J Neurogastroenterol Motil 2024; 30(1): 17-28  https://doi.org/10.5056/jnm23145
Refractory Gastroesophageal Reflux Disease: Diagnosis and Management
Trevor A Davis1 and C Prakash Gyawali2*
1Division of Pediatric Gastroenterology, Washington University School of Medicine, Saint Louis Children’s Hospital, St. Louis, MO, USA; and 2Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
Correspondence to: *C Prakash Gyawali, MD
Division of Gastroenterology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8124, St. Louis, MO 63110, USA
Tel: +1-314-454-8201, E-mail: cprakash@wustl.edu
Received: September 11, 2023; Accepted: October 16, 2023; Published online: January 30, 2024
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Gastroesophageal reflux disease (GERD) is common, with increasing worldwide disease prevalence and high economic burden. A significant number of patients will remain symptomatic following an empiric proton pump inhibitor (PPI) trial. Persistent symptoms despite PPI therapy are often mislabeled as refractory GERD. For patients with no prior GERD evidence (unproven GERD), testing is performed off antisecretory therapy to identify objective evidence of pathologic reflux using criteria outlined by the Lyon consensus. In proven GERD, differentiation between refractory symptoms (persisting symptoms despite optimized antisecretory therapy) and refractory GERD (abnormal reflux metrics on ambulatory pH impedance monitoring and/or persistent erosive esophagitis on endoscopy while on optimized PPI therapy) can direct subsequent management. While refractory symptoms may arise from esophageal hypersensitivity or functional heartburn, proven refractory GERD requires personalization of the management approach, tapping from an array of non-pharmacologic, pharmacologic, endoscopic, and surgical interventions. Proper diagnosis and management of refractory GERD is critical to mitigate undesirable long-term complications such as strictures, Barrett’s esophagus, and esophageal adenocarcinoma. This review outlines the diagnostic workup of patients presenting with refractory GERD symptoms, describes the distinction between unproven and proven GERD, and provides a comprehensive review of the current treatment strategies available for the management of refractory GERD.
Keywords: Endoscopy; Esophageal pH monitoring; Gastroesophageal reflux; Refractory GERD
Introduction

Gastroesophageal reflux disease (GERD) is a frequently encountered diagnosis in clinical practice, with an estimated prevalence ranging from 8-33% of the general population, and associated economic impact in the United States totaling as much as $10 billion on an annual basis.1-4 Almost one-third of adults report typical GERD symptoms (ie, heartburn, regurgitation, and esophageal chest pain) on a weekly basis.5,6 The mainstay of initial GERD management hinges on a proton pump inhibitor (PPI) trial to determine if symptoms improve with effective acid suppression.5 While approximately two-thirds of patients with erosive esophagitis (EE) and one-half with non-erosive reflux disease (NERD) will achieve symptomatic response with an empiric PPI trial, patients presenting with atypical symptoms, especially laryngeal symptoms such as hoarseness, cough, throat clearing, and sore throat, are much less likely to improve.3,4,6-8 Although PPI response is utilized as a surrogate for diagnostic findings of GERD on objective testing, available literature suggests suboptimal sensitivity (ranging from 71-78%) and specificity (ranging from 44-54%) of a PPI trial when compared to GERD evidence on endoscopy and/or reflux monitoring studies.3,9,10 Furthermore, symptom relief does not always associate with evidence of pathologic GERD, as symptomatic improvement has been demonstrated in more than one-third of patients with normal upper endoscopy and reflux monitoring, likely related to placebo effect and/or incomplete GERD evidence on 24-hour reflux monitoring.3,11 Nevertheless, a PPI trial is a pragmatic initial step for typical GERD symptoms, even though as many as 54% of patients will remain symptomatic despite the PPI trial.3,5,8,12 With the availability of potassium competitive acid blockers (PCABs) that demonstrate highly efficient acid suppression right from the first dose, these agents might replace PPIs as the agents of choice for an initial empiric therapeutic trial.

Persistent symptoms despite acid suppressive therapy may be inappropriately labeled as refractory GERD. Indeed, the literature highlights failure to meet diagnostic criteria for GERD in 47-65% of patients with persistent symptoms despite PPI therapy.4,8,13 Without confirmatory testing to identify the presence or absence of pathologic reflux, over-diagnosis of GERD is likely, since > 60% of patients who do not respond to a PPI trial do not have abnormal reflux metrics on reflux monitoring performed off therapy.8,13 In this review, we illustrate the recommended diagnostic evaluation for patients suspected to have refractory GERD and discuss available management strategies in this population.

Definitions

The defining features of GERD include an abnormal reflux monitoring study and/or findings on upper endoscopy that corroborate pathologic acid exposure, such as EE or Barrett’s esophagus (BE).3,4,8,14-16 Unproven GERD indicates that the patient either has not undergone testing to define features that identify objective GERD, or has negative testing while off anti-secretory therapy. In contrast, proven GERD implies that objective evidence of GERD has been previously demonstrated on either endoscopy or ambulatory reflux monitoring.3,16 Persisting symptoms while on treatment in patients with a history of proven GERD should be referred to as ‘refractory symptoms’ rather than refractory GERD. Given that symptoms do not necessarily correlate with pathologic reflux, further evaluation can define whether the patient truly has refractory GERD versus esophageal hypersensitivity and/or functional heartburn. This designation is dependent on whether GERD has been previously proven with diagnostic testing.

Much variability exists in the current literature regarding the definition of refractory GERD. Persistent evidence of pathologic reflux (abnormal ambulatory reflux monitoring and/or EE on endoscopy) while on antisecretory therapy defines refractory GERD. Conversely, for patients with proven GERD who have normal pH-impedance monitoring despite symptoms while on optimized PPI treatment, esophageal hypersensitivity, functional heartburn, or an alternate process is the likely culprit.17,18 The core difference between esophageal hypersensitivity (reflux hypersensitivity) and functional heartburn is determined by presence or absence of reflux-symptom association, which is best assessed using pH-impedance monitoring.18 Without proper investigation for ongoing symptoms, however, pathologic reflux is difficult to differentiate from esophageal disorders of gut-brain interaction (DGBI).18

Evaluation of Refractory Symptoms in Unproven Gastroesophageal Reflux Disease

Diagnostic testing for the objective presence of GERD parameters can direct further management in the patient with persistent symptoms despite empiric acid suppressive therapy (Fig. 1). Evaluation starts with an upper endoscopy to inspect the esophagus for evidence of reflux-related mucosal changes, which consist of high-grade EE categorized using the Los Angeles (LA) grades to B, C, or D, biopsy proven BE, or peptic esophageal stricture.3,6,15,16 Emerging data indicates that LA grade B esophagitis in symptomatic patients is sufficient for an objective diagnosis of GERD.3,8,19,20 Optimally, endoscopy is performed after withholding acid suppression for 2-4 weeks whenever possible. Since high-grade esophagitis is only observed in one-third of treatment naive symptomatic patients and in one-tenth of symptomatic patients on acid suppression, further diagnostic evaluation is typically needed if upper endoscopy is unrevealing.3,21 Low-grade esophagitis (LA grade A esophagitis) can be seen in healthy asymptomatic individuals, and therefore does not constitute conclusive evidence of GERD. Recent data indicates that histopathology has a low diagnostic yield, and only provides helpful clues to an underlying inflammatory mucosal disorder such as eosinophilic esophagitis when presentation consists of dysphagia or food impaction, or when endoscopic findings of eosinophilic esophagitis are found.22 Mucosal damage from reflux can lead to dilated intracellular spaces, but this requires advanced techniques such as electron microscopy for optimal characterization.3,23

Figure 1. Algorithm for evaluation and management of esophageal symptoms suspicious for reflux disease. The concepts of proven gastroesophageal reflux disease (GERD) (prior objective evidence for GERD is present) and unproven GERD (no prior objective evidence for GERD) determine the optimal methodology of investigation of symptoms that persist despite proton pump inhibitor (PPI) therapy. The intent of evaluation of unproven GERD is to determine if GERD exists, while the intent in proven GERD is to determine if GERD persists despite therapy, which may need to be escalated if testing suggests persisting GERD evidence. LA, Los Angeles classification; RH, reflux hypersensitivity; RSA, reflux-symptom association; FH, functional heartburn.

