GASTROENTEROLOGY 2008;135:1383–1391

AGA INSTITUTE
American Gastroenterological Association Medical Position Statement on
the Management of Gastroesophageal Reflux Disease

The American Gastroenterological Association (AGA) Institute Medical Position Panel consisted of the authors of the technical
review, a community-based gastroenterologist (Stephen W. Hiltz, MD, MBA, AGAF), an insurance provider representative (Edgar
Black, MD, Medical Director, Policy Resources Technology Evaluation Center, BlueCross BlueShield Association), a general
surgeon (Irvin M. Modlin, MD), a patient advocate (Gregory Lane), a primary care physician (Steve P. Johnson, MD), a
gastroenterologist with expertise in health services research (Philip S. Schoenfeld, MD), the Chair of the AGA Institute Clinical
Practice and Quality Management Committee (John Allen, MD, MBA, AGAF), and the Chair of the AGA Institute Practice
Management and Economics Committee and the AGA Institute CPT Advisor (Joel V. Brill, MD, AGAF).

I n the development of this medical position statement, 12

broad questions pertinent to diagnostic and management
strategies for patients with gastroesophageal reflux disease
Montreal consensus defined GERD as “a condition which
develops when the reflux of stomach contents causes trou-
blesome symptoms and/or complications.” Symptoms are
(GERD) were developed by interaction among the authors of “troublesome” if they adversely affect an individual’s well-
the technical review,1 representatives from the American Gas- being. Esophageal GERD syndromes are categorized as
troenterological Association (AGA) Institute Council, and the those that are symptom based and those that are defined by
AGA Institute Clinical Practice and Quality Management tissue injury, while the extraesophageal syndromes are clas-
Committee. The questions were designed to encapsulate the sified as of established or proposed association with GERD,
major management issues encountered in patients with GERD acknowledging that while the evidence on hand is sufficient
in current clinical practice. The issue of management of Bar- to link these syndromes to reflux, it is insufficient to estab-
rett’s esophagus was intentionally excluded, because this will lish causation.
be the focus of a subsequent medical position statement. For A distinguishing feature of the Montreal definition is
each question, a comprehensive literature search was con- that it does not use the term “nonerosive reflux disease” but
ducted, pertinent evidence reviewed, and the quality of relevant rather subdivides esophageal syndromes into symptomatic
data evaluated. The details of development methodology, lit- syndromes and syndromes with esophageal injury. Hence,
erature search methodology, and literature search yield associ- functional heartburn does not fit the Montreal definition of
ated with each of the questions are available on the AGA GERD, whereas it is included under the umbrella of non-
Institute Web site as a separate document.2 The resultant erosive reflux disease. The distinction between GERD and
conclusions were based on the best available evidence or, in the episodic heartburn in the Montreal definition is in the word
absence of quality evidence, expert opinion. The strength of “troublesome.” In the absence of esophageal injury, heart-
these conclusions was weighed using US Preventive Services burn symptoms of insufficient frequency or severity to be
Task Force (USPSTF) grades. Of note, none of the formulated perceived as troublesome by the patient (after assurance of
practice recommendations were judged to be sufficiently un- their benign nature) do not meet the Montreal definition of
equivocal to be proposed as performance measures for gauging a symptomatic esophageal GERD syndrome.
quality of care.
2. What Is the Efficacy of Lifestyle
Modifications for GERD? Which Elements
Diagnosis and Initial Therapy Should Be Recommended and in Which
1. What Is an Operational Definition of Circumstances?
GERD? What Is the Distinction Between
GERD and Episodic Heartburn?
Grade B: recommended with fair evidence that it
There can be no criterion standard definition of
improves important outcomes
INSTITUTE

GERD because the threshold distinction between physio-

AGA

logic reflux and reflux disease is ultimately arbitrary. Hence, I. Weight loss should be advised for overweight or obese
these questions can only be answered by opinion (USPSTF patients with esophageal GERD syndromes.
grade not applicable). Fortuitously, a recent consensus in
defining GERD (the Montreal consensus) emanated from a
panel of world experts. The Montreal definition was © 2008 by the AGA Institute
adopted in the technical review as a suitable framework 0016-5085/08/$34.00
upon which to build management recommendations. The doi:10.1053/j.gastro.2008.08.045
 1384 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE GASTROENTEROLOGY Vol. 135, No. 4

II. Elevation of the head of the bed for selected patients Grade B: recommended with fair evidence that it
who are troubled with heartburn or regurgitation when improves important outcomes
recumbent. Other lifestyle modifications including, but
I. Twice-daily PPI therapy for patients with an esophageal
not limited to, avoiding late meals, avoiding specific
syndrome with an inadequate symptom response to
foods, or avoiding specific activities should be tailored
once-daily PPI therapy.
to the circumstances of the individual patient.
II. A short course or as-needed use of antisecretory drugs in
Grade Insuff: no recommendation, insufficient ev- patients with a symptomatic esophageal syndrome
idence to recommend for or against without esophagitis when symptom control is the pri-
mary objective. For a short course of therapy, PPIs are
I. Broadly advocating lifestyle changes for all (as opposed
more effective than H2RAs, which are more effective
to selected) patients with GERD.
than placebo.
Grade D: recommend against, fair evidence that it
Broadly speaking, lifestyle modifications recom- is ineffective or harms outweigh benefits
mended for GERD fall into 3 categories: (1) avoidance of
foods that may precipitate reflux (eg, coffee, alcohol, I. Metoclopramide as monotherapy or adjunctive therapy
chocolate, fatty foods), (2) avoidance of acidic foods that in patients with esophageal or suspected extraesophageal
may precipitate heartburn (eg, citrus, carbonated drinks, GERD syndromes.
spicy foods), and (3) adoption of behaviors that may
reduce esophageal acid exposure (weight loss, smoking
cessation, raising the head of the bed, and avoiding re- The current consensus is that empirical therapy is
cumbency for 2–3 hours after meals). The problem with appropriate initial management for patients with uncom-
these is that there are simply too many recommendations plicated heartburn. Abundant data support treating pa-
and each is too narrowly applicable to enforce the whole tients with esophageal GERD syndromes with antisecretory
set on every patient. However, it is also clear that there are drugs, and there is ample evidence that, as a drug class, PPIs
subsets of patients who may benefit from specific lifestyle are more effective in these patients than are H2RAs, which
modifications, and it is good practice to make those are in turn more effective than placebo. However, the data
recommendations to those patients based on their spe- supporting the use of PPIs (or H2RAs) in doses higher than
cific history. A patient with symptoms of nighttime the standard are weak. Similarly, there is no evidence of
heartburn or regurgitation of sufficient severity to dis- improved efficacy by adding a nocturnal dose of an H2RA to
turb his or her sleep despite acid suppressive therapy may twice-daily PPI therapy. A notable disconnect between clin-
benefit from elevation of the head of the bed. Similarly, a ical trial data and clinical practice is in the use of PPIs twice
patient who consistently experiences troublesome heart- daily. Almost all efficacy data on these medications are from
burn after ingestion of alcohol, coffee, or spicy foods will once-daily dosing studies, even though the pharmacody-
benefit from avoidance of these. Finally, if a patient is
namics of the drugs logically supports twice-daily dosing.
overweight or obese, it is reasonable to suggest weight
Hence, guidance on this issue comes primarily from expert
loss as an intervention that may prevent, or at least
opinion, which is essentially unanimous in recommending
postpone, the need for acid suppression.
twice-daily dosing of PPIs to improve symptom relief in
3. How Do Antisecretory Therapies Compare patients with an esophageal GERD syndrome with an un-
in Efficacy and Under What Circumstances satisfactory response to once-daily dosing. Patients whose
Might One Be Preferable to Another? What Is heartburn has not adequately responded to twice-daily PPI
an Acceptable Upper Limit of Empirical
therapy should be considered treatment failures, making
Therapy in Patients With Suspected Typical
Esophageal GERD Syndromes Before that a reasonable upper limit for empirical therapy.
Performing Esophagogastroduodenoscopy? Circumstances in which one antisecretory drug might be
preferable to another primarily relate to side effects or when
the onset of effect is a prime consideration. The most
Grade A: strongly recommended based on good evi- common side effects of PPIs are headache, diarrhea, consti-
dence that it improves important health outcomes pation, and abdominal pain. Switching among alternative
INSTITUTE
AGA

