INTRODUCTION
A lot has changed, much remains the same. Gastroesophageal reflux disease (GERD) continues to be among the most common diseases seen by gastroenterologists, surgeons, and primary care physicians. Since publication of the last American College of Gastroenterology guideline on reflux management (1
Summary and strength of the recommendations can be found in Table 1 with key concepts summarized in Table 2 .
Table 1.: Summary and strength of recommendations
Table 2.: Key concept statements
METHODS
The guideline is structured in the format of statements that are considered to be clinically important by the content authors for evaluation and treatment of GERD. The authors developed PICO questions and performed a literature search for each question with assistance from a research librarian. The Grading of Recommendations, Assessment, Development, and Evaluation process was used to assess the quality of evidence for each statement (3 4 5
Our goal is to showcase a document that offers best practice recommendations for clinicians caring for patients with GERD.
These guidelines are established to support clinical practice and suggest preferable approaches to a typical patient with a particular medical problem based on the currently available published literature. When exercising clinical judgment, particularly when treatments pose significant risks, health care providers should incorporate this guideline in addition to patient-specific medical comorbidities, health status, and preferences to arrive at a patient-centered care approach.
DIAGNOSIS OF GERD
The below recommendations for the diagnosis of GERD are also illustrated in Figure 1 .
Recommendations
1. For patients with classic GERD symptoms of heartburn and regurgitation who have no alarm symptoms, we recommend an 8-week trial of empiric PPIs once daily before a meal (strong recommendation, moderate level of evidence).
2. We recommend attempting to discontinue the PPIs in patients whose classic GERD symptoms respond to an 8-week empiric trial of PPIs (conditional recommendation, low level of evidence).
3. We recommend diagnostic endoscopy, ideally after PPIs are stopped for 2–4 weeks, in patients whose classic GERD symptoms do not respond adequately to an 8-week empiric trial of PPIs or whose symptoms return when PPIs are discontinued (strong recommendation, low level of evidence).
4. In patients who have chest pain without heartburn and who have had adequate evaluation to exclude heart disease, objective testing for GERD (endoscopy and/or reflux monitoring) is recommended (conditional recommendation, low level of evidence).
5. We do not recommend the use of a barium swallow solely as a diagnostic test for GERD (conditional recommendation, low level of evidence).
6. We recommend endoscopy as the first test for evaluation of patients presenting with dysphagia or other alarm symptoms (weight loss and GI bleeding) and for patients with multiple risk factors for Barrett's esophagus (strong recommendation, low level of evidence).
7. In patients for whom the diagnosis of GERD is suspected but not clear, and endoscopy shows no objective evidence of GERD, we recommend reflux monitoring be performed off therapy to establish the diagnosis (strong recommendation, low level of evidence).
8. We recommend against performing reflux monitoring off therapy solely as a diagnostic test for GERD in patients known to have endoscopic evidence of Los Angeles (LA) grade C or D reflux esophagitis or in patients with long-segment Barrett's esophagus (strong recommendation, low level of evidence).
Figure 1.: Diagnosis of GERD. EGD, esophagogastroduodenoscopy; GERD, gastroesophageal reflux disease; LA, Los Angeles; PPI, proton pump inhibitor; QOL, quality of life.
Key concept
1. We do not recommend high-resolution manometry (HRM) solely as a diagnostic test for GERD.
Defining GERD
A single unifying definition of GERD is difficult. In preparing this guideline, we have blended the multiple definitions in the literature to create the following: GERD is the condition in which the reflux of gastric contents into the esophagus results in symptoms and/or complications. GERD is objectively defined by the presence of characteristic mucosal injury seen at endoscopy and/or abnormal esophageal acid exposure demonstrated on a reflux monitoring study.
Pathophysiology of GERD
The pathophysiology of GERD includes a poorly functioning esophagogastric junction; the antireflux barrier composed of the LES and crural diaphragm, coupled with impaired esophageal clearance and alterations in esophageal mucosal integrity. Reflux esophagitis develops when refluxed gastric juice triggers the release of cytokines and chemokines that attract inflammatory cells and that also might contribute to symptoms. Other contributors to GERD symptoms may include decreased salivary production, delayed gastric emptying, and esophageal hypersensitivity. As such, GERD can no longer be approached as a single disease, but one with multiple phenotypic presentations and different diagnostic considerations.
Symptoms
Typical symptoms of GERD include heartburn and regurgitation. Heartburn is the most common GERD symptom and is described as substernal burning sensation rising from the epigastrium up toward the neck. Regurgitation is the effortless return of gastric contents upward toward the mouth, often accompanied by an acid or bitter taste. Although both heartburn and regurgitation are major symptoms of GERD, the genesis of these symptoms is not the same, and the diagnostic and management approaches vary depending on which symptom predominates. Chest pain, indistinguishable from cardiac pain, may present in conjunction with heartburn and regurgitation or as the only GERD symptom. The symptoms of GERD are nonspecific and may overlap or be confused with those of other disorders such as rumination, achalasia, eosinophilic esophagitis (EoE), reflux hypersensitivity, functional disease, cardiac or pulmonary disease, and paraesophageal hernia.
Extraesophageal manifestations of GERD can include laryngeal and pulmonary symptoms such as hoarseness, throat clearing, and chronic cough and conditions such as laryngitis, pharyngitis, and pulmonary fibrosis. It also has been proposed that GERD might exacerbate asthma. These extraesophageal manifestations are challenging for patients and physicians because, although they may result from GERD, they may also be due to a host of other causes. Even in patients with established GERD, it can be difficult to establish that GERD is the cause of these extraesophageal problems.
There is no gold standard for the diagnosis of GERD. Thus, the diagnosis is based on a combination of symptom presentation, endoscopic evaluation of esophageal mucosa, reflux monitoring, and response to therapeutic intervention. Heartburn and regurgitation remain the most sensitive and specific symptoms for GERD, although not as reliable as one might believe. A well-performed but older systematic review found a variable sensitivity of heartburn and regurgitation for erosive esophagitis (EE) (30%–76%), with the specificity ranging from 62 to 96% (6 7,8
Chest pain is commonly listed as a symptom of GERD. Similar to heartburn, a PPI trial has often been used for diagnosis of suspected GERD-related chest pain (9 10 11
Atypical extraesophageal symptoms and conditions such as chronic cough, dysphonia, asthma, sinusitis, laryngitis, and dental erosions have been associated with GERD. However, these symptoms and conditions have poor sensitivity and specificity for the diagnosis of GERD. Diagnoses of GERD by extraesophageal symptoms alone or by their response to PPIs are unreliable because of poor sensitivity and specificity for GERD and not recommended (see additional discussion in the "Extraesophageal GERD" section below).