When upper endoscopy is unrevealing, ambulatory reflux monitoring performed off PPI therapy can detect abnormal reflux burden to conclusively diagnose GERD. Although both pH and pH-impedance monitoring options provide accurate assessment of distal esophageal acid exposure and symptom correlation with reflux episodes, pH-impedance monitoring can distinguish weakly acidic from acidic reflux, provide an assessment of baseline mucosal impedance, and identify proximal extent of refluxate.24 On the other hand, ambulatory (wireless) pH monitoring allows for up to 96 hours of pH monitoring, which can overcome day-to-day variation in reflux burden, and may guide PPI discontinuation if reflux is physiologic.25 Moreover, the wireless pH probe can be placed during index endoscopy when no conclusive reflux changes are seen, if scheduled off PPI therapy. In contrast, catheter based pH and pH-impedance monitoring requires high-resolution manometry (HRM) to localize the lower esophageal sphincter (LES) for accurate positioning, and only provides a one-day assessment, which could be the patient’s average day, best day, or worst day in terms of reflux burden.26

The primary metric assessed from reflux monitoring studies is acid exposure time (AET), the percent time distal esophageal pH is < 4.0 over the course of each day for wireless pH studies, or for the extent of the study for catheter based pH and pH-impedance studies.3,16 Increasing AET correlates with increasing severity of esophagitis and increased length of intestinal metaplasia.3,4,16 The role of weakly acidic refluxate in pathologic mucosal damage is less clear.8,14 Reflux episodes on pH-impedance monitoring are identified according to the principles outlined by the Wingate consensus.24 Interpretation of reflux monitoring data is based on criteria established by the recently updated Lyon consensus 2.0, with AET < 4%, total reflux episodes < 40 and/or mean nocturnal baseline impedance (MNBI) > 2500 ohms comprising physiologic acid burden within the “normal” spectrum.27 At the opposite end of the spectrum, AET > 6% and total reflux episodes > 80 are considered conclusively abnormal.3,24 When metrics are inconclusive (AET 4-6% and/or 40-80 total reflux episodes), adjunctive evidence such as low MNBI, reflux-symptom association and/or > 80 reflux episodes mark abnormal reflux burden and may sway the diagnosis toward conclusive GERD.3,15,28,29

Within the physiologic spectrum (AET < 4.0%), reflux-symptom association evaluation may allow further segregation of the symptomatic phenotype into reflux hypersensitivity (positive symptom association) or functional heartburn (negative reflux association); normal MNBI and postreflux swallow-induced peristaltic wave index are additional supportive evidence of these diagnoses.18

When considering alternative diagnoses in a patient with refractory symptoms, evaluation of esophageal motor function using HRM can be of value. Specifically, achalasia should be ruled out since approximately 1% of preoperative HRM studies have been demonstrated to show evidence of achalasia spectrum disorders.30 In addition to accurate localization of the LES for placement of pH or pH impedance catheters, HRM can detect pathophysiologic markers of GERD including suboptimal esophagogastric junction (EGJ) barrier function, abnormal EGJ morphology based on degree of separation between the LES and crural diaphragm, and compromised esophageal body peristaltic function.15,31,32 Increasing prevalence of esophageal hypomotility (ineffective esophageal motility [IEM] and absent contractility) associate with increasing severity of GERD, hypothesized to be related to poor refluxate clearance, especially in the supine position.15,30,31,33,34 Moreover, peristaltic integrity may have significance, with increasing length of esophageal body peristaltic breaks (fragmented and failed peristalsis) associating better with abnormal AET in comparison to weak swallows.35

Evaluation of Symptomatic Patients With Proven Gastroesophageal Reflux Disease

Suboptimal symptom control in patients with proven GERD despite optimized antisecretory therapy warrants further investigation aimed at determining whether refractory GERD symptoms are secondary to inadequate reflux control versus alternate non-GERD esophageal and/or non-esophageal disorders. Evaluation starts with an upper endoscopy, during which persisting EE (LA grade B or higher) or recurrent peptic stricture confirms refractory GERD, while LA grade A esophagitis is inconclusive requiring further supportive evidence. A significant proportion of patients with prior erosive disease will demonstrate mucosal healing on repeat upper endoscopy, which may limit the diagnostic utility of endoscopy.8,21

Reflux evaluation using pH-impedance monitoring while on optimized PPI therapy is the mainstay in diagnostic assessment when endoscopy is unrevealing, regardless of how GERD was initially confirmed. A lower AET threshold of 4% is adequate to affirm refractory GERD in this context; a finding of reflux episodes > 80 is supportive.3,8,36,37 High proximal migration of refluxate has been demonstrated to associate with symptoms on pH-impedance monitoring; reflux symptom association with < 40 reflux episodes, or < 80 episodes without other supportive GERD evidence might suggest overlapping reflux hypersensitivity rather than refractory GERD.38-40 If not previously performed, HRM can add pathophysiologic evidence supporting GERD. In patients with IEM, provocative testing using multiple rapid swallows assesses contraction reserve, which can be used to counsel patients regarding risk of postoperative dysphagia if antireflux surgery (ARS) is being considered.3,8,31 Functional lumen imaging probe can assess integrity of secondary peristalsis but this has not been studied in the context of refractory GERD and further research is needed.

Conversely, when pH-impedance monitoring is abnormal and refractory GERD is diagnosed, the treatment plan should be re-evaluated and management should be optimized with the goal of better reflux control to improve symptoms and subsequently quality of life, and prevent GERD-related complications. When esophageal evaluation is negative, both esophageal DGBIs (such as reflux hypersensitivity and functional heartburn) and non-esophageal disorders (rumination, supragastric belching, laryngeal and pulmonary disorders, gastroparesis, and cardiac disease) need to be considered as potential mechanisms of symptom generation.

Management

An understanding of the mechanism of GERD refractoriness to existing treatment using clinical evaluation, upper endoscopy, and esophageal physiologic testing can help personalize further management. Nevertheless, approaches recommended for reflux symptoms at initial presentation also apply to refractory GERD, and these need to be implemented prior to escalation of management especially to non-reversible options (Fig. 2).

Figure 2. Management of refractory gastroesophageal reflux disease (GERD). Lifestyle adjustments are useful in any patient with reflux symptoms. Antisecretory therapy should be optimized and escalated if indicated. Adjunctive and topical agents, as well as adjunctive measures can be employed to improve symptoms. In patients with objective evidence of refractory GERD, escalation of management to anti-reflux surgery or other invasive interventions may be appropriate. H2RA, histamine H2 receptor antagonist; PPI, proton pump inhibitor; PCAB, potassium competitive acid blocker; G-POEM, gastric peroral endoscopic myotomy.
Lifestyle Measures

No matter the clinical presentation, lifestyle modifications should be incorporated into the management strategy of all patients with refractory GERD. Weight management is an important consideration for overall health, and is beneficial in improving both symptoms and acid burden.41-45 Although weight loss may be achieved by the patient independently, a structured weight loss program may be more impactful in improving reflux symptoms, as demonstrated using validated reflux questionnaires following a 6-month weight loss program in overweight and obese individuals.42 Although a graded response has been demonstrated between degree of body mass index decline and improvement of reflux symptoms, benefits specific to refractory GERD have not explicitly been reported.44 Beyond weight loss, cessation of tobacco and alcohol use should be generally considered for overall health benefits.

