ACG Guideline GERD March 2013 Plus Corrigendum

8/11/2019 ACG Guideline GERD March 2013 Plus Corrigendum

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nature publishing groupERRATA, CORRIGENDA AND RETRACTIONS72

TheAmerican Journal ofGASTROENTEROLOGY VOLUME 108 |OCTOBER 2013 www.amjgastro.com

Corrigendum: Diagnostic Testing in Extraesophageal GERD: Another Case

of Furor Medicus?

Brennan SpiegelAm J Gastroenterol2013; 108:912914; doi:10.1038/ajg.2013.80

In the Conict o Interest section, the inormation under Financial support was incorrect. No unding was received rom Shire.

Corrigendum: Guidelines for the Diagnosis and Management of

Gastroesophageal Reflux Disease

Philip O. Katz, Lauren B. Gerson and Marcelo F. VelaAm J Gastroenterol2013; 108:308328; doi:10.1038/ajg.2012.444

1. On page 317, in the fh paragraph o the Summary o the Evidence section, it is stated that certain endoscopic therapies,including radiorequency augmentation to the lower esophageal sphincter, were removed rom the US market. However, radio-requency therapy was returned to the US market in 2010 and remains available. In stating that the therapy had been removedrom the marketplace, the authors o the Guidelines neither implied nor intended to imply that there was any health, effi cacy, orsaety reasons or the removal.2. On page 316, recommendation 6 under Surgical Options or GERD correctly notes that current endoscopic therapiescannot be recommended as an alternative to medical or traditional surgical therapy, and this was described as a conditionalrecommendation with a moderate level o evidence. However, recommendation 6 in the summary table on page 309, underSurgical Options or GERD, erroneously described the recommendation as strong.


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nature publishing groupPRACTICE GUIDELINES08

TheAmerican Journal ofGASTROENTEROLOGY VOLUME 108 |MARCH 2013 www.amjgastro.com

see related editorial on page x

Gastroesophageal reux disease (GERD) is arguably the most

common disease encountered by the gastroenterologist. It is

equally likely that the primary care providers will nd that com-

plaints related to reux disease constitute a large proportion otheir practice. Te ollowing guideline will provide an overview

o GERD and its presentation, and recommendations or the

approach to diagnosis and management o this common and

important disease.

Te document will review the presentations o any risk actors

or GERD, the diagnostic modalities and their recommendation

or use and recommendations or medical, surgical and endo-

scopic management including comparative effectiveness o differ-

ent treatments. Extraesophageal symptoms and complications will

be addressed as will the evaluation and management o rerac-

tory GERD. Te document will conclude with the potential risks

and side effects o the main treatments or GERD and their impli-cations or patient management.

Each section o the document will present the key recommen-

dations related to the section topic and a subsequent summary

o the evidence supporting those recommendations. An overall

summary o the key recommendations is presented in Table 1.

A search o OVID Medline, Pubmed and ISI Web o Science was

conducted or the years rom 19602011 using the ollowing major

search terms and subheadings including heartburn, acid regur-

gitation, GERD, liestyle interventions, proton pump inhibitor

(PPI), endoscopic surgery, extraesophageal symptoms, Nissen

undoplication, and GERD complications. We used systematic

reviews and meta-analyses or each topic when available ollowed

by a review o clinical trials.Te GRADE system was used to evaluate the strength o the

recommendations and the overall level o evidence (1,2). Te level

o evidence could range rom high (implying that urther research

was unlikely to change the authors condence in the estimate o

the effect) to moderate (urther research would be likely to have

an impact on the condence in the estimate o effect) or low

(urther research would be expected to have an important impact

on the condence in the estimate o the effect and would be likely

to change the estimate). Te strength o a recommendation was

graded as strong when the desirable effects o an interventionclearly outweigh the undesirable effects and as conditional when

there is uncertainty about the trade-offs.

It is important to be aware that GERD is dened by consensus

and as such is a disease comprising symptoms, end-organ effects

and complications related to the reux o gastric contents into

the esophagus, oral cavity, and/or the lung. aking into account

the multiple consensus denitions previously published (35),

the authors have used the ollowing working denition to dene

the disease: GERD should be dened as symptoms or compli-

cations resulting rom the reux o gastric contents into the

esophagus or beyond, into the oral cavity (including larynx)

or lung. GERD can be urther classied as the presence osymptoms without erosions on endoscopic examination (non-

erosive disease or NERD) or GERD symptoms with erosions

present (ERD).

SYMPTOMS AND EPIDEMIOLOGY

Epidemiologic estimates o the prevalence o GERD are based pri-

marily on the typical symptoms o heartburn and regurgitation. A

systematic review ound the prevalence o GERD to be 1020% o

the Western world with a lower prevalence in Asia (6). Clinically

troublesome heartburn is seen in about 6% o the population (7).

