Altman et al.: A Review of Clinical Practice Guidelines for Reflux Disease

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1 The Laryngoscope VC 2011 The American Laryngological, Rhinological and Otological Society, Inc. Contemporary Review A Review of Clinical Practice Guidelines for Reflux Disease: Toward Creating a Clinical Protocol for the Otolaryngologist Kenneth W. Altman, MD, PhD; Neil Prufer, MD; Michael F. Vaezi, MD, PhD Objectives: Reflux disease, including gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR), is an extremely common condition that is diagnosed and treated routinely in an otolaryngology practice. There is great variability in the methods of both diagnosis and treatment amongst otolaryngologists. Our aim is to review current clinical practice guidelines on reflux disease, to identify areas of agreement and controversy, and to begin to work toward a clinical protocol for reflux disease for the otolaryngologist. Study Design: Literature review with discussion. Methods: A PubMed search was performed looking for clinical practice guidelines on either GERD or LPR. Five hundred seventy articles were identified and the most clinically relevant practice guidelines were selected. Results: Thirteen key articles were identified. Eleven of these come from the gastroenterology literature, and none of them come from the otolaryngology literature. There appears to be a consensus on empiric medication trial as first-line therapy for presumed uncomplicated GERD and on prioritizing early identification of patients with severe disease complications. Areas of controversy include the definition of GERD and LPR, which diagnostic algorithm to use in which patient, and the long-term management of medical therapy. Conclusions: Although there are many clinical aspects of reflux disease that still remain a mystery, there is enough literature to support a rudimentary clinical protocol at this time. As further data become available from outcomes measurements, such a protocol may result in improved quality and standardization. Key Words: Gastroesophageal reflux, GERD, laryngopharyngeal reflux, LPR, clinical practice guidelines, clinical protocol. Level of Evidence: 2a. Laryngoscope, 121: , 2011 From the Department of Otolaryngology (K.W.A., N.P.), Mount Sinai School of Medicine, New York, New York, U.S.A.; Division of Gastroenterology (M.F.V.), Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A. Editor s Note: This Manuscript was accepted for publication November 3, This article was submitted for presentation at the Triological Society Combined Section Meeting, January 27 30, 2011, Scottsdale, AZ. The authors have no financial disclosures for this article. The authors have no conflicts of interest to declare. Send correspondence to Dr. Kenneth W. Altman, Department of Otolaryngology, The Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1189, New York, NY Kenneth.altman@mountsinai.org DOI: /lary INTRODUCTION Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are important diseases, being highly prevalent as well as having the potential to directly cause disease complications. As we move to a more value-based healthcare system, there is renewed emphasis on practicing evidence-based medicine, and introducing standardization in our approach to diagnosis and treatment of diseases. GERD and LPR are particularly interesting from this standpoint, as they involve collaboration between otolaryngologists and gastroenterologists, and have the potential to further complicate respiratory disease. Thus, it would be beneficial to establish the framework for disseminating evidence-based clinical practice guidelines to physicians. The prevalence of GERD and LPR is high in the general population, and the impact on health systems is growing dramatically. Postal surveys in the United Kingdom, 1 Belgium, 2 and New Zeland 3 document heartburn and regurgitation symptoms in 28.4% to 45.2% of the population. In the United States, Locke et al. 4 found 20% of their questionnaire sample to have weekly heartburn and almost 60% with occasional symptoms. Similarly, Johanson 5 summarized occasional or monthly heartburn at 21% to 58%, and daily heartburn at 4% to 7%. However, occasional and mild incidental symptoms of reflux may be considered normal, or physiologic. Nevertheless, GERD and LPR account for striking growth and impact on healthcare delivery, confirming that it is truly a public health concern rather than a symptomatic nuisance. In a study from the National Ambulatory Medical Care Survey (NAMCS), ambulatory 717

