch, and gas bloating measured using participant-reported outcomes/GORD-HRQoL and foregut symptom questionnaire at 6 weeks and 6 and 12 months after surgery. Prevalence and severity of dysphagia and regurgitation measured using participant-reported outcomes/GORD-HRQoL questionnaire at 6 weeks and 6, 12, and 24 months after surgery. Global HRQoL measured using participant-reported outcomes/EQ-5D-5L25 questionnaire at 6 weeks and 6, 12, and 24 months after surgery. Utilization of antireflux medications measured using participant-reported outcomes/questionnaire at 6 weeks and 6, 12, and 24 months after surgery. 24-h pH measurement or BRAVO test at 12 months after surgery. 30- and 90-day and 12- and 24-month postoperative complication rates, including reoperation and endoscopic re-intervention, measured using participant’s medical records/postoperative outcomes. Cost-effectiveness measured using incremental cost per quality-adjusted life year (QALY)26 at 6 weeks and 6, 12 and 24 months after surgery. The total duration of trial recruitment is expected to be 30 months. Patients will be followed up for 24 months after surgery. The GOLF trial will be embedded within the Association of Upper Gastrointestinal Surgeons for Great Britain and Ireland (AUGIS) benign surgical registry, which will permit follow-up reports at 5 and 10 years after surgery. Patient consent will also be obtained to link their data and ensure comprehensive follow-up to assess the long-term outcome and safety of the LINX procedure compared with fundoplication. Sample size calculations were based on a hierarchical analysis and non-inferiority between the study arms for HRQoL including control of reflux (primary outcome) and superiority in favour of the LINX procedure for gas bloating and inability to belch (core secondary outcomes). A non-inferiority margin was set at two scores in difference on GORD-HRQoL based on a previous systematic review by the authors13, co-investigator consensus, and patient workshops. For a one-sided α level of 0.025 and expecting 10% loss to follow-up, 230 patients per group will be necessary to show non-inferiority with 90% power. A α level of and 10% loss to follow-up were for the superiority outcomes. postoperative gas meta-analysis of postoperative gas bloating of for fundoplication and a meta-analysis of showed an OR of 0.34 in favour of which to a of gas bloating for a in postoperative gas bloating of to is According to patients per group will be necessary to that change with 90% power. will be performed using a to ensure between the two treatment groups using Age and at and at to the and and of during pH monitoring used to objectively and of treatment and 24 months after the patients will be is informed or about which operation and will be followed up to the standard of care in their treating This study will be is the patients and the outcome will be to the trial All postoperative will be from patients or by interviews conducted by research study 12 months after patients will undergo a pH study or BRAVO as well as manometry by will be evaluated for patients and outcome using the Surgeons and will not be due to the nature of the surgical The surgeons and will be for the patient to the benign surgical which will be used for follow-up 2 when the patients will be an treatment will be to the for participants and the operating In the of a site staff may be if necessary to ensure patient All will be on the is all patients will be in the group that were randomized to of the treatment is not anticipated that there will be however, in the that the primary analysis will be for the from the will be in the will be used to the between the two follow-up and standard or and as for and and for and All comparative outcomes will be presented as summary and reported with All will be at a 5% The analysis of GORD-HRQoL will be performed using a This will as an GORD-HRQoL based on the and will as the effects, the intervention as well as the and preoperative will as the effects, a by centre. between the centre and the intervention will also be included in the The will be and the GORD-HRQoL scores will be The of the LINX procedure on GORD-HRQoL will be and through mean differences between for the included in the the interval of the mean differences will be A of the primary may be performed to the of the A analysis will be conducted to assess the of laparoscopic LINX compared with fundoplication. and will be used for the analysis and a will be presented in the analysis. The primary outcome used in the study will be incremental cost per practice guidelines will be followed when the analysis. A use questionnaire will be used to all healthcare (primary care and the hospital contact with other healthcare and use of patients undergoing of the procedures assessed in the The questionnaire will be to patients at and at 6 weeks and 6, 12, and 24 months after surgery. The used will be using national cost such as and The will be used to HRQoL at and at 6 weeks and 6, 12, and 24 months after surgery. The will be using NICE at the of the using a UK set or into the with a and using the UK set for will be using the under the which the between each follow-up and it by and standard as a will be reported for and at each follow-up The differences in use and between the trial arms will be and these differences will be for using the most recommended All and effects will be at NICE practice will be followed for data in data on at will be This study is by the National Institute for Health and Care and The no of data can be from the