Barium radiography
Barium radiographs should not be used solely as a diagnostic test for GERD. The presence of reflux on a barium esophagram or upper GI series has poor sensitivity and specificity for GERD when compared with pH testing. In a recent prospective study, only about one-half of patients with abnormal reflux on a barium study were found to have abnormal pH monitoring (12,13 14
Endoscopy
Upper endoscopy is the most widely used objective test for evaluating the esophageal mucosa. For patients with GERD symptoms who also have alarm symptoms such as dysphagia, weight loss, bleeding, vomiting, and/or anemia, endoscopy should be performed as soon as feasible. The endoscopic findings of EE and Barrett's esophagus are specific for the diagnosis of GERD. The LA classification of EE is the most widely used and validated scoring system (15 16,17
For patients having endoscopy for typical GERD symptoms, normal mucosa is the most common finding. There are limited data on the frequency of finding EE in patients undergoing endoscopy while taking PPIs, but, because PPIs are highly effective for healing EE, underlying EE clearly can be missed in this setting. Consequently, a diagnosis of nonerosive reflux disease (NERD) should only be made if endoscopy is performed off PPIs. To maximize the yield of GERD diagnosis and assess for EE, diagnostic endoscopy should ideally be performed after PPIs have been stopped for 2 weeks and perhaps as long as 4 weeks if possible. In a small prospective study assessing relapse of EE in patients with LA grade C EE that was healed with PPIs, discontinuation of PPI therapy led to return of EE in as little as 1 week (18 19 19
Esophageal manometry
HRM can be used to assess motility abnormalities associated with GERD, but HRM is not alone a diagnostic test for GERD. Weak lower esophageal sphincter (LES) pressure and ineffective esophageal motility often accompany severe GERD, but no manometric abnormality is specific for GERD. For esophageal impedance-pH monitoring, HRM is used to locate the LES for positioning of transnasal pH-impedance catheters. HRM also has a role in the evaluation of patients considering surgical or endoscopic antireflux procedures, primarily to evaluate for achalasia. Patients with achalasia can have heartburn and regurgitation that are mistaken for GERD symptoms, and antireflux procedures performed for such a mistaken diagnosis of GERD can result in devastating dysphagia. Thus, HRM should ideally be performed in all patients before any antireflux procedure. Although esophageal manometry has been proposed as a means to “tailor” antireflux operations, with Nissen (complete) fundoplication reserved for patients with normal peristalsis and partial fundoplication used for those with ineffective esophageal motility, studies on this issue have not supported the efficacy of this approach. Nevertheless, absent contractility is for most a contraindication to fundoplication. Newer developments in HRM include physiologic assessment of esophagogastric junction morphology and provocative testing with multiple rapid swallows or the rapid drink challenge. In patients undergoing surgical treatment of GERD, reduced contractile reserve documented by multiple rapid swallows on HRM is associated with postoperative dysphagia (20
Reflux monitoring
Ambulatory reflux monitoring (pH or impedance-pH) allows for assessment of esophageal acid exposure to establish or refute a diagnosis of GERD and for correlating symptoms with reflux episodes using the symptom index (SI) or symptom association probability (SAP). The main methods of reflux testing include a wireless telemetry capsule (Bravo Reflux Capsule; Medtronic, Minneapolis, MN) attached to the esophageal mucosa during endoscopy and transnasal catheter-based testing, and there are strengths and weaknesses to each approach. With transnasally positioned pH and pH/impedance catheters, the monitoring period generally is limited to 24 hours, while wireless pH telemetry capsule monitoring can last from 48 to 96 hours. In addition, the capsule avoids the physical discomfort and embarrassment of a transnasal catheter, and so, patients are more likely to carry on normal daily activities during capsule pH monitoring (21,22 23
The relationship between symptoms and reflux events can be assessed using the SI or SAP. To calculate SI, the total number of reflux episodes associated with symptom episodes is divided by the total number of symptom episodes during the entire monitoring period; an SI ≥ 50% is considered positive. To determine the SAP, the 24-hour monitoring period is divided into 720 two-minute increments, and each increment is evaluated for the occurrence of reflux and symptom episodes. A Fisher exact test is performed to determine a P value for the probability that reflux and symptom events are randomly distributed, and the SAP is determined by subtracting the calculated P value from 1 and multiplying the remainder by 100%; an SAP > 95% is considered positive. The validity of both of these indices has been questioned, and neither has been demonstrated superior to the other for clinical purposes. The sensitivity and specificity of reflux monitoring is high in patients with GERD with EE, although perhaps not as accurate in those with a normal endoscopy. Impedance monitoring that enables detection of weakly acidic and nonacidic reflux has been shown to be useful in identifying patients with reflux hypersensitivity who might respond to antireflux surgery (24
An issue that frequently arises is whether esophageal pH monitoring should be performed on or off PPI therapy. It is generally recommended to monitor after PPIs are stopped for 7 days if the diagnosis of GERD is not clear and before antireflux surgery or endoscopic therapy for GERD to document abnormal acid reflux (17 Figure 1 outlines an overall approach to the diagnosis of GERD.
Diagnosis of GERD in pregnancy
Approximately two-thirds of pregnant women experience heartburn, which can begin in any trimester (25 26 27 27
New developments
A recently approved device for evaluation of GERD uses a catheter-based balloon lined by sensors that measure mucosal impedance during endoscopy. This technique has shown promise for differentiating GERD from EoE and may develop to be a useful adjunct to endoscopy in the diagnosis of GERD (28
GERD MEDICAL MANAGEMENT
Recommendations
1. We recommend weight loss in overweight and obese patients for improvement of GERD symptoms (strong recommendation, moderate level of evidence).
2. We suggest avoiding meals within 2–3 hours of bedtime (conditional recommendation, low level of evidence).
3. We suggest avoidance of tobacco products/smoking in patients with GERD symptoms (conditional recommendation, low level of evidence).
4. We suggest avoidance of “trigger foods” for GERD symptom control (conditional recommendation, low level of evidence).
5. We suggest elevating head of bed for nighttime GERD symptoms (conditional recommendation, low level of evidence).
6. We recommend treatment with PPIs over treatment with histamine-2-receptor antagonists (H2RA) for healing EE (strong recommendation, high level of evidence).
7. We recommend treatment with PPIs over H2RA for maintenance of healing from EE (strong recommendation, moderate level of evidence).
8. We recommend PPI administration 30–60 minutes before a meal rather than at bedtime for GERD symptom control (strong recommendation, moderate level of evidence).
9. For patients with GERD who do not have EE or Barrett's esophagus, and whose symptoms have resolved with PPI therapy, an attempt should be made to discontinue PPIs or to switch to on-demand therapy in which PPIs are taken only when symptoms occur and discontinued when they are relieved (conditional recommendation, low level of evidence).
10. For patients with GERD who require maintenance therapy with PPIs, the PPIs should be administered in the lowest dose that effectively controls GERD symptoms and maintains healing of reflux esophagitis (conditional recommendation, low level of evidence).
11. We recommend against routine addition of medical therapies in PPI nonresponders (conditional recommendation, moderate level of evidence).