Tobacco use has finite associations with GERD pathophysiology, demonstrated on meta-analysis of the significantly higher risk of GERD and associated symptoms in smokers compared to non-smokers.45-47 In contrast, literature describing the role of alcohol use in GERD pathophysiology is mixed. Although alcohol can potentially trigger esophageal symptoms in some patients and use should be limited accordingly, most studies suggest no significant cause-and-effect association.46-48 There are no systematic studies defining complete dietary exclusion of food groups for symptom improvement, but avoidance of triggering foods and drinks should be individualized.8,45,48 However, separating the last meal of the day from bedtime by several hours can reduce supine acid exposure, with available evidence demonstrating significant decrease in night-time acid burden with an earlier evening meal.49 Additionally, supine acid exposure is lower with elevation of the head of the bed and sleeping in the left lateral decubitus position.4,8,50-56

Optimization of Anti-secretory Therapy

The efficacy of PPI therapy is dependent on the proportion of time intragastric pH is > 4.0 in the 24-hour period following administration, which is maximal if the PPI is taken the first meal of the day. When evaluating the effectiveness of a PPI regimen in patients with refractory GERD, it is critical to first confirm adherence.57 An astonishing number of patients do not take their PPI as prescribed, with approximately one-half only using the medication on an intermittent basis.58-60 For the most effective blockade of gastric acid secretion, optimal timing of PPI administration is 30-60 minutes before a meal.8,61 The importance of a good history to confirm adherence and timing has been emphasized in prior studies that demonstrated as few as 10% were taking their PPI as prescribed.58,62

The benefit of PPI therapy can be further optimized by increasing dose frequency to twice daily, which can provide incremental symptom benefit, esophagitis healing, and lower acid burden compared to once-daily administration in refractory GERD.63-65 There is no evidence that dosing more often than twice daily has additional benefit.66 Inadequate symptom response or esophagitis healing despite optimized twice daily dosing for 4-8 weeks may require transition to a more potent PPI.66,67 Although available literature is limited, some studies suggest differing omeprazole-equivalent potencies between PPIs while others support interchangeable use without difference in outcomes.64,66,67 Moreover, when evaluating omeprazole-equivalent potencies, pantoprazole has lower potency, while esomeprazole, dexlansoprazole, and rabeprazole have higher potency compared to omeprazole; lansoprazole is mostly equivalent to omeprazole.66

Pharmacokinetics, particularly metabolism through the hepatic cytochrome P450 (CYP2C19) system is a consideration when deciding the optimal PPI regimen.65,68,69 While twice daily PPI therapy appears to provide adequate symptomatic response in up to 90% of refractory GERD patients, rapid PPI metabolization has been identified as a risk factor for refractory GERD in some patients.65,68-70 A higher prevalence of rapid metabolizers has been identified in Caucasian patients while African Americans are less likely to have CYP mutations associated with rapid metabolism.71 Comparatively, patients of Asian descent are more likely to possess CYP mutations associated with normal, intermediate, and poor metabolism phenotypes.72 Nevertheless, in patients at risk for rapid metabolizer status with an unsatisfactory response, a PPI that bypasses hepatic CYP metabolism such as esomeprazole and rabeprazole may be an option.65,68,69 Although genotying of CYP metabolizer status is possible, this is not widely available and can add a significant cost burden; thus, this is not typically recommended over switching to an alternate PPI.73

Other Acid Suppressants

Alternative classes of antisecretory medications may have benefit as adjunctive therapy in refractory GERD. Nocturnal acid breakthrough, defined as at least 1 overnight hour of intragastric pH < 4.0 despite optimal PPI therapy, can manifest as night-time symptoms. Histamine H2 receptor antagonists (H2RAs) are sometimes utilized at bedtime, since histamine release can be a mechanism underlying nocturnal acid secretion,71 and histamine blockade can provide symptom relief from reduced nocturnal acid breakthrough in the short term.71,74-80 When effective, tachyphylaxis and medication tolerance can return nocturnal acid production to baseline levels within 1 week to 1 month despite continued use of the medication, limiting H2RA efficacy.71,74-80 Patients with H2RA tachyphylaxis may ultimately benefit from as needed use rather than adherence to a fixed regimen.

PCABs are an emerging class of acid suppressants that are promising in the management of refractory GERD. Although similar to PPIs in that they both inhibit the gastric hydrogen-potassium ATPase, PCABs achieve acid suppression through a reversible potassium-competitive inhibition of the proton pump, resulting in faster, more potent acid control without need for pre-meal administration.81 Multicenter randomized trials in Asia and North America have demonstrated non-inferiority of the PCABs vonoprazan, tegoprazan, and fexuprazan compared to traditional PPIs, with particular effectiveness in advanced grade esophagitis, including in rapid PPI metabolizers since PCABs are metabolized by a different CYP enzyme system (CYP 3A4).82-84 Faster symptom benefit has also been demonstrated with PCABs, especially symptoms associated with acidic reflux.85

Reflux Inhibitors and Mucosal Protective Agents

Baclofen, a gamma aminobutyric acid-B (GABA-B) receptor agonist, can reduce frequency of transient LES relaxations (TLESRs). Since TLESRs are the primary mechanism of gastroesophageal reflux, baclofen has proven useful by reducing number and duration of reflux episodes that could be contributing to refractory symptoms.8,86-88 Baclofen has been shown to be effective in reducing symptoms both with and without large hiatal hernias.89 However, its use is limited by side effects including sedation, lightheadedness, central nervous system depression, and short half-life necessitating multiple daily doses for results.86,88 Unfortunately, attempts at pharmacokinetic optimization of alternate GABA-B receptor-targeting agents have fallen short of expectations, and no reflux-specific GABA-B agonist is currently available.90,91

Mucosal protective agents, on the other hand, are useful adjuncts for managing breakthrough heartburn and regurgitation despite PPI therapy. These agents can form a raft or mechanical barrier at the interface between meal-stimulated gastric acid (the postprandial acid pocket) and the esophageal mucosa to provide symptomatic benefit in patients with refractory GERD, with a favorable side effect profile.4,8,92-94 Specifically, antacid preparations combined with alginate (Gaviscon Advance), as well as a hyaluronic acid-chondroitin sulfate based bioadhesive formulation (Esoxx) demonstrated benefit when used as an adjunct to PPI therapy compared to placebo with or without PPI in multicenter randomized-controlled trials.92-94 Although relief of persistent GERD symptoms has been demonstrated with the addition of mucosal protective agents, there is a paucity of literature detailing effect on objective reflux metrics through pH-impedance monitoring.

Invasive Anti-reflux Management

In patients with objective evidence of refractory GERD and persistent symptoms despite optimization of medical therapy, invasive surgical, or endoscopic anti-reflux interventions are options (Fig. 2). When conclusive GERD evidence exists, laparoscopic ARS has demonstrated long-term efficacy comparable to PPI therapy in several randomized trials.95-97 This benefit extends to patients with refractory GERD despite optimized PPI therapy, where ARS may be superior to medical management in symptom relief.97 Long-term monitoring demonstrates sustained benefit over follow-up as long as 17 years, with at least 60% of patients able to remain off antisecretory therapy.98,99 However, some patients require re-intervention for recurrent GERD or fundoplication failure, and dysphagia as well as gas bloat syndrome remain problematic side effects in others. While postoperative obstructive symptoms may arise because of a mechanical post-operative complication, thorough preoperative evaluation including HRM may partially mitigate the risk by identifying patients as higher risk of postoperative dysphagia, such as pre-existing dysphagia or IEM without contraction reserve.6,100-105 Although data are mixed, considering a partial wrap could reduce the likelihood of late postoperative dysphagia.102-104 Roux-en-Y gastric bypass is an option as primary treatment for refractory GERD, for failed fundoplication, or for refractory GERD following sleeve gastrectomy, especially for morbidly obese patients where morbidity is lower compared to ARS.6,8,106,107