2 physician visits for GERD over the 12-year period from 1990 to 2001 were reviewed. 6 Between and there was a significant increase in U.S. ambulatory care visits for GERD, from a rate of 1.7/100 to 4.7/100. Emphasizing the atypical presentations seen with LPR, office visits to Otolaryngologists increased from 89,000 to 421,000 over the same 12-year period. Although factors contributing to this growth are controversial, no single factor is likely to be responsible. Furthermore, a wide spectrum of respiratory tract disease has been associated with the presence of GERD and LPR, including chronic laryngitis, 7 hoarseness, 8 laryngeal carcinoma, 9 globus sensation, 10 cough and paradoxical vocal fold motion, 11 laryngeal stenosis, 10 laryngomalacia, 10 sudden infant death syndrome, 12 sleep disturbance, 13 and chronic rhinosinusitis. 14 The pathophysiology of these disease complications is likely to be complex. 15 Nevertheless, this growing list reinforces the significant impact it has on healthcare delivery. The larynx is particularly prone to the effects of LPR because it is at the epicenter of the upper and lower respiratory tract, and at the apex of the gastrointestinal tract. The significance on ambulatory medical practice, the likely high costs associated with over-the-counter self-medication use, and the potential for serious disease complications makes evidence-based diagnosis and treatment of GERD and LPR imperative. The purpose of this article is to review the literature on evidence-based clinical practice guidelines (CPG) for GERD and LPR, to identify areas of agreement and of controversy, and to begin to work toward a clinical protocol for reflux disease for the otolaryngologist. METHODS A Pubmed search was performed separately by two authors (N.P., K.W.A.), searching for the following terms: GERD or reflux or laryngopharyngeal reflux or esophageal disease, and clinical practice guideline. Five hundred seventy articles were identified. The inclusion criteria were that an article must: 1) be a clinical practice guideline; 2) address the diagnosis and/or management of reflux disease; 3) be in English. This yielded 25 articles. We then excluded pediatric studies, as well as outdated versions of guidelines when the same organization had produced a more recent guideline, yielding 13 articles from 2002 to Eleven of these come from the gastroenterology literature, and none of them come from the otolaryngology literature. RESULTS Eleven CPGs on GERD are summarized in Table I, with an emphasis on diagnostic and treatment options This table excludes two references based on their narrow focus, being diagnosis, surveillance, and therapy of Barrett s esophagus, 27 and the use of endoscopic therapy for gastroesophageal reflux disease. 28 Empiric Diagnosis and Treatment There was general agreement throughout the guidelines that for the first encounter with a patient that has a history and physical examination consistent with GERD, the initial diagnosis should be made on clinical grounds. Both the initial treatment, as well as the firstline test for confirmation of the diagnosis, should be an empiric trial of therapy. The gold standard of medical therapy is a proton pump inhibitor (PPI); there is some controversy as to whether the initial dosing regimen should be once or twice a daymost guidelines recommend once a day to start, reserving the possibility of twice a day dosing for failure of an adequate trial of once-a-day therapy. Lifestyle recommendations, especially for weight loss, are included in most guidelines, although their efficacy is uncertain. Head of bed elevation may help in patients with nocturnal symptoms. In terms of other medications, H2 receptor antagonists are not considered first-line for empiric therapy, as they have been shown to have lower efficacy and patients develop tachyphylaxis over time. Prokinetic agents, including metoclopramide and cisapride, have both proponents. 21,23 and opponents 18,22,24 for use in the setting of GERD, given that they have more significant side effects. Patients who Respond to Medical Therapy As to those patients who are preliminarily diagnosed with GERD and respond well to medical therapy, most authors agree that the medication should be tapered to the lowest effective dose, with the exception of one that was published before data on adverse effects came to light. 23 Two guidelines specifically suggest a trial of intermittent therapy, 16,24 whereas another recommends tapering after a therapeutic effect of 4 to 8 weeks. 25 The rationale is to limit, as much as possible, the known adverse effects of long-term proton pump inhibitor use. It is also unclear whether a diagnostic test is necessary for patients who respond to medical therapy but cannot be weaned off of their medications. Patients with Alarm Symptoms or Who Fail Medical Therapy There was also agreement on the principle of identifying patients who are at risk for more serious and possibly life-threatening diseases early, and then using various diagnostic modalities as soon as possible, perhaps even before starting empiric medication. Most studies employ the concept of alarm symptoms such as dysphagia or odynophagia to select for these patients. However, there is divergence as to the definition of alarm symptoms. Although most authors suggest that the primary diagnostic approach for patients with alarm symptoms should be esophagogastroduodenoscopy (EGD), there is significant controversy over what the next step should be for patients that have a preliminary diagnosis of GERD but fail a trial of medical therapy. Some guidelines recommend EGD as the next step for failure of twice a day therapy, followed by 24-hour ph probe, whereas others recommend going directly to a 24-hour ph probe. These differences in opinions can be explained by the principles and the literature on which they are based: although a 24-hour ph probe has the best combined sensitivity and specificity of any test for the diagnosis of reflux disease, an EGD exam can give much different information. This includes the presence of multiple types of 718