12. We recommend maintenance PPI therapy indefinitely or antireflux surgery for patients with LA grade C or D esophagitis (strong recommendation, moderate level of evidence).
13. We do not recommend baclofen in the absence of objective evidence of GERD (strong recommendation, moderate level of evidence).
14. We recommend against treatment with a prokinetic agent of any kind for GERD therapy unless there is objective evidence of gastroparesis (strong recommendation, low level of evidence).
15. We do not recommend sucralfate for GERD therapy except during pregnancy (strong recommendation, low level of evidence).
16. We suggest on-demand or intermittent PPI therapy for heartburn symptom control in patients with NERD (conditional recommendation, low level of evidence).
Key concepts
1. There is conceptual rationale for a trial of switching PPIs for patients who have not responded to one PPI. For patients who have not responded to one PPI, more than one switch to another PPI cannot be supported.
2. Use of the lowest effective PPI dose is recommended and logical but must be individualized. One area of controversy relates to abrupt PPI discontinuation and potential rebound acid hypersecretion, resulting in increased reflux symptoms. Although this has been demonstrated to occur in healthy controls, strong evidence for an increase in symptoms after abrupt PPI withdrawal is lacking.
Management of GERD requires a multifaceted approach, taking into account the symptom presentation, endoscopic findings, and likely physiological abnormalities. Management decisions may differ depending on hiatal hernia type and size, on the presence of EE and/or Barrett's esophagus, body mass index (BMI), and on accompanying physiologic abnormalities such as gastroparesis or ineffective motility with absence of contractile reserve. Medical management includes lifestyle modifications and pharmacologic therapy, principally with medications that reduce gastric acid secretion. Surgical and endoscopic options are discussed in other sections. Nonpharmacologic lifestyle modifications include recommendations for diet modification (content and timing), body positioning with meals and while sleeping, and weight management (Table 3 ).
Table 3.: Recommendations based on results of a review of studies involving lifestyle modifications
Diet and lifestyle changes
Common recommendations include weight loss for overweight patients, elevating the head of the bed, tobacco and alcohol cessation, avoidance of late night meals and bedtime snacks, staying upright during and after meals, and cessation of foods that potentially aggravate reflux symptoms such as coffee, chocolate, carbonated beverages, spicy foods, acidic foods such as citrus and tomatoes, and foods with high fat content (29 30,31 32–35
Several studies have evaluated the effects of various foods on LES pressure to try to determine which items might lead to GERD. In laboratory studies, coffee, caffeine, citrus, and spicy food had little to no effect on LES pressure (36,37 38 39
A recent article, using data collected from the prospective Nurses' Health Study, evaluated women without a known history of GERD for the impact of coffee, tea, soda, milk, water, and juice on reflux symptoms. Six servings of coffee, tea, and soda were associated with increased reflux symptoms compared with zero servings per day. By contrast, milk and juice were not associated with increased reflux symptoms, despite the acidic nature of some of these beverages (40
The timing of food intake can also affect GERD symptoms. A short interval (<3 hours) between eating and bedtime or lying supine is associated with increased GERD symptoms and need for medication (41 42 43 44 45 46
Medications
The backbone of pharmacologic therapy for GERD are medications that are directed at neutralization or reduction of gastric acid. Agents in this class include antacids, H2RA, and PPIs. Antacids are used exclusively for on-demand symptom relief with little evidence to favor 1 type over another. Studies with an alginic acid preparation manufactured in the United Kingdom suggest potential efficacy in symptom relief compared with other products, but alginate content of preparations sold in other countries is variable (47
Proton pump inhibitors
PPIs are the most commonly prescribed medication based on ample data demonstrating consistently superior heartburn and regurgitation relief, as well as improved healing compared with H2RAs. A meta-analysis (published when only 2 PPIs were available) provides important insight into PPI efficacy. PPIs showed a significantly faster healing rate (12%/week) vs H2RAs (6%/week), and faster, more complete heartburn relief (11.5%/week) vs H2RAs (6.4%/week) (48,49
Studies on GERD treatment typically last only 8–12 weeks, in part because symptom relief and healing seem to peak in that time frame. The healing rates of EE are not linear; thus, clinicians and patients need to understand that symptom relief and healing may not be rapid. PPIs are associated with a greater rate of “complete” symptom relief (usually assessed at 4 weeks) in patients with EE (∼70%–80%) compared with patients with so-called NERD in which symptom relief approximates 50%–60% (50
Meta-analyses suggest that overall GERD symptom relief and healing rates differ little among the 7 available PPIs, despite studies demonstrating differences in pH control. A meta-analysis examining efficacy of different PPIs for healing of EE included 10 studies (15,316 patients) (51 52,53
PPIs can bind only to proton pumps that are actively secreting acid. Because meals stimulate proton pump activity, enteric-coated PPIs control intragastric pH best when given before a meal (30–60 minutes before breakfast for once-daily dosing and 30–60 minutes before breakfast and dinner for twice-daily dosing (54,55 56
Dexlansoprazole, a dual delayed release PPI, in which first absorption is in the duodenum, then partially further down the small bowel, seems to have similar efficacy in pH control regardless of meal timing. An omeprazole-sodium bicarbonate combination that is not enteric-coated provides good control of intragastric pH in the first 4 hours of sleep when dosed at bedtime (57 58 59
Maintenance PPI therapy should be administered for patients with GERD complications including severe EE (LA grade C or D) and Barrett's esophagus (60 61,62 63 18
In some cases, patients with NERD and otherwise noncomplicated GERD can be managed successfully with on-demand or intermittent PPI therapy. In 1 RCT, 83% of patients with NERD randomized to 20 mg of omeprazole on demand were in remission at 6 months compared with 56% of patient on placebo (64 65,66
Use of the lowest effective dose is recommended and logical but must be individualized. One area of controversy relates to abrupt PPI discontinuation and potential rebound acid hypersecretion, resulting in increased reflux symptoms. Although rebound acid hypersecretion has been demonstrated to occur in healthy controls, strong evidence for an increase in symptoms after abrupt PPI withdrawal is lacking (67–69
H2RA taken at bedtime
Medical options for patients with GERD with incomplete symptom response on PPI therapy are limited. The addition of bedtime H2RA has been suggested for patients on PPIs with persistent nocturnal symptoms. This approach gained popularity after several studies demonstrated improved overnight intragastric pH control with the addition of an H2RA (70 71
Prokinetics
There are limited data on the use of prokinetic agents for patients with GERD. Metoclopramide has been shown to increase LES pressure, enhance esophageal peristalsis, and augment gastric emptying. However, data on its efficacy in GERD are scant, and significant adverse events have been reported with long-term and high-dose metoclopramide use, including central nervous system side effects such as drowsiness, agitation, irritability, depression, dystonic reactions, and tardive dyskinesia (72,73 74
Baclofen
Baclofen, a GABAB agonist, reduces the transient LES relaxations that enable reflux episodes. Baclofen decreases the number of postprandial acid and nonacid reflux events, nocturnal reflux activity, and belching episodes (75–77 75–77 24
Sucralfate
Sucralfate is a mucosal protective agent, but few data document its efficacy in GERD. Limited studies have suggested similar efficacy to H2RAs, but there are no comparative data to PPIs nor any combination studies with these agents. Sucralfate is largely unabsorbed and has no systemic toxicity. There is little to recommend for this agent in GERD outside of pregnancy.