An alternative minimally invasive surgical option is magnetic sphincter augmentation (MSA) where a bracelet of magnets encased in titanium is implanted around the EGJ.108,109 As many as 58% normalize esophageal AET within 1 year after MSA, and > 90% are able to halve their use of antisecretory therapy.109,110 Although MSA appears beneficial in all PPI-refractory GERD, regurgitation-predominant symptoms achieve particularly favorable results.8,111-113 Number of total reflux episodes > 80 on preoperative pH-impedance monitoring despite optimized medical therapy predicts patient satisfaction and improved symptom scores following MSA.113 Sustained symptom improvement has been demonstrated 5 years from implantation, with reduction in PPI use from 100% to 15.3%, and moderate-to-severe regurgitation symptoms from 57% to 1.2%.114 Dysphagia post-MSA was typically mild, with resolution in most patients (89% at 1 year and 96% at 3 years), and the need for device explant was infrequent.109-111,114

Among endoscopic approaches, transoral incisionless fundoplication (TIF) 2.0 creates a 3 cm valve with a 270° circumferential wrap without need for laparoscopic surgery.115-120 Although TIF has reported success despite presence of < 2 cm hiatal hernia, laparoscopic crural repair can be performed in conjunction with TIF when necessary.115-120 Short-term benefits are well demonstrated over PPI therapy in randomized trials, particularly for regurgitation-predominant symptoms.115,117-120 Even refractory atypical GERD symptoms may improve, with nearly three-fourths of patients off PPI therapy at 12-month follow-up.116 Long-term efficacy data are mixed; one 10-year study reported > 90% of patients off PPI or on doses 50% lower than baseline, yet others have reported decreased effectiveness over time.115,117-120 Radiofrequency application (RFA, also termed Stretta) to the EGJ attempts to improve EGJ barrier function while reducing TLESR frequency through altering esophageal nerve and muscle function, and potentially through reduction in sensation perception.121-124 While generally safe, efficacy of RFA remains under debate.121-126 Separate meta-analyses have reported unchanged LES pressures and inconsistent outcomes in regards to PPI discontinuation, improvement in quality of life, and esophageal AET normalization.122,123,125,126

A newer endoscopic technique termed antireflux mucosectomy creates scarring around the EGJ using crescentic or circumferential mucosal resection to reduce reflux burden.120,127-129 In observational antireflux mucosectomy studies, improvement in reflux-related quality of life has been demonstrated.128 Other antireflux mucosal interventions reduce reflux in a similar fashion, including antireflux band mucosectomy (ARBM) and antireflux mucosal ablation (ARMA) using argon plasma coagulation.129,130 A pooled success rate of 73.8% has been reported over short-term follow up with antireflux mucosal interventions in a meta-analysis of uncontrolled trials.129 Post-procedure dysphagia requiring dilation was reported by 10%, while perforation occurred in 2.2%.129

For the subset of refractory GERD patients where gastroparesis co-exists, improving gastric emptying can improve reflux symptoms. Medical management with prokinetics is typically utilized at the outset. Gastric per-oral endoscopic myotomy can be an option for persistent delay in gastric emptying, especially when this is believed to contribute to refractory GERD symptoms. A recent multicenter retrospective study of 20 lung transplant patients with concomitant GERD and gastroparesis demonstrated normalization of pH testing in 90% with improvement in gastric emptying and ability to wean off PPI therapy in 75%.131

Other Measures

Complementary approaches benefit some refractory GERD patients. Diaphragmatic breathing can increase LES pressure and reduce postprandial reflux episodes.132 In a randomized trial of patients with NERD or healed esophagitis, diaphragmatic breathing reduced abnormal AET with improvement in quality of life scores.133 Benefits may last for as long as 9 months, with sustained improvement in quality of life as well as PPI discontinuation.133 Both acupuncture and hypnotherapy can improve symptom intensity, especially chest pain, in refractory GERD.133,134 Heightened psychological stress, anxiety, and/or depression exacerbate refractory GERD symptoms in population-based studies, which may benefit from targeted therapy administered by a behavioral psychologist.135

Prognosis

Identification and management of refractory GERD can reduce likelihood of undesirable effects of longstanding abnormal acid exposure, including erosive esophagitis, peptic stricture, BE, and esophageal adenocarcinoma. Optimized antireflux pharmacotherapy has been shown to successfully heal esophagitis in 72-93% of patients, while ARS has demonstrated comparable long-term outcomes in randomized controlled trials.4,95,96 Beyond damage to mucosal integrity, refractory GERD may exacerbate physical symptoms that can significantly impact health-related quality of life. Conversely, despite adequate endoscopic healing and alleviation of abnormal acid burden, symptoms can persist because of overlapping alternative mechanisms of symptom generation such as reflux hypersensitivity or functional heartburn among others. Delineating refractory GERD symptoms from refractory GERD is essential, as the treatment paradigm relies on this differentiation to achieve optimal clinical outcomes. In general, pharmacologic, endoscopic, and surgical interventions for refractory GERD have benefits that outweigh risks in well-characterized GERD, and management needs to be personalized to each patient’s unique presentation. Each therapeutic option has a risk-benefit profile that should be reviewed with the patient.

Conclusions

Persistent esophageal symptoms despite seemingly adequate acid suppressive therapy is the starting point for evaluation to determine if GERD evidence exists. Refractory GERD is diagnosed when abnormal reflux metrics persist on endoscopy and/or pH impedance monitoring performed on optimized GERD therapy in patients with previously proven GERD. While several non-pharmacologic, pharmacologic, endoscopic, and surgical interventions are available at the disposal of the clinician for effective treatment of refractory GERD, the management strategy should be personalized to each patient, taking into account underlying comorbidities, risk-benefit profile, and patient preference.

Financial support

None.

Conflicts of interest

Trevor A Davis: none; and C Prakash Gyawali: consultant for Medtronic and Diversatek, speaker for Carnot.

