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GASTROENTEROLOGY 2008;135:1392–1413

merican Gastroenterological Association Institute Technical Review on
he Management of Gastroesophageal Reflux Disease
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Learning ObjectivesAt the end of this activity, the successful learner

hould:

. Demonstrate an understanding of the natural historyand manifestations of reflux disease

. Evaluate the role of diagnostic testing such as endos-copy, esophageal manometry, ambulatory pH moni-toring, and impedance-pH monitoring in the manage-ment of patients with gastroesophageal reflux disease

. Evaluate the options for treatment of patients withcomplicated and uncomplicated reflux disease.

The objectives of this technical review were to evaluateiagnostic and management strategies for patients withastroesophageal reflux disease (GERD). Specifically, 12road questions were developed by interaction amonghe authors, the American Gastroenterological Associa-ion (AGA) Institute, the Clinical Practice and Quality

anagement Committee, and representatives from theGA Institute Council. The questions were designed toncapsulate the major management issues leading toonsultations for GERD in clinical practice in 2008. Thessue of management of Barrett’s esophagus was inten-ionally excluded, because this will be the focus of a laterreatise. However, the indications for performing endos-opy were within our purview. For each question, a com-rehensive literature search was conducted, pertinent ev-

dence reviewed, and the quality of relevant datavaluated. The resultant conclusions were based on theest available evidence or, in the absence of quality evi-ence, the expert opinion of the authors of the technicaleview and medical position statement. The strength ofhese conclusions was weighed using US Preventive Ser-ices Task Force (USPSTF) grades detailed in Table 1.he details of the development methodology used for

his and subsequent AGA Institute technical reviews andedical position statements as well as the literature

earch methodology and yield associated with each of theuestions in this technical review are available as a sep-rate document on the AGA Institute Web site.

GERD has been the most common gastrointestinaliagnosis recorded on outpatient physician visits since006, even surpassing abdominal pain.1 This is remark-ble considering the vagaries of the diagnosis. Most pa-ients with heartburn do not have esophagitis, even be-ore treatment,2 and this disconnect becomes morexaggerated after empirical antisecretory therapy or withtypical GERD symptoms. Furthermore, although theathogenesis of reflux esophagitis and reflux symptoms
hare common elements, the two have several indepen-
ent determinants as well. Finally, with respect to treat-ent, potent inhibition of gastric acid secretion reduces

he lethality of gastric juice to esophageal epithelial cellsuch that esophagitis will heal, irrespective of whether orot gastroesophageal reflux is reduced or symptoms areesolved. Ironically, as refractory esophagitis has becomerare clinical problem, refractory “GERD” symptoms hasecome a substantial one. In the post–proton pump

nhibitor (PPI) world, it is patients with symptoms, notsophagitis, who confront the practitioner in the over-helming majority of clinical encounters for GERD.

Diagnosis and Initial Therapy

1. What Is an Operational Definition ofGERD? What Is the Distinction BetweenGERD and Episodic Heartburn?Regardless of how many citations are identified by

iterature review, there can be no criterion standard def-nition of GERD because the threshold distinction be-ween physiologic reflux and reflux disease is ultimatelyrbitrary. Hence, these questions can only be answered bypinion, and presumably the best opinion upon which toase the answers is that of experts (USPSTF grade anduality not applicable). Fortuitously, a recent and unpar-lleled attempt at gaining consensus in defining GERDmanated from a panel of world experts utilizing a 4-it-ration Delphi process that spanned a 2-year period.3 Thetated objective of that unique international consensusroup was “to develop a global definition and classifica-ion of GERD, using rigorous methodology, that coulde used clinically by primary care physicians and thatmbraces the needs of physicians, patients, researchers,nd regulatory bodies from different parts of the world.”3

he output of the Montreal consensus group was a seriesf 50 statements pertaining to the diagnosis of GERDyndromes. For each statement, the level of consensusas determined by vote along a 6-point scale of agree-ent ranging from strong agreement to strong disagree-ent and, when applicable, the quality of supporting

vidence was evaluated.An overarching definition of GERD must encompass

sophageal as well as extraesophageal syndromes: syn-

Abbreviations used in this paper: AGA, American Gastroenterologi-al Association; GERD, gastroesophageal reflux disease; H2RA, hista-ine2 receptor antagonist; PPI, proton pump inhibitor; USPSTF, USreventive Services Task Force.

© 2008 by the AGA Institute0016-5085/08/$34.00

doi:10.1053/j.gastro.2008.08.044

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October 2008 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE 1393

romes with tissue injury as well as those without. Grap-ling with this dilemma, the Montreal consensus paneleached very strong agreement in defining GERD as “aondition which develops when the reflux of stomachontents causes troublesome symptoms and/or compli-ations.”3 Thereafter, the panel specified that symptomsere “troublesome” if they adversely affected an individ-al’s well-being and delineated the broad array of GERDyndromes that have been demonstrated or proposedFigure 1). Note that the extraesophageal syndromes arelassified as of established or proposed association, ac-nowledging that while the evidence on hand is sufficiento link these syndromes to reflux, it is insufficient tostablish causation.

A test of the word “troublesome” in the Montreal defini-ion of GERD comes in attempting to draw a distinctionetween GERD and episodic heartburn. The Montreal

able 1. USPSTF Recommendations and Grades

trength of recommendations: The USPSTF strongly recommends that clinicians provide [theservice] to eligible patients. The USPSTF found good evidencethat [the service] improves important health outcomes andconcludes that benefits substantially outweigh harms.

: The USPSTF recommends that clinicians provide [this service] toeligible patients. The USPSTF found at least fair evidence that[the service] improves important health outcomes and concludesthat benefits outweigh harms.

: The USPSTF makes no recommendation for or against routineprovision of [the service]. The USPSTF found at least fairevidence that [the service] can improve health outcomes butconcludes that the balance of benefits and harms is too close tojustify a general recommendation.

: The USPSTF recommends against routinely providing [theservice] to asymptomatic patients. The USPSTF found at leastfair evidence that [the service] is ineffective or that harmsoutweigh benefits.

nsuff: The USPSTF concludes that the evidence is insufficient torecommend for or against routinely providing [the service].Evidence that the [service] is effective is lacking, of poor quality,or conflicting and the balance of benefits and harms cannot bedetermined.

uality of evidenceood: Evidence includes consistent results from well-designed,well-conducted studies in representative populations that directlyassess effects on health outcomes.

air: Evidence is sufficient to determine effects on healthoutcomes, but the strength of the evidence is limited by thenumber, quality, or consistency of the individual studies,generalizability to routine practice, or indirect nature of theevidence on health outcomes.

oor: Evidence is insufficient to assess the effects on healthoutcomes because of limited number or power of studies,important flaws in their design or conduct, gaps in the chain ofevidence, or lack of information on important health outcomes.

OTE. The USPSTF grades its recommendations according to one ofclassifications (A, B, C, D, Insuff) reflecting the strength of evidence

nd magnitude of net benefit (benefits minus harms). The USPSTFrades the quality of the overall evidence for a service on a 3-pointcale (good, fair, poor).

roup believed that for the typical esophageal GERD syn- t

rome, defining a threshold at which heartburn becomesroublesome was useful in planning treatment trials orpidemiologic studies but not in clinical practice. In thendividual case, symptom frequency, symptom intensity,nd psychosocial factors must also be considered. Hence, inlinical practice, the determination of whether or not heart-urn is troublesome should be made by the patient withouthe use of arbitrary cutoffs for frequency or duration andfter the patient is assured of the benign nature of occa-ional symptomatic heartburn. Presumably, a patient willonclude that if heartburn regularly interferes with his orer normal daily activities, it is troublesome; the moreubstantial the limitations imposed on his or her life, the

ore troublesome it is.In clinical trials of symptomatic GERD, a thresholdeasure of heartburn severity needs to be established for

niformity in the study population. However, there haseen little consistency among symptomatic GERD trials

n how this was done, with different studies utilizingymptom thresholds as low as 2 mild episodes of heart-urn per week and as high as 5 daytime episodes and 1ighttime episode per week as minimal entry criteria.4,5

ropping the threshold of heartburn severity required toefine symptomatic GERD clearly enlarges the “disease”opulation, and variability in the definition makes com-arisons of results among trials difficult, if not impossi-le. Moving forward with this, the Food and Drug Ad-inistration recently issued guidance on the criteria thatill be required in the future to support labeling claims.6

he catchphrase has become “patient-reported out-omes.” Patient-reported outcomes measure a patient’sealth status in terms of symptoms and quality of life aselayed by the patient without the interpretation of theatient’s responses by a physician. Disease-specific pa-ient-reported outcomes must be developed and acceptedy the Food and Drug Administration before their use inupporting a labeling claim. Acceptance of a patient-eported outcome is predicated on its demonstrated va-idity, reliability, and ability to identify meaningful dif-erences in disease-specific measures of importance in thentended treatment population. For the example of aatient-reported outcome for symptomatic GERD, bothhe defining symptom burden and the minimal meaning-ul increment of improvement attributable to therapyould need to be developed through patient focusroups and vetted by the Food and Drug Administration.ence, the development of a symptomatic GERD pa-

ient-reported outcome will result in defining the thresh-ld symptom burden required for the diagnosis. Needlesso say, few, if any, existing trials substantiating treatmentfficacy in symptomatic GERD would meet the criteriaow mandated by the Food and Drug Administration.In summary, the Montreal definition of GERD was

dopted to use as a framework throughout this docu-ent. A distinguishing feature of the Montreal defini-

ion is that it does not use the term “nonerosive reflux

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isease,” but rather subdivides esophageal syndromesnto symptomatic syndromes and syndromes withsophageal injury. Hence, functional heartburn doesot fit the Montreal definition of GERD, whereas it is

ncluded under the umbrella of nonerosive reflux dis-ase. The distinction between GERD and episodiceartburn in the Montreal definition is in the wordtroublesome.” In the absence of esophageal injury,eartburn of insufficient intensity to be perceived asroublesome by the patient (after assurance of its be-ign nature) does not meet the Montreal definition ofsymptomatic esophageal GERD syndrome.

2. What Is the Efficacy of LifestyleModifications for GERD? Which ElementsShould Be Recommended and in WhichCircumstances?There are a multitude of recommendations re-

arding lifestyle modifications as GERD therapy. Broadlypeaking, these fall into 3 categories: (1) avoidance ofoods that may precipitate reflux (coffee, alcohol, choco-ate, fatty foods), (2) avoidance of acidic foods that mayrecipitate heartburn (citrus, carbonated drinks, spicyoods), and (3) adoption of behaviors that may reducesophageal acid exposure (weight loss, smoking cessa-ion, raising the head of the bed, and avoiding recum-ency for 2–3 hours after meals). Most evidence support-

ng such recommendations is weak, coming frombservational and uncontrolled studies of small sampleize, often with surrogate end points. In some cases, suchs with dietary fat, the evidence is conflicting. Early stud-es suggested that a high-fat diet was harmful because itiminished lower esophageal sphincter (LES) pressure.7

owever, a subsequent controlled study comparing a

igure 1. The Montreal definition of GERD. The overarching definitionegardless of syndrome(s) present and that those syndromes are caus

ow-fat diet with a high-fat diet did not find any change p

n LES pressure or objective reflux parameters by pHonitoring.8 Similarly, the reported reduction in LES

ressure with smoking has not extrapolated to improve-ent of GERD parameters with cessation of smoking.9

The recommendation to elevate the head of the bed by– 8 inches in patients with reflux is intuitively based on

educing esophageal acid exposure by improving clear-nce. A corollary to this recommendation is to avoidating for the 2- to 3-hour period before going to bed,ecause this is the period during which the most refluxvents would be anticipated. There is some merit to thisecommendation based on a randomized controlled trialf patients with moderately severe esophagitis (USPSTFrade B, quality fair).10 The therapeutic gain from raisinghe head of the bed with a 20-cm block for the 6-weekuration of the study was 20%–30%. However, the sub-roup studied (moderate to severe esophagitis) is partic-larly prone to supine reflux and the applicability of theecommendation of elevation of the head of the bed tohe majority of patients with GERD experiencing heart-urn predominantly confined to the postprandial period

s dubious.Obesity merits special consideration because it has

een the object of substantial study in recent years. Theres good evidence that GERD is associated with obesity.pecifically, epidemiologic data from the Nurses’ Healthtudy suggest a dose-dependent relationship between

ncreasing body mass index and frequent reflux symp-oms,11 and a large meta-analysis similarly demonstrated

dose-response relationship between body mass indexnd the risk of reporting symptoms of GERD amongoth men and women.12 Evidence also suggests that acideflux measured by pH monitoring is increased in obese

dates that troublesome symptoms and/or complications are presentreflux.3

man

atients.13 Proposed mechanisms for the obesity effect

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nclude alteration in the pressure dynamics and anatomyf the esophagogastric junction14 and an increase inransient LES relaxation and reflux frequency.15 However,he contention that losing weight will improve GERD isess robustly supported by the literature (USPSTF grade, quality fair). One observational study of 34 overweightnd obese patients found that weight loss resulted inmprovement in GERD symptoms,16 and the Nurses’

ealth Study analysis found that reflux symptoms werexacerbated or improved over time concomitant witheight gain or loss, respectively.11 On the other hand, a

andomized controlled study did not find any objectiver subjective improvement of GERD in 20 obese patientsfter a significant weight loss.17

In summary, the problem with advocating lifestyle mod-fications as GERD therapy is that there are simply too

any and each is too narrowly applicable to enforce thehole set on every patient. The Genval Workshop Reportn evidence-based reflux management concluded thatthere is currently a significant overestimation of the pos-ibility of patients deriving adequate relief from life style

odification.”18 Thus, from the vantage point of high-uality evidence, there are insufficient data to suggest aonsistent benefit of lifestyle changes for all patients withERD (USPSTF grade Insuff). However, it is also clear that

here are subsets of patients who may benefit from specificifestyle modifications and it is good practice to make thoseecommendations to those patients. A patient with symp-oms of nighttime heartburn of sufficient severity to disturbis or her sleep despite acid suppressive therapy may benefit

rom elevation of the head of the bed. Similarly, a patientho consistently experiences troublesome heartburn after

ngestion of alcohol, coffee, or spicy foods despite aciduppressive therapy will benefit from avoidance of theseactors. Finally, if the development of troublesome heart-urn paralleled weight gain, it is perfectly reasonable toropose weight loss as an intervention that may prevent, ort least postpone, the need for continuous acid suppressiveherapy.