Regurgitation was reported in 16% in the systematic review noted

above. Chest pain may be a symptom o GERD, even the pre-senting symptom (2,3). Distinguishing cardiac rom non-cardiac

chest pain is required beore considering GERD as a cause o chest

pain. Although the symptom o dysphagia can be associated with

uncomplicated GERD, its presence warrants investigation or a

potential complication including an underlying motility disorder,

stricture, ring, or malignancy (8). Chronic cough, asthma, chronic

Guidelines for the Diagnosis and Management of

Gastroesophageal Reflux Disease

Philip O. Katz, MD1, Lauren B. Gerson, MD, MSc2and Marcelo F. Vela, MD, MSCR3

Am J Gastroenterol2013; 108:308328; doi:10.1038/ajg.2012.444; published online 19 February 2013

1Division of Gastroenterology, Einstein Medical Center, Philadelphia, Pennsylvania, USA; 2Division of Gastroenterology and Hepatology, Stanford University School

of Medicine, Stanford, California, USA; 3Division of Gastroenterology, Baylor College of Medicine & Michael E. DeBakey VA Medical Center , Houston, Texas, USA.

Correspondence: Lauren B. Gerson, MD, MSc, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 450 Broadway Street,

4th Floor Pavilion C, MC: 6341, Redwood City, California 94063, USA. E-mail: [email protected] 22 May 2012; accepted 10 December 2012

CME


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2013 by the American College of Gastroenterology TheAmerican Journal ofGASTROENTEROLOGY

3Guidelines for the Diagnosis and Management of GERD

Table 1. Summary and strength of recommendations

Establishing the diagnosis of Gastroesophageal Reflux Disease (GERD)

1. A presumptive diagnosis of GERD can be established in the setting of typical symptoms of heartburn and regurgitation. Empiric medical therapy with a proton pump

inhibitor (PPI) is recommended in this setting. (Strong recommendation, moderate level of evidence)

2. Patients with non-cardiac chest pain suspected due to GERD should have diagnostic evaluation before institution of therapy. (Conditional recommendation, moderate

level of evidence). A cardiac cause should be excluded in patients with chest pain before the commencement of a gastrointestinal evaluation (Strong recommendation,

low level of evidence)

3. Barium radiographs should not be performed to diagnose GERD (Strong recommendation, high level of evidence)

4. Upper endoscopy is not required in the presence of typical GERD symptoms. Endoscopy is recommended in the presence of alarm symptoms and for screening

of patients at high risk for complications. Repeat endoscopy is not indicated in patients without Barretts esophagus in the absence of new symptoms. (Strong recom-

mendation, moderate level of evidence)

5. Routine biopsies from the distal esophagus are not recommended specifically to diagnose GERD. (Strong recommendation, moderate level of evidence)

6. Esophageal manometry is recommended for preoperative evaluation, but has no role in the diagnosis of GERD. (Strong recommendation, low level of evidence)

7. Ambulatory esophageal reflux monitoring is indicated before consideration of endoscopic or surgical therapy in patients with non-erosive disease, as part of the

evaluation of patients refractory to PPI therapy, and in situations when the diagnosis of GERD is in question. (Strong recommendation, low level of evidence).

Ambulatory reflux monitoring is the only test that can assess reflux symptom association (strong recommendation, low level of evidence).

8. Ambulatory reflux monitoring is not required in the presence of short or long-segment Barretts esophagus to establish a diagnosis of GERD. (Strong

recommendation, moderate level of evidence)

9. Screening for Helicobacter pyloriinfection is not recommended in GERD patients. Treatment of H. pyloriinfection is not routinely required as part of antireflux therapy.

(Strong recommendation, low level of evidence)

Management of GERD

1. Weight loss is recommended for GERD patients who are overweight or have had recent weight gain. (Conditional recommendation, moderate level of evidence)

2. Head of bed elevation and avoidance of meals 23 h before bedtime should be recommended for patients with nocturnal GERD. (Conditional recommendation,


3. Routine global elimination of food that can trigger reflux (including chocolate, caffeine, alcohol, acidic and/or spicy foods) is not recommended in the treatment of

GERD. (Conditional recommendation, low level of evidence)

4. An 8-week course of PPIs is the therapy of choice for symptom relief and healing of erosive esophagitis. There are no major differences in efficacy between the different

PPIs. (Strong recommendation, high level of evidence)

5. Traditional delayed release PPIs should be administered 3060 min before meal for maximal pH control. (Strong recommendation, moderate level of

evidence). Newer PPIs may offer dosing flexibility relative to meal timing. (Conditional recommendation, moderate level of evidence)

6. PPI therapy should be initiated at once a day dosing, before the first meal of the day. (Strong recommendation, moderate level of evidence). For patients with partial

response to once daily therapy, tailored therapy with adjustment of dose timing and/or twice daily dosing should be considered in patients with night-time symptoms,

variable schedules, and/or sleep disturbance. (Strong recommendation, low level of evidence).