References
  1. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2014;63:871-880.
    Pubmed KoreaMed CrossRef
  2. Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastrointestinal and liver diseases, 2006. Am J Gastroenterol 2006;101:2128-2138.
    Pubmed CrossRef
  3. Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of GERD: the lyon consensus. Gut 2018;67:1351-1362.
    Pubmed KoreaMed CrossRef
  4. Gyawali CP, Fass R. Management of gastroesophageal reflux disease. Gastroenterology 2018;154:302-318.
    Pubmed CrossRef
  5. Yadlapati R, Gyawali CP, Pandolfino JE; CGIT GERD Consensus Conference Participants. AGA clinical practice update on the personalized approach to the evaluation and management of GERD: expert review. Clin Gastroenterol Hepatol 2022;20:984-994, e1.
    Pubmed KoreaMed CrossRef
  6. Katz PO, Dunbar KB, Schnoll-Sussman FH, Greer KB, Yadlapati R, Spechler SJ. ACG clinical guideline for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2022;117:27-56.
    Pubmed KoreaMed CrossRef
  7. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900-1920.
    Pubmed CrossRef
  8. Zerbib F, Bredenoord AJ, Fass R, et al. ESNM/ANMS consensus paper: diagnosis and management of refractory gastro-esophageal reflux disease. Neurogastroenterol Motil 2021;33:e14075.
    Pubmed CrossRef
  9. Bytzer P, Jones R, Vakil N, et al. Limited ability of the proton-pump inhibitor test to identify patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2012;10:1360-1366.
    Pubmed CrossRef
  10. Numans ME, Lau J, de Wit NJ, Bonis PA. Short-term treatment with proton-pump inhibitors as a test for gastroesophageal reflux disease: a meta-analysis of diagnostic test characteristics. Ann Intern Med 2004;140:518-527.
    Pubmed CrossRef
  11. Dent J, Vakil N, Jones R, et al. Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the diamond study. Gut 2010;59:714-721.
    Pubmed CrossRef
  12. Delshad SD, Almario CV, Chey WD, Spiegel BMR. Prevalence of gastroesophageal reflux disease and proton pump inhibitor-refractory symptoms. Gastroenterology 2020;158:1250-1261, r2.
    Pubmed KoreaMed CrossRef
  13. Herregods TV, Troelstra M, Weijenborg PW, Bredenoord AJ, Smout AJ. Patients with refractory reflux symptoms often do not have GERD. Neurogastroenterol Motil 2015;27:1267-1273.
    Pubmed CrossRef
  14. Savarino E, Zentilin P, Frazzoni M, et al. Characteristics of gastro-esophageal reflux episodes in barrett's esophagus, erosive esophagitis and healthy volunteers. Neurogastroenterol Motil 2010;22:1061-e280.
    Pubmed CrossRef
  15. Savarino E, Bredenoord AJ, Fox M, et al. Expert consensus document: advances in the physiological assessment and diagnosis of GERD. Nat Rev Gastroenterol Hepatol 2017;14:665-676.
    Pubmed CrossRef
  16. Roman S, Gyawali CP, Savarino E, et al. Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group. Neurogastroenterol Motil 2017;29:1-15.
    Pubmed CrossRef
  17. Weijenborg PW, Smout AJ, Bredenoord AJ. Esophageal acid sensitivity and mucosal integrity in patients with functional heartburn. Neurogastroenterol Motil 2016;28:1649-1654.
    Pubmed CrossRef
  18. Aziz Q, Fass R, Gyawali CP, Miwa H, Pandolfino JE, Zerbib F. Functional esophageal disorders. Gastroenterology 2016;150:1368-1379.
    Pubmed CrossRef
  19. Akdamar K, Ertan A, Agrawal NM, McMahon FG, Ryan J. Upper gastrointestinal endoscopy in normal asymptomatic volunteers. Gastrointest Endosc 1986;32:78-80.
    Pubmed CrossRef
  20. Visaggi P, Gyawali CP, Del Corso G, et al. 938 impedance-pH findings confirm that grade B esophagitis provides objective diagnosis of gastroesophageal reflux disease. Gastroenterology 2023;164:S-202.
    CrossRef
  21. Poh CH, Gasiorowska A, Navarro-Rodriguez T, et al. Upper GI tract findings in patients with heartburn in whom proton pump inhibitor treatment failed versus those not receiving antireflux treatment. Gastrointest Endosc 2010;71:28-34.
    Pubmed CrossRef
  22. Oude Nijhuis RAB, Curvers WL, van der Ende M, et al. Utility of routine esophageal biopsies in patients with refractory reflux symptoms. Am J Gastroenterol 2021;116:816-820.
    Pubmed CrossRef
  23. Vela MF, Craft BM, Sharma N, Freeman J, Hazen-Martin D. Refractory heartburn: comparison of intercellular space diameter in documented GERD vs. functional heartburn. Am J Gastroenterol 2011;106:844-850.
    Pubmed CrossRef
  24. Gyawali CP, Rogers B, Frazzoni M, Savarino E, Roman S, Sifrim D. Inter-reviewer variability in interpretation of pH-impedance studies: the wingate consensus. Clin Gastroenterol Hepatol 2021;19:1976-1978, e1.
    Pubmed CrossRef
  25. Pandolfino JE, Richter JE, Ours T, Guardino JM, Chapman J, Kahrilas PJ. Ambulatory esophageal ph monitoring using a wireless system. Am J Gastroenterol 2003;98:740-749.
    Pubmed CrossRef
  26. Yadlapati R, Masihi M, Gyawali CP, et al. Ambulatory reflux monitoring guides proton pump inhibitor discontinuation in patients with gastroesophageal reflux symptoms: a clinical trial. Gastroenterology 2021;160:174-182, e1.
    Pubmed KoreaMed CrossRef
  27. Gyawali C, Yadlapati R, Fass R, et al. Update to the modern diagnosis of GERD: lyon consensus 2.0. Gut Published Online First: 21 Sep 2023. doi:10.1136/gutjnl-2023-330616.
    Pubmed CrossRef
  28. Farré R, Blondeau K, Clement D, et al. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut 2011;60:885-892.
    Pubmed CrossRef
  29. Frazzoni M, Savarino E, de Bortoli N, et al. Analyses of the post-reflux swallow-induced peristaltic wave index and nocturnal baseline impedance parameters increase the diagnostic yield of impedance-pH monitoring of patients with reflux disease. Clin Gastroenterol Hepatol. 2016;14:40-46.
    Pubmed CrossRef
  30. Chan WW, Haroian LR, Gyawali CP. Value of preoperative esophageal function studies before laparoscopic antireflux surgery. Surg Endosc 2011;25:2943-2949.
    Pubmed CrossRef
  31. Gyawali CP, Roman S, Bredenoord AJ, et al. Classification of esophageal motor findings in gastro-esophageal reflux disease: conclusions from an international consensus group. Neurogastroenterol Motil 2017;29:e13104.
    Pubmed CrossRef
  32. Rengarajan A, Gyawali CP. High-resolution manometry can characterize esophagogastric junction morphology and predict esophageal reflux burden. J Clin Gastroenterol 2020;54:22-27.
    Pubmed CrossRef
  33. Savarino E, Gemignani L, Pohl D, et al. Oesophageal motility and bolus transit abnormalities increase in parallel with the severity of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2011;34:476-486.
    Pubmed CrossRef
  34. Ho SC, Chang CS, Wu CY, Chen GH. Ineffective esophageal motility is a primary motility disorder in gastroesophageal reflux disease. Dig Dis Sci 2002;47:652-656.
    Pubmed CrossRef
  35. Rogers BD, Rengarajan A, Mauro A, et al. Fragmented and failed swallows on esophageal high-resolution manometry associate with abnormal reflux burden better than weak swallows. Neurogastroenterol Motil 2020;32:e13736.
    Pubmed CrossRef
  36. Gyawali CP, Tutuian R, Zerbib F, et al. Value of pH impedance monitoring while on twice-daily proton pump inhibitor therapy to identify need for escalation of reflux management. Gastroenterology 2021;161:1412-1422.
    Pubmed CrossRef