3. How Do Antisecretory Therapies Comparein Efficacy and Under What CircumstancesMight One Be Preferable to Another? WhatIs an Acceptable Upper Limit of EmpiricalTherapy in Patients With Suspected TypicalEsophageal GERD Syndromes BeforePerforming Esophagogastroduodenoscopy?Initiating empirical treatment with a PPI amounts

o a pragmatic therapeutic trial; if a patient reports symp-oms consistent with GERD and responds to therapy forERD, then he or she must have GERD. However, theotion that this constitutes a clinical test blurs the dis-inction between healing esophagitis and resolving puta-ive reflux symptoms, the latter of which are neithererfectly sensitive nor specific for GERD. Such reasoninglso ignores the existence of other diagnostic possibilities
hat may benefit from PPI therapy or a possible placebo t
esponse. The strategy of empirical therapy is also limitedy the observation that PPI therapy is not as robust atesolving GERD symptoms as it is resolving esophagitis;negative response to a PPI trial does not exclude GERD

s a diagnostic possibility. Furthermore, it dampens theiagnostic utility of endoscopy because esophagitis,hich would otherwise have been a robust marker ofERD, will likely be healed with treatment regardless ofhether or not symptoms resolve. Nonetheless, these

imitations withstanding, the current consensus is thatmpirical PPI therapy is appropriate for uncomplicatedeartburn.3,19,20

As for the choice of therapeutic agent, there is anbundance of data demonstrating the effectiveness ofPIs in healing esophagitis and in relieving heartburn. Aecent Cochrane review examined 134 treatment trialsncluding 36,978 patients with esophagitis and con-luded that PPIs exhibit a better healing effect and fasterymptom relief than histamine2 receptor antagonistsH2RAs), which are in turn better than placebo.21 Thateview also concluded that there is no major difference infficacy among the currently available PPIs (esomepra-ole, lansoprazole, omeprazole, pantoprazole, rabepra-ole) and that the gain achieved by doubling the standardose of PPI therapy is modest. Available 6- to 12-monthata also suggest that PPIs are effective for maintainingymptom relief and preventing recurrence of esophagitisn patients who respond to an acute course of the sameherapy. Table 2 summarizes the major observationsrom this voluminous pool of therapeutic data.22–31

hus, abundant data support treating patients withsophageal GERD syndromes with antisecretory drugsUSPSTF grade A, quality good) and there is ample evi-ence that, as a drug class, PPIs are more effective inhese patients than are H2RAs (USPSTF grade A, qualityood). However, the data supporting the use of PPIs withoses higher than the standard are minimal. Similarly,here is no evidence of improved long-term efficacy bydding a nocturnal dose of an H2RA to twice-daily PPIherapy (USPSTF grade Insuff). This combination wasroposed to suppress “nocturnal acid breakthrough” onhe assumption that this was clinically relevant.32 How-ver, subsequent data have failed to show any associatedlinical benefit.33–35 There are also no high-quality dataupporting the use of metoclopramide as either mono-herapy or adjunctive therapy in esophageal or suspectedxtraesophageal GERD syndromes, making the toxicityrofile of the drug36 ample grounds for recommendinggainst its use (USPSTF grade D, quality fair). Finally, dataupporting the use of PPIs for treatment of patients withxtraesophageal GERD syndromes with an establishedssociation are weak (USPSTF grade B, quality fair).

The data in Table 2 are very robust with respect to thehort-term healing of esophagitis but much more limitedith respect to defining the parameters for maintenance

herapy or the management of patients with an inade-

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uate symptom response to once-daily PPI therapy, basi-ally the 2 most common issues faced by the clinician.he other notable disconnect between clinical trial datand clinical practice is in the use of PPIs twice daily;lthough the pharmacodynamics of the drugs logicallyupports twice-daily dosing, the pharmaceutical industryas been reluctant to advocate it, primarily due to mar-eting considerations. Hence, guidance on these issuesomes primarily from expert opinion based on clinicalxperience. Expert opinion is essentially unanimous inecommending twice-daily dosing of PPIs to improveymptom relief in patients with an esophageal GERDyndrome with an unsatisfactory response to once-dailyosing (USPSTF grade B, quality fair). The general prin-iple of maintenance therapy is to titrate the strength ofntisecretory therapy up or down to find the lowest dosehat provides satisfactory control of heartburn. As a rulef thumb, 80% symptom relief is a reasonable, albeitomewhat arbitrary, target; at that point, persistentymptoms are often triggered only by indulgence. Fur-hermore, the significance of these unresolved symptomss only in the lifestyle compromises they impose: limitediet, restricting physical activity, poor sleep, and so on.

able 2. Summary of GERD Treatment Data With Inhibitors o

sophagitis healing (all severities) PPIs are superioPPIs dose-respon

standard vs hiPPIs are superioH2RA are superioH2RAs show no

eartburn resolution (patients withesophagitis)

PPIs are superioPPIs show no do

standard vs hiPPIs are superioH2RAs are super

eartburn resolution (endoscopynegative or uninvestigated patients)

PPIs are superioPPIs show no doPPIs are superio

interval � 0.6H2RAs are superH2RAs show no

aintenance of esophagitis healing orsymptom control (6-12 months)

PPIs are superioLow-dose PPI the

patients with eLow-dose on-dem

endoscopy-negxtraesophageal syndromes (withestablished association)

High-dose PPIs aheartburn29

High-dose PPIs ssubgroup of as

Standard- or highsyndrome with

OTE. Low and standard doses of PPIs are as follows: esomeprazolell omeprazole and rabeprazole data were 20 mg. Standard doses of50 mg, ranitidine 150 mg.NT, estimated number of patients needed to treat to demonstrate tach group.

hey should not be framed as a threat to one’s well-being. i

Although PPIs are more effective overall, H2RAs have aore rapid onset of action and will suffice for some

atients. If patients need to take a PPI twice daily becausehey are experiencing breakthrough symptoms towardhe end of the day or during the night, the optimaliming is 30 – 60 minutes before breakfast and dinner.atients may find on-demand or intermittent shortourses of therapy sufficient. However, antacids are mostffective once heartburn is already present; PPIs and

2RAs are more effective in preventing heartburn. Pa-ients whose heartburn has not adequately responded towice-daily PPI therapy should be considered treatmentailures; in other words, that is a reasonable upper limitor empirical therapy.

Circumstances in which one antisecretory drug mighte preferable to another primarily relate to side effects orhen the onset of effect is a prime consideration. Theost common side effects of PPIs are headache, diarrhea,

onstipation, and abdominal pain, none of which occurore frequently than with placebo, but all of which can

ccur with any drug in the class and can be confirmed inome patients with a test-retest strategy. Potential sideffects should also be considered in wholesale transition-

stric Acid Secretion

lacebo: 83% vs 18% at 8 wk, NNT � 1.721

urve exhibits a plateau: low vs standard dose, NNT � 10 at 4 wk;split dose, NNT � 25 at 4 wk21

2RAs: 84% vs 52%,20 RR � 0.5121

placebo: 41% vs 20% at 6 wk, NNT � 521

response curve (standard vs high or split dose)21

lacebo: 56% vs 8% at 4 wk, NNT � 2–322

sponse curve: low vs standard dose, 75% vs 79% at 4 wk;split dose, 73% vs 76% at 4 wk21

2RAs: 77% vs 48% at 4–12 wk23

placebo: 56% vs 45% at 12 wk24

lacebo: 36.7% vs 9.5%, NNT � 3–422

sponse curve (low vs standard dose)2RAs: 61% vs 40%, NNT � 5,25 RR � 0.66, 95% confidence7326

placebo: RR � 0.77, 95% confidence interval � 0.60–0.9926

response curve (standard vs high dose): 45.8% vs 44.8% at 8 wk27

lacebo for maintaining healing: 93% vs 29%28

is sufficient to maintain endoscopic remission in 35%–95% ofagitis20

PPI therapy yields acceptable symptom control in 83%–92% ofpatients20

better than placebo for reflux laryngitis syndrome without frequent

modest benefit in morning peak expiratory flow vs placebo fortic patients with nocturnal GERD symptoms30

PPIs show some improvement in some patients with reflux coughctively demonstrated GERD: NNT � 531

g, 40 mg; lansoprazole 15 mg, 30 mg; pantoprazole 20 mg, 40 mg.As (all twice daily): cimetidine 400 mg, famotidine 20 mg, nizatidine

nefit; RR, risk ratio, compares the probability of treatment failure in

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8% of patients who failed the switch from omeprazole toansoprazole because of either therapeutic failure (15%)r side effects (13%) in a VA hospital experience of 78atients.37 Switching among alternative PPI drugs or to a

ower dose can usually circumvent side effects; it is rareor a patient to exhibit intolerance to any dose of thentire drug class. As for the issue of onset of action, thisrimarily pertains to on-demand therapy. If a patient

ntends to take a drug only in response to symptoms,hen it should be a rapidly acting drug. The most rapidlycting agents are antacids, the efficacy of which can beustained by combining them with an H2RA or a PPI.owever, the clinical benefits of such combination ther-

pies have yet to be demonstrated in clinical trials.Some data suggest differences among the various PPIs

ith respect to healing of erosive esophagitis.38,39 How-ver, absolute differences in efficacy in these studies areodest,21 and subgroup analyses have suggested that

ifferences in healing rates may be more pronounced inrade C and D disease. Given that these medications areften given empirically and that grade C and D esoph-gitis will be present in only a small fraction of thoseith GERD symptoms, medication selection predicatedn prescription plan coverage, side effects, and onset ofction will likely govern the selection of the initial ther-py for most patients.

4. What Is the Role and Priority of DiagnosticTests (Endoscopy With or Without Biopsy,Esophageal Manometry, Ambulatory pHMonitoring, Combined Impedance-pHMonitoring) in the Evaluation of Patients WithSuspected Esophageal GERD Syndromes?As evident in Figure 1, widely accepted diagnostic

riteria for esophageal GERD syndromes are (1) a symp-om complex attributable to gastroesophageal reflux andf sufficient severity to compromise quality of life or (2)ndoscopic findings of erosive esophagitis, stricture, orarrett’s metaplasia. In the simplest case, when symp-

oms are typical and the patient responds to therapyntended to address those symptoms, no diagnostic testsre requisite. Rather, diagnostic testing is invoked in 3road scenarios: (1) to avert misdiagnosis, (2) to identifyomplications of reflux disease, and (3) in the evaluationf empirical treatment failures. With respect to perform-

ng endoscopy to screen for Barrett’s metaplasia, al-hough clearly a mainstream issue, this is specificallyddressed in the section on chronic management (seeuestion 11 in the following text).