3 TABLE I. List of Clinical Practice Guidelines on GERD, Specifying Indications for Diagnostic Tests and Interventions. Lifestyle Changes Trial of Meds When to Taper Meds EGD BaS ph Probe/Impedance Testing Mano-metry Fundoplication Refer to specialist Fennerty, 2009 First line To lowest effective dose, intermittently Kahrilas, 2008 (NEJM) Kahrilas, 2008 (Gastroenterology) First line First line To lowest effective dose First line First line To lowest effective dose Odynophagia, dysphagia, GI bleed, anemia Troublesome dysphagia, failed PPI bid Select patients Select patients Failure of therapy Normal EGD and manometry Normal EGD Failed or can t tolerate medication Hirano, 2007 Normal EGD/ to show causality Hirota, 2006 Select pts with chronic GERD Irwin, 2006 First line First line If ph probe is normal Armstrong, 2005 Not effective First line To lowest effective dose DeVault, 2005 First line, but not effective First line Should not usually taper Katelaris, 2002 First line First line To lowest effective dose, intermittently Moraes-Filho, 2002 Pts with alarm symptoms Suspicion of Barrett s or GERD complications Alarm symptoms, failed PPI bid First line First line 4 8 weeks Age over 40, alarm symptoms SAGES, 1998 Mandatory preoperative evaluation Cough patients who fail meds Patients who fail medication Not recommended Patients who fail medication Limited use Failed meds and normal EGD Limited use Failed meds and normal EGD, or EES Some preoperative patients Select preoperative patients Failure of maximal medical therapy Failed or cannot tolerate medication To consider To consider To consider Mandatory preoperative evaluation Option for maintenance, or for medication failures Failed or cannot tolerate medication Failed or cannot tolerate medication, or young patients who cannot wean off of therapy, or GERD complications Failed or cannot tolerate medication, or EES, or GERD complications Failure of PPI bid Failure of PPI qd Two of the 13 guidelines were excluded from this table because of their narrow scope. PPI ¼ proton pump inhibitor; EGD ¼ esophagogastroduodenoscopy; BaS ¼ barium swallow test; EES ¼ extra-esophageal symptoms. 719

4 TABLE II. Stratification of Disease Complications or Associations, and Possible Alarm Symptoms. Degree of Severity Clinical Examples Possible Alarm Symptoms Mild Incidental symptoms None Symptomatic nuisance (physiologic reflux) Managed with diet, lifestyle, or intermittent medications Moderate Esophagitis Los Angeles Dysphagia grade A B Significant hiatal Odynophagia hernia Esophageal/gastric Hematemasis motility disorders Bilious Anemia regurgitation Barrett s metaplasia (may not cause symptoms) Weight loss LPR complications cricopharyngeal spasm, laryngospasm, vocal process granuloma, and other lesions, disabling cough, aspiration pneumonitis, others Respiratory disturbance Severe Esophageal carcinoma Dysphagia Esophagitis Los Odynophagia Angeles grade C D Massive gastric Hematemasis outlet obstruction Mediastinal mass, Anemia esophageal compression Cardiac etiologies Weight loss Hemoptysis Respiratory distress Note that the Los Angeles classification system for reflux esophagitis has been thoroughly tested and validated for both interobserver reliability, as well as high correlation to ph testing, response to PPI, and risk of symptom relapse off of PPI. Grade A is a mucosal break (or breaks) less than 5 mm, bounded by two mucosal folds; grade B is a mucosal break (or breaks) more than 5 mm, bounded by two mucosal folds; grade C is a mucosal break (or breaks) extending beyond two mucosal folds but less than 75% of the circumference; grade D is a mucosal break (or breaks) involving at least 75% of the circumference. 42 pathology, including Barrett s esophagus, esophageal dysplasia, and carcinoma, as well as esophagitis. Patients with Los Angeles grades C and D esophagitis have a greater tendency toward relapse of symptoms when taken off medication, which would affect patient counseling. (Table II lists our stratification of disease complications with possible alarm symptoms, and defines the Los Angeles classification system for reflux esophagitis). It is outside the scope of this article to delve into the controversy whether a 48-hour Bravo capsule probe is significantly superior to a 24-hour probe, or whether impedance testing changes clinical decision making significantly compared to ph testing. It is equally outside our scope to discuss the management and screening protocols of Barrett s esophagus, which is diagnosed not infrequently on EGD for patients with GERD. Once this diagnosis is made, a referral to a gastroenterologist is prudent. There is agreement that for those few patients that have proven reflux disease with persistent symptoms despite maximal medical therapy, or for those that cannot tolerate the therapy, surgical procedures (i.e., laparoscopic fundoplication) may be considered, although there is significant risk of persistence or relapse of symptoms. Endoscopic therapy is still being explored, and initial results are promising, but there is not enough data to support it yet. 22,23,28 Ten papers address and recommend the use of endoscopy for patients with either basic symptoms