I. Antisecretory drugs for the treatment of patients with PPI drugs or to a lower dose can usually circumvent these
esophageal GERD syndromes (healing esophagitis and side effects. As for the issue of onset of action, this primarily
symptomatic relief). In these uses, proton pump inhibi- pertains to on-demand therapy. If a patient intends to take
tors (PPIs) are more effective than histamine2 receptor a drug only in response to symptoms, then it should be a
antagonists (H2RAs), which are more effective than rapidly acting drug. The most rapidly acting agents are
placebo. antacids, the efficacy of which can be sustained by combin-
ing them with an H2RA or a PPI.
October 2008 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE 1385

4. What Is the Role and Priority of Diagnostic Diagnostic testing for esophageal GERD syndromes
Tests (Endoscopy With or Without Biopsy, is invoked in 3 broad scenarios: (1) to avert misdiagnosis, (2)
Esophageal Manometry, Ambulatory pH to identify complications of reflux disease, and (3) in the
Monitoring, Impedance-pH Monitoring) in the evaluation of empirical treatment failures. The discussion of
Evaluation of Patients With Suspected misdiagnosis and identifying complications of reflux dis-
Esophageal GERD Syndromes? ease usually revolves around the concept of “alarm features”
that are suggestive of an alternative diagnosis. Important
alternative diagnoses include coronary artery disease, gall-
Grade B: recommended with fair evidence that it bladder disease, gastric or esophageal malignancy, peptic
improves important outcomes ulcer disease, and eosinophilic, infectious, or caustic esoph-
I. Endoscopy with biopsy for patients with an esophageal agitis. High-quality evidence supporting the broad utility of
GERD syndrome with troublesome dysphagia. Biopsies alarm features as a diagnostic tool is quite limited. However,
should target any areas of suspected metaplasia, dysplasia, individual alarm features with the best performance for
or in the absence of visual abnormalities, normal mucosa identifying esophageal or gastric malignancies are weight
(at least 5 samples to evaluate for eosinophilic esophagitis). loss, dysphagia, and epigastric mass on examination, mak-
II. Endoscopy to evaluate patients with a suspected esophageal ing it appropriate to evaluate these with endoscopy. A ca-
GERD syndrome who have not responded to an empirical veat in the endoscopic evaluation of dysphagia is that the
trial of twice-daily PPI therapy. Biopsies should target any endoscopist should have a low threshold for obtaining
area of suspected metaplasia, dysplasia, or malignancy. multiple (preferably at least 5) esophageal mucosal biopsy
III. Manometry to evaluate patients with a suspected esophageal specimens to evaluate for eosinophilic esophagitis.
GERD syndrome who have not responded to an empirical The other broad scenario under which diagnostic testing
trial of twice-daily PPI therapy and have normal findings on is performed is in the evaluation of troublesome symptoms
endoscopy. Manometry will serve to localize the lower esoph- that have not adequately responded to empirical twice-daily
ageal sphincter for potential subsequent pH monitoring, to PPI therapy. Did therapy fail because of troublesome symp-
evaluate peristaltic function preoperatively, and to diagnose toms attributable to reflux that did not resolve with PPI
subtle presentations of the major motor disorders. Evolving therapy or because the symptoms under consideration are
information suggests that high-resolution manometry has not attributable to reflux? Endoscopy is again the first
superior sensitivity to conventional manometry in recogniz- diagnostic test to consider because it may demonstrate
ing atypical cases of achalasia and distal esophageal spasm. Barrett’s metaplasia, stricture, or an alternative upper gas-
IV. Ambulatory impedance-pH, catheter pH, or wireless pH trointestinal diagnosis. After a normal endoscopy, priority
monitoring (PPI therapy withheld for 7 days) to evaluate should be given to identifying conditions for which an
patients with a suspected esophageal GERD syndrome effective alternative therapy exists. In the case of GERD, the
who have not responded to an empirical trial of PPI only alternative, potentially more effective, therapy is anti-
therapy, have normal findings on endoscopy, and have no reflux surgery. High-quality evidence on the efficacy of an-
major abnormality on manometry. Wireless pH monitor- tireflux surgery exists only for esophagitis and/or excessive
ing has superior sensitivity to catheter studies for detect- distal esophageal acid exposure when PPI therapy is with-
ing pathological esophageal acid exposure because of the held. Another requirement for antireflux surgery is that
extended period of recording (48 hours) and has also some peristaltic function be preserved. Finally, it is impor-
shown superior recording accuracy compared with some tant to identify alternative diagnoses that may masquerade
catheter designs. as GERD: functional heartburn, atypical cases of achalasia,
or distal esophageal spasm. Given these priorities, the sec-
Grade Insuff: no recommendation, insufficient ev-
ond diagnostic evaluation should be esophageal manome-
idence to recommend for or against
try and the third should then be to ascertain whether or not
I. Using alarm symptoms (other than troublesome dys- there is excessive esophageal acid exposure when PPI ther-
phagia) as a screening tool to identify patients with apy is withheld. Whether this examination should be per-
GERD at risk for esophageal adenocarcinoma. formed with the patient on acid suppressive therapy is
II. Combined impedance-pH, catheter pH, or wireless pH debated. The unclear relevance of “normative” data for im-
monitoring studies to distinguish hypersensitivity syn- pedance-pH studies performed on PPI therapy makes it
INSTITUTE

dromes from functional syndromes, the distinction being difficult to interpret such studies. If normal values are not
AGA

that in hypersensitivity syndromes symptoms are attrib- adjusted, then such an on-PPI study could show an un-
utable to reflux events, whereas in functional syndromes equivocal PPI nonresponse. That, however, rarely occurs. At
they are not. this point in the diagnostic algorithm, troublesome symp-
III. Combined impedance-pH, catheter pH, or wireless pH toms of heartburn, chest pain, regurgitation, or dysphagia
esophageal monitoring studies performed while taking persist despite normal findings on endoscopy (including
PPIs. mucosal biopsy in the case of dysphagia), normal esopha-
geal acid exposure, and a manometry study that ruled out a
 1386 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE GASTROENTEROLOGY Vol. 135, No. 4

major motor disorder. Current thinking is that the major

Grade D: recommend against, fair evidence that it
remaining possibilities are a hypersensitivity syndrome or a
is ineffective or harms outweigh benefits
functional syndrome, the distinction being that in the case
of a hypersensitivity syndrome symptoms are attributable to I. Once- or twice-daily PPIs (or H2RAs) for acute treat-
reflux events, whereas in the case of a functional syndrome ment of patients with potential extraesophageal GERD
they are not. This is a subtle distinction and a domain in syndromes (laryngitis, asthma) in the absence of a con-
which there is currently no high-quality evidence support- comitant esophageal GERD syndrome.
ing one management approach or another.
Grade Insuff: no recommendation, insufficient ev-
5. What Are the Unique Management idence to recommend for or against
Considerations in Patients With Suspected I. Once- or twice-daily PPIs for patients with suspected
Reflux Chest Pain Syndrome?
reflux cough syndrome.