The discussion of misdiagnosis and identifying com-lications of reflux disease usually revolves around theoncept of “alarm features” found on clinical evaluation.larm features dictate circumstances in which diagnostic

esting is indicated as part of the initial evaluation, eitherecause they suggest that complications of GERD areresent or because they suggest an alternative diagnosis.
mportant alternative diagnoses include coronary artery b
isease, gallbladder disease, gastric or esophageal malig-ancy, peptic ulcer disease, and eosinophilic, infectious,r caustic esophagitis. Proposed alarm features includeomiting, evidence of gastrointestinal blood loss, invol-ntary weight loss, dysphagia, anemia, chest pain, orpigastric mass.20,40 It is not always endoscopy that isnvoked, but some specific evaluation as mandated by theuspected disease entity. High-quality evidence support-ng the broad utility of alarm features as a diagnostic tools quite limited (USPSTF grade Insuff). However, a recent

eta-analysis addressed the specific issue of the utility oflarm signs and symptoms in diagnosing upper gastro-ntestinal malignancy based on 15 published prospectivevaluations encompassing 46,161 patients, 8669 with oner more alarm feature, and 150 subsequently found toave gastric or esophageal cancer on endoscopy.40 Al-hough those investigators concluded that alarm featureserformed poorly as a diagnostic test, they reported theverall pooled sensitivity and specificity to be 67% (95%onfidence interval, 54%– 83%) and 66% (95% confidencenterval, 55%–79%), respectively. Individual alarm featuresith the best performance were weight loss, dysphagia,nd epigastric mass on examination. Given those num-ers, and viewing this as a screening test rather than aiagnostic test, it seems reasonable that patients beingvaluated for GERD should be queried regarding dyspha-ia and weight loss and examined for an epigastric mass.f judged significant, any of these should be evaluatedith endoscopy (USPSTF grade B, quality fair).Dysphagia merits special consideration as an alarm

ymptom because it can be indicative of a stricture oralignancy. However, dysphagia was also reported by 37%

f 11,945 patients with esophagitis without stricture orarrett’s esophagus participating in esophagitis clinical tri-ls, and it resolved in 83% with PPI therapy.41 This discrep-ncy led the Montreal consensus group to suggest that notll dysphagia, but only “troublesome” dysphagia, warrantsnvestigation3 (USPSTF grade B, quality fair). Troublesomeysphagia is present when patients need to alter their eatingatterns, when patients have symptoms of solid food get-ing impacted, when it exhibits a worsening pattern, orhen it does not resolve with PPI therapy. Although not

pecifically mentioned by the Montreal consensus group,he latter circumstance is significantly associated with failedsophagitis healing.41 A final caveat in the endoscopic eval-ation of dysphagia is that the endoscopist should have a

ow threshold for obtaining multiple (preferably 5) esoph-geal mucosal biopsy specimens or even biopsy specimensrom multiple levels to evaluate for eosinophilic esophagi-is.42 The increasing recognition of eosinophilic esophagitiss a confounding clinical entity has increased the potentialalue of biopsies when performing upper endoscopy forERD. The traditional teaching that histologic assessmentf mucosa in the setting of GERD is of limited utility dueo the poor specificity of histologic findings for GERD has
een tempered by the need to differentiate eosinophilic

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sophagitis from GERD. A recent systematic review andonsensus conference on eosinophilic esophagitis suggestedhat

mucosal pinch biopsy specimens should be obtained from all pa-tients in whom EE (eosinophilic esophagitis) is in the differentialdiagnosis. Biopsy specimens should be obtained regardless of thegross appearance of the mucosa, and multiple biopsy specimensshould be obtained from different esophageal locations along thelength of the esophagus.43

Given the high rate of eosinophilic disease in theetting of dysphagia without an obvious obstructing le-ion, such subjects may benefit from mucosal biopsies44

USPSTF grade B, quality fair). No evidence demonstrateshe utility of routine esophageal biopsies in the setting ofeflux symptoms without dysphagia.

The other broad scenario under which diagnostic testings performed is in the evaluation of troublesome symptomshat have not responded to empirical twice-daily PPI ther-py. Did therapy fail because of troublesome symptomsttributable to reflux that did not resolve with PPI therapyr because the symptoms under consideration are not at-ributable to reflux? In current practice, this dilemma issually faced when the patient has already been treated withwice-daily PPI therapy for a significant period and it isnlikely that endoscopy will reveal esophagitis. Endoscopyay, however, still demonstrate Barrett’s metaplasia, stric-

ure, or an alternative upper gastrointestinal diagnosis, so its still the most useful initial diagnostic test (USPSTF grade, quality fair).In the setting of persistent troublesome symptoms and

ormal findings on endoscopy, priority should be given todentifying conditions for which an effective alternativeherapy exists. In the case of GERD, the only alternative,otentially more effective, therapy is antireflux surgery. Log-

cally then, further evaluation should be targeted to theetection of conditions that are likely to respond to antire-ux surgery. High-quality evidence on the efficacy of anti-eflux surgery exists only for esophagitis and/or excessiveistal esophageal acid exposure determined by ambulatorysophageal pH monitoring in a study obtained when PPIherapy was withheld (see discussion of question 12 in theollowing text). Another requirement for antireflux surgerys that some peristaltic function be preserved. Although therecise cutoff is uncertain, severe peristaltic dysfunction is aelative contraindication for antireflux surgery.45 Certainly,omplete absence of peristalsis is an absolute contraindica-ion. Finally, it is important to identify alternative diagnoseshat may masquerade as GERD: functional heartburn, eo-inophilic esophagitis, subtle cases of achalasia, or distalsophageal spasm. Given these priorities, the second diag-ostic evaluation should be an esophageal manometrytudy, which will serve to localize the LES for subsequentH monitoring, to evaluate peristaltic function preopera-ively, and to diagnose the major motor disorders. Recenttudies suggest that high-resolution manometry has supe-
ior sensitivity in recognizing atypical cases of achalasia and G
istal esophageal spasm compared with conventional ma-ometry46,47 (USPSTF grade B, quality fair). The third eval-ation should then be to ascertain whether or not there isxcessive esophageal acid exposure, data that can be ob-ained with a conventional catheter-type pH monitoringtudy, a combined impedance-pH study, or a wireless pH

onitoring study (USPSTF grade B, quality fair). Whetherhis examination should be performed with the patient onr off acid suppressive therapy is debated. The unclearelevance of “normative” data for impedance-pH studieserformed on PPI therapy makes it difficult to interpretuch studies. If normal values are not adjusted, then such ann-PPI study could unequivocally demonstrate PPI nonre-ponse. That, however, rarely occurs. However, a study per-ormed with PPIs withheld that demonstrates only margin-lly abnormal esophageal acid exposure and poor symptomorrelation in a patient being evaluated for persistent symp-oms despite twice-daily PPI therapy raises concern aboutausality. Given that the next therapeutic consideration inhis clinical setting is often antireflux surgery, further works urgently needed to answer this question.

At this point in the diagnostic algorithm, troublesomeymptoms of heartburn, chest pain, regurgitation, or dys-hagia persist despite normal findings on endoscopy (in-luding mucosal biopsy in the case of dysphagia), normalsophageal acid exposure, and a manometry study thatuled out a major motor disorder. Current thinking is thathe major remaining possibilities are a hypersensitivity syn-rome or a functional syndrome, the distinction being that

n the case of a hypersensitivity syndrome symptoms arettributable to reflux events, whereas in the case of a func-ional syndrome they are not. This is a subtle distinctionnd a domain in which there is no high-quality evidenceupporting one management approach or anotherUSPSTF grade Insuff). Because of its added ability to detecteakly and nonacidic reflux, the best tool available to test

eflux-symptom association is impedance-pH monitor-ng,48,49 but the optimal algorithm to use in data analysisas yet to be validated.50 Conversely, the value of a negative

mpedance-pH monitoring study on or off therapy is morelear. In the absence of endoscopic findings, with normalsophageal acid exposure, without significant manometricndings, and with an impedance-pH monitoring study that

ailed to show significant symptom association probabilityetween reflux events and troublesome symptoms, one hasone as far as currently possible to rule out GERD.

5. What Are the Unique ManagementConsiderations in Patients With SuspectedReflux Chest Pain Syndrome?Reflux chest pain syndrome was accepted as one

f the esophageal syndromes without mucosal injuryy the Montreal consensus group (Figure 1), and thereas strong agreement that chest pain indistinguish-ble from ischemic cardiac pain can be caused by
ERD.3 Often referred to as noncardiac chest pain, the

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pidemiology of this disorder is poorly understood,ut population-based studies report community prev-lence rates ranging from 23% to 33%.51–53 In a studysing the General Practice Research Database thatompared 13,740 patients with new-onset chest painith 20,000 age- and sex-matched patients without

hest pain, the odds of patients with chest pain havingschemic heart disease was 14.9, having GERD was 3.0,aving peptic ulcer disease was 3.0, and having dys-epsia was 2.7.54 Another community sample of pa-ients with chest pain concluded that low socioeco-omic status increased the likelihood of cardiactiology, while affluent social strata favored noncar-iac etiologies.55

Because the morbidity and mortality associated withschemic heart disease are substantially greater than thatf GERD and because of the impressive array of availableherapeutic interventions, this diagnosis must be thor-ughly considered before accepting a diagnosis of refluxhest pain syndrome. This important priority substan-ially increases the economic impact of the reflux chestain syndrome.53,54,56 However, once ischemic heart dis-ase has been adequately considered, the relative rarity ofsophageal motor disorders in this group of patients, asell as results from empirical treatment trials of acid

uppressive therapy, suggest that GERD may be the nextost likely etiology.57–59 Illustrative of the rarity of sig-

ificant motility disorders in this patient group, a man-metric study of 140 patients with noncardiac chest painound diffuse esophageal spasm in 2%, nutcracker esoph-gus in 10%, hypertensive LES in 10%, and normal mo-ility in 70% of patients.58 Thus, although esophageal

otility disorders are potential etiologies of noncardiachest pain, significant motility disorders are rare.59

With finding support for a diagnosis of GERD the nextriority, a common clinical strategy in chest pain is anmpirical trial of PPI therapy. Meta-analyses of treatmentrials in patients with suspected reflux chest pain (basedn objective findings from endoscopy or pH monitoring)uggest clinical benefit with twice-daily PPI therapy overlacebo.57,60 The reported pooled sensitivity, specificity,nd diagnostic odds ratio for a short course of PPIherapy are 80%, 74%, and 13.83 (95% confidence interval,.48 –34.91), respectively. Extending the duration of PPIherapy beyond 4 weeks was not beneficial in these pa-ients.60 A cost-effectiveness analysis has also found em-irical treatment with PPIs to be superior to other clin-

cal strategies for this patient group.61

In summary, the first priority in patients with sus-ected reflux chest pain syndrome is to exclude ischemiceart disease as a potential etiology. Once a cardiac eti-logy is excluded, there is sufficient evidence (USPSTFrade A, quality good) to recommend empirical therapyith twice-daily PPIs for 4 weeks. If a patient continues toave chest pain despite this course of therapy, diagnostic
esting with esophageal manometry and pH or imped- a
nce-pH monitoring can exclude motility disorders orefractory reflux symptoms (see also question 4 in therevious text).

6. What Is the Best Initial Management forPatients With Suspected ExtraesophagealReflux Syndromes (Asthma, Laryngitis,Cough)? What Are the Unique ManagementConsiderations With Each? What Is theAppropriate Dose and Course of AntisecretoryTherapy in Each?The Montreal consensus group divided manifes-

ations of GERD into esophageal and extraesophagealyndromes, with the latter divided into those with estab-ished or proposed association (Figure 1).3 Chronicough, laryngitis, and asthma were accepted to have anstablished association with GERD on the basis of pop-lation-based studies confirming an increased risk ofhese symptoms among patients with either esophagitisr esophageal reflux symptoms,51,62,63 with odds ratiosanging from 1.2 to 3.0. However, because cough, laryn-itis, and asthma have a multitude of potential etiologiesther than GERD, they are clearly nonspecific for GERD.urthermore, the causal relationship of GERD with theseonspecific syndromes in the absence of a concomitantsophageal GERD syndrome remains controversial andnproven. The only randomized controlled trials demon-trating a significant treatment effect for a GERD ther-py in these syndromes were in patients who had esoph-geal GERD syndromes in addition to either chronicaryngitis64 or asthma.30,65,66 Considering these data, the

ontreal consensus group concluded that existing evi-ence supports

1) the existence of an association between these syndromes andGERD, 2) the rarity of extraesophageal syndromes occurring inisolation without concomitant manifestations of the typical esoph-ageal syndrome, 3) that these syndromes are usually multifactorialwith GERD as one of the several potential aggravating cofactors,and 4) that data substantiating a beneficial effect of reflux treat-ments on the extraesophageal syndromes are weak.3

Recognizing the difficulty in establishing a causal re-ationship between extraesophageal syndromes and re-ux, substantial investigational effort has been expended

n validating diagnostic tests. However, clinical predictorsmplicating GERD in the extraesophageal syndromesave proven elusive, and the premature adoption ofawed diagnostic criteria has likely resulted in the over-iagnosis of extraesophageal GERD syndromes. Theealth care impact of this overdiagnosis is substantial,sually resulting in multiple (often repeated) diagnosticests and expensive unsuccessful therapies. Alternativeactors (or cofactors) that are often insufficiently ex-lored in these nonspecific extraesophageal syndromes

nclude postnasal drip, allergic rhinitis, infections, habit-al throat clearing, tobacco, alcohol, excessive voice use,
llergens, exercise, temperature or climate changes, emo-

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ional conflicts, and environmental irritants.67,68 Evi-ence supporting the multifactorial nature of the extrae-ophageal syndromes comes from therapeutic trialsargeting GERD in which these nonspecific syndromesmproved but were not resolved.64,69 –71

Given the nonspecific nature of the extraesophagealymptoms and the poor sensitivity and specificity ofiagnostic tests such as pH monitoring, laryngoscopy, orndoscopy for establishing an etiology of GERD,68 em-irical therapy with PPIs has become common practice.he majority of therapeutic trials of these syndromesave used twice-daily dosing of PPIs for treatment peri-ds of 3– 4 months.68,69 The rationale for this unap-roved dosing for unapproved indications comes fromH monitoring data demonstrating that the likelihoodf normalizing esophageal acid exposure with twice-dailyPI therapy in patients with GERD is 93% and in thoseith chronic cough, asthma, or laryngeal symptoms is9%,72 the logic then being that lesser dosing does notxclude the possibility of a poor response because ofnadequate acid suppression. Having said that, there areo controlled studies investigating the optimal dosage oruration of PPI therapy in patients with extraesophagealERD syndromes. The only supportive data for twice-aily PPI dosing are uncontrolled open-label studies ofatients with suspected reflux laryngitis71 or asthma.73

urthermore, despite widespread treatment with PPIswice daily, high-quality evidence supporting treatmentfficacy in these syndromes is still scant.3,68,69 Most en-husiastically supportive studies were uncontrolled withmall sample size. Subsequent attempts to confirm thesendings with controlled trials have shown no therapeuticenefit of PPIs over placebo for chronic cough31 or lar-ngitis.74 A recent controlled trial in patients withsthma suggested slight therapeutic benefit with PPIsnly in the subgroup of asthmatic patients with bothocturnal respiratory and GERD symptoms but no ben-fit in those without nocturnal GERD symptoms.30 Table

summarizes the evidence-based treatment recommen-ations that can currently be made for these extraesopha-eal syndromes.