Treatment of GERD during pregnancy
A small RCT found that sucralfate was superior to dietary and lifestyle modifications for relieving heartburn and regurgitation in pregnant women (78
EXTRAESOPHAGEAL GERD SYMPTOMS
The below recommendations for the diagnosis for extraesophageal GERD are also illustrated in Figure 2 .
Recommendations
1. We recommend evaluation for non-GERD causes in patients with possible extraesophageal manifestations before ascribing symptoms to GERD (strong recommendation, moderate level of evidence).
2. We recommend that patients who have extraesophageal manifestations of GERD without typical GERD symptoms (e.g., heartburn and regurgitation) undergo reflux testing for evaluation before PPI therapy (strong recommendation, moderate level of evidence).
3. For patients who have both extraesophageal and typical GERD symptoms, we suggest considering a trial of twice-daily PPI therapy for 8–12 weeks before additional testing (conditional recommendation, low level of evidence).
4. We suggest that upper endoscopy should not be used as the method to establish a diagnosis of GERD-related asthma, chronic cough, or laryngopharyngeal reflux (LPR) (conditional recommendation, low level of evidence).
5. We suggest against a diagnosis of LPR based on laryngoscopy findings alone and recommend additional testing should be considered (conditional recommendation, low level of evidence).
6. In patients treated for extraesophageal reflux disease, surgical or endoscopic antireflux procedures are only recommended in patients with objective evidence of reflux (conditional recommendation, low level of evidence).
Figure 2.: Diagnostic algorithm for extraesophageal GERD symptoms. BID, twice-daily; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor.
Key concepts
1. Although GERD may be a contributor to extraesophageal symptoms in some patients, careful evaluation for other causes should be considered for patients with laryngeal symptoms, chronic cough, and asthma.
2. Diagnosis, evaluation, and management of potential extraesophageal symptoms of GERD is limited by lack of a gold-standard test, variable symptoms, and other disorders which may cause similar symptoms.
3. Because of difficulty in distinguishing between patient with laryngeal symptoms and normal controls, salivary pepsin testing is not recommended for evaluation of patients with extraesophageal reflux symptoms.
4. For patients whose extraesophageal symptoms have not responded to a trial of twice-daily PPIs, we recommend upper endoscopy, ideally off PPIs for 2–4 weeks. If endoscopy is normal, consider reflux monitoring. Demonstration of EE by endoscopy establishes a diagnosis of GERD, but does not confirm that GERD is the cause of the extraesophageal symptoms. Confirmation may require pH/impedance testing.
5. For patients with extraesophageal symptoms, we do not routinely recommend oropharyngeal or pharyngeal pH monitoring.
Numerous extraesophageal symptoms and conditions have been attributed to GERD, including chronic cough, throat-clearing, hoarseness, globus, asthma, and laryngitis. These are vexing for patients as well as physicians because the symptoms ascribed to extraesophageal GERD are often nonspecific and overlap with other disorders. Evaluation by otorhinolaryngology, allergy, and pulmonary specialists should be considered in these patients, depending on the constellation of symptoms. Currently available diagnostic tools to establish GERD as the cause of extraesophageal symptoms have substantial limitations. PPI treatment is relied on as both a diagnostic tool and treatment for extraesophageal GERD symptoms, but is often ineffective, and prolonged treatment trials with PPIs may delay diagnosis and care for patients with nonreflux laryngeal and pulmonary disorders.
Symptoms
The association between GERD and extraesophageal symptoms has been examined in multiple studies. In a case-control study of veterans, patients with esophagitis or esophageal strictures were more likely to have a diagnosis of laryngitis (odds ratio [OR] 2.01), aphonia (OR 1.81), asthma (OR 1.51), and pharyngitis (OR 1.48) compared with control patients (79 80 81
However, because of the wide variety of causes of chronic cough, the American College of Chest Physicians guideline for evaluation of chronic cough suggests looking for other sources before attributing chronic cough to GERD (82
GERD may also have a role in asthma, with 1 systematic review of 28 studies identifying GERD symptoms in 59% of patients with asthma and abnormal pH testing in 51% (83 84,85
Endoscopy
Endoscopy is frequently used for assessing classic symptoms of GERD, such as heartburn and regurgitation, but its role in assessment of extraesophageal GERD symptoms is less clear. In patients with extraesophageal GERD symptoms, the reported frequency of EE ranges from 18% to 52% (86,87 88
Laryngoscopy
Laryngoscopy performed by an otorhinolaryngologist (ENT) is commonly used to assess for signs of extraesophageal GERD, in particular, LPR. Findings on laryngoscopy that are associated with reflux include posterior commissure hypertrophy, laryngeal and arytenoid inflammation, vocal cord edema, and endolaryngeal mucus. Several scoring systems have been developed for grading the laryngoscopic findings, the most common of which is the reflux finding score (RFS) (89 90 91 92 93 94 95
Reflux testing
Multichannel pH-impedance testing, traditional catheter-based pH testing, and wireless pH testing have been used to evaluate patients with extraesophageal GERD symptoms. Reflux testing using pH-impedance can detect acidic (pH < 4), weakly acidic (pH 4–7), and nonacidic reflux (pH > 7), and determine the extent of proximal reflux, which may be important in the evaluation of extraesophageal GERD symptoms. pH-impedance testing in patients with LPR symptoms is abnormal in 40% of cases (96 97,98 99,100 101
Presently, the clinical significance of proximal reflux is unclear, and studies have varied in their criteria for defining this entity (102 103 104 105
The choice to test on or off PPIs in patients with extraesophageal symptoms has no clear answer. Testing off PPIs can be used to determine whether pathologic esophageal acid exposure is present and should be considered when the pretest probability for GERD is low. Testing on PPIs can be considered in patients already known to have pathologic acid exposure, such as those with Barrett's esophagus or with LA grade C or D EE (106 107 108,109 108
Wireless pH testing also has been used for evaluation of patients with extraesophageal symptoms. In 1 series of patients with extraesophageal GERD symptoms who had wireless pH testing, 81% had abnormal acid exposure, typically mild to moderate reflux, and more often in the upright position (110
Pharyngeal and oropharyngeal reflux monitoring
Catheter-based pharyngeal pH monitoring with dual sensor probes and oropharyngeal pH monitoring have been proposed as methods to better detect LPR compared with traditional pH monitoring and pH-impedance. However, the reliability of pharyngeal pH measurement has been questioned, and proximal sensor data may be unreliable because of placement issues (111–114 115–118 119
Early studies of oropharyngeal pH testing were promising and seemed to predict success of antireflux surgery (120,121 122–126 127 128
Salivary pepsin testing
Salivary pepsin testing has been proposed as a noninvasive method of detecting LPR. A recent meta-analysis of 11 observational studies examined the role of salivary pepsin testing in diagnosing LPR (129 130 131 132 130 131 133
PPIs and extraesophageal symptoms