7. Non-responders to PPI should be referred for evaluation. (Conditional recommendation, low level of evidence, see refractory GERD section).

8. In patients with partial response to PPI therapy, increasing the dose to twice daily therapy or switching to a different PPI may provide additional symptom relief. (Conditional

recommendation, low level evidence).

9. Maintenance PPI therapy should be administered for GERD patients who continue to have symptoms after PPI is discontinued, and in patients with complications

including erosive esophagitis and Barretts esophagus. (Strong recommendation, moderate level of evidence). For patients who require long-term PPI therapy, it should be

administered in the lowest effective dose, including on demand or intermittent therapy. (Conditional recommendation, low level of evidence)

10. H2-receptor antagonist (H

2RA) therapy can be used as a maintenance option in patients without erosive disease if patients experience heartburn relief. (Conditional

recommendation, moderate level of evidence). Bedtime H2RA therapy can be added to daytime PPI therapy in selected patients with objective evidence of night-time

reflux if needed, but may be associated with the development of tachyphlaxis after several weeks of use. (Conditional recommendation, low level of evidence)

11. Therapy for GERD other than acid suppression, including prokinetic therapy and/or baclofen, should not be used in GERD patients without diagnostic evaluation.

(Conditional recommendation, moderate level of evidence)

12. There is no role for sucralfate in the non-pregnant GERD patient. (Conditional recommendation, moderate level of evidence)

13. PPIs are safe in pregnant patients if clinically indicated. (Conditional recommendation, moderate level of evidence)

Surgical options for GERD

1. Surgical therapy is a treatment option for long-term therapy in GERD patients. (Strong recommendation, high level of evidence)

2. Surgical therapy is generally not recommended in patients who do not respond to PPI therapy. (Strong recommendation, high level of evidence)

3. Preoperative ambulatory pH monitoring is mandatory in patients without evidence of erosive esophagitis. All patients should undergo preoperative

manometry to rule out achalasia or scleroderma-like esophagus. (Strong recommendation, moderate level of evidence)

4. Surgical therapy is as effective as medical therapy for carefully selected patients with chronic GERD when performed by an experienced surgeon.

(Strong recommendation, high level of evidence)

5. Obese patients contemplating surgical therapy for GERD should be considered for bariatric surgery. Gastric bypass would be the preferred operation in these patients.

(Conditional recommendation, moderate level of evidence)

6. The usage of current endoscopic therapy or transoral incisionless fundoplication cannot be recommended as an alternative to medical or traditional surgical therapy.

(Strong recommendation, moderate level of evidence)


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10 Katzet al.

Table 1. Continued

Potential risks associated with PPIs

1. Switching PPIs can be considered in the setting of side-effects. (Conditional recommendation, low level of evidence)

2. Patients with known osteoporosis can remain on PPI therapy. Concern for hip fractures and osteoporosis should not affect the decision to use PPI long-term except in

patients with other risk factors for hip fracture. (Conditional recommendation, moderate level of evidence)

3. PPI therapy can be a risk factor for Clostridium difficileinfection, and should be used with care in patients at risk. (Moderate recommendation, moderate level of

evidence)

4. Short-term PPI usage may increase the risk of community-acquired pneumonia. The risk does not appear elevated in long-term users. (Conditional recommendation,

moderate level of evidence)

5. PPI therapy does not need to be altered in concomitant clopidogrel users as there does not appear to be an increased risk for adverse cardiovascular events.

(Strong recommendation, high level of evidence)

Extraesophageal presentations of GERD: Asthma, chronic cough, and laryngitis

1. GERD can be considered as a potential co-factor in patients with asthma, chronic cough, or laryngitis. Careful evaluation for non-GERD causes should be undertaken in

all of these patients. (Strong recommendation, moderate level of evidence).

2. A diagnosis of reflux laryngitis should not be made based solely upon laryngoscopy findings. (Strong recommendation, moderate level of evidence)

3. A PPI trial is recommended to treat extraesophageal symptoms in patients who also have typical symptoms of GERD. (Strong recommendation, low level of evidence)

4. Upper endoscopy is not recommended as a means to establish a diagnosis of GERD-related asthma, chronic cough, or laryngitis. (Strong recommendation, low level of

evidence)

5. Reflux monitoring should be considered before a PPI trial in patients with extraesophageal symptoms who do not have typical symptoms of GERD.