In summary, patients with suspected extraesophagealERD syndromes may have GERD as a contributing

tiology but rarely as the sole cause. However, the increas-ng incrimination of GERD as an etiologic factor alongith the lack of accurate confirmatory diagnostic tests

able 3. Recommendation for or Against PPI Therapy (Daily oRecommendation for Treatment of Patients With Su

With concomitant esophageal sy

hronic cough Yes (USPSTF grade Insuff)aryngitis Yes (USPSTF grade B, qualitysthma Yes (USPSTF grade B, quality

OTE. The evidence evaluated pertains to the treatment response of

ave resulted in widespread overdiagnosis and overtreat- c

ent of these conditions. Nonetheless, empirical therapyith twice-daily PPIs for 2 months remains a pragmatic

linical strategy for subsets of these patients if they haveconcomitant esophageal GERD syndrome (USPSTF

rade B, quality fair; Table 3). However, once- or twice-aily PPIs (or H2RAs) for acute treatment of potentialxtraesophageal GERD syndromes, including laryngitisnd asthma, in the absence of a concomitant esophagealERD syndrome cannot be supported and appears inef-

ective based on presently available data (USPSTF grade, quality fair).The role of pH or impedance-pH monitoring in estab-

ishing these diagnoses is controversial and unproven.onversely, similar to the case with symptomatic esoph-geal syndromes, the value of a negative pH or imped-nce-pH monitoring study is clearer. In the absence ofroublesome esophageal symptoms or endoscopic find-ngs, with a failed 8-week therapeutic trial of twice-dailyPI therapy, and with normal esophageal acid exposure

PPI therapy withheld) on 24-hour monitoring, one hasone as far as currently possible to rule out GERD as aignificant contributor to these nonspecific syndromes.uch patients should have etiologies other than GERDxplored.

Chronic Management

7. Does GERD Progress in Severity, SuchThat Symptomatic Patients WithoutEsophagitis Develop Esophagitis and Barrett’sMetaplasia, or Are These Distinct DiseaseManifestations That Do Not Exist Along aContinuum? If Patients Do Progress, at WhatRate Does This Occur, and Does It WarrantEndoscopic Monitoring?Two potential paradigms for viewing the natural

istory of GERD exist. In the first, GERD is viewed as arogressive disease such that, in the absence of effective

ntervention, today’s patient with nonerosive disease be-omes tomorrow’s patient with erosive disease, who thenecomes a candidate for the development of Barrett’ssophagus.75 This “spectrum of disease” approach haseen contrasted with the view that GERD may be aisease with phenotypically discrete “categories,” such asonerosive disease, erosive esophagitis, and Barrett’ssophagus.76 In this phenotypically preordained view,

ice Daily) and the Strength of Evidence Supporting Thatted Extraesophageal GERD Syndromes

e Without concomitant esophageal syndrome

No (USPSTF grade D, quality fair)31



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onversion from one disease manifestation to another is

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istinctly unusual, and subjects generally stay in theirnitial category.

Given the high prevalence of GERD in Western popu-ations, there is a decided paucity of data with which toddress the question of long-term manifestations ofERD and the risk of progression in an evidence-basedanner. Add to this the fact that essentially all reported

ohorts are treatment cohorts, and our ability to describehe natural history of the disease becomes even moreimited. Several long-term cohort studies have been re-orted and are described in Table 4, along with reportedonversion rates to more severe forms of disease.2,77– 87 Ashown, length of follow-up and disease progression varyubstantially among the studies. Furthermore, whetherhese data represent true progression or the relapsing andemitting nature of a chronic disease is unclear. However,he data do permit some generalizations. First, in sub-ects with GERD treated in an uncontrolled fashion,here is some risk of progression from nonerosive disease

able 4. Cohort Studies of the Natural History of Reflux Dise

AuthorsCohort size and

compositionMean or rangeyears followed

chindlbeck et al, 199277 24 3.4(NERD, 16; EE, 8)

solauri et al, 199778 60 17–22Severe GERD

symptomscDougall et al, 1997and 199879,80

77 3–4.5

(NERD, 23;EE, 33)

etscher et al, 200181 83 2Mild EE

anabe et al, 200282 105 5.5First diagnosis EE

ace et al, 200483 18 10NERD

ajbouj et al, 200584 34 2.9NERD

awanishi, 200685 497 5.0 NERD5.3 Normal(NERD, 47; normal,

450)abenz et al, 200686 3894 2

(NERD, 1717;LA A/B, 1512;LA C/D, 278;BE, 387)

toltey et al, 200787 684 3.4(GERD, 515

[103 erosive];BE, 169)

ontag et al, 20062 2306 7.6 (1–20)(NERD, 1313; EE,

957; BEexcluded)

ERD, nonerosive reflux disease; EE, erosive esophagitis; BE, Basophagitis.

o erosive esophagitis. However, the risk of developing a s

tricture, conversion to Barrett’s metaplasia, or develop-ng adenocarcinoma appears to be low within the 2- to0-year time frame of these studies. Substantial numbersf subjects, especially if treated with antisecretory medi-ations,2 appear to regress to lesser grades of erosivesophagitis and even to nonerosive disease. Progressionnd regression are not predictable based on symptomuration or demographics.88

Patients with GERD often inquire how often theyhould undergo endoscopy to monitor the condition ofheir mucosa. The role of endoscopy in the managementf GERD will be discussed more completely in the fol-

owing text, but there are no data demonstrating thatoutine endoscopy to assess for disease progression inubjects with erosive or nonerosive reflux disease resultsn improved patient outcomes, and this practice shoulde discouraged (USPSTF grade D, quality fair). However,

t is likely that slow disease progression will occur over aeriod of decades in a small subset of patients, because

Progression dataRegression data

(treatment variable)

NERD to EE: 25%Grade 2 to grade 3: 12.5%

Grade 3 to grade 1: 25%

NERD to esophagitis: 17%Worsened esophagitis: 40%Esophagitis to BE: 0%

NR

NERD to esophagitis: 24%Esophagitis to BE: 11%Symptoms only to positive pH study

and/or esophagitis: 31%

NR

14.5% mild esophagitis to BE NR

10.5% (to more severe EE) 29.5% (EE to nonerosive)

NERD to esophagitis: 89% NR

5.9% NERD to BE —

Normal to LA A/B: 11.3%NERD to LA A/B: 36.2%

NERD to normal: 10.6%

NERD to LA A/B: 24.9%LA A/B to LA C/D: 1.6%NERD to LA C/D: 0.6%NERD to BE: 0.5%LA A/B to BE: 1.4%LA C/D to BE: 5.8%

LA A/B to NERD: 61.3%,LA C/D to LA A/B: 41.8%LA C/D to NERD: 50.4%

EE to BE: 1%Nonerosive to BE: 0%Nonerosive to EE: NR

NR

NERD to erosive: 15.6%NERD to stricture: 0.1%Erosive to stricture: 1.9%GERD to adenocarcinoma: 0.1%

EE to NERD: 43.7%

s esophagus; NR, not reported; LA, Los Angeles classification of

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denocarcinoma are all more prevalent among older in-ividuals.89

In summary, data suggest that while subjects withERD may sometimes progress from nonerosive disease

o erosive esophagitis, demonstrating that it is not atrictly categorical disease, the reported rates of progres-ion are relatively low over a 20-year period, the longestime frame for which published data exist. In patients inhom stricture, Barrett’s metaplasia, and adenocarci-oma were carefully excluded in the setting of a healeducosa at index endoscopy, the likelihood of these de-

eloping within a 7-year follow-up period is on the orderf 1.9%, 0.0%, and 0.1%, respectively.2 On the other hand,he likelihood of developing Barrett’s esophagus after theealing of high-grade esophagitis (or unmasking preva-

ent disease) is about 6%,86 making endoscopy in theetting of Los Angeles grade C or D esophagitis an inad-quate examination to exclude the presence of Barrett’ssophagus. Most importantly, upper endoscopy has noteen shown to diminish the risk of cancer in the settingf chronic GERD symptoms (USPSTF grade Insuff).

8. What Maintenance Therapy Is Indicatedfor Patients With the Typical EsophagealReflux Syndrome (With or WithoutEsophagitis)? When and How ShouldAntisecretory Therapy Be Decreased orDiscontinued? What, If Any, Risks AreAssociated With This?The utility of maintenance therapy in patients

ith GERD depends on the manifestation of the diseaseeing monitored, with the strongest data pertaining torosive esophagitis. Subjects not maintained on contin-ous acid suppressive therapy have high rates of recur-ence of erosive disease, with some studies documenting�80% recurrence rate within 12 months of discontinu-

ng treatment.90,91 Multiple rigorous randomized con-rolled trials,92,93 summarized in a recent high-quality

eta-analysis,94 show that the recurrence of erosivesophagitis in subjects with GERD is dramatically de-reased by PPI treatment. The meta-analysis found thatn 10 studies assessing maintenance therapy with main-enance doses of PPI (generally half the healing dose) for6 –52 weeks, 36% of subjects taking PPIs experiencedelapse of erosive disease, compared with 75% takinglacebo. The relative risk of relapse in PPI users was 0.46,nd the number needed to treat was 2.4. Reflux symp-oms were also better controlled with maintenance-dosePI therapy than with placebo (44.4% vs 73.4% had sig-ificant symptoms). The therapeutic gain was even moreubstantial when healing-dose PPI therapy was comparedith placebo. Although several of the comparisons showedeterogeneity among individual trial results, on balance, theata strongly suggest that, when compared with placebo,hronic acid suppression with PPIs prevents relapse of ero-ive esophagitis for at least 6–12 months in subjects healed
f the condition (USPSTF grade A, quality good). Similarly t
trong are randomized controlled trials between H2RAs andither healing- or maintenance-dose PPIs, with subjects ran-omized to H2RAs up to twice as likely to have recurrentsophagitis.95,96

The role of daily maintenance therapy in patients withonerosive disease is less clear. Patients with an esopha-eal GERD syndrome without esophagitis who initiallyesponded to a PPI randomized to maintenance-dose PPIherapy are less likely to have recurrent symptoms thanhen randomized to an H2RA97 or placebo.98 WhetherPI dosing needs to be continuous as opposed to “on-emand” (daily until resolution of symptoms) has alsoeen studied, using the willingness of the patient toontinue on-demand therapy and the proportion of dayshat the patient self-medicates as outcomes. A systematiceview of 17 such studies (15 of which were randomizedontrolled trials) showed that subjects with either non-rosive or uninvestigated GERD did well with on-de-and regimens.99 For example, Tsai et al randomized 622

ubjects with nonerosive disease to either on-demandsomeprazole 20 mg or daily lansoprazole 15 mg.100 Sub-ects assigned to on-demand therapy were actuallylightly more likely to be willing to continue therapy thanubjects in the continuous therapy arm (93% vs 88%) andsed much less medication (0.3 vs 0.8 doses per day). Onalance, the data suggest that on-demand therapy is aeasonable strategy in patients with an esophageal GERDyndrome without esophagitis where symptom control ishe primary objective (USPSTF grade B, quality good). Inontrast, in those with known erosive esophagitis whore healed with continuous PPI therapy and then ran-omized to either continuous or on-demand therapy, theecurrence rates of erosive disease are high in subjectsreated with on-demand compared with continuous ther-py (42% vs 19% at 6 months; P � .00001).101 Therefore,n-demand therapy cannot be recommended for main-aining healing of erosive esophagitis (USPSTF grade D,uality good).