A clinical response to PPI therapy has been proposed as a method to both diagnose and treat extraesophageal GERD (134–136 137,138 139,140 139 140 139,141
Although PPI treatment is often the first step in the management of LPR, this approach may need to be reconsidered. One study comparing up-front reflux testing for LPR patients rather than starting them on empiric PPI therapy found that overall evaluation and treatment costs were lower with initial pH-impedance and esophageal manometry testing (142 142
Recent studies have questioned the role of PPI therapy for patients with asthma. Two RCTs, 1 in adults and 1 in children, showed no benefit in controlling asthma symptoms in patients on twice-daily PPIs (84,85 143 144 82,145–147
Surgery
Antireflux surgery has been used to treat patients with extraesophageal GERD symptoms, but outcomes are inferior to those of antireflux surgery for patients with traditional GERD symptoms. Two systematic reviews (involving primarily studies that were small, retrospective, and uncontrolled) have examined the relationship among extraesophageal GERD symptoms, esophageal acid exposure, and surgical outcomes (148,149
In 1 study, patients for whom PPIs provided only incomplete relief of laryngeal symptoms despite normalizing esophageal acid exposure were offered antireflux surgery. At 1 year, only 10% of patients who underwent surgery and 7% of patients who continued medical therapy for GERD had improvement in laryngeal symptoms. However, two-thirds of patients who pursued nonsurgical, non-GERD treatments for laryngeal symptoms had improved symptoms at 1 year (150 151 151–153
Predicting which patients with extraesophageal symptoms will improve with antireflux surgery is challenging. In 1 study of patients with extraesophageal symptoms, predictors of symptomatic improvement after surgery included the presence of heartburn with or without regurgitation and abnormal acid exposure time on pH testing (104 154
REFRACTORY GERD
The below recommendations for the management of refractory GERD are also illustrated in Figure 3A and 3B.
Recommendations
1. We recommend optimization of PPI therapy as the first step in management of refractory GERD (strong recommendation, moderate level of evidence).
2. We suggest esophageal pH monitoring (Bravo, catheter-based, or combined impedance-pH monitoring) performed OFF PPIs if the diagnosis of GERD has not been established by a previous pH monitoring study or an endoscopy showing long-segment Barrett's esophagus or severe reflux esophagitis (LA grade C or D) (conditional recommendation, low level of evidence).
3. We suggest esophageal impedance-pH monitoring performed ON PPIs for patients with an established diagnosis of GERD whose symptoms have not responded adequately to twice-daily PPI therapy (conditional recommendation, low level of evidence).
4. For patients who have regurgitation as their primary PPI-refractory symptom and who have had abnormal gastroesophageal reflux documented by objective testing, we suggest consideration of antireflux surgery or TIF (conditional recommendation, low level of evidence).
Figure 3.: (a ) Management algorithm of symptoms suspected because of GERD incompletely responsive to PPIs, previously empirically treated with PPI without objective workup. GERD, gastroesophageal reflux disease; EGD, esophagogastroduodenoscopy; LA, Los Angeles; PPI, proton pump inhibitor. (b ) Management algorithm of symptoms suspected because of GERD incompletely responsive to PPIs in patients previously objectively defined as GERD. *LA B/C/D GERD, gastroesophageal reflux disease; EGD, esophagogastroduodenoscopy; LA, Los Angeles; MSA, magnetic sphincter augmentation; PPI, proton pump inhibitor; TIF, transoral incisionless fundoplication.
Key concepts
1. It is important to stop PPI therapy in patients whose off-therapy reflux testing is negative, unless another indication for continuing PPIs is present.
2. Esophageal manometry should be considered as part of the evaluation for refractory GERD in patients with a normal endoscopy and pH monitoring study and for patients being considered for surgical or endoscopic treatment.
3. If not already performed off PPIs, we recommend diagnostic upper endoscopy after discontinuing PPI therapy, ideally for 2 to 4 weeks. Esophageal biopsies should be performed even if endoscopy reveals normal mucosa.
4. We recommend performing high-resolution esophageal manometry in patients with refractory GERD if reflux monitoring and endoscopy are unrevealing.
It has been suggested that up to 40% of patients treated with PPIs will report persistent symptoms of heartburn and regurgitation, with negative effects on quality of life (155–157 156 158 159 160
Similarly, the terms “complete relief/response,” “partial relief/response,” and “no response” have been arbitrarily and poorly defined, and duration of symptoms and PPI dosing vary across studies (156,161 Table 4 lists 4 potential mechanisms of refractory GERD.
Table 4.: Potential mechanisms underlying symptoms suspected due to GERD but refractory to PPI therapy
There are 2 broad groups of patients with symptoms despite PPI therapy. One group is patients with symptoms suspected to be GERD-related who have been empirically treated with a PPI (typically once-daily then increased to twice-daily) yet remain symptomatic. The second group of patients has objective evidence of GERD, with endoscopic findings of EE or Barrett's esophagus and/or reflux testing showing abnormal esophageal acid exposure, who have incomplete or no response to PPIs. When discussing the overall approach to patients with GERD symptoms not relieved by PPIs, it is prudent to discuss management of these 2 groups separately.
History and physical examination
The evaluation of refractory GERD should begin with a careful history and physical examination. This will enable the clinician to make a meaningful assessment of the likelihood that GERD is causing the bothersome symptoms and may provide clues to the presence of nonesophageal disorders. If no obvious nonesophageal disorders are present, then optimization of PPI therapy is recommended. This is critical for managing patients with persistent GERD symptoms, regardless of whether the patient has been empirically treated or carries an objective diagnosis of GERD.
Optimization of PPI therapy
Optimization of PPI therapy includes verifying compliance, confirming that the PPI is taken 30–60 minutes before the first meal of the day for daily dosing and before the first and dinner meal for twice-daily dosing (162 53 163 81 24 164 ad lib dosing and found improvement in symptoms and GERD quality-of-life scores in those receiving education on proper dosing of daily PPIs (165 59,166
Endoscopy
Endoscopy is the next step to investigate persistent GERD symptoms and evaluate alternative diagnoses. Performing endoscopy after a PPI holiday might increase the yield for identifying EE or determine whether an alternative diagnosis, such as EoE, is responsible for symptoms. A recent study found that EE can relapse within 2 weeks after stopping PPIs, with some patients even developing LA grade C EE (63 24,167–170 17,171
Reflux monitoring
Regardless of symptom presentation, it is imperative to document the presence of abnormal or ongoing reflux to plan treatment options for patients with persistent GERD symptoms. Reflux monitoring can identify patients with ongoing acid reflux, weakly acidic, nonacidic reflux, adequate acid control but ongoing symptoms, and normal reflux parameters. Depending on the clinical situation, performing monitoring off PPIs for 7 days or testing for acid, weakly acidic, and nonacid reflux while on PPIs can be considered.