Grade A: strongly recommended based on good ev-

idence that it improves important health outcomes Chronic cough, laryngitis, and asthma have an
established association with GERD on the basis of pop-
I. Twice-daily PPI therapy as an empirical trial for patients
ulation-based studies. However, cough, laryngitis, and
with suspected reflux chest pain syndrome after a cardiac
asthma have a multitude of potential etiologies other
etiology has been carefully considered.
than GERD, making them nonspecific for GERD. Fur-
thermore, the causal relationship of GERD with these
nonspecific syndromes in the absence of a concomitant
Chest pain indistinguishable from ischemic car-
esophageal GERD syndrome remains controversial and
diac pain can be caused by GERD. Because the morbidity
unproven. The only randomized controlled trials show-
and mortality associated with ischemic heart disease is
ing a treatment effect for GERD therapies in these syn-
substantially greater than that of GERD and because of
dromes were in patients with esophageal GERD syn-
the impressive array of available therapeutic interven-
dromes in addition to either laryngitis or asthma. Hence,
tions, this diagnosis must be thoroughly considered be-
existing evidence supports the following: (1) the associa-
fore accepting a diagnosis of reflux chest pain syndrome.
tion between these syndromes and GERD, (2) the rarity
Once ischemic heart disease has been adequately consid-
of extraesophageal GERD syndromes without concomi-
ered, the relative rarity of esophageal motor disorders in
tant esophageal symptoms or findings, (3) that suspected
this group of patients, as well as results from empirical
extraesophageal GERD syndromes are usually multifac-
treatment trials of acid suppressive therapy, suggest that
torial, and (4) that data substantiating benefit from the
GERD may be the next most likely etiology. Meta-analy-
treatment of reflux for the extraesophageal syndromes
ses of placebo-controlled treatment trials in patients with
are very weak. Furthermore, clinical predictors implicat-
suspected reflux chest pain suggest benefit from a 4-week
ing GERD in the extraesophageal syndromes have proven
trial with twice-daily PPI therapy. If a patient continues
elusive, and the premature adoption of flawed diagnostic
to have chest pain despite this course of therapy, diag-
criteria has likely resulted in the overdiagnosis of extra-
nostic testing with esophageal manometry and pH or
esophageal GERD syndromes.
impedance-pH monitoring can exclude motility disorders
Given the nonspecific nature of the extraesophageal
or refractory reflux symptoms.
symptoms and the poor sensitivity and specificity of
6. What Is the Best Initial Management for diagnostic tests such as pH monitoring, laryngoscopy, or
Patients With Suspected Extraesophageal endoscopy for establishing an etiology of GERD, empir-
Reflux Syndromes (Asthma, Laryngitis, ical therapy with PPIs has become common practice.
Cough)? What Are the Unique Management Most therapeutic trials of these syndromes have used
Considerations With Each? What Is the twice-daily dosing of PPIs for treatment periods of 3– 4
Appropriate Dose and Course of Antisecretory months. The rationale for this unapproved dosing for
Therapy in Each? unapproved indications comes from pH monitoring data
showing that the likelihood of normalizing esophageal
INSTITUTE

acid exposure with twice-daily PPIs in patients with

Grade B: recommended with fair evidence that it
AGA

GERD is 93%–99%, the logic then being that lesser dosing

improves important outcomes
does not exclude the possibility of a poor response be-
I. Acute or maintenance therapy with once- or twice-daily cause of inadequate acid suppression. Having said that,
PPIs (or H2RAs) for patients with a suspected extra- there are no controlled studies investigating the optimal
esophageal GERD syndrome (laryngitis, asthma) with a dosage or duration of PPI therapy in patients with ex-
concomitant esophageal GERD syndrome. traesophageal GERD syndromes. The only supportive
data for twice-daily PPI dosing are uncontrolled open-
October 2008 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE 1387

label studies of suspected reflux laryngitis or asthma. prevalent disease) with healing of Los Angeles C or D esoph-
Furthermore, despite widespread treatment with PPIs agitis is about 6%. Most importantly, endoscopically mon-
twice daily, high-quality evidence supporting treatment itoring patients with chronic GERD symptoms has not
efficacy in these syndromes is scant. been shown to diminish the risk of cancer, and this practice
In summary, patients with suspected extraesophageal is discouraged.
GERD syndromes may have GERD as a contributing
8. What Maintenance Therapy Is Indicated
etiology but rarely as the sole cause. However, the increas-
for Patients With the Typical Esophageal
ing incrimination of GERD as an etiologic factor along Reflux Syndrome (With or Without
with the lack of accurate confirmatory diagnostic tests Esophagitis)? When and How Should
has resulted in widespread overdiagnosis and overtreat- Antisecretory Therapy Be Decreased or
ment of these conditions. Nonetheless, empirical therapy Discontinued? What, If Any, Risks Are
with twice-daily PPIs for 2 months remains a pragmatic Associated With This?
clinical strategy for subsets of these patients if they have
a concomitant esophageal GERD syndrome. Failing such
a trial, etiologies other than GERD should be explored. Grade A: strongly recommended based on good evi-
dence that it improves important health outcomes
Chronic Management I. Long-term use of PPIs for the treatment of patients with
7. Does GERD Progress in Severity, Such esophagitis once they have proven clinically effective.
That Symptomatic Patients Without Long-term therapy should be titrated down to the lowest
Esophagitis Develop Esophagitis and Barrett’s effective dose based on symptom control.
Metaplasia, or Are These Distinct Disease Grade D: recommend against, fair evidence that it
Manifestations That Do Not Exist Along a
Continuum? If Patients Do Progress, at What is ineffective or harms outweigh benefits
Rate Does This Occur, and Does It Warrant I. Less than daily dosing of PPI therapy as maintenance
Endoscopic Monitoring? therapy in patients with an esophageal syndrome who
previously had erosive esophagitis.
Grade D: recommend against, fair evidence that it
is ineffective or harms outweigh benefits
The utility of maintenance therapy in patients with
I. Routine endoscopy in subjects with erosive or nonerosive GERD depends on the manifestation of the disease being
reflux disease to assess for disease progression. monitored, with the strongest data pertaining to erosive
esophagitis. Subjects not maintained on continuous acid
suppressive therapy have high rates of recurrence of erosive
Two potential paradigms for viewing the natural disease. Several randomized controlled trials have shown
history of GERD exist. In the first, GERD is viewed as a that the recurrence of erosive esophagitis in subjects with
progressive disease such that, in the absence of effective GERD is dramatically decreased by daily PPI treatment.
intervention, today’s patient with nonerosive disease be- Similarly strong are randomized controlled trials between
comes tomorrow’s patient with erosive disease, who then H2RAs and either healing-dose or maintenance-dose (usu-
becomes a candidate for the development of Barrett’s ally half) PPIs, with subjects randomized to H2RAs up to
esophagus. This “spectrum of disease” approach has been twice as likely to have recurrent esophagitis. The role of
contrasted with the view that GERD may be a disease with daily maintenance therapy in nonerosive disease is less clear.
phenotypically discreet “categories,” such as nonerosive dis- Patients with esophageal GERD syndrome without esoph-
ease, erosive esophagitis, and Barrett’s esophagus. In this agitis who initially responded to PPI therapy are less likely
phenotypically preordained view, conversion from one dis- to have recurrent symptoms when randomized to continu-
ease manifestation to another is distinctly unusual, and ing PPI therapy than to H2RAs or placebo. Whether PPI
subjects generally stay in their initial category. Available, dosing needs to be continuous as opposed to “on demand”
albeit limited, data suggest that while subjects with GERD has also been studied, and patients with uninvestigated
may sometimes progress from nonerosive disease to erosive GERD or patients with an esophageal GERD syndrome
INSTITUTE