The evidence presented in the previous text makes itasy to say that continuous PPI therapy is recommendedo maintain a healed mucosa and that discontinuingherapy will likely result in recurrent heartburn.102,103

owever, there are no high-quality data to suggest thatontinuous antisecretory therapy alters the natural his-ory of reflux disease other than to reduce the (alreadyow) incidence of peptic stricture.2 There are also no datao the effect that intermittent esophageal erosions orome degree of residual symptomatology is harmful.ence, the main identifiable risk associated with reduc-

ng or discontinuing PPI therapy is of an increased symp-om burden. It follows that the decision regarding theeed for (and dosage of) maintenance therapy is driveny the impact of those residual symptoms on the pa-ient’s quality of life rather than as a disease control

easure. Certainly, the data in Table 4 do not support
he contention that residual GERD symptoms predispose

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atients to the development of Barrett’s esophagus orsophageal adenocarcinoma. Pragmatically, this meanshat many subjects beginning PPI therapy will receive thisherapy chronically, but often intermittently. Interest-ngly, an accumulating body of literature now shows thatven when subjects are instructed to take daily PPI ther-py for GERD, compliance plummets within 3 months ofnstituting therapy, such that the majority of subjectsecome noncompliant with daily dosing.104

In summary, chronic PPI therapy will be required fordequate symptom control in the majority of subjectsith GERD symptoms severe enough to warrant initialPI therapy. While many subjects may tolerate dose re-uction of their PPI and maintain adequate symptomontrol, the likelihood of long-term spontaneous remis-ion of disease is low and conservative measures arenlikely to suffice on their own. Beyond recurrence ofymptoms and/or erosive disease, the risks associatedith cessation of therapy, including the possible devel-pment of Barrett’s esophagus, are minimal. Data sug-est that on-demand dosing or intermittent courses ofPIs is the regimen preferred by most patients regardlessf physician instructions.

9. What Maintenance Therapy Is Indicatedfor Patients With Suspected ExtraesophagealReflux Syndromes (Asthma, Laryngitis,Cough)? When and How Should AntisecretoryTherapy Be Decreased or Discontinued?Owing to the nonspecificity of the extraesopha-

eal reflux syndromes for GERD, at least 40%–50% ofatients will have persistent symptoms after 8 weeks ofmpirical PPI therapy. In this group of patients, the needor continued PPI therapy is predicated on the presencend severity of concomitant esophageal syndromes withr without mucosal injury. Although the true prevalencef esophageal mucosal abnormalities in this group ofatients is unknown, uncontrolled observational studiesf small sample sizes suggest the presence of esophagitisnd Barrett’s mucosa in 12% and 7%, respectively.105,106 Inhe absence of concomitant esophageal GERD syn-romes, PPI therapy should be discontinued and otheriagnostic and/or therapeutic avenues explored.There are no trials showing the effectiveness of main-

enance therapy for patients in whom empirical therapyith twice-daily PPI therapy results in improvement ofsthma, cough, or laryngitis. Thus, recommendationsegarding maintenance therapy in this group of patientsre based on expert opinion extrapolated from the typicalsophageal reflux syndrome literature (see discussion ofuestion 8 in the previous text) (USPSTF grade Insuff).lthough early observations suggested some associationetween reflux-induced laryngeal inflammation and la-yngeal cancer,107 critical appraisal of these data suggestshat such associations are inconclusive and mostly bi-
sed.108 Hence, the objective of continued maintenance e
herapy in patients with an extraesophageal reflux syn-rome is symptom control and, just as with the typicalsophageal syndromes, step-down therapy should be at-empted. The likelihood of symptom recurrence withtep-down therapy in patients with an extraesophagealeflux syndrome is currently unknown. However, a dou-le-blind placebo-controlled trial addressing the issue ofiscontinuing PPI therapy in an unselected group ofatients on chronic PPI therapy reported a disappointing1% likelihood of remaining PPI free at 1 year in patientsith typical GERD symptoms and 48% in patients with-ut typical GERD symptoms, highlighting the tendencyoward long-term use in many patients.109

In summary, step-down therapy should be attemptedn all patients with extraesophageal reflux syndromesfter empirical twice-daily PPI therapy. Continuing main-enance PPI therapy should be predicated on either theequirements of therapy for concomitant esophagealERD syndromes or extraesophageal syndrome symp-

om response. In both cases, maintenance therapy shoulde with the lowest PPI dose necessary for adequate symp-om relief.

10. What Are the Clinical Consequences ofChronic Potent Acid Inhibition? Do ThesePotential Side Effects Warrant SpecificTesting (eg, Bone Density Studies, CalciumSupplementation, Helicobacter pyloriScreening, and so on)?Most of the mortality from reflux disease stems

rom its link with esophageal adenocarcinoma, and theres no high-level evidence that the risk is reduced by anyurrently available GERD therapy.110 Epidemiologic evi-ence does, however, suggest a substantial risk reductionith aspirin or nonsteroidal anti-inflammatory drugse.111 Apart from esophageal adenocarcinoma, the mor-ality associated with reflux disease is very low, estimatedt 0.46/100,000 in the year 2000.112 Given the profoundlyow mortality rate of this disease, therapies for GERD

ust be extremely safe to satisfy an acceptable risk-enefit ratio.

Because PPIs work by profoundly reducing gastric acidecretion, which in turn results in a reactive increase inastrin secretion, most consideration of long-term risk isocused on unwanted effects of secondary hypergastrine-

ia, hypochlorhydria, or even achlorhydria. Other, moreeneric considerations have to do with drug-drug inter-ctions and potential teratogenicity. In general, theseisks are slight if even demonstrable, but the widespreadse of PPIs coupled with the frequent need for chronic,ften open-ended therapy mandate that they be scruti-ized. Table 5 summarizes the available data on the risksf long-term PPI use.113–128

The data in Table 5 show no worrisome safety signalsith PPIs. The most convincing data link PPI use with an

ncrease in Clostridium difficile colitis and bacterial gastro-
nteritis, but in each case the magnitude of risk is slight.

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ith respect to the hip fracture issue, there are manyotential confounders to the data, but the putative mech-nism would be decreased calcium absorption, which haseen shown with PPI use.129 Regardless, it is good med-

cal practice to screen and treat the elderly for osteopo-osis irrespective of PPI use. To summarize all availableisk/benefit data on PPIs, their use is strongly justifiedhen clinically indicated (USPSTF grade A, qualityood). Conversely, there is inadequate evidence to man-ate bone density studies, calcium supplementation, Hylori screening, or any other routine precautions becausef PPI use (USPSTF grade Insuff). Having said that, manyf the potential rare side effects of PPIs are dose related,nd PPIs should be used for conditions in which theyave proven efficacy and at the minimal effective dosage.fter all, in the absence of benefit, a risk-benefit ratio islways unacceptable.

11. What Is the Role of Endoscopy in Long-term Management of Patients With GERD,and Under What Circumstances ShouldMucosal Biopsy Specimens Be Obtained WhenEndoscopy Is Performed?Because PPI treatment is usually rendered empir-

able 5. Potential Risks of Long-term PPI Therapy

otential risks of hypochlorhydria (trophic, absorptive)Hypergastrinemia-induced carcinoid tumorsAccelerated progression of atrophic gastritis/gastric cancer with

concomitant H pylori gastritis115

Formation of gastric fundic gland polyps168

Vitamin B12 malabsorption

Calcium malabsorption

Iron malabsorption

otential risks of hypochlorhydria (infectious)Increased risk of C difficile colitis

Increased risk of community-acquired pneumonia (presumablyaspiration)

Gastric colonization with bacteria that convert nitrates tocarcinogenic N-nitroso compounds that then reflux117

eneric pharmacologic risksSafety in pregnancy (omeprazole crosses placenta and is

pregnancy safety category C; other PPIs are category B)Drug-drug interactions; PPIs metabolized by cytochrome P450

and may induce or inhibit drug metabolism (phenytoin,warfarin, and so on)

AnaphylaxisAcute interstitial nephritis

Pancreatitis

cally before testing, the sensitivity of endoscopy as a s

iagnostic test for GERD is poor. Hence, the principalse of endoscopy in patients with suspected GERD is thevaluation of treatment failures and risk management.

ost of the morbidity and mortality from reflux diseasetems from its link with esophageal adenocarcinoma, andhat risk has not been shown to be decreased by anyurrent GERD therapy.110 Otherwise, the mortality asso-iated with reflux disease is very low, estimated at 0.46/00,000 in the year 2000, and mainly attributable toemorrhagic esophagitis (38%), ulcer perforation orsophageal rupture (19%), aspiration pneumonia (19%),nd complications of antireflux surgery (11%).112 Puttinghe risk of adenocarcinoma in perspective, data from theurveillance Epidemiology and End Results database sug-est that there were about 8000 incident cases of esoph-geal adenocarcinoma in the United States in 2004130

nd, depending on interpretation of the data, this diseaseurden has increased anywhere from 2- to 6-fold relativeo 20 years prior.131,132

The 5-year survival of patients with esophageal adenocar-inoma is very poor, but it is greatly improved by earlyetection: 58% for patients with tumors detected in situersus 10% for patients with tumors detected after regional

Risk magnitude/possible consequenceNot demonstrated in humans113

No documentation of an increase in atrophic gastritis and no basisto recommend testing or treatment for H pylori before long-termPPI use116

Odds ratio of 2.2 for developing fundic gland polyps within 1–5years,168 negligible, if any, risk of dysplasia

Some patients show decreased vitamin B12 levels after years ofacid inhibition,113 case reports (2) of clear deficiency114

Nested case-control study of UK patients older than 50 years;adjusted odds ratio of 1.44 (95% confidence interval,1.30–1.59) of hip fracture with PPI use longer than 1 year122

Poor response to oral iron supplement absorption in 2 iron-deficient individuals improved after cessation of omeprazole; noclear clinical relevance169

PPI use is independent risk of C difficile diarrhea in antibioticusers, odds ratio of 2.1 (95% confidence interval, 1.2–3.5)120

Nested case-control analysis, adjusted odds ratio for pneumoniawith PPI use of 1.73 (95% confidence interval, 1.33–2.25)121

Data on PPI use and increased gastric N-nitrosamine remainuncertain and the risk of cancer is speculative113

Based on 345 accidental exposures compared with 787 controls,no observed increased teratogenecity123

Clinically significant PPI drug-drug interactions are rare (�1/millionprescriptions)124

One case report with lansoprazole125

64 cases worldwide, partially reversible (one case requiresdialysis, no deaths), estimated risk 1/12,500 patient-years oftherapy126,127

Population-based case-control study adjusted odds ratio of 3.2(95% confidence interval, 1.4–7.4128

pread.133 The other potential benefit of endoscopy in the

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etting of chronic GERD is detection of Barrett’s esophagus,metaplastic change of the distal esophageal mucosa ac-

nowledged to be a premalignant condition. The risk ofeveloping esophageal adenocarcinoma in Barrett’s esoph-gus is estimated at 0.5% per year.134 Thus, the proposedtrategy for controlling the risk of cancer is to screen theERD population for Barrett’s esophagus, to survey iden-

ified individuals for the development of dysplasia and ad-nocarcinoma, and to resect or ablate these lesions whenound. In the hope of controlling the risk of adenocarci-oma, past societal guidelines, including those of the Amer-

can Society of Gastrointestinal Endoscopy135 and themerican College of Gastroenterology,136,137 have sup-orted consideration of the use of at least once-in-a-lifetimendoscopy to screen subjects with chronic GERD symp-oms for the presence of Barrett’s esophagus or early cancer.owever, these guidelines are based solely on expert opinion

ecause no direct data exist to substantiate the utility ofcreening or surveillance endoscopy to detect Barrett’ssophagus or to monitor the condition for progression toancer.

Evidence supporting the strategy of reducing esopha-eal adenocarcinoma mortality by screening for Barrett’ssophagus is scarce. For such a strategy to work well,atients with Barrett’s esophagus would need to consti-ute the majority of patients at risk for cancer, the sever-ty of reflux symptoms would have to be predictive ofnding Barrett’s esophagus, and endoscopy would effec-ively identify patients with Barrett’s esophagus, leadingo altered clinical management that improved the clinicalutcome. To date, none of these conditions have beenorne out in clinical trials. (1) In a Swedish population-ased endoscopy study, the prevalence of Barrett’s esoph-gus (1.6%) was not correlated with reflux symptoms.138

2) In a nationwide case-control study, more than 40% ofwedes destined to develop esophageal adenocarcinomaeported no antecedent reflux symptoms.139 (3) In a Kai-er Permanente cohort study, 454 of 589 patients withsophageal or gastric cardia adenocarcinoma had nodentifiable Barrett’s metaplasia evident in any pathologypecimen.140 (4) In the same cohort, among 64 patientsho had undergone endoscopy before detection of can-

er, only 38% had Barrett’s esophagus identified.140 (5)nalyses of 2 large Barrett’s esophagus surveillance pro-rams concluded that, although a small number of inci-ent esophageal adenocarcinomas were detected, thereas no improvement in survival attributable to the sur-

eillance program.141,142 These data were reviewed by anGA consensus workshop composed of 18 experts in

he field of Barrett’s esophagus in 2004.143 After con-ucting an evidence-based review of the utility of en-oscopic screening of subjects with chronic GERDymptoms for the detection of Barrett’s esophagus orancer, this group strongly rejected the statement thatEndoscopic screening for Barrett’s esophagus and
ysplasia has been shown to improve mortality from c
sophageal adenocarcinoma” and concluded that therade of evidence in support of this intervention wasinsufficient to form an opinion” (USPSTF grade In-uff). Regarding the corollary statement that “Endo-copic screening for BE and dysplasia should be per-ormed in all adults �50 years of age with �5–10 yearsf heartburn,” the supporting evidence was againraded only at the level of expert opinion, and againhe majority of the group either rejected the statementr rejected it with reservation (USPSTF grade Insuff).In summary, despite the ubiquity of the practice, no

irect evidence supports the use of endoscopy as a screen-ng test for Barrett’s esophagus or esophageal adenocar-inoma in the setting of chronic GERD. Regarding theriteria for obtaining mucosal biopsy specimens in theourse of performing an endoscopy, there is no basis todvocate doing this routinely but, clearly, biopsy speci-ens of any areas suspected of being metaplastic should

e obtained and carefully evaluated for dysplasia.