The choice of test and whether to test on or off PPIs is dependent on the question being asked. If the patient has been empirically treated (never had an objective diagnosis of GERD), or the clinician believes the likelihood that reflux is the cause of symptoms is low, or for patients considering surgery, an off-therapy study should be considered (17,159 172
On-therapy monitoring is suggested before surgery or endoscopic intervention in patients with previous objective findings of GERD (such as Barrett's esophagus or LA grade C/D EE) who have continued symptoms despite PPI treatment (17 108 173
Several studies have attempted to address the question of testing on or off PPIs in patients with persistent GERD. The total number of reflux episodes detected by impedance is similar between testing on and off PPIs (108,174,175
Reflux testing combined with other testing, such as esophageal manometry, gastric emptying studies, and endoscopy, identified a diagnosis of GERD in only 34.5% of cases in 1 study (176 24 24 24 160 2
Esophageal manometry
Some patients with motility disorders such as achalasia or esophageal spasm will report heartburn symptoms. In studies of patients with refractory GERD, 1%–3% of patients are found to have achalasia when manometry is performed (24,177 177
Surgery
Recent publications have changed the thought process on surgical intervention for some patients with refractory GERD. Randomized trials compared MSA with continued medical therapy in patients with regurgitation refractory to PPIs. MSA improved symptoms more than continued medical therapy in patients with objective documentation of abnormal reflux (178,179 180 24
Identifying patients with true refractory GERD is crucial because surgery (or endoscopic treatment) may truly be best in this group. For patients with regurgitation refractory to PPI therapy, care should be taken to distinguish regurgitation from rumination, a functional disorder characterized by effortless food regurgitation during or soon after eating, typically with rechewing, reswallowing, or spitting out of the regurgitated material. Surgical treatment is not recommended for patients with rumination (181
SURGICAL AND ENDOSCOPIC OPTIONS FOR GERD
Recommendations
1. We recommend antireflux surgery performed by an experienced surgeon as an option for long-term treatment of patients with objective evidence of GERD, especially those who have severe reflux esophagitis (LA grade C or D), large hiatal hernias, and/or persistent, troublesome GERD symptoms (strong recommendation, moderate level of evidence).
2. We recommend consideration of MSA as an alternative to laparoscopic fundoplication for patients with regurgitation who fail medical management (strong recommendation, moderate level of evidence).
3. We suggest consideration of Roux-en-Y gastric bypass (RYGB) as an option to treat GERD in obese patients who are candidates for this procedure and who are willing to accept its risks and requirements for lifestyle alterations (conditional recommendation, low level of evidence).
4. Because data on the efficacy of radiofrequency energy (Stretta) as an antireflux procedure is inconsistent and highly variable, we cannot recommend its use as an alternative to medical or surgical antireflux therapies (conditional recommendation, low level of evidence).
5. We suggest consideration of TIF for patients with troublesome regurgitation or heartburn who do not wish to undergo antireflux surgery and who do not have severe reflux esophagitis (LA grade C or D) or hiatal hernias >2 cm (conditional recommendation, low level of evidence).
Key concepts
1. We recommend HRM before antireflux surgery or endoscopic therapy to rule out achalasia and absent contractility. For patients with ineffective esophageal motility, HRM should include provocative testing to identify contractile reserve (e.g., multiple rapid swallows).
2. Before performing invasive therapy for GERD, a careful evaluation is required to ensure that GERD is present and as best as possible determine is the cause of the symptoms to be addressed by the therapy, to exclude achalasia (which can be associated with symptoms such as heartburn and regurgitation that can be confused with GERD), and to exclude conditions that might be contraindications to invasive treatment such as absent contractility.
In most patients, the symptoms and endoscopic signs of GERD resolve readily with medical treatment, and invasive antireflux therapies are neither required nor desired by patients. However, GERD is a chronic disease, and patients often require protracted medical treatment, which is inconvenient and carries some risk. Severe reflux esophagitis (LA grade C and D) does not heal reliably with any medical therapy other than PPIs, and studies have demonstrated that severe EE returns quickly in most patients when PPIs are stopped (18,182,183
GERD that fails to respond to medical therapy is another valid indication for antireflux procedures, but one that requires meticulous preprocedure evaluation to achieve good surgical outcomes. Before the advent of PPIs, failure to respond to medical therapy was the major indication for antireflux surgery. Today, however, PPI therapy is so effective for treating typical GERD symptoms such as heartburn and regurgitation that failure to respond to PPIs should be regarded as a red flag that GERD may not be the underlying cause. Indeed, patients who have the best response to antireflux surgery are those with typical GERD symptoms who respond well to PPIs (184,185 186,187
In a recent study of medical vs surgical treatment for PPI-refractory heartburn that included 366 patients referred to GI clinics because of heartburn that failed to respond to PPIs, extensive workup revealed that the heartburn was truly PPI-refractory and reflux-related in only 78 patients (21%) (24 P = 0.007) and placebo medical (3/26, 11.5%, P < 0.001) treatments.
Although heartburn is the cardinal symptom of GERD, the aforementioned study shows that PPI-refractory heartburn is uncommonly due to GERD. As discussed above establishing a clear causal relationship with GERD can be even more difficult for so-called “extraesophageal GERD symptoms” such as throat clearing, hoarseness, and chronic cough. Surgical treatment of extraesophageal GERD is reviewed in detail in the “extraesophageal GERD section.” Few high-quality data have established the benefit of invasive treatments for patients with these extraesophageal GERD symptoms, and physicians should be extra cautious in recommending such treatments for patients with LPR and other “extraesophageal GERD symptoms.” Only persistent abnormal acid reflux and reflux hypersensitivity are likely to benefit from antireflux procedures.