  37. Sifrim D, Gyawali CP. Prolonged wireless pH monitoring or 24-hour catheter-based pH impedance monitoring: who, when, and why?. Am J Gastroenterol 2020;115:1150-1152.
    Pubmed CrossRef
  38. Sifrim D, Zerbib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut 2012;61:1340-1354.
    Pubmed CrossRef
  39. Tutuian R, Vela MF, Hill EG, Mainie I, Agrawal A, Castell DO. Characteristics of symptomatic reflux episodes on acid suppressive therapy. Am J Gastroenterol 2008;103:1090-1096.
    Pubmed CrossRef
  40. Karamanolis G, Stevens W, Vos R, Tack J, Clave P, Sifrim D. Oesophageal tone and sensation in the transition zone between proximal striated and distal smooth muscle oesophagus. Neurogastroenterol Motil 2008;20:291-297.
    Pubmed CrossRef
  41. Mathus-Vliegen EM, Tygat GN. Gastro-oesophageal reflux in obese subjects: influence of overweight, weight loss and chronic gastric balloon distension. Scand J Gastroenterol 2002;37:1246-1252.
    Pubmed CrossRef
  42. Singh M, Lee J, Gupta N, et al. Weight loss can lead to resolution of gastroesophageal reflux disease symptoms: a prospective intervention trial. Obesity (Silver Spring) 2013;21:284-290.
    Pubmed KoreaMed CrossRef
  43. Ness-Jensen E, Lindam A, Lagergren J, Hveem K. Weight loss and reduction in gastroesophageal reflux. A prospective population-based cohort study: the HUNT study. Am J Gastroenterol 2013;108:376-382.
    Pubmed CrossRef
  44. Fraser-Moodie CA, Norton B, Gornall C, Magnago S, Weale AR, Holmes GK. Weight loss has an independent beneficial effect on symptoms of gastro-oesophageal reflux in patients who are overweight. Scand J Gastroenterol 1999;34:337-340.
    Pubmed CrossRef
  45. Nocon M, Labenz J, Willich SN. Lifestyle factors and symptoms of gastro-oesophageal reflux -- a population-based study. Aliment Pharmacol Ther 2006;23:169-174.
    Pubmed CrossRef
  46. Ness-Jensen E, Lagergren J. Tobacco smoking, alcohol consumption and gastro-oesophageal reflux disease. Best Pract Res Clin Gastroenterol 2017;31:501-508.
    Pubmed CrossRef
  47. Eusebi LH, Ratnakumaran R, Yuan Y, Solaymani-Dodaran M, Bazzoli F, Ford AC. Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: a meta-analysis. Gut 2018;67:430-440.
    Pubmed CrossRef
  48. Nilsson M, Johnsen R, Ye W, Hveem K, Lagergren J. Lifestyle related risk factors in the aetiology of gastro-oesophageal reflux. Gut 2004;53:1730-1735.
    Pubmed KoreaMed CrossRef
  49. Piesman M, Hwang I, Maydonovitch C, Wong RK. Nocturnal reflux episodes following the administration of a standardized meal. Does timing matter?. Am J Gastroenterol 2007;102:2128-2134.
    Pubmed CrossRef
  50. Hamilton JW, Boisen RJ, Yamamoto DT, Wagner JL, Reichelderfer M. Sleeping on a wedge diminishes exposure of the esophagus to refluxed acid. Dig Dis Sci 1988;33:518-522.
    Pubmed CrossRef
  51. Khan BA, Sodhi JS, Zargar SA, et al. Effect of bed head elevation during sleep in symptomatic patients of nocturnal gastroesophageal reflux. J Gastroenterol Hepatol 2012;27:1078-1082.
    Pubmed CrossRef
  52. Khoury RM, Camacho-Lobato L, Katz PO, Mohiuddin MA, Castell DO. Influence of spontaneous sleep positions on nighttime recumbent reflux in patients with gastroesophageal reflux disease. Am J Gastroenterol 1999;94:2069-2073.
    Pubmed CrossRef
  53. van Herwaarden MA, Katzka DA, Smout AJ, Samsom M, Gideon M, Castell DO. Effect of different recumbent positions on postprandial gastroesophageal reflux in normal subjects. Am J Gastroenterol 2000;95:2731-2736.
    Pubmed CrossRef
  54. Person E, Rife C, Freeman J, Clark A, Castell DO. A novel sleep positioning device reduces gastroesophageal reflux: a randomized controlled trial. J Clin Gastroenterol 2015;49:655-659.
    Pubmed CrossRef
  55. Allampati S, Lopez R, Thota PN, Ray M, Birgisson S, Gabbard SL. Use of a positional therapy device significantly improves nocturnal gastroesophageal reflux symptoms. Dis Esophagus 2017;30:1-7.
    Pubmed CrossRef
  56. Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med 2006;166:965-971.
    Pubmed CrossRef
  57. Domingues G, Moraes-Filho JP. Noncompliance is an impact factor in the treatment of gastroesophageal reflux disease. Expert Rev Gastroenterol Hepatol 2014;8:761-765.
    Pubmed CrossRef
  58. Van Soest EM, Siersema PD, Dieleman JP, Sturkenboom MC, Kuipers EJ. Persistence and adherence to proton pump inhibitors in daily clinical practice. Aliment Pharmacol Ther 2006;24:377-385.
    Pubmed CrossRef
  59. Gosselin A, Luo R, Lohoues H, et al. The impact of proton pump inhibitor compliance on health-care resource utilization and costs in patients with gastroesophageal reflux disease. Value Health 2009;12:34-39.
    Pubmed CrossRef
  60. Hungin AP, Rubin G, O'Flanagan H. Factors influencing compliance in long-term proton pump inhibitor therapy in general practice. Br J Gen Pract 1999;49:463-464.
    Pubmed KoreaMed
  61. Hasak S, Yadlapati R, Altayar O, et al. Prolonged wireless pH monitoring in patients with persistent reflux symptoms despite proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2020;18:2912-2919.
    Pubmed KoreaMed CrossRef
  62. Gunaratnam NT, Jessup TP, Inadomi J, Lascewski DP. Sub-optimal proton pump inhibitor dosing is prevalent in patients with poorly controlled gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2006;23:1473-1477.
    Pubmed CrossRef
  63. Kahrilas PJ, Boeckxstaens G, Smout AJ. Management of the patient with incomplete response to PPI therapy. Best Pract Res 2013;27:401-414.
    Pubmed KoreaMed CrossRef
  64. Klok RM, Postma MJ, Van Hout BA, Brouwers JR. Meta-analysis: comparing the efficacy of proton pump inhibitors in short-term use. Aliment Pharmacol Ther 2003;17:1237-1245.
    Pubmed CrossRef
  65. Chen WY, Chang WL, Tsai YC, Cheng HC, Lu CC, Sheu BS. Double-dosed pantoprazole accelerates the sustained symptomatic response in overweight and obese patients with reflux esophagitis in Los angeles grades A and B. Am J Gastroenterol 2010;105:1046-1052.
    Pubmed CrossRef
  66. Graham DY, Tansel A. Interchangeable use of proton pump inhibitors based on relative potency. Clin Gastroenterol Hepatol 2018;16:800-808, e7.
    Pubmed KoreaMed CrossRef
  67. Kirchheiner J, Glatt S, Fuhr U, et al. Relative potency of proton-pump inhibitors-comparison of effects on intragastric pH. Eur J Clin Pharmacol 2009;65:19-31.
    Pubmed CrossRef
  68. Sagar M, Tybring G, Dahl ML, Bertilsson L, Seensalu R. Effects of omeprazole on intragastric pH and plasma gastrin are dependent on the CYP2C19 polymorphism. Gastroenterology 2000;119:670-676.
    Pubmed CrossRef
  69. Furuta T, Sugimoto M, Shirai N, Ishizaki T. CYP2C19 pharmacogenomics associated with therapy of Helicobacter pylori infection and gastro-esophageal reflux diseases with a proton pump inhibitor. Pharmacogenomics 2007;8:1199-1210.
    Pubmed CrossRef
  70. Ichikawa H, Sugimoto M, Sugimoto K, Andoh A, Furuta T. Rapid metabolizer genotype of CYP2C19 is a risk factor of being refractory to proton pump inhibitor therapy for reflux esophagitis. J Gastroenterol Hepatol 2016;31:716-726.
    Pubmed CrossRef
  71. Rackoff A, Agrawal A, Hila A, Mainie I, Tutuian R, Castell DO. Histamine-2 receptor antagonists at night improve gastroesophageal reflux disease symptoms for patients on proton pump inhibitor therapy. Dis Esophagus 2005;18:370-373.