(Conditional recommendation, low level of evidence)

6. Non-responders to a PPI trial should be considered for further diagnostic testing and are addressed in the refractory GERD section below. (Conditional recommendation,


7. Surgery should generally not be performed to treat extraesophageal symptoms of GERD in patients who do not respond to acid suppression with a PPI. (Strong


GERD refractory to treatment withPPIs

1. The first step in management of refractory GERD is optimization of PPI therapy. (Strong recommendation, low level of evidence)

2. Upper endoscopy should be performed in refractory patients with typical or dyspeptic symptoms principally to exclude non-GERD etiologies. (Conditional recommendation,


3. In patients in whom extraesophageal symptoms of GERD persist despite PPI optimization, assessment for other etiologies should be pursued through concomitant

evaluation by ENT, pulmonary, and allergy specialists. (Strong recommendation, low level of evidence)

4. Patients with refractory GERD and negative evaluation by endoscopy (typical symptoms) or evaluation by ENT, pulmonary, and allergy specialists (extraesophageal

symptoms), should undergo ambulatory reflux monitoring. (Strong recommendation, low level of evidence)

5. Reflux monitoring off medication can be performed by any available modality (pH or impedance-pH). (Conditional recommendation, moderate level evidence). Testing on

medication should be performed with impedance-pH monitoring in order to enable measurement of nonacid reflux. (Strong recommendation, moderate level of evidence).

6. Refractory patients with objective evidence of ongoing reflux as the cause of symptoms should be considered for additional antireflux therapies, which may include

surgery or TLESR inhibitors. (Conditional recommendation, low level of evidence). Patients with negative testing are unlikely to have GERD and PPI therapy should be

discontinued. (Strong recommendation, low level of evidence)

Complications Associated with GERD

1. The Los Angeles (LA) classification system should be used when describing the endoscopic appearance of erosive esophagitis. (Strong recommendations, moderate level

of evidence). Patients with LA Grade A esophagitis should undergo further testing to confirm the presence of GERD. (Conditional recommendation, low level of evidence)

2. Repeat endoscopy should be performed in patients with severe erosive reflux disease after a course of antisecretory therapy to exclude underlying Barretts esophagus.

(Conditional recommendation, low level of evidence)

3. Continuous PPI therapy is recommended following peptic stricture dilation to improve dysphagia and reduce the need for repeated dilations. (Strong recommendation,moderate level of evidence)

4. Injection of intralesional corticosteroids can be used in refractory, complex strictures due to GERD. (Conditional recommendation, low level of evidence)

5. Treatment with a PPI is suggested following dilation in patients with lower esophageal (Schatzki) rings. (Conditional recommendation, low level of evidence)

6. Screening for Barretts esophagus should be considered in patients with GERD who are at high risk based on epidemiologic profile. (Conditional


7. Symptoms in patients with Barretts esophagus can be treated in a similar fashion to patients with GERD who do not have Barretts esophagus. (Strong recommendation,

moderate level of evidence)

8. Patients with Barretts esophagus found at endoscopy should undergo periodic surveillance according to guidelines. (Strong recommendation, moderate level of evidence)

ENT, ear, nose, and throat; GERD, gastroesophageal reflux disease; LA, Los Angeles; PPI, proton pump inhibitor.


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laryngitis, other airway symptoms and so-called extraesophageal

symptoms are discussed in a subsequent section. Atypical symp-

toms including dyspepsia, epigastric pain, nausea, bloating, and

belching may be indicative o GERD but overlap with other con-

ditions. A systematic review ound that ~38% o the general popu-

lation complained o dyspepsia. Dyspepsia was more requent in

GERD patients than those without. Tese patients were at risk or

a new diagnosis o GERD. Epigastric pain, early satiety, belching

and bloating were more likely to respond to a PPI therapy com-

pared with nausea. Overall, these symptoms can be considered to

be associated with GERD i they respond to a PPI trial (9).

A recent systematic review on the burden o GERD on quality

o lie (QOL) included 19 studies. Patients with disruptive GERD

(daily or > weekly symptoms) had an increase in time off work and

decrease in work productivity. Low scores on sleep scales were seen

compared with patients with less requent symptoms. A decrease

in physical unctioning was also seen (10). Nocturnal GERD has a

greater impact on QOL compared with daytime symptoms. Both

nocturnal symptoms and sleep disturbances are critical to eluci-date when evaluating the GERD patient (11).

Te balance o evidence suggests that symptom requency does

not change as we age, however, the intensity o symptoms may

decrease afer the age o 50 (12). Aging increases the prevalence

o erosive esophagitis, Los Angeles (LA) grades C and D (13).

Barretts esophagus increases in prevalence afer age 50, especially

in Caucasian males (14). Tere are little data addressing the ea-

tures o GERD in women distinct rom men. Patients with erosive

esophagitis are more likely to be men, and women are more likely

to have NERD. Barretts esophagus is more requent in men com-

pared with women (15). Te gender ratio or esophageal adenocar-

cinoma is estimated to be 8:1 male to emale (14).Tere is a denite relationship between GERD and obesity.