Fundoplication
Fundoplication, especially Nissen fundoplication, is widely regarded as the “gold standard” among the antireflux procedures for its efficacy in improving the physiologic parameters of GERD such as LES pressure and esophageal acid exposure time (188
Interest in surgical antireflux therapy intensified in the 1980s when observational studies described >90% efficacy for fundoplication in controlling GERD symptoms over a 10-year period (189 190 191
Laparoscopic antireflux surgery (LARS) was introduced in 1991, and this has since become the standard operative approach to fundoplication, essentially replacing open antireflux surgery. Studies focusing on the durability of modern surgical technique have found a wide range of GERD recurrence rates. Cohort studies often found high rates of postoperative antireflux medication usage (up to 43%) (192–196 197–199
A recent systematic review and meta-analysis focusing on patient-relevant outcomes of fundoplication vs PPI-based medical management of GERD found that heartburn and regurgitation were less frequent with surgical than with medical therapy and, although a considerable proportion of patients still needed antireflux medications after fundoplication, surgical patients were significantly more satisfied with their treatment in the short and medium term (200 201 202–205 205
A recent report of a retrospective, population-based cohort study has shed considerable light on the outcome of LARS performed in a “real-world” setting (206
In summary, modern medical antireflux therapy and laparoscopic fundoplication seem to have similar efficacy in healing the symptoms and endoscopic signs of GERD. Recent concerns about the safety of long-term PPI therapy and refinements in surgical technique that have substantially decreased its morbidity and mortality have rekindled interest in fundoplication. Clearly, antireflux surgery is not a permanent cure for GERD in all patients as it was once touted to be, and the operation occasionally can have severe adverse effects. Nevertheless, most patients obtain long-term benefit from fundoplication, and patient satisfaction with successful surgery seems to be greater than that for chronic medical therapy. The major question for patients considering antireflux surgery is this: Does the >80% possibility of long-term freedom from PPIs and their attendant risks warrant the 4% risk of acute complications of fundoplication and its 17.7% risk of GERD recurrence? (207
Magnetic sphincter augmentation
MSA with the LINX Reflux Management System, a necklace of titanium beads with magnetic cores that encircles the distal esophagus to bolster the LES and prevent reflux, was developed as a less invasive and more readily reversible GERD treatment than fundoplication. The initial target population for MSA was patients with GERD with abnormal acid reflux documented by esophageal pH monitoring (off PPIs) who experienced only partial relief with PPIs and who did not have large hiatal hernias or severe reflux esophagitis (208 208 209
Although large hiatal hernias and severe reflux esophagitis were contraindications to MSA in early studies of the technique, subsequent studies have found that the short-term clinical outcomes of MSA for patients with those conditions are similar to those described for patients with less severe forms of GERD (210–212
One problem with implantation of the metallic MSA device is that patients cannot have magnetic resonance imaging with scanning systems >1.5 T. An early concern regarding MSA was that the device would erode into the esophagus. A recent study of data provided by the manufacturer (Ethicon, Summit, NJ) and the MAUDE database on 9,453 devices placed between 2007 and 2017 found that the risk of erosion was 0.3% at 4 years (213
To date, there has been no publication of a randomized trial directly comparing MSA with the gold-standard surgical treatment of laparoscopic fundoplication. However, observational cohort studies have compared the techniques, and systematic reviews and meta-analyses of those reports have arrived at generally similar conclusions (214–217
A recent randomized trial has established the unequivocal superiority of MSA over twice-daily PPIs for the control of regurgitation (179
MSA also seems to have a role in the treatment of GERD that worsens or develops after bariatric operations such as sleeve gastrectomy and RYGB (218
In summary, MSA seems to be a safe and effective alternative to laparoscopic fundoplication. Clinical outcomes of the 2 procedures are similar, and both have unique advantages and disadvantages. The minimal surgical dissection required for MSA results in greater technical ease, shorter operative times, and shorter durations of hospital stays than for fundoplication. MSA is also easier to reverse, and MSA may result in less gas-bloat and greater ability to belch and vomit than fundoplication. The magnetic resonance imaging restriction after MSA is a disadvantage, and compared with fundoplication, there is a paucity of long-term data on MSA outcomes. With no randomized trials comparing the 2 procedures, it is difficult to recommend one over the other at this time.
Roux-en-Y gastric bypass
GERD is strongly associated with obesity. Compared with individuals with a normal BMI, the prevalence of GERD in those whose BMI exceeds 35 is increased up to 6-fold (219 220,221
One reason for the controversy is the substantial variability in results of studies on outcomes and rates of complications for fundoplication in obese patients. Some studies have documented poorer results of fundoplication in the obese (222 223 P = 0.001) (224 225 226 218
With all the above-noted uncertainty, an argument can be made to regard RYGB primarily as a highly effective weight loss operation that has the added potential benefit of controlling acid reflux, rather than as an antireflux operation primarily. Obese patients with GERD should be adequately counseled and willing to accept the risks and lifestyle demands of bariatric surgery before undergoing RYGB for control of GERD.
Endoscopic antireflux therapies
A number of endoscopic devices for treating GERD have been introduced over the past 2 decades, and most have been withdrawn from the marketplace because of concerns regarding safety and efficacy. Presently, the only endoscopic GERD treatments still widely available are radiofrequency antireflux treatment (Stretta; Restech, Houston, TX) and TIF (endogastric solutions). Studies of the endoscopic procedures generally have excluded patients with hiatal hernias >2 cm, grade C and D EE, esophageal strictures, and long-segment Barrett's esophagus. Consequently, if these devices are to be used at all, based on data, their use should be limited to patients with milder forms of GERD.
The Stretta procedure is difficult to evaluate, in part because it is not totally clear how it functions as an antireflux therapy. Initially, it was believed to control reflux by inducing swelling and mechanical alteration at the esophagogastric junction. However, an early, sham-controlled trial found that, 6 months after treatment, Stretta had significantly improved GERD symptoms and quality of life, but it did not decrease esophageal acid exposure (227 228 229 230
TIF attempts to create a flap valve involving 180° to 270° of the circumference of the esophagogastric junction by plicating a portion of the proximal stomach using a series of T-fasteners. Randomized trials have shown that TIF is effective for treating troublesome regurgitation (180,231 217 232 233
LONG-TERM PPI ISSUES
Key concepts
1. Regarding the safety of long-term PPI usage for GERD, we suggest that patients should be advised as follows: “PPIs are the most effective medical treatment for GERD. Some medical studies have identified an association between the long-term use of PPIs and the development of numerous adverse conditions including intestinal infections, pneumonia, stomach cancer, osteoporosis-related bone fractures, chronic kidney disease, deficiencies of certain vitamins and minerals, heart attacks, strokes, dementia, and early death. Those studies have flaws, are not considered definitive, and do not establish a cause-and-effect relationship between PPIs and the adverse conditions. High-quality studies have found that PPIs do not significantly increase the risk of any of these conditions except intestinal infections. Nevertheless, we cannot exclude the possibility that PPIs might confer a small increase in the risk of developing these adverse conditions. For the treatment of GERD, gastroenterologists generally agree that the well-established benefits of PPIs far outweigh their theoretical risks.”
2. Switching PPIs can be considered for patients who experience minor PPI side effects including headache, abdominal pain, nausea, vomiting, diarrhea, constipation, and flatulence.
3. For patients with GERD on PPIs who have no other risk factors for bone disease, we do not recommend that they raise their intake of calcium or vitamin D or that they have routine monitoring of bone mineral density.
4. For patients with GERD on PPIs who have no other risk factors for vitamin B12 deficiency, we do not recommend that they raise their intake of vitamin B12 or that they have routine monitoring of serum B12 levels.