    Pubmed CrossRef
  72. El Rouby N, Lima JJ, Johnson JA. Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine. Expert Opin Drug Metab Toxicol 2018;14:447-460.
    Pubmed KoreaMed CrossRef
  73. Lima JJ, Franciosi JP. Pharmacogenomic testing: the case for CYP2C19 proton pump inhibitor gene-drug pairs. Pharmacogenomics 2014;15:1405-1416.
    Pubmed CrossRef
  74. Mainie I, Tutuian R, Castell DO. Addition of a H2 receptor antagonist to PPI improves acid control and decreases nocturnal acid breakthrough. J Clin Gastroenterol 2008;42:676-679.
    Pubmed CrossRef
  75. Wang Y, Pan T, Wang Q, Guo Z. Additional bedtime H2-receptor antagonist for the control of nocturnal gastric acid breakthrough. Cochrane Database Syst Rev. [abstract] 2009;CD004275.
    CrossRef
  76. Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut 2009;58:295-309.
    Pubmed CrossRef
  77. Orr WC, Harnish MJ. The efficacy of omeprazole twice daily with supplemental H2 blockade at bedtime in the suppression of nocturnal oesophageal and gastric acidity. Aliment Pharmacol Ther 2003;17:1553-1558.
    Pubmed CrossRef
  78. Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998;115:1335-1339.
    Pubmed CrossRef
  79. Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology 2002;122:625-632.
    Pubmed CrossRef
  80. Xue S, Katz PO, Banerjee P, Tutuian R, Castell DO. Bedtime H2 blockers improve nocturnal gastric acid control in GERD patients on proton pump inhibitors. Aliment Pharmacol Ther 2001;15:1351-1356.
    Pubmed CrossRef
  81. Hori Y, Imanishi A, Matsukawa J, et al. 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases. J Pharmacol Exp Ther 2010;335:231-238.
    Pubmed CrossRef
  82. Sugano K. Vonoprazan fumarate, a novel potassium-competitive acid blocker, in the management of gastroesophageal reflux disease: safety and clinical evidence to date. Ther Adv Gastroenterol 2018;11:1756283X17745776.
    Pubmed KoreaMed CrossRef
  83. Echizen H. The first-in-class potassium-competitive acid blocker, vonoprazan fumarate: pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet 2016;55:409-418.
    Pubmed CrossRef
  84. Ashida K, Sakurai Y, Hori T, et al. Randomised clinical trial: vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the healing of erosive oesophagitis. Aliment Pharmacol Ther 2016;43:240-251.
    Pubmed KoreaMed CrossRef
  85. Abe Y, Koike T, Saito M, et al. The ameliorating effect of switching to vonoprazan: a novel potassium-competitive acid blocker in patients with proton pump inhibitor refractory non-erosive reflux disease. Digestion 2021;102:480-488.
    Pubmed CrossRef
  86. van Herwaarden MA, Samsom M, Rydholm H, Smout AJ. The effect of baclofen on gastro-oesophageal reflux, lower oesophageal sphincter function and reflux symptoms in patients with reflux disease. Aliment Pharmacol Ther 2002;16:1655-1662.
    Pubmed CrossRef
  87. Vela MF, Tutuian R, Katz PO, Castell DO. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther 2003;17:243-251.
    Pubmed CrossRef
  88. Li S, Shi S, Chen F, Lin J. The effects of baclofen for the treatment of gastroesophageal reflux disease: a meta-analysis of randomized controlled trials. Gastroenterol Res Pract 2014;2014:307805.
    Pubmed KoreaMed CrossRef
  89. Beaumont H, Boeckxstaens GE. Does the presence of a hiatal hernia affect the efficacy of the reflux inhibitor baclofen during add-on therapy?. Am J Gastroenterol 2009;104:1764-1771.
    Pubmed CrossRef
  90. Vakil NB, Huff FJ, Cundy KC. Randomised clinical trial: arbaclofen placarbil in gastro-oesophageal reflux disease--insights into study design for transient lower sphincter relaxation inhibitors. Aliment Pharmacol Ther 2013;38:107-117.
    Pubmed CrossRef
  91. Boeckxstaens GE, Beaumont H, Hatlebakk JG, et al. A novel reflux inhibitor lesogaberan (AZD3355) as add-on treatment in patients with GORD with persistent reflux symptoms despite proton pump inhibitor therapy: a randomised placebo-controlled trial. Gut 2011;60:1182-1188.
    Pubmed CrossRef
  92. Reimer C, Lødrup AB, Smith G, Wilkinson J, Bytzer P. Randomised clinical trial: alginate (Gaviscon Advance) vs. placebo as add-on therapy in reflux patients with inadequate response to a once daily proton pump inhibitor. Aliment Pharmacol Ther 2016;43:899-909.
    Pubmed CrossRef
  93. Savarino V, Pace F, Scarpignato C; Esoxx Study Group. Randomised clinical trial: mucosal protection combined with acid suppression in the treatment of non-erosive reflux disease - efficacy of Esoxx, a hyaluronic acid-chondroitin sulphate based bioadhesive formulation. Aliment Pharmacol Ther 2017;45:631-642.
    Pubmed KoreaMed CrossRef
  94. Coyle C, Crawford G, Wilkinson J, Thomas SJ, Bytzer P. Randomised clinical trial: addition of alginate-antacid (Gaviscon Double Action) to proton pump inhibitor therapy in patients with breakthrough symptoms. Aliment Pharmacol Ther 2017;45:1524-1533.
    Pubmed CrossRef
  95. Galmiche JP, Hatlebakk J, Attwood S, et al. Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial. JAMA 2011;305:1969-1977.
    Pubmed CrossRef
  96. Lundell L, Attwood S, Ell C, et al. Comparing laparoscopic antireflux surgery with esomeprazole in the management of patients with chronic gastro-oesophageal reflux disease: a 3-year interim analysis of the LOTUS trial. Gut 2008;57:1207-1213.
    Pubmed KoreaMed CrossRef
  97. Mehta S, Bennett J, Mahon D, Rhodes M. Prospective trial of laparoscopic nissen fundoplication versus proton pump inhibitor therapy for gastroesophageal reflux disease: seven-year follow-up. J Gastrointest Surg 2006;10:1312-1316; discussion 1316-1317.
    Pubmed CrossRef
  98. Oor JE, Roks DJ, Broeders JA, Hazebroek EJ, Gooszen HG. Seventeen-year outcome of a randomized clinical trial comparing laparoscopic and conventional nissen fundoplication: a plea for patient counseling and clarification. Ann Surg 2017;266:23-28.
    Pubmed CrossRef
  99. Dallemagne B, Weerts J, Markiewicz S, et al. Clinical results of laparoscopic fundoplication at ten years after surgery. Surg Endosc 2006;20:159-165.
    Pubmed CrossRef
  100. Campos GM, Peters JH, DeMeester TR, et al. Multivariate analysis of factors predicting outcome after laparoscopic nissen fundoplication. J Gastrointest Surg 1999;3:292-300.
    Pubmed CrossRef
  101. Patti MG, Arcerito M, Tamburini A, et al. Effect of laparoscopic fundoplication on gastroesophageal reflux disease-induced respiratory symptoms. J Gastrointest Surg 2000;4:143-149.
    Pubmed CrossRef
  102. Shaker A, Stoikes N, Drapekin J, Kushnir V, Brunt LM, Gyawali CP. Multiple rapid swallow responses during esophageal high-resolution manometry reflect esophageal body peristaltic reserve. Am J Gastroenterol 2013;108:1706-1712.
    Pubmed KoreaMed CrossRef
  103. Mello MD, Shriver AR, Li Y, Patel A, Gyawali CP. Ineffective esophageal motility phenotypes following fundoplication in gastroesophageal reflux disease. Neurogastroenterol Motil 2016;28:292-298.
    Pubmed KoreaMed CrossRef
  104. Patti MG, Allaix ME, Fisichella PM. Analysis of the causes of failed antireflux surgery and the principles of treatment: a review. JAMA Surg 2015;150:585-590.
    Pubmed CrossRef