Several meta-analysis suggest an association between body mass

index (BMI), waist circumerence, weight gain and the presence

o symptoms and complications o GERD including ERD and

Barretts esophagus (16,17). Te ProGERD study, likely the largest o

its kind ( > 5,000 patients) used logistic regression analysis to iden-

tiy several independent risk actors or ERD. Te odds or higher

degrees o ERD increased as BMI rose (18). It is o greatest concern

that there has been a well-documented association between BMI

and carcinoma o the esophagus and gastric cardia (19).

ESTABLISHING THE DIAGNOSIS OF GERDRecommendations

1. A presumptive diagnosis o GERD can be established in the

setting o typical symptoms o heartburn and regurgitation.

Empiric medical therapy with a PPI is recommended in this set-

ting. (Strong recommendation, moderate level o evidence).

2. Patients with non-cardiac chest pain suspected due to GERD

should have diagnostic evaluation beore institution o

therapy. (Conditional recommendation, moderate level o

evidence) A cardiac cause should be excluded in patients with

chest pain beore the commencement o a gastrointestinal

evaluation (Strong recommendation, low level o evidence)

3. Barium radiographs should not be perormed to diagnose

GERD (Strong recommendation, high level o evidence)

4. Upper endoscopy is not required in the presence o typical

GERD symptoms. Endoscopy is recommended in the presence

o alarm symptoms and or screening o patients at high risk or

complications. Repeat endoscopy is not indicated in patients

without Barretts esophagus in the absence o new symptoms.

(Strong recommendation, moderate level o evidence)

5. Routine biopsies rom the distal esophagus are not recom-

mended specically to diagnose GERD. (Strong recommen-

dation, moderate level o evidence)

6. Esophageal manometry is recommended or preoperative

evaluation, but has no role in the diagnosis o GERD. (Strong

recommendation, low level o evidence)

7. Ambulatory esophageal reux monitoring is indicated beore

consideration o endoscopic or surgical therapy in patients

with NERD, as part o the evaluation o patients reractory to

PPI therapy, and in situations when the diagnosis o GERD

is in question. (Strong recommendation, low level evidence).Ambulatory reux monitoring is the only test that can assess

reux symptom association (Strong recommendation, low

level o evidence).

8. Ambulatory reux monitoring is not required in the presence o

short or long-segment Barretts esophagus to establish a diagnosis

o GERD. (Strong recommendation, moderate level o evidence).

9. Screening or Helicobacter pyloriinection is not recom-

mended in GERD. Eradication o H. pyloriinection is not

routinely required as part o antireux therapy (Strong


Te diagnosis o GERD is made using some combination osymptom presentation, objective testing with endoscopy, ambu-

latory reux monitoring, and response to antisecretory therapy.

(Table 2) Te symptoms o heartburn and regurgitation are the

most reliable or making a presumptive diagnosis based on his-

tory alone; however, these are not as sensitive as most believe. A

systematic review o seven studies ound the sensitivity o heart-

burn and regurgitation or the presence o erosive esophagitis to

be 3076% and the specicity rom 6296% (20). Empiric PPI

therapy (a PPI trial) is a reasonable approach to conrm GERD

when it is suspected in patients with typical symptoms. A res-

ponse to therapy would ideally conrm the diagnosis; however,

a well done meta-analysis suggested some limitations o this

approach with a sensitivity o 78% and specicity o 54% (21).Tereore, empiric therapy (or a so called PPI trial) has some

limitations.

Non-cardiac chest pain has ofen been associated with the pres-

ence o GERD, and can be the presenting symptom. A meta-anal-

ysis ound a high probability that non-cardiac chest pain responds

to aggressive acid suppression (22). Tis study supported earlier

work suggesting the effi cacy and cost effectiveness o a PPI trial

(PPI twice daily in variable doses) in patients with chest pain in

whom a cardiac cause had been excluded. However, a more re-

cent systematic review suggested that the response o non-cardiac

chest pain to a PPI trial was signicantly higher than placebo in


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12 Katzet al.

Te nding o barium reux above the thoracic inlet with or with-

out provocative maneuvers including the water siphon test does

increase the sensitivity o the barium test; however, not suffi ciently

to be recommended as a diagnostic test without dysphagia (26).

Te endoscope has long been the primary tool used to evaluate

the esophageal mucosa in patients with symptoms suspected due

to GERD. Findings o GERD include erosive esophagitis, stric-

tures, and a columnar lined esophagus ultimately conrmed to be

Barretts esophagus. As such, endoscopy has excellent specicity

or the diagnosis o GERD especially when erosive esophagitis

is seen and the LA classication is used (27). However, the vast

majority o patients with heartburn and regurgitation will not

have erosions (or Barretts) limiting upper endoscopy as an initial

diagnostic test in patients with suspected GERD (28). Endoscopy

allows or biopsy o rings and strictures and screening or Barretts.