12. What Are Indications for AntirefluxSurgery, and What Is the Efficacy of ThisTherapy?Few topics in the management of patients with

ERD are as controversial as the indications for andfficacy of antireflux surgery. With the introduction ofaparoscopic Nissen fundoplication in 1991, the numberf adult antireflux surgeries performed in the Unitedtates rapidly increased from 11,000 per year in 1985 to1,695 in 1999.144 This increase was largely driven by thenthusiastic endorsement of the procedure by endo-copic surgeons and surgery departments in a number ofisease scenarios, typified by guidelines from the Societyor Gastrointestinal and Endoscopic Surgeons claiminghat the procedure was curative in 85%–93% of cases.145

owever, since 1999, the number of adult antirefluxurgeries performed in the United States has steadilyallen; by 2003, it had declined by 30% to 23,998 cases.144

he decline has been greatest among young patients,8 –39 years of age (38%), and at teaching versus non-eaching hospitals (36% vs 23%). There is also substantialegional variation in the utilization of antireflux surgery,uggesting a lack of consensus among practitioners withespect to the appropriate indications.144

Just as with PPI therapy, evidence of the utility ofntireflux surgery depends on the manifestation of theisease being monitored, with the strongest data pertain-

ng to erosive esophagitis. However, the utility of olderata randomizing subjects to either medical care with2RAs or Nissen fundoplication by the open approach146

re limited because of advances in care in both domains.ore recent data comparing laparoscopic fundoplicationith PPI therapy are more germane to current practicend will be considered here. Illustrative of this, Lundell etl have reported 5- and 7- year results of a randomized
ontrolled trial of patients with esophagitis treated with

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meprazole 20 – 60 mg/day or antireflux surgery. At 7ears, the 2 treatment arms were similar with respect tohe incidence of recurrent esophagitis (10.3% omeprazoles 11.8% antireflux surgery).147 Hence, if the outcome ofmportance is maintaining a healed esophageal mucosa,he 2 therapies appear to be equivalent.

As for other manifestations of the esophageal GERDyndromes with esophageal injury, there are no data com-aring the efficacy of PPIs with antireflux surgery in stric-ure prevention, and controlled data have shown no changen the prevalence of Barrett’s esophagus or in the incidencef adenocarcinoma when patients treated surgically wereompared with those treated medically.110,148 It is importantor providers and patients to understand that the risk ofhis cancer to the average subject with reflux symptoms isxtremely low (�1 in 10,000 per patient-year).149 Evenhough the safety profile of antireflux surgery is excellentor a surgical procedure, the low risks of morbidity and

ortality still dwarf any potential benefit in reduction ofancer risk. Even among subjects with Barrett’s esophagus,ho have a higher risk of cancer than the general GERDopulation, randomized controlled trial data150 and a re-ent meta-analysis151 fail to substantiate any protective ef-ect of surgery against cancer.

The relative efficacy of antireflux surgery to PPIs in con-rolling symptomatic esophageal syndromes and extrae-ophageal syndromes with an established association withERD is less clear. If the analysis is restricted to the controlf heartburn and acid regurgitation as determined by inves-igator interview or questionnaire, studies suggest modestuperiority of antireflux surgery to PPI therapy, on the orderf a 10% therapeutic gain.147,152 However, the data areidely divergent. As many as 30% of subjects who undergo

his procedure continue to use medical therapy by 5 yearsfter the procedure and surgical revision is common. Also,lthough community-based outcome data are sparse com-ared with that generated from specialized referral centers,he data suggest that subjects from community-based series

ay have poorer outcomes and lower patient satisfactionhan those in specialized, presumably higher-volume cen-ers.153,154 With respect to the extraesophageal syndromes,here are no controlled data comparing PPIs with antirefluxurgery, but observational studies suggest some benefit ofntireflux surgery for highly selected patients with refluxough syndrome66,155 and reflux asthma syndrome.65,156

ence, if the outcome of importance is controlling eitherymptomatic esophageal syndromes or extraesophagealymptoms in carefully selected patients, antireflux surgeryas greater efficacy than PPI therapy. However, these bene-ts must be weighed against the deleterious effect of newymptoms consequent from antireflux surgery. Dysphagiaf sufficient severity to require esophageal dilation occurs inbout 6% of patients treated with antireflux surgery,157,158

nd both controlled147 and uncontrolled trials159 havehown a significant increase in flatulence, an inability to
elch, and increased bowel symptoms after antireflux sur- p
ery. Given this balance, the recommendation for antirefluxurgery is stronger in the case of the symptomatic esopha-eal syndromes, especially with troublesome regurgitationUSPSTF grade B, quality fair), than for extraesophagealymptoms (USPSTF grade C, quality fair).

As alluded to in the discussion of the risks associatedith chronic PPI therapy (question 10), the otherwise loworbidity and mortality associated with GERD mandate

hat GERD therapies must be extremely safe to satisfy ancceptable risk-benefit ratio. Table 6 summarizes thevailable morbidity and mortality data on antireflux sur-ery.153,157,160 –165 Note that unlike the treatment efficacyata, in which case it is reasonable to restrict the analysiso controlled studies from highly specialized centers, it is

ore relevant to assess morbidity and mortality datarom the perspective of larger data sets reflective of theverall impact of the intervention on public health. Sim-

larly, it is reasonable to compare the data in Table 6 withhat in Table 5, detailing what is known of the risks ofong-term PPI therapy. Given that comparison, from theantage point of risk, if antireflux surgery and PPI ther-py were estimated to be equally effective for a patient,PI therapy should be strongly recommended (USPSTFrade A, quality good).

In contrast to the data regarding antireflux surgery,igh-quality data on endoluminal antireflux proceduresemain sparse. Most available studies were designed tohow proof of principle in this rapidly evolving area. Toate, no studies compare the efficacy of these devicesith either optimal medical therapy or antireflux surgery.lthough the latest of these devices show promise,166,167

he dearth of comparative data, as well as the smallumber and relatively short follow-up of subjects treated,ake it premature to frame recommendations for their

se in GERD (USPSTF grade Insuff).In summary, the current indications for antireflux sur-

ery are well circumscribed. Patients with esophagitisho are well maintained on medical therapy have noth-

ng to gain from antireflux surgery and incur significantisk; they should be advised against surgery (USPSTFrade A, quality good). Patients with esophagitis who arentolerant of PPIs will likely benefit from antireflux sur-ery and should be so advised (USPSTF grade A, qualityood). Patients with symptoms of the esophageal GERDyndrome poorly controlled by PPIs may benefit fromurgery, especially in the setting of persistent trouble-ome regurgitation (USPSTF grade B, quality fair). How-ver, the recommendation for antireflux surgery must bealanced with a thorough discussion of potential post–ntireflux surgery symptoms. Finally, carefully selectedatients with extraesophageal GERD syndromes inhom a reflux causality has been established to thereatest degree possible (see question 4) may benefit fromntireflux surgery, and it should be recommended withppropriate restraint (USPSTF grade C, quality fair). The
aucity of comparative data on endoluminal antireflux

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rocedures with either optimal medical therapy or anti-eflux surgery makes it impossible to define the role ofuch techniques in our current treatment algorithmUSPSTF grade Insuff).

ConclusionsIn formulating guidelines for the management of

atients with GERD, we found the Montreal definition ofERD3 (Figure 1) to be very useful and structured our

ecommendations around it. Contemplating the broadomain of the Montreal definition, an immediate con-lusion was that much of the management of patientsith GERD in terms of diagnostic tests and diseaseanagement is based on uncontrolled trials, clinical ex-

erience, or expert opinion rather than randomized con-rolled clinical trials; high-quality trials in these areasimply do not exist. Randomized controlled clinical trialsre, however, ubiquitous in the domain of therapy for thesophageal GERD syndromes, especially pharmacologicherapies for esophagitis. Hence, it is not surprising that

ost of the highest-level evidence-based recommenda-

able 6. Complications From Antireflux Surgery

eathPopulation-based, Finland; January 1, 1987, to January 1, 1996; n

Danish, population-based; 1997–2005; n � 2465 primary fundopl

US VA database; October 1, 1990, to January 29, 2001; n � 314US population-based cohorts, Washington state and US Health Ca

1997164

Meta-analysis of reports published from 1991 to 1995; specialty c0–36 mo160

ife-threatening complicationsPopulation-based, Finland; January 1, 1987, to January 1, 1996; n

Danish, population-based; 1997–2005; n � 2465 primary FP and

US population-based cohorts, Washington state and US Health Ca1997164

Meta-analysis of reports published from 1991 to 1995; specialty cWisconsin managed care network; community practices, n � 8715

eoperations (redo)Danish, population-based; 1997–2005; n � 2465 primary fundopl

US VA database; October 1, 1990, to January 29, 2001; n � 3144.5 yr157

Wisconsin managed care network; community practices, n � 8715

ysphagia severe enough to require dilationUS VA database; October 1, 1990, to January 29, 2001; n � 314

4.5 yr157

Meta-analysis of reports published from 1991 to 1995; specialty c0–36 mo160

Wisconsin managed care network; community practices, n � 8715

Specialty center, retrospective review of June 1996 to October 19

NF, laparoscopic fundoplication; OF, open fundoplication; RF, redo f

ions that can be made pertain to that scenario. However,

he acute management of patients with esophagitis isarely a clinical dilemma in current practice. Hence, weocused instead on the clinical quandaries that do con-ront the clinician with great regularity and examined thevidence that could be brought to bear on those issues.

e used the USPSTF grades detailed in Table 1 to ascer-ain whether or not particular practices or therapiesould be recommended based on published evidence.onceptually, USPSTF grades evaluate a risk-benefit as-

essment for diagnostic or therapeutic interventions. Al-hough relatively few of our conclusions achieved theighest USPSTF grade, a substantial number achieved andequate grade upon which to base pro or con recom-endations. Our major conclusions follow.

Grade A: Strongly Recommended Based onGood Evidence That It Improves ImportantHealth Outcomes

I. Antisecretory drugs for the treatment of patientswith esophageal GERD syndromes (healing esoph-

162 LNF; n � 3993 OF163 LNF � 0.1%OF � 0.2%

n and 124 RF162 Primary � 0.45%RF � 0.81%LNF and OF � 0.8%

ilization Project, 1992– Washington � 0.4%US Health CareUtilization Project � 0.8%

rs, n � 2453; follow-up, LNF � 0.2%

162 LNF; n � 3993 OF163 LNF � 1.2%OF � 0.6%

RF162 Primary FP � 1.3%RF � 1.6%

ilization Project, 1992– Washington � 2.0%US Health CareUtilization Project � 3.4%

rs, n � 2453160 LNF � 1.5%LNF � 3.4%

ns162 1.5%/yr in first 2 yr1.0%/yr next 2 yr0.3%/yr in following years

h a median follow-up of LNF and OF � 2.3%

LNF � 7.0%

h a median follow-up of LNF and OF � 6.4%

rs, n � 2453; follow-up, LNF � 3.5%

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of esophagitis). In these uses, PPIs are more effectivethan H2RAs, which are more effective than placebo.

II. Long-term use of PPIs for the treatment of patientswith esophagitis once they have proven clinically effec-tive. Long-term therapy should be titrated down to thelowest effective dose based on symptom control.

II. When antireflux surgery and PPI therapy are judgedto offer similar efficacy in a patient with an esopha-geal GERD syndrome, PPI therapy should be recom-mended as initial therapy because of superior safety.

IV. When a patient with an esophageal GERD syndromeis responsive to, but intolerant of, acid suppressivetherapy, antireflux surgery should be recommendedas an alternative.

IV. Twice-daily PPI therapy as an empirical trial for pa-tients with suspected reflux chest pain syndromeafter a cardiac etiology has been carefully considered.

Grade B: Recommended With Fair EvidenceThat It Improves Important Outcomes

I. Weight loss should be advised for overweight orobese patients with esophageal GERD syndromes.

II. Elevation of the head of the bed for selected pa-tients who are troubled with heartburn or regurgi-tation when recumbent. Other lifestyle modifica-tions including, but not limited to, avoiding latemeals, avoiding specific foods, or avoiding specificactivities should be tailored to the circumstances ofthe individual patient.

III. Twice-daily PPI therapy for patients with an esoph-ageal syndrome with an inadequate symptom re-sponse to once-daily PPI therapy.

IV. A short course or as-needed use of antisecretorydrugs in patients with a symptomatic esophagealsyndrome without esophagitis when symptom con-trol is the primary objective. For a short course oftherapy, PPIs are more effective than H2RAs, whichare more effective than placebo.