attributable to GERD or alarm symptoms. There is evidence from Bowrey and colleagues 29 that by limiting the use of upper endoscopy to patients with alarm symptoms, there are patients with esophageal adenocarcinoma that will be overlooked until their cancer is more advanced. It can thus be inferred that by limiting screening endoscopies, there is a small percentage of patients who will die from disease that could have been cured. Although their 3% detection rate of carcinoma in people with dyspepsia or dysphagia with or without alarm symptoms is unusually high compared to other literature, their point deserves consideration. The question to be answered, difficult though it may be, is this: How much, in terms of economic and medical resources, are we willing to invest in order to cure esophageal carcinoma in a very small segment of the population? How many screening endoscopies need to be done in order to save one life? Existing Protocols A few of the studies reviewed went beyond the concept of a clinical practice guideline and included a protocol. Fennerty et al. 16 focus on the standpoint of the primary care practitioner, including management decisions on initial and maintenance medical therapy, while referring complex cases and medication failures to a specialist. On the other hand, the American Gastroenterologic Association position statement 18 offers a more complete protocol, including a diagnostic algorithm in addition to an algorithm for medical therapy. They suggest an EGD for patients with alarm symptoms, and for patients who fail medical therapy, an EGD to begin, followed by manometry if the EGD is normal, and then a 24-hour ph-probe study if the manometry is normal. Katelaris et al. 24 differ in that they recommend lifelong PPI therapy for patients with Los Angeles grade C and D esophagitis, given their high symptom relapse rate, and they do not include a role for manometry in the routine diagnostic workup. Finally, Moraes-Filho et al. 25 recommend EGD for all patients with suspected GERD, especially those over 40 and those with alarm symptoms. They recommend that manometry and ph testing be used only in select circumstances. DISCUSSION Although the clinical practice guidelines reviewed here overwhelmingly come from the gastroenterology literature, meta-analyses and reviews on laryngopharyngeal reflux are represented in the otolaryngology literature The difference between CPG and the latter is the scrutiny 720

5 to which level of evidence supports recommendations, and the broad consensus panel that goes into final recommendations. Nevertheless, CPG evidence-based recommendations are guidelines rather than rote requirements, which need to be placed into the context of the clinician s experience and qualifying patient-related issues. These recommendations may still be used to formulate a suggested approach to the patient with reflux. It is instructive then to revisit the alarm symptoms in the context of the spectrum of patients encountered with reflux. In Table II we stratify the severity of reflux disease complications with possible alarm symptoms in terms of mild (low complexity, low risk), moderate (complications or associations with reflux that require further evaluation and monitoring), and severe (those that may result in life-threatening complications). Although this stratification is not explicitly stated in the above-mentioned protocols, it is clear that identifying, evaluating, and treating higher risk disease should be integral to any clinical practice model for reflux. Based on the existing evidence-based CPG literature and the risk stratification introduced in Table II, the general principles that should be applied to the care of patients with reflux disease are: 1. Early warning or alarm symptoms should be identified at the time of each patient encounter and prompt a workup. 2. Patients should be stratified by risk. 3. The majority of lower risk patients do not need expensive and time-consuming testing. 4. Empiric therapy with medication at pharmacologicallyappropriate dosing and/or lifestyle changes, if it relieves symptoms, is sufficient for a diagnosis in most cases of reflux disease. 5. For patients that fail empiric therapy, diagnostic testing should be undertaken for two primary reasons: (a) confirm whether or not reflux disease is present, and (b) evaluate for complications of reflux disease, or to establish a different diagnosis altogether. 6. Proton pump inhibitors have risks that may be significant in the long term. Patients should be weaned to the lowest dose or off of therapy as soon as is medically safe. These principles can be used as a rudimentary protocol; however, timing and specifics of a refined protocol or critical pathway are beyond the scope of this article with respect to the following discussion. There are many controversies associated with GERD and LPR, and only a partial list is included in Table III, relative to clinical practice guidelines and generation of a clinical protocol. Some experts suggest that LPR is a different clinical entity than GERD. 33 This based on differing diagnosing physician subspecialist (gastroenterologists for GERD and otolaryngology for LPR), presence of heartburn in GERD and lack of this classic symptom in LPR, and the presence of upright reflux