  105. Jobe BA, Richter JE, Hoppo T, et al. Preoperative diagnostic workup before antireflux surgery: an evidence and experience-based consensus of the esophageal diagnostic advisory panel. J Am Coll Surg 2013;217:586-597.
    Pubmed CrossRef
  106. Kim M, Navarro F, Eruchalu CN, Augenstein VA, Heniford BT, Stefanidis D. Minimally invasive Roux-en-Y gastric bypass for fundoplication failure offers excellent gastroesophageal reflux control. Am Surg 2014;80:696-703.
    Pubmed CrossRef
  107. Varela JE, Hinojosa MW, Nguyen NT. Laparoscopic fundoplication compared with laparoscopic gastric bypass in morbidly obese patients with gastroesophageal reflux disease. Surg Obes Relat Dis 2009;5:139-143.
    Pubmed CrossRef
  108. Ganz RA, Gostout CJ, Grudem J, Swanson W, Berg T, DeMeester TR. Use of a magnetic sphincter for the treatment of GERD: a feasibility study. Gastrointest Endosc 2008;67:287-294.
    Pubmed CrossRef
  109. Ganz RA, Peters JH, Horgan S, et al. Esophageal sphincter device for gastroesophageal reflux disease. N Engl J Med 2013;368:2039-2040.
    Pubmed CrossRef
  110. Bonavina L, Saino GI, Bona D, et al. Magnetic augmentation of the lower esophageal sphincter: results of a feasibility clinical trial. J Gastrointest Surg 2008;12:2133-2140.
    Pubmed CrossRef
  111. Bell R, Lipham J, Louie B, et al. Laparoscopic magnetic sphincter augmentation versus double-dose proton pump inhibitors for management of moderate-to-severe regurgitation in GERD: a randomized controlled trial. Gastrointest Endosc 2019;89:14-22, e2.
    Pubmed CrossRef
  112. Patel A, Gyawali CP. The role of magnetic sphincter augmentation in the gastroesophageal reflux disease treatment pathway: the gastroenterology perspective. Dis Esophagus 2023;36(supplment_1):doad005.
    Pubmed KoreaMed CrossRef
  113. Rogers BD, Valdovinos LR, Crowell MD, Bell R, Vela MF, Gyawali CP. Number of reflux episodes on pH-impedance monitoring associates with improved symptom outcome and treatment satisfaction in gastro-oesophageal reflux disease (GERD) patients with regurgitation. Gut 2021;70:450-455.
    Pubmed CrossRef
  114. Ganz RA, Edmundowicz SA, Taiganides PA, et al. Long-term outcomes of patients receiving a magnetic sphincter augmentation device for gastroesophageal reflux. Clin Gastroenterol Hepatol 2016;14:671-677.
    Pubmed CrossRef
  115. Huang X, Chen S, Zhao H, et al. Efficacy of transoral incisionless fundoplication (TIF) for the treatment of GERD: a systematic review with meta-analysis. Surg Endosc 2017;31:1032-1044.
    Pubmed CrossRef
  116. Haseeb M, Brown JRG, Hayat U, et al. Impact of second-generation transoral incisionless fundoplication on atypical GERD symptoms: a systematic review and meta-analysis. Gastrointest Endosc 2023;97:394-406, e2.
    Pubmed CrossRef
  117. Nabi Z, Reddy DN. Endoscopic management of gastroesophageal reflux disease: revisited. Clin Endosc 2016;49:408-416.
    Pubmed KoreaMed CrossRef
  118. Testoni PA, Testoni S, Distefano G, Mazzoleni G, Fanti L, Passaretti S. Transoral incisionless fundoplication with EsophyX for gastroesophageal reflux disease: clinical efficacy is maintained up to 10 years. Endosc Int Open 2019;7:E647-E654.
    Pubmed KoreaMed CrossRef
  119. Hunter JG, Kahrilas PJ, Bell RC, et al. Efficacy of transoral fundoplication vs omeprazole for treatment of regurgitation in a randomized controlled trial. Gastroenterology 2015;148:324-333, e5.
    Pubmed CrossRef
  120. Kalapala R, Singla N, Reddy DN. Endoscopic management of gastroesophageal reflux disease: panacea for proton pump inhibitors dependent/refractory patients. Dig Endosc 2022;34:687-699.
    Pubmed CrossRef
  121. Pandolfino JE, Krishnan K. Do endoscopic antireflux procedures fit in the current treatment paradigm of gastroesophageal reflux disease?. Clin Gastroenterol Hepatol 2014;12:544-554.
    Pubmed KoreaMed CrossRef
  122. Triadafilopoulos G. Stretta: a valuable endoscopic treatment modality for gastroesophageal reflux disease. World J Gastroenterol 2014;20:7730-7738.
    Pubmed KoreaMed CrossRef
  123. Arts J, Bisschops R, Blondeau K, et al. A double-blind sham-controlled study of the effect of radiofrequency energy on symptoms and distensibility of the gastro-esophageal junction in GERD. Am J Gastroenterol 2012;107:222-230.
    Pubmed CrossRef
  124. Arts J, Sifrim D, Rutgeerts P, Lerut A, Janssens J, Tack J. Influence of radiofrequency energy delivery at the gastroesophageal junction (the stretta procedure) on symptoms, acid exposure, and esophageal sensitivity to acid perfusion in gastroesophagal reflux disease. Dig Dis Sci 2007;52:2170-2177.
    Pubmed CrossRef
  125. Lipka S, Kumar A, Richter JE. No evidence for efficacy of radiofrequency ablation for treatment of gastroesophageal reflux disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2015;13:1058-1067, e1.
    Pubmed CrossRef
  126. Fass R, Cahn F, Scotti DJ, Gregory DA. Systematic review and meta-analysis of controlled and prospective cohort efficacy studies of endoscopic radiofrequency for treatment of gastroesophageal reflux disease. Surg Endosc 2017;31:4865-4882.
    Pubmed CrossRef
  127. Inoue H, Ito H, Ikeda H, et al. Anti-reflux mucosectomy for gastroesophageal reflux disease in the absence of hiatus hernia: a pilot study. Ann Gastroenterol 2014;27:346-351.
    Pubmed KoreaMed
  128. Wong HJ, Su B, Attaar M, et al. Anti-reflux mucosectomy (ARMS) results in improved recovery and similar reflux quality of life outcomes compared to laparoscopic Nissen fundoplication. Surg Endosc 2021;35:7174-7182.
    Pubmed CrossRef
  129. Yeh JH, Lee CT, Hsu MH, et al. Antireflux mucosal intervention (ARMI) procedures for refractory gastroesophageal reflux disease: a systematic review and meta-analysis. Ther Adv Gastroenterol 2022;15:17562848221094959.
    Pubmed KoreaMed CrossRef
  130. Deshmukh A, Parsa N, Elmeligui A, Nieto J. Antireflux band mucosectomy: a novel minimally invasive approach for the treatment of refractory gastroesophageal reflux disease. VideoGIE 2022;7:340-343.
    Pubmed KoreaMed CrossRef
  131. Ichkhanian Y, Hwang JH, Ofosu A, et al. Role of gastric per-oral endoscopic myotomy (G-POEM) in post-lung transplant patients: a multicenter experience. Endosc Int Open 2022;10:E832-E839.
    Pubmed KoreaMed CrossRef
  132. Halland M, Bharucha AE, Crowell MD, Ravi K, Katzka DA. Effects of diaphragmatic breathing on the pathophysiology and treatment of upright gastroesophageal reflux: a randomized controlled trial. Am J Gastroenterol 2021;116:86-94.
    Pubmed CrossRef
  133. Eherer AJ, Netolitzky F, Högenauer C, et al. Positive effect of abdominal breathing exercise on gastroesophageal reflux disease: a randomized, controlled study. Am J Gastroenterol 2012;107:372-378.
    Pubmed CrossRef
  134. Jones H, Cooper P, Miller V, Brooks N, Whorwell PJ. Treatment of non-cardiac chest pain: a controlled trial of hypnotherapy. Gut 2006;55:1403-1408.
    Pubmed KoreaMed CrossRef
  135. Jansson C, Nordenstedt H, Wallander MA, et al. Severe gastro-oesophageal reflux symptoms in relation to anxiety, depression and coping in a population-based study. Aliment Pharmacol Ther 2007;26:683-691.
    Pubmed CrossRef


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