V. Endoscopy with biopsy for patients with an esoph-ageal GERD syndrome with troublesome dyspha-gia. Biopsies should target any areas of suspectedmetaplasia, dysplasia, or in the absence of visualabnormalities, normal mucosa (at least 5 samples toevaluate for eosinophilic esophagitis).

VI. Endoscopy to evaluate patients with a suspectedesophageal GERD syndrome who have not re-sponded to an empirical trial of twice-daily PPItherapy. Biopsies should target any area of sus-pected metaplasia, dysplasia, or malignancy.

VII. Manometry to evaluate patients with a suspectedesophageal GERD syndrome who have not respondedto an empirical trial of twice-daily PPI therapy andhave normal findings on endoscopy. Manometry willserve to localize the LES for potential subsequent pHmonitoring, to evaluate peristaltic function preopera-
tively, and to diagnose subtle presentations of the
major motor disorders. Evolving information suggeststhat high-resolution manometry has superior sensitiv-ity to conventional manometry in recognizing atypicalcases of achalasia and distal esophageal spasm.

III. Ambulatory impedance-pH, catheter pH, or wirelesspH monitoring (PPI therapy withheld for 7 days) toevaluate patients with a suspected esophagealGERD syndrome who have not responded to anempirical trial of PPI therapy, have normal findingson endoscopy, and have no major abnormality onmanometry. Wireless pH monitoring has superiorsensitivity to catheter studies for detecting patho-logical esophageal acid exposure because of theextended period of recording (48 hours) and hasalso shown superior recording accuracy comparedwith some catheter designs.

IX. Antireflux surgery for patients with an esophagealGERD syndrome with persistent troublesomesymptoms, especially troublesome regurgitation,despite PPI therapy. The potential benefits or anti-reflux surgery should be weighed against the dele-terious effect of new symptoms consequent fromsurgery, particularly dysphagia, flatulence, an in-ability to belch, and postsurgery bowel symptoms.

X. Acute or maintenance therapy with once- or twice-daily PPIs (or H2RAs) for patients with a suspectedextraesophageal GERD syndrome (laryngitis, asthma)with a concomitant esophageal GERD syndrome.

Grade C: Balance of Benefits and Harms IsToo Close to Justify a General Recommendation

. Patients with an extraesophageal GERD syndrome withpersistent troublesome symptoms despite PPI therapyshould be considered for antireflux surgery. The potentialbenefits of antireflux surgery should be weighed againstthe deleterious effect of new symptoms consequent fromsurgery, particularly dysphagia, flatulence, an inability tobelch, and postsurgery bowel symptoms.

Grade D: Recommend Against, Fair EvidenceThat It Is Ineffective or Harms OutweighBenefits

I. Metoclopramide as monotherapy or adjunctive ther-apy in patients with esophageal or suspected extrae-sophageal GERD syndromes.

II. Once- or twice-daily PPIs (or H2RAs) for acute treat-ment of patients with potential extraesophagealGERD syndromes (laryngitis, asthma) in the absenceof a concomitant esophageal GERD syndrome.

II. Routine endoscopy in subjects with erosive or nonero-sive reflux disease to assess for disease progression.

IV. Less than daily dosing of PPI therapy as maintenancetherapy in patients with an esophageal syndromewho previously had erosive esophagitis.

V. Antireflux surgery for patients with an esophagealsyndrome with or without tissue damage who are
symptomatically well controlled on medical therapy.

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VI. Antireflux surgery as an antineoplastic measure inpatients with Barrett’s metaplasia.

Grade Insuff: No Recommendation, InsufficientEvidence to Recommend for or Against

I. Broadly advocating lifestyle changes for all (as op-posed to selected) patients with GERD.

II. Using alarm symptoms (other than troublesomedysphagia) as a screening tool to identify patientswith GERD at risk for esophageal adenocarcinoma.

III. Adding a nocturnal dose of an H2RA for patientswith an esophageal syndrome with an inadequatesymptom response to twice-daily PPI therapy.

IV. Routine upper endoscopy in the setting of chronicGERD symptoms to diminish the risk of deathfrom esophageal cancer.

V. Endoscopic screening for Barrett’s esophagus anddysplasia in adults 50 years or older with �5–10years of heartburn to reduce mortality from esoph-ageal adenocarcinoma.

VI. Combined impedance-pH, catheter pH, or wirelesspH monitoring studies to distinguish hypersensi-tivity syndromes from functional syndromes, thedistinction being that in hypersensitivity syn-dromes symptoms are attributable to reflux events,whereas in functional syndromes they are not.

VII. Combined impedance-pH, catheter pH, or wirelesspH esophageal monitoring studies performed whiletaking PPIs.

III. Maintenance therapy with once- or twice-daily PPIs(or H2RAs) for patients with potential extraesophagealGERD syndromes (laryngitis, asthma) in the absenceof a concomitant esophageal GERD syndrome.

IX. Once- or twice-daily PPIs for patients with sus-pected reflux cough syndrome.

X. Advocating bone density studies, calcium supple-mentation, H pylori screening, or any other routineprecaution because of PPI use.

XI. The use of currently commercially available endolu-minal antireflux procedures in the management ofpatients with an esophageal syndrome.

PETER J. KAHRILASDepartment of Medicine, Gastroenterology DivisionNorthwestern University Feinberg School of MedicineChicago, Illinois

NICHOLAS J. SHAHEENDepartment of MedicineUniversity of North Carolina at Chapel HillChapel Hill, North Carolina

MICHAEL F. VAEZIDepartment of Gastroenterology and HepatologyVanderbilt University Medical Center
Nashville, Tennessee
Supplementary Data

Note: To access the supplementary material ac-ompanying this article, visit the online version ofastroenterology at www.gastrojournal.org, and at doi:0.1053/j.gastro.2008.08.044.

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60. Perdikis G, Hinder RA, Lund RJ, et al. Laparoscopic Nissenfundoplication: where do we stand? Surg Laparosc Endosc1997;7:17–21.

61. Madan A, Minocha A. Despite high satisfaction, majority ofgastro-oesophageal reflux disease patients continue to useproton pump inhibitors after antireflux surgery. Aliment Pharma-col Ther 2006;23:601–605.

62. Funch-Jensen P, Bendixen A, Iversen MG, et al. Complicationsand frequency of redo antireflux surgery in Denmark: a nation-wide study, 1997-2005. Surg Endosc 2008;22:627–630.

63. Rantanen TK, Salo JA, Sipponen JT. Fatal and life-threateningcomplications in antireflux surgery: analysis of 5,502 opera-tions. Br J Surg 1999;86:1573–1577.

64. Flum DR, Koepsell T, Heagerty P, et al. The nationwide fre-quency of major adverse outcomes in antireflux surgery and therole of surgeon experience, 1992-1997. J Am Coll Surg 2002;195:611–618.

65. Malhi-Chowla N, Gorecki P, Bammer T, et al. Dilation afterfundoplication: timing, frequency, indications, and outcome.Gastrointest Endosc 2002;55:219–223.

66. Cadiere GB, Rajan A, Rqibate M, et al. Endoluminal fundoplication(ELF)—evolution of EsophyX, a new surgical device for transoralsurgery. Minim Invasive Ther Allied Technol 2006;15:348–355.

67. Rothstein R, Filipi C, Caca K, et al. Endoscopic full-thicknessfundoplication for the treatment of gastroesophageal reflux dis-ease: a randomized, sham-controlled trial. Gastroenterology2006;131:704–712.

68. Jalving M, Koornstra JJ, Wesseling J, et al. Increased risk offundic gland polyps during long-term proton pump inhibitor ther-apy. Aliment Pharmacol Ther 2006;24:1341–1348.

69. Sharma VR, Brannon MA, Carloss EA. Effect of omeprazole onoral iron replacement in patients with iron deficiency anemia.South Med J 2004;97:887–889.

Address requests for reprints to: Chair, Clinical Practice and Eco-omics Committee, AGA Institute National Office, c/o Membershipepartment, 4930 Del Ray Avenue, Bethesda, Maryland 20814. Fax:

301) 654-5920Supported by grant R01 DC00646 from the Public Health Service.Peter J. Kahrilas is a consultant for AstraZeneca and TAP Pharma-

eutical Products, Inc. Nicholas J. Shaheen is on the speaker’s bureauor AstraZeneca and is a consultant for AstraZeneca and TAP Phar-aceutical Products, Inc and receives support (grant/research) fromstraZeneca, TAP Pharmaceutical Products, Inc, Proctor&Gamble,CS Medical and Barrx Medical. Michael F. Vaezi is on the speaker’sureau of AstraZeneca, a consultant for AstraZeneca, Santarus, andestech, and receives support (grant/research) from TAP Pharmaceu-

ical Products, Inc, AstraZeneca, and Restech.

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1413.e1 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE GASTROENTEROLOGY Vol. 135, No. 4

American GastroenterologicalAssociation Institute GuidelineDevelopment Methodology forManagement of GastroesophagealReflux Disease

In July 2007, the American Gastroenterologicalssociation (AGA) Institute began the implementation ofnew process for developing clinical practice guidelines

ummarized in a policy statement entitled “AGA Insti-ute Practice Recommendations Development Manual.”he guideline on management of patients with gastro-sophageal reflux disease (GERD) was the first to beeveloped using this new process, which we briefly de-cribe in the following text. Because this was the first trialf the new process, practical modifications were made asecessary to facilitate the process; these modifications arelso noted.

AGA Institute clinical practice guidelines are com-osed of 2 main elements: a technical review (TR) and aedical position statement (MPS). The TR is written by

xperts in the field and provides a thorough review of theiterature concerning the topic. The MPS is a conciseocument derived from the TR summarizing the finalanagement recommendations. The MPS is intended to

erve as a brief document to which a clinician can refer toetermine, for a given condition, “what is the best evi-ence based care for my patient?” The TR is intended asreference for the clinician desiring to dig deeper into

he literature (specific citations, quality and level of evi-ence, and so on) behind the recommendations. Bothocuments combined are referred to as the “clinical prac-ice guideline” or “guideline” for short.

One difference between the old and new process in AGAnstitute guideline development is the involvement of theGA Institute Council in the selection of TR authors andxternal reviewers. The AGA Institute Council is composedf elected representatives from the 12 AGA Institute sec-ions. Including the Council in the guideline developmentrocess fulfills one element of their mission, which is toevelop guidelines/standards of practice and other educa-ional resources to help members of the AGA Instituterovide high-quality clinical care. For the GERD guideline,list of potential authors and external reviewers was ini-

ially generated by the Council; the list was subsequentlyefined to improve the balance among the coauthors inerms of their specific areas of interest. A lead author and 2oauthors were selected.

The 12 broad GERD management questions addressedy the TR were developed by interaction among theuthors, the AGA Institute Clinical Practice and Qualityanagement Committee, and representatives from the

GA Institute Council. Thereafter, primary responsibilityor drafting answers to each question was assigned to theuthors by the lead author. With the assistance of AGA
taff, literature searches pertinent to each question were t
erformed. To conserve space in GASTROENTEROLOGY ando allow a more detailed and comprehensive descriptionf the evidence reviewed, the authors decided that theetails of the literature search methodology and the yieldf the process would appear as a separate online appen-ix for readers rather than within the TR itself. Thisction was also mandated in response to strict TR wordount and citation limits specified in the AGA Instituteractice Recommendations Development Manual.Another difference from the old guideline develop-ent process is in the formation of a Medical Position

anel (MPP), consisting of the authors of the TR, aommunity-based gastroenterologist, a payer, a generalurgeon, a patient (or patient advocate), a primary carehysician, and a gastroenterologist with expertise inealth services research. The intended purpose of havinghis wide stakeholder representation on the MPP was todd strength and credibility to the guideline develop-ent process. The composition of the MPP may vary

epending on the guideline topic and the required exper-ise. For the GERD guideline, all of the aforementionedarticipants were included. Members of the MPP wereelected by members of the Clinical Practice and Quality

anagement Committee with input from AGA Instituteouncil and TR authors.The TR was subject to external peer review before the

ace-to-face meeting of the MPP. Hence, before the MPPeeting, members of the panel had both the draft TR

nd the critiques of 4 external peer reviewers to consider.hen, during the MPP meeting, held in Bethesda, Mary-

and, on April 2, 2008, the TR authors led an openiscussion regarding both the specific practice recom-endations pertinent to each management question in

he TR and the reviewer commentary relevant to each.he MPP then charged the TR authors to make specificodifications to the TR in view of their own and peer

eviewer feedback and tasked them to draft the MPS.hese revised documents were again reviewed by the MPPnd the AGA Institute Clinical Practice and Quality Man-gement Committee. Final feedback was obtained, andontinuing medical education (CME) questions wererafted. Thereafter, the documents were sent to membersf the AGA Institute Governing Board for review andpproval. The final TR, MPS, and CME questions werehen sent to the AGA Institute Clinical Practice anduality Management Committee for review and approval

fter Digestive Disease Week 2008.For each question, a comprehensive literature search

as conducted on MEDLINE and the Cochrane Library.ertinent evidence was reviewed, and the quality of rele-ant data was evaluated. Studies involving adults andnglish-only papers published after 1990 were consid-red; letters, commentaries, narrative reviews, and caseeports were excluded from the search. Meta-analyses,ractice guidelines, randomized controlled trials, and sys-
ematic reviews were included. The connector word “and”

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as used to combine terms; the connector word “not”as used to exclude nonrelevant papers, and the connec-

or word “or” was used to eliminate duplicate papers.ibliographies of retrieved articles were reviewed for ad-itional relevant publications. The final reference list wasurther modified and augmented in the peer review pro-ess. The specifics of the search strategy used are pro-ided below each question.