5. For patients with GERD on PPIs who have no other risk factors for kidney disease, we do not recommend that they have routine monitoring of serum creatinine levels.
6. For patients with GERD on clopidogrel who have LA grade C or D esophagitis or whose GERD symptoms are not adequately controlled with alternative medical therapies, the highest quality data available suggest that the established benefits of PPI treatment outweigh their proposed but highly questionable cardiovascular risks.
7. PPIs can be used to treat GERD in patients with renal insufficiency with close monitoring of renal function or consultation with a nephrologist.
PPIs are widely considered the mainstay of medical treatment for GERD. Side effects of PPIs that have been identified in clinical trials and listed on FDA labels as the “most common adverse reactions” include headache, abdominal pain, nausea, vomiting, diarrhea, constipation, and flatulence. These relatively minor side effects occur infrequently and abate when the medications are stopped. Limited data also suggest that these side effects sometimes can be PPI preparation-specific and, for patients who experience them, a trial of switching from 1 PPI to another is a reasonable management strategy (234 235,236
Table 5 lists the major putative adverse effects of chronic PPI therapy and the proposed underlying mechanisms. Some of these effects are assumed to be a consequence of PPI-induced suppression of gastric acid secretion. For example, gastric acid suppression can enable ingested pathogens that ordinarily would have been destroyed by gastric acid to survive and cause enteric infections or to be aspirated and cause pneumonia (236 236
Table 5.: Major putative adverse effects of chronic PPI therapy
Mechanisms other than gastric acid inhibition have been proposed to underlie a number of other adverse effects that have been associated with PPI usage such as kidney disease and cardiovascular events (Table 5 ).
One area of considerable persistent controversy relates to the association between chronic PPI use and hypomagnesemia. Two meta-analyses on this issue concluded that long-term PPI use is significantly associated with hypomagnesemia (310,314 311,312 315 http://www.fda.gov/Drugs/DrugSafety/ucm245011.htm
It is important to appreciate that the mere identification of an association between PPIs and adverse conditions in observational studies cannot establish a cause-and-effect relationship and that such studies are highly susceptible to biases that can prejudice results. Observational studies on potential PPI side effects are especially susceptible to the biases of confounding by indication (in which the medical indication for a PPI, not the PPI itself, is responsible for the adverse effect) and protopathic bias (in which the PPI does not cause an adverse condition, but is prescribed to treat symptoms of that already-present yet unrecognized condition) (316,317
The epidemiologist/statistician Sir Austin Bradford Hill, in his Presidential Address to the Section of Occupational Medicine of the Royal Society of Medicine in 1965, proposed 9 criteria that can strengthen the case for a cause-and-effect relationship in associations between exposures and diseases identified through observational studies (318 319
It has been noted that most reported associations in observational clinical research are spurious, and the minority that are real are often exaggerated (320 320 261 321 322
A recent, large, placebo-controlled randomized trial reported by Moayyedi et al. (323 Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, dementia, cardiovascular disease, cancer, and all-cause mortality. The investigators found no significant differences between the PPI and placebo groups in rates of occurrence for any of those potential side effects except for enteric infections (1.4% vs 1.0% in the PPI and placebo groups, respectively; OR 1.33; 95% CI, 1.01–1.75). Table 5 lists the hazard ratios (HRs) and ORs for all the putative adverse events evaluated in this study. The authors concluded that the use of pantoprazole for 3 years was not associated with any adverse event other than a modestly increased risk of developing enteric infections.
Moayyedi's report provides high-quality evidence to suggest that most of the associations between PPI usage and adverse events that have been identified in observational studies were the result of residual confounding and other biases and unlikely to represent cause-and-effect relationships. Reassuring as this study is, it is important to consider several caveats. First, the trial had a maximum follow-up of 5 years, which might not be sufficient time for some adverse events to develop (e.g., gastric cancer) (324 C. difficile –associated diarrhea) occurred so infrequently that conclusions regarding possible PPI involvement are limited. Finally, and perhaps most important, the 95% CIs around some of the HRs and ORs observed in this prospective trial, large as it is, still are relatively wide. It is reassuring that the HRs and ORs for some events (pneumonia, fracture, cardiovascular disease, dementia, and all-cause mortality) are even lower than the lower limits of the 95% CIs reported in earlier observational studies. Nevertheless, this study cannot exclude the possibility that PPIs confer a modest risk of any of these adverse events (i.e., the upper limit of the 95% CIs all are >1), and even a modest risk of such serious events is cause for concern. As the authors themselves acknowledge, the possibility that PPIs confer a modest risk of these putative adverse events can never be excluded no matter how large the study sample size (323
SUMMARY
We have made every effort to review and grade all available evidence to develop this guideline. Much is new and different compared with the 2013 guideline, particularly because it relates to approaching extraesophageal symptoms, refractory GERD, and surgical and endoscopic therapies. Each section provides a separate review of the evidence supporting our recommendations; therefore, some repetition was necessary to do this effectively. Our algorithms offer an overall approach to diagnosis and management of the major presentations of the disease and reflect our discussion in the body of the article. We have attempted to address all the key issues in PPI management and adverse events, so clinicians will have a comprehensive, go-to source in the guideline. We have performed our best to present a thorough review of the evidence for our recommendations and key concepts and to provide an evidence-based approach to GERD that can be used effectively in everyday practice.
We expect that new diagnostic tools and treatments will be developed and those that we have will be further refined. Mucosal integrity testing, e.g., is available commercially but is not developed sufficiently to warrant discussion in this guideline. Esophageal function testing is addressed in detail in another guideline, whereas other extensive reviews focus on valuable additions to our clinical armamentarium such as MSA and TIF. Potassium-competitive acid blockers are exciting potential new agents for pharmacologic treatment of GERD. One, currently available in Japan, presently is undergoing phase 3 trials in the United States as we complete this document and may well be approved for clinical use soon after this review is published. Future research with advanced endoscopic techniques, data on long-term efficacy of surgical intervention, and advances in artificial intelligence and basic science will almost certainly change the way we manage GERD going forward.
CONFLICTS OF INTEREST
Guarantor of the article: Philip O. Katz, MD, MACG.
Specific author contributions: All authors contributed to the planning, data analysis, writing, and the final version of the manuscript.
Financial support: None to report.
Potential competing interests: P.O.K.: Has served as consultant for Phathom Pharma and Medtronic; Research Support: Diversatek; and Royalties: up to date. K.D.: None currently. Previous research funding from Ironwood. F.H.S.-S.: Consultant for Ethicon, Interpace Biosciences, and Medtronic. K.B.G.: None. R.Y.: Consultant through institutional agreement: Medtronic, Ironwood, and Diversatek; Research Support: Ironwood; Advisory Board: Phathom Pharma; and Stock Options: RJS Mediagnostics. S.J.S.: Has served as a consultant for Interpace Diagnostics, Cernostics, Phathom Pharmaceuticals, Takeda, and Ironwood Pharmaceuticals; and Royalties: up to date.
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