Although epidemiologic risk actors or Barretts esophagus have

been well-dened (age over 50, symptoms or >510 years, obes-

ity, male sex) the sensitivity and specicity o these symptoms or

abnormal endoscopy makes the utility o screening or Barretts acontroversial topic. Recent data indicate that it may be reasonable

to perorm endoscopy or screening in certain high-risk groups

in particular overweight white males over the age o 50 with

chronic GERD symptoms (12). Te nding o any Barretts eso-

phagus segment has been associated with pathologic GERD and

generally obviates the need or pH testing (29). In a 2009 study,

90% o short-segment BE patients were ound to have abnormal

pH-impedance testing (30).

Te addition o esophageal biopsies as an adjunct to an endo-

scopic examination has been re-emphasized because o the in-

creased prevalence o eosinophilic esophagitis (EoE). Many clini-

cians routinely biopsy the esophagus in patients with reux-typesymptoms to look or EoE in the setting o an endoscopy that does

not reveal erosive changes. Unortunately, differentiating GERD

rom EoE using only biopsy is diffi cult and risks making a diagno-

sis and instituting treatment without supportive data. Low eosi-

nophil counts in the distal esophagus while suggestive o GERD

are not specic. In addition, a high eosinophil count may be seen

with GERD and respond to PPIs (PPI responsive eosinophilia)

(31). Te sensitivity o the other histologic ndings; basal cell hy-

perplasia, elongation o the rete pegs, papillary elongation, and

even neutrophils, are o limited clinical useulness (32,33). Tere

are no studies examining the effi cacy o PPIs based on microscop-

ic ndings alone. Te use o routine biopsy o the esophagus to

diagnose GERD cannot be recommended in a patient with heart-burn and a normal endoscopy based on current literature. In ad-

dition, the practice o obtaining mucosal biopsies rom a normal

appearing esophagogastric junction has not been demonstrated to

be useul in GERD patients (34).

Esophageal manometry is o limited value in the primary diag-

nosis o GERD. Neither a decreased lower esophageal sphincter

pressure, nor the presence o a motility abnormality is specic

enough to make a diagnosis o GERD. Manometry should be used

to aid in placement o transnasal pH-impedance probes and is

recommended beore consideration o antireux surgery prima-

rily to rule out achalasia or severe hypomotility (scleroderma-like

patients with objective evidence o GERD (ERD on endoscopyand/or abnormal pH monitoring) (23). Te response to PPIs

compared with placebo was almost non-existent in the absence o

objective documentation o GERD. As such, a diagnostic evalu-

ation with endoscopy and pH monitoring should be considered

beore a PPI trial (24). Te presence o heartburn in conjunction

with chest pain was not predictive o PPI response o the chest

pain component.

Dysphagia has historically been an alarm symptom or warning

sign and an indication or early endoscopy to rule out a GERD

complication. Respiratory symptoms have been associated with

GERD, based on retrospective casecontrol studies. In addition,

dental erosions, erosion o dental enamel, sinusitis, chronic laryn-

gitis and voice disturbance have similarly been associated withGERD. Tese are discussed later in the article. Overall, heartburn

and regurgitation remain reliable symptoms o GERD as does

non-cardiac chest pain. Other symptoms, while associated with

GERD, are not as reliable. Te causal relationship between GERD

and the so-called atypical and extraesophageal maniestations

remains diffi cult with only a history.

Barium radiographs have been historically considered part o

the potential diagnostic armamentarium in the patient with eso-

phageal symptoms, including GERD. Although well-perormed

barium esophagrams with double contrast can detect signs o eso-

phagitis, the overall sensitivity o this test is extremely low (25).

Table 2. Diagnostic testing for GERD and utility of tests

Diagnostic

test Indication

Highest level

of evidence Recommendation

PPI trial Classic symptoms,

no warning signs,

Meta-analysis Negative trial does

not rule out GERD

Barium

swallow

Not for GERD

diagnosis. Use

for evaluation of

dysphagia

Casecontrol Do not use

unless evaluating

for complication

(stricture, ring)

Endoscopy Alarm symptoms,

screening of

high-risk patients,

chest pain

Randomized

Controlled

Trial

Consider early for

elderly, those at risk

for Barretts, non-

cardiac chest pain,

patients unrespon-

sive to PPI

Esophageal

biopsy

Exclude non-

GERD causes for

symptoms

CaseControl Not indicated for

diagnosis of GERD

Esophageal

manometry

Preoperative

evaluation for

surgery

Observational Not recommen-

ded for GERD

diagnosis. Rule

out achalasia/

scleroderma-like

esophagus preop

Ambulatory

reflux

monitoring

Preoperatively

for non-erosive

disease. refractory

GERD symptoms,

GERD diagnosis in

question

Observational Correlate symptoms

with reflux, docu-

ment abnormal

acid exposure or

reflux frequency

GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor.