1. What Is an Operational Definition ofGERD? What Is the Distinction BetweenGERD and Episodic Heartburn?

To identify relevant papers on an operationalefinition of GERD and those describing the distinc-ion between GERD and episodic heartburn, the textords “definition” and “episodic heartburn” were

ombined with the MeSH search term “GERD.” Rele-ant papers were selected by the authors from a yield of14.

CommentaryAlthough many citations were found by this

earch, the relevance of most of them was minimal.he exception was reference 1, describing the Montrealefinition of reflux disease, which was the result of an

nternational workshop convened with the specific in-ention of developing an evidence-based definition ofERD.1 The output of that report was a series of

tatements that were distilled by an internationalanel of experts using a Delphi process of 4 iterationsver 2 years. The Montreal definition was adopted forhe purposes of this report because it was found to beery operational.

2. What Is the Efficacy of LifestyleModifications for GERD? WhichElements Should Be Recommendedand in Which Circumstances?

To identify papers describing the efficacy of non-harmacologic therapy for GERD, the following textords were searched: “GERD” or “reflux” or “LES” and

ither “weight loss,” “obesity,” “diet,” “exercise,” or “non-harmacologic therapy.” Reports describing recom-ended elements for nonpharmacologic therapy and un-

er which circumstances they are to be used weredentified excluding the text words “bariatric surgery,”pediatric,” and “functional gastrointestinal disorder.” Aotal of 407 publications were retrieved.

CommentaryRelevant articles from the many citations were

eviewed and highlighted in the text. References 2 and 3ere based on references within the retrieved citationsnd by themselves were not identified in the primary
earch.2,3 Overall, most rigorous studies were those re- g
ently published regarding the role of obesity and GERD.ost identified citations were case series and of poor

tudy design otherwise.

3. How Do Antisecretory TherapiesCompare in Efficacy and Under WhatCircumstances Might One Be Preferableto Another? What Is an Acceptable UpperLimit of Empirical Therapy in PatientsWith Suspected Typical EsophagealGERD Syndromes Before Performing anEsophagogastroduodenoscopy?

To identify relevant papers comparing the efficacyf antisecretory therapies, the text words “proton pump

nhibitors” and “histamine (H2) receptor antagonists”ere combined with the MeSH term “GERD.” The textords “empiric therapy” and “EGD” were then combinedith the text word “esophageal GERD syndrome,” which

esulted in a yield of 400. Relevant papers describingtudies involving the comparison of 2 or more treatmentsere selected by authors.

CommentaryAdditionally, data regarding the efficacy of various

orms of acid suppressive therapies have recently under-one rigorous meta-analysis by the Cochrane Library,hich encompassed a much larger data set with extensivenalysis.4 Data from illustrative individual trials as well ashis meta-analysis are reported.

4. What Is the Role and Priority ofDiagnostic Tests (Endoscopy, EsophagealManometry, Ambulatory pH Monitoring,Combined Multichannel IntraluminalImpedance-pH Testing) in the Evaluationof Patients With Suspected EsophagealGERD Syndromes?

To identify papers on the role and priority ofiagnostic tests, the text words “diagnostic interven-ions,” “endoscopy,” “esophageal manometry,” “ambula-ory pH monitoring,” “pH testing,” and “diagnostic eval-ation” were combined with the text words “esophagealERD syndrome.” The MeSH term “GERD” and textords “multichannel intraluminal impedance” were then

ombined with the preceding terms to yield 125 relevantapers.

CommentaryThis was a particularly difficult question to ad-

ress in an evidence-based fashion because of the naturef the literature on the topic. Very little of the literatureocused on testing management strategy trials but ratherended to demonstrate the capabilities of new technolo-
ies without rigorously testing the clinical validity of the

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esult. This was especially true of impedance monitoringhere, despite the large number of citations, there wereo high-quality outcome trials. Hence, there was only one-level recommendation regarding the reflux testingethodologies and it failed to distinguish among them;ith respect to the unique capabilities of impedanceonitoring, only an “I” level recommendation could beade.

5. What Are the Unique ManagementConsiderations in Patients With SuspectedReflux Chest Pain Syndrome?

To identify papers describing unique manage-ent considerations in suspected reflux chest pain

yndrome, the text words “non cardiac chest pain oron-cardiac chest pain” were searched alone and inombination with “GERD”; the text words “GERDhest pain” and “esophageal chest pain” was combinedith the text word “management.” The following textords were excluded: “pediatrics,” “children,” “in-

ants,” “pediatrics,” “bariatric surgery,” “constipation,”dyspepsia,” “functional gastrointestinal disorder,”nd “duodenal ulcer.” This resulted in 388 relevantrticles.

CommentaryAdditional relevant references5– 8 were derived

rom reviews of the articles above and from referencesithin the review of a recent global evidence-based con-

ensus.1 Most citations in this field were case seriesnd/or highlighted the prevalence of reflux symptoms inatients with GERD and were not mechanistically de-igned to address causal or physiologic association be-ween patients’ symptoms of GERD and chest pain.

6. What Is the Best Initial Management forPatients With Suspected ExtraesophagealReflux Syndromes (Asthma, Laryngitis,Cough)? What Are the UniqueManagement Considerations With Each?What Is the Appropriate Dose and Courseof Antisecretory Therapy in Each?

Relevant papers were identified using the searcherms “GERD” and ““asthma,” “cough,” “laryngitis,” anddental erosion.” The text words “proton pump inhibi-ors” and “histamine (H2) receptor antagonists” wereombined with the results, and duplicate papers wereliminated. The text words “children,” “infants,” and “pe-iatrics” were excluded to yield 477 relevant papers.

CommentaryThe relevant citations were reviewed and used as

he basis for the text. Important articles needing special
mphasis include the meta-analysis of reflux therapy in m
aryngitis9 and the critical analysis of the role of medicalherapy in asthma.10

7. Does GERD Progress in Severity,Such That Symptomatic Patients WithoutEsophagitis Develop Esophagitis andBarrett’s Metaplasia, or Are TheseDistinct Disease Manifestations That DoNot Exist Along a Continuum? If PatientsDo Progress, at What Rate Does ThisOccur, and Does It Warrant EndoscopicMonitoring?

To identify papers describing GERD disease pro-ression, the text word “GERD progression” wasearched; the text word “Barrett*” was then combinedith the MeSH term “GERD.” The truncation symbol *as used to allow for a search that includes all forms of

he word “Barretts” (eg, “Barrett’s,” “Barrets,” “Barretts,”nd so on). Relevant papers were selected by authors outf a yield of 620.

CommentaryThe number of studies with careful follow-up of

ubjects with GERD for periods longer than 3 years wasery limited and patient groups were somewhat hetero-eneous, making conclusions with respect to certainransition rates tenuous. Additionally, most data wererom tertiary centers, raising the issue of generalizabilityo the general population.

8. What Maintenance Therapy IsIndicated for Patients With the TypicalEsophageal Reflux Syndrome (With orWithout Esophagitis)? When and HowShould Antisecretory Therapy BeDecreased or Discontinued? What, IfAny, Risks Are Associated With This?

The text words “erosive esophagitis” and “nonero-ive symptomatic GERD” were searched to identify pa-ers on maintenance therapy for patients with typicalsophageal reflux syndrome. The text terms “nonerosivesophagitis” were then combined with the text wordsmaintenance,” “erosive maintenance,” and “protonump inhibitors” to result in a yield of 157 papers.elevant papers were selected by authors.

CommentaryAdditionally, data regarding the efficacy of various

orms of acid suppressive therapies have recently under-one rigorous meta-analysis by the Cochrane Library.11

ata from illustrative individual trials as well as this
eta-analysis are reported.

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9. What Maintenance Therapy IsIndicated for Patients With SuspectedExtraesophageal Reflux Syndromes(Asthma, Laryngitis, Cough)? Whenand How Should Antisecretory TherapyBe Decreased or Discontinued?

To identify papers on maintenance therapy indi-ated for patients with extraesophageal reflux syndromes,he search terms “asthma,” “cough,” and “laryngitis” wereombined with “maintenance therapy” and “GERD.”

CommentaryThe search for maintenance therapy in patients

ith possible reflux-related asthma, laryngitis, or coughesulted in only 7 citations, none of which were relevanto the question. There were no studies addressing thismportant clinical issue, and most suggestions wereased on expert opinion and data from typical GERD.

10. What Are the Clinical Consequencesof Chronic Potent Acid Inhibition? DoThese Potential Side Effects WarrantSpecific Testing (eg, Bone DensityStudies, Calcium Supplementation,Helicobacter pylori Screening, and so on)?

The text word “proton pump inhibitors” were firstombined with “side effects” and the MeSH term “GERD”as combined with the text words “histamine (H2) receptorntagonists” and “H pylori screening” to yield 67 articles.

CommentaryThis was a rather straightforward search because

he MeSH terms effectively retrieved the relevant data.dditional references were found by cross-referencing.

11. What Is the Role of Endoscopy inLong-term Management of Patients WithGERD, and Under What CircumstancesShould Mucosal Biopsy Specimens BeObtained When Endoscopy Is Performed?

The MeSH term “GERD” was combined with theext words “endoscopy,” “biopsies,” and “role of endos-opy”; the text word “dysphagia” was then combinedith the text word “eosinophilic esophagitis.” These

earches resulted in a yield of 2766 papers. These werehen limited to clinical trials. Relevant papers were se-ected by authors.

CommentaryEvidence-based TRs and guidelines for the use of

ndoscopy from various professional organizations werelso reviewed. Randomized data comparing subjects man-
ged with routine endoscopy with those managed with
ndoscopy only in response to preset indications were notvailable. Therefore, conclusions in this section are based onxpected yield of endoscopy, derived largely from data fromohort studies.

12. What Are Indications for AntirefluxSurgery, and What Is the Efficacy ofThis Therapy?

To identify relevant papers on indications for andfficacy of surgical antireflux procedures, the text wordsNissen,” “efficacy,” and “laparoscopy” were combinedith the MeSH term “GERD. This resulted in a yield of72 articles; relevant papers were selected by authors.

Commentary

Several randomized controlled trials of medicalersus surgical therapy of complicated and uncompli-ated reflux disease have been reported. These studies, asell as outcomes studies of cohorts of medically and

urgically treated patients with GERD, form the evidencease for this section.

PETER J. KAHRILASDepartment of Medicine, Gastroenterology DivisionNorthwestern University Feinberg School of MedicineChicago, Illinois

NICHOLAS J. SHAHEENDepartment of MedicineUniversity of North Carolina at Chapel HillChapel Hill, North Carolina

MICHAEL F. VAEZIDepartment of Gastroenterology and HepatologyVanderbilt University Medical CenterNashville, Tennessee

References

1. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition andclassification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900–1920.

2. Waring JP, Eastwood TF, Austin JM, et al. The immediate effectsof cessation of cigarette smoking on gastroesophageal reflux.Am J Gastroenterol 1989;84:1076–1078.

3. Harvey RF, Gordon PC, Hadley N, et al. Effects of sleeping with thebed-head raised and of ranitidine in patients with severe pepticoesophagitis. Lancet 1987;2:1200–1203.

4. Khan M, Santana J, Donnellan C, et al. Medical treatments in theshort term management of reflux oesophagitis. Cochrane Data-base Syst Rev 2007;2:CD003244.

5. Brattberg G, Parker MG, Thorslund M. A longitudinal study of pain:reported pain from middle age to old age. Clin J Pain 1997;13:144–149.

6. Garcia Rodriguez LA, Wallander M, Johansson S. Natural history
of chest pain in GERD. Gut 2005;54(Suppl VII):A75. OP-G-325.

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7. Richards H, McConnachie A, Morrison C, et al. Social and gendervariation in the prevalence, presentation and general practitionerprovisional diagnosis of chest pain. J Epidemiol CommunityHealth 2000;54:714–718.

8. Kahn SE. The challenge of evaluating the patient with chest pain.Arch Pathol Lab Med 2000;124:1418–1419.

9. Qadeer MA, Phillips CO, Lopez AR, et al. Proton pump inhibitor
therapy for suspected GERD-related chronic laryngitis: a meta-
analysis of randomized controlled trials. Am J Gastroenterol2006;101:2646–2654.

0. Field SK, Sutherland LR. Does medical antireflux therapy improveasthma in asthmatics with gastroesophageal reflux?: a criticalreview of the literature. Chest 1998;114:275–283.

1. Donnellan C, Sharma N, Preston C, et al. Medical treatments for themaintenance therapy of reflux oesophagitis and endoscopic negative
reflux disease. Cochrane Database Syst Rev 2005;2:CD003245.

Documents

Aga Erge Guidelines 2007