esophagitis (making it not a strictly categorical disease), the without esophagitis did well with on-demand regimens. On
AGA

reported rates of progression are relatively low over a 20-year balance, the data suggest that on-demand therapy is a rea-
period. In patients in whom stricture, Barrett’s metaplasia, sonable strategy in patients with an esophageal GERD syn-
and adenocarcinoma were excluded in the setting of a drome without esophagitis, where symptom control is the
healed mucosa at index endoscopy, the likelihood of these primary objective. In contrast, in those with a known his-
developing within a 7-year follow-up period is on the order tory of erosive esophagitis who are healed with continuous
of 1.9%, 0.0%, and 0.1%, respectively. On the other hand, the PPI therapy and then randomized to either continuous or
likelihood of developing Barrett’s esophagus (or unmasking on-demand therapy, the recurrence rates of erosive disease
 1388 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE GASTROENTEROLOGY Vol. 135, No. 4

are high with on-demand compared with continuous ther- persistent symptoms after 8 weeks of empirical PPI ther-
apy, and on-demand therapy cannot be recommended. apy. The need for continued PPI therapy in this group is
The previously described evidence makes it easy to say predicated on the presence and severity of concomitant
that continuous PPI therapy is recommended to main- esophageal syndromes with or without mucosal injury. In
tain a healed mucosa and that discontinuing therapy will the absence of concomitant esophageal GERD syn-
likely result in recurrent heartburn. However, there are no dromes, PPI therapy should be discontinued and other
high-quality data to suggest that continuous antisecre- diagnostic and/or therapeutic avenues pursued. There are
tory therapy alters the natural history of reflux disease no trials showing the effectiveness of maintenance ther-
other than to reduce the (already low) incidence of peptic apy for patients in whom empirical therapy with twice-
stricture. There are also no data to the effect that inter- daily PPI therapy results in improvement of asthma,
mittent esophageal erosions or some degree of residual cough, or laryngitis. Thus, recommendations regarding
symptomatology is harmful. Hence, the main identifiable maintenance therapy in this group of patients are based
risk associated with reducing or discontinuing PPI ther- on expert opinion extrapolated from the typical esopha-
apy is an increased symptom burden. It follows that the geal reflux syndrome literature. Hence, the objective of
decision regarding the need for (and dosage of) mainte- continued maintenance therapy in patients with extra-
nance therapy is driven by the impact of those residual esophageal reflux syndrome is symptom control and, just
symptoms on the patient’s quality of life rather than as a as with the typical esophageal syndromes, step-down
disease control measure. Pragmatically, this means that therapy should be attempted. The likelihood of symptom
many subjects beginning PPI therapy will receive this recurrence with step-down therapy in patients with an
therapy chronically, but often intermittently. extraesophageal reflux syndrome is currently unknown.
In summary, chronic PPI therapy will be required for
10. What Are the Clinical Consequences of
adequate symptom control in the majority of subjects
Chronic Potent Acid Inhibition? Do These
with GERD symptoms severe enough to warrant initial Potential Side Effects Warrant Specific
PPI therapy. While many subjects may tolerate dose re- Testing (eg, Bone Density Studies, Calcium
duction of their PPI and maintain adequate symptom Supplementation, Helicobacter pylori
control, the likelihood of long-term spontaneous remis- Screening, and so on)?
sion of disease is low. Beyond recurrence of symptoms
and/or erosive disease, the risks associated with cessation
of therapy, including the possible development of Bar- Grade Insuff: no recommendation, insufficient ev-
rett’s esophagus, appear minimal. idence to recommend for or against

9. What Maintenance Therapy Is Indicated I. Advocating bone density studies, calcium supplementa-
for Patients With Suspected Extraesophageal tion, H pylori screening, or any other routine precaution
Reflux Syndromes (Asthma, Laryngitis, because of PPI use.
Cough)? When and How Should Antisecretory
Therapy Be Decreased or Discontinued?
Because PPIs work by profoundly reducing gas-
tric acid secretion, which in turn results in a reactive
Grade B: recommended with fair evidence that it
increase in gastrin secretion, most consideration of
improves important outcomes
long-term risk is focused on unwanted effects of sec-
I. Acute or maintenance therapy with once- or twice-daily ondary hypergastrinemia, hypochlorhydria, or even
PPIs (or H2RAs) for patients with a suspected extra- achlorhydria. Other, more generic considerations have
esophageal GERD syndrome (laryngitis, asthma) with a to do with drug-drug interactions and potential ter-
concomitant esophageal GERD syndrome. atogenicity. In general, these risks are slight if even
demonstrable. Available data show no worrisome
Grade Insuff: no recommendation, insufficient ev-
safety signals with PPIs. The most convincing data link
idence to recommend for or against
PPI use with an increase in Clostridium difficile colitis
I. Maintenance therapy with once- or twice-daily PPIs (or and bacterial gastroenteritis, but in each case, the
H2RAs) for patients with potential extraesophageal magnitude of risk is slight. With respect to the hip
INSTITUTE