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esophagus), conditions that would be contraindications to Nissen

undoplication, but not to tailor the operation.

Ambulatory reux monitoring (pH or impedance-pH) is the

only test that allows or determining the presence o abnormal

esophageal acid exposure, reux requency, and symptom asso-

ciation with reux episodes. Perormed with either a telemetry

capsule (usually 48 h) or transnasal catheter (24 h), pH monitoring

has excellent sensitivity (77100%) and specicity (85100%) in

patients with erosive esophagitis; however, the sensitivity is lower

in those with endoscopy-negative reux symptoms ( < 71%) when

a diagnostic test is more likely to be needed (24). A consensus

statement (35) suggested that impedance added to pH moni-

toring increased the sensitivity o reux monitoring to close to

90%. elemetry capsule pH monitoring offers increased patient

tolerability and the option to extend the monitoring period to

48 or perhaps to 96 h. Te additional monitoring period allows

or combining and on and off therapy study in selected situations

and offers additional opportunity to correlate symptoms with acid

reux. Catheter-based monitoring allows or the addition oimpedance and detection o weakly acidic or non-acid reux.

Optimal use o these two options is certainly debated as is wheth-

er to test on or off therapy. As a true diagnostic test (is abnor-

mal acid exposure present) and or evaluation beore considering

surgery in a patient with NERD an off therapy test is recommend-

ed. Te use o on and off therapy monitoring in reractory GERD

is discussed subsequently.

When symptom correlation is required, the decision is more

diffi cult. Te two symptom association measures most ofen

used are symptom index (SI) and symptom association proba-

bility (SAP). Both have methodological shortcomings that have

been reviewed elsewhere (36) and prospective data to validatethe ability o these symptom association measures to predict

response to treatment is scarce. Both the SI and SAP have been

validated when pH monitoring is perormed off therapy in a

patient with heartburn. A positive test on therapy, coupled with

a symptom relationship, theoretically suggests GERD as a cause

or symptoms but outcome studies are lacking or any symptom

other than heartburn. For patient management, a strongly posi-

tive SI or SAP may suggest the need or a therapeutic interven-

tion and a negative result supports the notion that the patients

symptoms are unlikely to be due to reux. However, these indi-

ces should not be used in isolation and other reux monitoring

parameters as well the patients presentation have to be taken

into account.Te relationship between H. pylori inection and GERD is

controversial. As such, a ull discussion is beyond the scope o

this article. One issue most ofen discussed is whether treat-

ment o H. pylorishould be altered because o an exacerbation

o GERD and i patients on long-term PPIs require screening

and subsequent eradication o the bug to prevent the possibility

o increasing risk o gastric cancer. A meta-analysis o 12 stud-

ies ound no increase in GERD (erosive esophagitis) in patients

with dyspeptic symptoms who were eradicated compared with

those not. Tis same study ound, in subgroup analysis, patients

with peptic ulcer disease might experience the new onset o

GERD symptoms afer H. pylorieradication (37). Concern or

the use o long-term PPI therapy in patients with H. pyloriinec-

tion has been raised because o the potential or development o

atrophic gastritis in inected patients on long-term PPI (38). Tis

study prompted a Food and Drug Administration (FDA) review

panel that concluded that the evidence was not suffi cient to rec-

ommend testing o all patients on long-term PPI. Te aws in

this study and lack o observational data on negative outcomes

lead us to recommend against screening o GERD patients or

H. pylori despite the European recommendation in avor o

screening (39).

GERD is requent during pregnancy, maniests as heartburn,

and may begin in any trimester. One study ound onset o 52%

in the rst trimester, 40% in the second trimester, and 8% in

the third trimester (40). Among 607 pregnant women attend-

ing an antenatal clinic, 22% experienced heartburn in the rst

trimester, 39% in the second, and 72% in the third, whereas

only 14% o these women reported mild heartburn beore their

pregnancy (41). Severity also increased throughout pregnancy.Signicant predictors o heartburn are increasing gestational

age, heartburn beore pregnancy, and parity. Maternal age is

inversely correlated with heartburn. Race, pre-pregnancy BMI,

and weight gain in pregnancy do not correlate with the onset o

heartburn. Despite its requent occurrence during pregnancy,

heartburn usually resolves afer delivery (42). Pregnancy and

amount o weight gain during pregnancy were risk actors or

requent GERD symptoms 1 year post delivery (43). No other

GERD symptom has been studied in pregnancy. Te diagnosis

o GERD during pregnancy should be based on symptoms and

treatment symptom-based. Additional diagnostic testing is gene-

rally not required or the majority o patients with suspectedGERD. In the occasional pregnant patient who does require

testing, upper endoscopy is the test o choice, but should be re-

served or patients whose symptoms are reractory to medical

therapy or who have suspected complications. I possible how-

ever, endoscopy should be delayed until afer the rst trimester.