pattern and normal esophageal motility testing in those labeled as LPR. This discrimination between the two entities ignores the common pathophysiology of TABLE III. Partial List of Controversies Associated with GERD and LPR, Relative to the Clinical Practice Guidelines and Generation of a Clinical Protocol. Are GERD and LPR the same? Definition of physiologic reflux versus pathologic reflux, and what is a positive ph probe? Duration and dose of empiric therapy Role of diagnostic testing ph monitoring off or on therapy Role of surgical fundoplication in those unresponsive to empiric PPI trial? Can a clinical protocol for GERD be formulated solely from CPGs? What is the benefit of a clinical protocol for GERD? What outcomes measures should be monitored in these patients? abnormal esophageal or laryngeal acid/pepsin exposure, which is based on transient lower esophageal sphincter relaxation and/or incompetent lower esophageal sphincter. However, effects of tissue damage in LPR may not be adequately addressed in the CPGs predominantly directed toward those patients with GERD. Further controversy surrounds the uncertainty of what constitutes abnormal pharyngeal acid exposure. Ambulatory ph monitoring is currently one of the best modes of detecting pharyngeal acid exposure. In addition to the uncertainty of what constitutes abnormal pharyngeal acid exposure, some experts question the sensitivity of ph testing, which is reported to be as low as 40% in the hypopharynx. 34,35 Although most experts agree empiric therapy with PPIs is the current recommendation in patients suspected of having LPR, the dose and duration of therapy is debated. The current practice of twice-daily PPI therapy in LPR is neither FDA approved nor based on controlled studies. In fact, a meta-analysis of controlled studies has suggested no benefit to PPIs over placebo in this disorder. 36 The use of twice-daily PPIs is mainly based on uncontrolled observational studies or physiologic ph data suggesting better acid control in the esophagus and subsequently in the hypopharynx. 18 In the otolaryngology literature, experts have suggested treating patients for up to 6 months or even longer before laryngeal signs improve; however, some suggest 1 to 2 months of therapy may be adequate. 18,37 The most controversial issue in LPR/GERD surrounds the role of diagnostic testing and continued role of acid/peptic reflux in those who remain symptomatic despite aggressive dose and duration of acid suppression. Do these patients truly have reflux as the cause for their continued symptoms? Should the tests (ph or impedance monitoring) be performed while patients are on or off therapy? Should PPI unresponsive patients undergo surgical fundoplication? If reflux is not the cause, what other conditions may explain the continued chronic symptoms and laryngeal signs? At this time there is no consensus among experts even within the same discipline regarding how to answer the above clinically crucial questions. 721

6 The gastroenterology community generally supports ph-probe testing while on PPI therapy to exclude reflux as the possibility in patients who are refractory to PPI therapy. 38 However, one may argue that those patients with LPR symptoms would benefit from ph probe testing off therapy to determine the severity of baseline disease, and the likelihood that LPR is truly causing laryngeal symptoms. Most experts in gastroenterology would recommend against surgical intervention in patients refractory to PPIs. 18 A concurrent controlled study in patients with LPR who were refractory to PPI therapy did not find a clinical benefit for surgical fundoplication. 39 However, a recent observational and uncontrolled study in patients with chronic cough who had abnormal impedance monitoring suggesting continued nonacid reflux despite acid suppressive therapy found a benefit to surgery. 40 Similarly, severe reflux disease documented on a ph or Bravo probe study does suggest a better likelihood of disease control with fundoplication. It is important to remember that surgical intervention, even if performed with the best of intent, in patients whose symptoms or laryngeal findings may not be due to GERD can and will introduce further complexity in the care of this difficult to treat population. Given many controversies in this field, in patients who continue to be symptomatic despite PPI therapy, the driving force behind continued testing and/or added medical therapy is the underlying fear by the patients that their continued laryngeal irritation and symptoms may be from, or lead to, more ominous diagnosis such as laryngeal cancer. First, the role of reflux in laryngeal cancer is controversial with conflicting data. 41 Second, the likelihood that patients with symptoms despite PPI therapy are continuing to reflux is very low. Thus, physicians caring for this group of patients must address and minimize the patients fears. However, a formal approach to risk stratification in these patients has yet to be elucidated in a clinical protocol. CONCLUSIONS Evidence-based clinical practice guidelines exist in the literature to support the routine care of patients with GERD, and these may be considered to be applicable to patients with LPR. 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