GERD syndromes (laryngitis, asthma) in the absence of fracture issue, there are many potential confounders to
AGA

a concomitant esophageal GERD syndrome. the data, but the putative mechanism would be de-
II. Once- or twice-daily PPIs for patients with suspected creased calcium absorption, which has been demon-
reflux cough syndrome. strated with PPI use. Regardless, it is good medical
practice to screen and treat the elderly for osteoporosis
irrespective of PPI use. To summarize all available
Owing to the nonspecificity of the extraesopha- risk/benefit data on PPIs, their use is strongly justified
geal reflux syndromes for GERD, many patients will have when clinically indicated and there is inadequate evi-
October 2008 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE 1389

dence to mandate bone density studies, calcium sup- to substantiate the utility of screening or surveillance
plementation, H pylori screening, or any other routine endoscopy to detect Barrett’s esophagus or to monitor
precautions because of PPI use. the condition for progression to cancer. The available
data were previously reviewed by an AGA Institute con-
11. What Is the Role of Endoscopy in Long- sensus workshop in 2004. This group, composed of 18
term Management of Patients With GERD, experts in the field of Barrett’s esophagus, strongly re-
and Under What Circumstances Should
Mucosal Biopsy Specimens Be Obtained When jected the statement “Endoscopic screening for Barrett’s
Endoscopy Is Performed? esophagus and dysplasia has been shown to improve
mortality from esophageal adenocarcinoma” and con-
cluded that the grade of evidence in support of this
Grade B: recommended with fair evidence that it intervention was insufficient to form an opinion. Regard-
improves important outcomes ing the corollary statement that “Endoscopic screening
for BE and dysplasia should be performed in all adults
I. Endoscopy with biopsy for patients with an esophageal
ⱖ50 years of age with ⬎5–10 years of heartburn,” the
GERD syndrome with troublesome dysphagia. Biopsies
supporting evidence was again graded only at the level of
should target any areas of suspected metaplasia, dyspla-
expert opinion, and again the majority of the group
sia, or in the absence of any visual abnormalities, normal
mucosa (at least 5 samples to evaluate for eosinophilic rejected it.
esophagitis). In summary, despite the ubiquity of the practice, no
direct evidence supports the use of endoscopy as a screen-
Grade Insuff: no recommendation, insufficient ev- ing test for Barrett’s esophagus or esophageal adenocar-
idence to recommend for or against cinoma in the setting of chronic GERD. Regarding the
I. Routine upper endoscopy in the setting of chronic criteria for obtaining mucosal biopsy specimens in the
GERD symptoms to diminish the risk of death from course of performing an endoscopy, there is no basis to
esophageal cancer. advocate doing this routinely but, clearly, biopsy speci-
II. Endoscopic screening for Barrett’s esophagus and mens of any areas suspected of being metaplastic ob-
dysplasia in adults 50 years or older with ⬎5–10 tained and carefully evaluated for dysplasia.
years of heartburn to reduce mortality from esopha-
geal adenocarcinoma. 12. What Are Indications for Antireflux
Surgery, and What Is the Efficacy of This
Therapy?
Because PPI treatment is usually initiated before
the test, the sensitivity of endoscopy as a diagnostic test
Grade A: strongly recommended based on good
for GERD is poor. Hence, the principal use of endoscopy
evidence that it improves important health out-
in suspected GERD is the evaluation of treatment fail-
comes
ures and risk management. Most of the morbidity and
mortality from reflux disease stems from its link with I. When antireflux surgery and PPI therapy are judged to
esophageal adenocarcinoma. Putting the risk of cancer in offer similar efficacy in a patient with an esophageal
perspective, data from the Surveillance Epidemiology and GERD syndrome, PPI therapy should be recommended
End Results (SEER) database suggest that there were as initial therapy because of superior safety.
about 8000 incident cases of esophageal adenocarcinoma II. When a patient with an esophageal GERD syndrome is
in the United States in 2004 and this disease burden has responsive to, but intolerant of, acid suppressive ther-
increased an estimated 2- to 6-fold relative to 20 years apy, antireflux surgery should be recommended as an
prior. alternative.
The 5-year survival of patients with esophageal adeno-
Grade B: recommended with fair evidence that it
carcinoma is very poor, but it is greatly improved by early
improves important outcomes
detection. The other potential benefit of endoscopy in
the setting of chronic GERD is detection of Barrett’s I. Antireflux surgery for patients with an esophageal
INSTITUTE

esophagus, an acknowledged premalignant condition. GERD syndrome with persistent troublesome symp-
AGA

The risk of developing esophageal adenocarcinoma in toms, especially troublesome regurgitation, despite PPI
Barrett’s esophagus is estimated at 0.5% per year. Thus, therapy. The potential benefits of antireflux surgery
the proposed strategy for controlling the risk of cancer is should be weighed against the deleterious effect of new
to screen the GERD population for Barrett’s esophagus, symptoms consequent from surgery, particularly dyspha-
to survey identified individuals for the development of gia, flatulence, an inability to belch, and postsurgery
dysplasia and adenocarcinoma, and to resect or ablate bowel symptoms.
these lesions when found. However, no direct data exist
 1390 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE GASTROENTEROLOGY Vol. 135, No. 4

analysis fail to substantiate any protective effect of

Grade C: balance of benefits and harms is too close
surgery against cancer.
to justify a general recommendation
The relative efficacy of antireflux surgery to PPIs in
I. Patients with an extraesophageal GERD syndrome with controlling symptomatic esophageal syndromes and
persistent troublesome symptoms despite PPI therapy extraesophageal syndromes with an established associ-
should be considered for antireflux surgery. The poten- ation with GERD is less clear. If the analysis is re-
tial benefits of antireflux surgery should be weighed stricted to the control of heartburn and acid regurgi-
against the deleterious effect of new symptoms conse- tation, studies suggest modest superiority of antireflux
quent from surgery, particularly dysphagia, flatulence, surgery to PPI therapy, on the order of a 10% thera-
an inability to belch, and postsurgery bowel symptoms. peutic gain. However, the data are widely divergent. As
Grade D: recommend against, fair evidence that it many as 30% of patients have resumed medical therapy
is ineffective or harms outweigh benefits by 5 years after antireflux surgery, and surgical revision
is common. Although community-based outcome data
I. Antireflux surgery for patients with an esophageal syn-
are sparse, the data suggest that patients from com-
drome with or without tissue damage who are symp-
munity-based antireflux surgery series may have poorer
tomatically well controlled on medical therapy.
II. Antireflux surgery as an antineoplastic measure in pa- outcomes and lower satisfaction than those from spe-
tients with Barrett’s metaplasia. cialized centers. With respect to the extraesophageal
syndromes, there are no controlled data comparing
Grade Insuff: no recommendation, insufficient ev- PPIs with antireflux surgery, but observational studies
idence to recommend for or against suggest some benefit of antireflux surgery for selected
I. The use of currently commercially available endoluminal patients with reflux cough syndrome and reflux
antireflux procedures in the management of patients asthma syndrome. Hence, if the outcome of impor-
with an esophageal syndrome. tance is controlling either symptomatic esophageal
syndromes or extraesophageal symptoms in carefully
selected patients, antireflux surgery has greater efficacy
Just as with PPI therapy, evidence on the utility than PPI therapy. However, these benefits must be
of antireflux surgery depends on the manifestation of weighed against the deleterious effect of new symp-
the disease being monitored, with the strongest data toms consequent from antireflux surgery. Dysphagia of
pertaining to erosive esophagitis. Illustrative of this are sufficient severity to require esophageal dilation occurs in
7-year results of a randomized controlled trial compar- about 6% of patients undergoing antireflux surgery, and
ing PPI therapy with laparoscopic antireflux surgery in both controlled and uncontrolled trials have shown a
patients with esophagitis. At 7 years, the 2 treatment significant increase in flatulence, an inability to belch,
arms were very similar with respect to the incidence of and increased bowel symptoms after antireflux surgery.
recurrent esophagitis. Hence, if the outcome of impor- Given this balance, the recommendation for antireflux
tance is maintaining a healed esophageal mucosa, the surgery is stronger in the case of the symptomatic esoph-
2 therapies are both effective and appear to be equiv- ageal syndromes, especially with troublesome regurgita-
alent. However, from the vantage point of risk, PPI tion, than for extraesophageal symptoms.
therapy should be strongly recommended as initial In summary, the current indications for antireflux sur-
therapy in view of its superior safety profile. As for gery are well circumscribed. Patients with esophagitis
other manifestations of the esophageal GERD syn- who are well maintained on medical therapy have noth-
dromes with esophageal injury, there are no data com- ing to gain from antireflux surgery and incur added risk;
paring the efficacy of PPIs with antireflux surgery in they should be advised against surgery. Patients with
stricture prevention, and controlled data have shown esophagitis who are intolerant of PPIs will likely benefit
no change in the prevalence of Barrett’s esophagus or from antireflux surgery and should be so advised. Pa-
in the incidence of adenocarcinoma when patients tients with esophageal GERD syndrome poorly con-
treated surgically were compared with those treated trolled by PPIs may benefit from surgery, especially in the
medically. Furthermore, even though the safety profile setting of persistent troublesome regurgitation. However,
INSTITUTE

the recommendation for antireflux surgery must be bal-

AGA

of antireflux surgery is excellent for a surgical proce-

dure, antireflux surgery mortality estimates exceed the anced with a thorough discussion of potential post–
low risk of mortality from esophageal adenocarcinoma antireflux surgery symptoms. Finally, patients with ex-
(less than 1 in 10,000 per patient-year). Even among traesophageal GERD syndromes in whom a reflux
subjects with Barrett’s esophagus, who have a higher causality has been established to the greatest degree pos-
risk of cancer than the general GERD population, sible may benefit from antireflux surgery, and it should
randomized controlled trial data and a recent meta- be recommended with appropriate restraint.
October 2008 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE 1391

PETER J. KAHRILAS References

Department of Medicine, Gastroenterology Division 1. Kahrilas PJ, Shaheen NJ, Vaezi MV. American Gastroenterological
Northwestern University Feinberg School of Medicine Association Institute technical review on the management of gas-
troesophageal reflux disease. Gastroenterology 2008;135:1392–
Chicago, Illinois 1413.
2. American Gastroenterological Association Institute technical re-
NICHOLAS J. SHAHEEN
view development document. Available at:
Department of Medicine
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina Address requests for reprints to: Chair, Clinical Practice and Eco-
nomics Committee, AGA National Office, c/o Membership Depart-
MICHAEL F. VAEZI ment, 4930 Del Ray Avenue, Bethesda, Maryland 20814. Fax: (301)
Department of Gastroenterology and Hepatology 654-5920.
Vanderbilt University Medical Center Peter J. Kahrilas is a consultant for AstraZeneca and TAP Phar-
Nashville, Tennessee maceutical Products, Inc. Nicholas J. Shaheen is on the speaker’s
bureau for AstraZeneca and is a consultant for AstraZeneca and
TAP Pharmaceutical Products, Inc and receives support (grant/
Supplementary Data research) from AstraZeneca, TAP Pharmaceutical Products, Inc,
Proctor&Gamble, CCS Medical and Barrx Medical. Michael F. Vaezi
Note: To access the supplementary material ac-
is on the speaker’s bureau of AstraZeneca, a consultant for Astra-
companying this article, visit the online version of Zeneca, Santarus, and Restech, and receives support (grant/re-
Gastroenterology at www.gastrojournal.org, and at doi: search) from TAP Pharmaceutical Products, Inc, AstraZeneca, and
10.1053/j.gastro.2008.08.045. Restech.

INSTITUTE
AGA
1391.e1 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE GASTROENTEROLOGY Vol. 135, No. 4

American Gastroenterological performed. To conserve space in GASTROENTEROLOGY and

Association Institute Guideline to allow a more detailed and comprehensive description
Development Methodology for of the evidence reviewed, the authors decided that the
Management of Gastroesophageal details of the literature search methodology and the yield
Reflux Disease of the process would appear as a separate online appen-
dix for readers rather than within the TR itself. This
In July 2007, the American Gastroenterological action was also mandated in response to strict TR word
Association (AGA) Institute began the implementation of count and citation limits specified in the AGA Institute
a new process for developing clinical practice guidelines Practice Recommendations Development Manual.
summarized in a policy statement entitled “AGA Insti- Another difference from the old guideline develop-
tute Practice Recommendations Development Manual.” ment process is in the formation of a Medical Position
The guideline on management of patients with gastro- Panel (MPP), consisting of the authors of the TR, a
esophageal reflux disease (GERD) was the first to be community-based gastroenterologist, a payer, a general
developed using this new process, which we briefly de- surgeon, a patient (or patient advocate), a primary care
scribe in the following text. Because this was the first trial physician, and a gastroenterologist with expertise in
of the new process, practical modifications were made as health services research. The intended purpose of having
necessary to facilitate the process; these modifications are this wide stakeholder representation on the MPP was to
also noted. add strength and credibility to the guideline develop-
AGA Institute clinical practice guidelines are com- ment process. The composition of the MPP may vary
posed of 2 main elements: a technical review (TR) and a depending on the guideline topic and the required exper-
medical position statement (MPS). The TR is written by tise. For the GERD guideline, all of the aforementioned
experts in the field and provides a thorough review of the participants were included. Members of the MPP were
literature concerning the topic. The MPS is a concise selected by members of the Clinical Practice and Quality
document derived from the TR summarizing the final Management Committee with input from AGA Institute
management recommendations. The MPS is intended to Council and TR authors.
serve as a brief document to which a clinician can refer to The TR was subject to external peer review before the
determine, for a given condition, “what is the best evi- face-to-face meeting of the MPP. Hence, before the MPP
dence based care for my patient?” The TR is intended as meeting, members of the panel had both the draft TR
a reference for the clinician desiring to dig deeper into and the critiques of 4 external peer reviewers to consider.
the literature (specific citations, quality and level of evi- Then, during the MPP meeting, held in Bethesda, Mary-
dence, and so on) behind the recommendations. Both land, on April 2, 2008, the TR authors led an open
documents combined are referred to as the “clinical prac- discussion regarding both the specific practice recom-
tice guideline” or “guideline” for short. mendations pertinent to each management question in
One difference between the old and new process in AGA the TR and the reviewer commentary relevant to each.
Institute guideline development is the involvement of the The MPP then charged the TR authors to make specific
AGA Institute Council in the selection of TR authors and modifications to the TR in view of their own and peer
external reviewers. The AGA Institute Council is composed reviewer feedback and tasked them to draft the MPS.
of elected representatives from the 12 AGA Institute sec- These revised documents were again reviewed by the MPP
tions. Including the Council in the guideline development and the AGA Institute Clinical Practice and Quality Man-
process fulfills one element of their mission, which is to agement Committee. Final feedback was obtained, and
develop guidelines/standards of practice and other educa- continuing medical education (CME) questions were
tional resources to help members of the AGA Institute drafted. Thereafter, the documents were sent to members
provide high-quality clinical care. For the GERD guideline, of the AGA Institute Governing Board for review and
a list of potential authors and external reviewers was ini- approval. The final TR, MPS, and CME questions were
tially generated by the Council; the list was subsequently then sent to the AGA Institute Clinical Practice and
refined to improve the balance among the coauthors in Quality Management Committee for review and approval
terms of their specific areas of interest. A lead author and 2 after Digestive Disease Week 2008.
coauthors were selected. For each question, a comprehensive literature search
The 12 broad GERD management questions addressed was conducted on MEDLINE and the Cochrane Library.
by the TR were developed by interaction among the Pertinent evidence was reviewed, and the quality of rele-
authors, the AGA Institute Clinical Practice and Quality vant data was evaluated. Studies involving adults and
Management Committee, and representatives from the English-only papers published after 1990 were consid-
AGA Institute Council. Thereafter, primary responsibility ered; letters, commentaries, narrative reviews, and case
for drafting answers to each question was assigned to the reports were excluded from the search. Meta-analyses,
authors by the lead author. With the assistance of AGA practice guidelines, randomized controlled trials, and sys-
staff, literature searches pertinent to each question were tematic reviews were included. The connector word “and”
October 2008 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE 1391.e2

was used to combine terms; the connector word “not” cently published regarding the role of obesity and GERD.
was used to exclude nonrelevant papers, and the connec- Most identified citations were case series and of poor
tor word “or” was used to eliminate duplicate papers. study design otherwise.
Bibliographies of retrieved articles were reviewed for ad-
ditional relevant publications. The final reference list was 3. How Do Antisecretory Therapies
further modified and augmented in the peer review pro- Compare in Efficacy and Under What
cess. The specifics of the search strategy used are pro- Circumstances Might One Be Preferable
vided below each question.
to Another? What Is an Acceptable Upper
Limit of Empirical Therapy in Patients
1. What Is an Operational Definition of
With Suspected Typical Esophageal
GERD? What Is the Distinction Between
GERD Syndromes Before Performing an
GERD and Episodic Heartburn?
Esophagogastroduodenoscopy?
To identify relevant papers on an operational
To identify relevant papers comparing the efficacy
definition of GERD and those describing the distinc-
of antisecretory therapies, the text words “proton pump
tion between GERD and episodic heartburn, the text
inhibitors” and “histamine (H2) receptor antagonists”
words “definition” and “episodic heartburn” were
were combined with the MeSH term “GERD.” The text
combined with the MeSH search term “GERD.” Rele-
words “empiric therapy” and “EGD” were then combined
vant papers were selected by the authors from a yield of
with the text word “esophageal GERD syndrome,” which
114.
resulted in a yield of 400. Relevant papers describing
Commentary studies involving the comparison of 2 or more treatments
Although many citations were found by this were selected by authors.
search, the relevance of most of them was minimal. Commentary
The exception was reference 1, describing the Montreal
Additionally, data regarding the efficacy of various
definition of reflux disease, which was the result of an
forms of acid suppressive therapies have recently under-
international workshop convened with the specific in-
gone rigorous meta-analysis by the Cochrane Library,
tention of developing an evidence-based definition of
which encompassed a much larger data set with extensive
GERD.1 The output of that report was a series of
statements that were distilled by an international analysis.4 Data from illustrative individual trials as well as
this meta-analysis are reported.
panel of experts using a Delphi process of 4 iterations
over 2 years. The Montreal definition was adopted for
the purposes of this report because it was found to be 4. What Is the Role and Priority of
very operational. Diagnostic Tests (Endoscopy, Esophageal
Manometry, Ambulatory pH Monitoring,
2. What Is the Efficacy of Lifestyle Combined Multichannel Intraluminal
Modifications for GERD? Which Impedance-pH Testing) in the Evaluation
Elements Should Be Recommended of Patients With Suspected Esophageal
and in Which Circumstances? GERD Syndromes?
To identify papers describing the efficacy of non- To identify papers on the role and priority of
pharmacologic therapy for GERD, the following text diagnostic tests, the text words “diagnostic interven-
words were searched: “GERD” or “reflux” or “LES” and tions,” “endoscopy,” “esophageal manometry,” “ambula-
either “weight loss,” “obesity,” “diet,” “exercise,” or “non- tory pH monitoring,” “pH testing,” and “diagnostic eval-
pharmacologic therapy.” Reports describing recom- uation” were combined with the text words “esophageal
mended elements for nonpharmacologic therapy and un- GERD syndrome.” The MeSH term “GERD” and text
der which circumstances they are to be used were words “multichannel intraluminal impedance” were then
identified excluding the text words “bariatric surgery,” combined with the preceding terms to yield 125 relevant
“pediatric,” and “functional gastrointestinal disorder.” A papers.
total of 407 publications were retrieved.
Commentary
Commentary This was a particularly difficult question to ad-
Relevant articles from the many citations were dress in an evidence-based fashion because of the nature
reviewed and highlighted in the text. References 2 and 3 of the literature on the topic. Very little of the literature
were based on references within the retrieved citations focused on testing management strategy trials but rather
and by themselves were not identified in the primary tended to demonstrate the capabilities of new technolo-
search.2,3 Overall, most rigorous studies were those re- gies without rigorously testing the clinical validity of the
1391.e3 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE GASTROENTEROLOGY Vol. 135, No. 4

result. This was especially true of impedance monitoring laryngitis9 and the critical analysis of the role of medical
where, despite the large number of citations, there were therapy in asthma.10
no high-quality outcome trials. Hence, there was only one
B-level recommendation regarding the reflux testing
methodologies and it failed to distinguish among them; 7. Does GERD Progress in Severity,
with respect to the unique capabilities of impedance Such That Symptomatic Patients Without
monitoring, only an “I” level recommendation could be Esophagitis Develop Esophagitis and
made. Barrett’s Metaplasia, or Are These
Distinct Disease Manifestations That Do
5. What Are the Unique Management Not Exist Along a Continuum? If Patients
Considerations in Patients With Suspected Do Progress, at What Rate Does This
Reflux Chest Pain Syndrome? Occur, and Does It Warrant Endoscopic
Monitoring?
To identify papers describing unique manage-
ment considerations in suspected reflux chest pain To identify papers describing GERD disease pro-
syndrome, the text words “non cardiac chest pain or gression, the text word “GERD progression” was
non-cardiac chest pain” were searched alone and in searched; the text word “Barrett*” was then combined
combination with “GERD”; the text words “GERD with the MeSH term “GERD.” The truncation symbol *
chest pain” and “esophageal chest pain” was combined was used to allow for a search that includes all forms of
with the text word “management.” The following text the word “Barretts” (eg, “Barrett’s,” “Barrets,” “Barretts,”
words were excluded: “pediatrics,” “children,” “in- and so on). Relevant papers were selected by authors out
fants,” “pediatrics,” “bariatric surgery,” “constipation,” of a yield of 620.
“dyspepsia,” “functional gastrointestinal disorder,”
and “duodenal ulcer.” This resulted in 388 relevant Commentary
articles. The number of studies with careful follow-up of
subjects with GERD for periods longer than 3 years was
Commentary
very limited and patient groups were somewhat hetero-
Additional relevant references5– 8 were derived geneous, making conclusions with respect to certain
from reviews of the articles above and from references transition rates tenuous. Additionally, most data were
within the review of a recent global evidence-based con- from tertiary centers, raising the issue of generalizability
sensus.1 Most citations in this field were case series to the general population.
and/or highlighted the prevalence of reflux symptoms in
patients with GERD and were not mechanistically de-
signed to address causal or physiologic association be- 8. What Maintenance Therapy Is
tween patients’ symptoms of GERD and chest pain. Indicated for Patients With the Typical
Esophageal Reflux Syndrome (With or
6. What Is the Best Initial Management for Without Esophagitis)? When and How
Patients With Suspected Extraesophageal Should Antisecretory Therapy Be
Reflux Syndromes (Asthma, Laryngitis, Decreased or Discontinued? What, If
Cough)? What Are the Unique Any, Risks Are Associated With This?
Management Considerations With Each? The text words “erosive esophagitis” and “nonero-
What Is the Appropriate Dose and Course sive symptomatic GERD” were searched to identify pa-
of Antisecretory Therapy in Each? pers on maintenance therapy for patients with typical
Relevant papers were identified using the search esophageal reflux syndrome. The text terms “nonerosive
terms “GERD” and “asthma,” “cough,” “laryngitis,” and esophagitis” were then combined with the text words
“dental erosion.” The text words “proton pump inhibi- “maintenance,” “erosive maintenance,” and “proton
tors” and “histamine (H2) receptor antagonists” were pump inhibitors” to result in a yield of 157 papers.
combined with the results, and duplicate papers were Relevant papers were selected by authors.
eliminated. The text words “children,” “infants,” and “pe-
diatrics” were excluded to yield 477 relevant papers. Commentary
Additionally, data regarding the efficacy of various
Commentary forms of acid suppressive therapies have recently under-
The relevant citations were reviewed and used as gone rigorous meta-analysis by the Cochrane Library.11
the basis for the text. Important articles needing special Data from illustrative individual trials as well as this
emphasis include the meta-analysis of reflux therapy in meta-analysis are reported.
October 2008 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE 1391.e4

9. What Maintenance Therapy Is endoscopy only in response to preset indications were not
Indicated for Patients With Suspected available. Therefore, conclusions in this section are based on
Extraesophageal Reflux Syndromes expected yield of endoscopy, derived largely from data from
(Asthma, Laryngitis, Cough)? When cohort studies.
and How Should Antisecretory Therapy
Be Decreased or Discontinued? 12. What Are Indications for Antireflux
To identify papers on maintenance therapy indi- Surgery, and What Is the Efficacy of
cated for patients with extraesophageal reflux syndromes, This Therapy?
the search terms “asthma,” “cough,” and “laryngitis” were
To identify relevant papers on indications for and
combined with “maintenance therapy” and “GERD.”
efficacy of surgical antireflux procedures, the text words
Commentary “Nissen,” “efficacy,” and “laparoscopy” were combined
with the MeSH term “GERD. This resulted in a yield of
The search for maintenance therapy in patients
with possible reflux-related asthma, laryngitis, or cough 572 articles; relevant papers were selected by authors.
resulted in only 7 citations, none of which were relevant
to the question. There were no studies addressing this Commentary
important clinical issue, and most suggestions were Several randomized controlled trials of medical
based on expert opinion and data from typical GERD. versus surgical therapy of complicated and uncompli-
cated reflux disease have been reported. These studies, as
10. What Are the Clinical Consequences well as outcomes studies of cohorts of medically and
of Chronic Potent Acid Inhibition? Do surgically treated patients with GERD, form the evidence
These Potential Side Effects Warrant base for this section.
Specific Testing (eg, Bone Density PETER J. KAHRILAS
Studies, Calcium Supplementation, Department of Medicine, Gastroenterology Division
Helicobacter pylori Screening, and so on)? Northwestern University Feinberg School of Medicine
The text word “proton pump inhibitors” were first Chicago, Illinois
combined with “side effects” and the MeSH term “GERD”
was combined with the text words “histamine (H2) receptor NICHOLAS J. SHAHEEN
antagonists” and “H pylori screening” to yield 67 articles. Department of Medicine
University of North Carolina at Chapel Hill
Commentary
Chapel Hill, North Carolina
This was a rather straightforward search because
the MeSH terms effectively retrieved the relevant data.
MICHAEL F. VAEZI
Additional references were found by cross-referencing.
Department of Gastroenterology and Hepatology
Vanderbilt University Medical Center
11. What Is the Role of Endoscopy in
Nashville, Tennessee
Long-term Management of Patients With
GERD, and Under What Circumstances
References
Should Mucosal Biopsy Specimens Be
1. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and
Obtained When Endoscopy Is Performed?
classification of gastroesophageal reflux disease: a global evidence-
The MeSH term “GERD” was combined with the based consensus. Am J Gastroenterol 2006;101:1900 –1920.
text words “endoscopy,” “biopsies,” and “role of endos- 2. Waring JP, Eastwood TF, Austin JM, et al. The immediate effects
copy”; the text word “dysphagia” was then combined of cessation of cigarette smoking on gastroesophageal reflux.
Am J Gastroenterol 1989;84:1076 –1078.
with the text word “eosinophilic esophagitis.” These 3. Harvey RF, Gordon PC, Hadley N, et al. Effects of sleeping with the
searches resulted in a yield of 2766 papers. These were bed-head raised and of ranitidine in patients with severe peptic
then limited to clinical trials. Relevant papers were se- oesophagitis. Lancet 1987;2:1200 –1203.
lected by authors. 4. Khan M, Santana J, Donnellan C, et al. Medical treatments in the
short term management of reflux oesophagitis. Cochrane Data-
Commentary base Syst Rev 2007;2:CD003244.
5. Brattberg G, Parker MG, Thorslund M. A longitudinal study of pain:
Evidence-based TRs and guidelines for the use of reported pain from middle age to old age. Clin J Pain 1997;13:
endoscopy from various professional organizations were 144 –149.
also reviewed. Randomized data comparing subjects man- 6. Garcia Rodriguez LA, Wallander M, Johansson S. Natural history
aged with routine endoscopy with those managed with of chest pain in GERD. Gut 2005;54(Suppl VII):A75. OP-G-325.
1391.e5 AMERICAN GASTROENTEROLOGICAL ASSOCIATION INSTITUTE GASTROENTEROLOGY Vol. 135, No. 4

7. Richards H, McConnachie A, Morrison C, et al. Social and gender analysis of randomized controlled trials. Am J Gastroenterol
variation in the prevalence, presentation and general practitioner 2006;101:2646 –2654.
provisional diagnosis of chest pain. J Epidemiol Community 10. Field SK, Sutherland LR. Does medical antireflux therapy improve
Health 2000;54:714 –718. asthma in asthmatics with gastroesophageal reflux?: a critical
8. Kahn SE. The challenge of evaluating the patient with chest pain. review of the literature. Chest 1998;114:275–283.
Arch Pathol Lab Med 2000;124:1418 –1419. 11. Donnellan C, Sharma N, Preston C, et al. Medical treatments for the
9. Qadeer MA, Phillips CO, Lopez AR, et al. Proton pump inhibitor maintenance therapy of reflux oesophagitis and endoscopic negative
therapy for suspected GERD-related chronic laryngitis: a meta- reflux disease. Cochrane Database Syst Rev 2005;2:CD003245.