It is uncommon to require ambulatory pH monitoring during

pregnancy.

MANAGEMENT OF GERD

Recommendations

1. Weight loss is recommended or GERD patients who are

overweight or have had recent weight gain. (Conditionalrecommendation, moderate level o evidence)

2. Head o bed elevation and avoidance o meals 23 h

beore bedtime should be recommended or patients with

nocturnal GERD. (Conditional recommendation, low level

o evidence)

3. Routine global elimination o ood that can trigger reux

(including chocolate, caffeine, alcohol, acidic and/or spicy

oods) is not recommended in the treatment o GERD.

(Conditional recommendation, low level o evidence)

4. An 8-week course o PPIs is the therapy o choice or

symptom relie and healing o erosive esophagitis. Tere are


8/22


14 Katzet al.

symptoms including caffeine, coffee, chocolate, spicy oods, highly

acidic oods such as oranges and tomatoes, and oods with high

at content.

A systematic review (44) evaluated the effect o dietary and other

liestyle modications on lower esophageal sphincter pressure,

esophageal pH, and GERD symptoms. Consumption o tobacco (12

trials), chocolate (2 trials), and carbonated beverages (2 trials) and

right lateral decubitus position (3 trials) were shown to lower pressure

o the lower esophageal sphincter (LES), whereas consumption o

alcohol (16 trials), coffee and caffeine (14 trials), spicy oods (2 trials),

citrus (3 trials), and atty oods (9 trials) had no effect. Tere was an

increase in esophageal acid exposure times with tobacco and alcohol

consumption in addition to ingestion o chocolate and atty oods.

However, tobacco and alcohol cessation (4 trials) were not shown to

raise LESP, improve esophageal pH, or improve GERD symptoms.

In addition, there have been no studies conducted to date that have

shown clinical improvement in GERD symptoms or complications

associated with cessation o coffee, caffeine, chocolate, spicy oods,

citrus, carbonated beverages, atty oods, or mint. A recent systematicreview concluded that there was lack o evidence that consumption o

carbonated beverages causes or provokes GERD (45).

Weight gain even in subjects with a normal BMI has been asso-

ciated with new onset o GERD symptoms (46). Multiple cohort

studies have demonstrated reduction in GERD symptoms with

weight loss (47,48). Roux-en-Y gastric bypass, but not vertical

banded gastroplasty, has been demonstrated to be effective in

reduction o GERD symptoms (49). A large casecontrol study

based on the Nurses Health Cohort demonstrated a 40% reduction

in requent GERD symptoms or women who reduced their BMI

by 3.5 or more compared with controls (46).

Assumption o the recumbent position has been associated withworsening o esophageal pH values and GERD symptoms. Tree

randomized controlled trials have demonstrated improvement

in GERD symptoms and esophageal pH values with head o bed

elevation using blocks or oam wedges (5052).

Medical options or patients ailing liestyle interventions

include antacids, histamine-receptor antagonists (H2RA), or PPI

therapy. A meta-analysis published in 2010 demonstrated that the

placebo response in GERD clinical trials approximated 20% and

was lower in patients with erosive esophagitis (11%) and PPI trials

(14%) compared with trials with H2RAs (25%) (53). PPI therapy

has been associated with superior healing rates and decreased

relapse rates compared with H2RAs and placebo or patients with

erosive esophagitis (54). A 1997 meta-analysis demonstrated supe-rior healing rates or all grades o erosive esophagitis using PPI

therapy compared with H2RAs, sucralate, or placebo (55). Te

mean ( s.d.) overall healing proportion irrespective o drug dose

or treatment duration was highest with PPIs (84% 11%) vs H2RAs

(52% 17%), sucralate (39% 22%), or placebo (28% 16%). PPIs

showed a signicantly aster healing rate (12%/week) vs. H2RAs

(6%/week) and placebo (3%/week). PPIs provided aster, more

complete heartburn relie (11.5%/week) vs. H2RAs (6.4%/week)

(35). PPIs are associated with a greater rate o symptom relie in

patients with ERD (~7080%) compared to patients with NERD

(where the symptom relie approximates 5060%) (56,57).

no major differences in effi cacy between the different PPIs.

(Strong recommendation, high level o evidence)

5. raditional delayed release PPIs should be administered

3060 min beore meal or maximal pH control. (Strong

recommendation, moderate level o evidence). Newer

PPIs may offer dosing exibility relative to meal timing

(Conditional recommendation, moderate level o evidence)

6. PPI therapy should be initiated at once a day dosing,

beore the rst meal o the day. (Strong recommendation,

moderate level o evidence). For patients with partial

response to once daily therapy, tailored therapy with adjust-

ment o dose timing and/or twice daily dosing should be

considered in patients with night-time symptoms, variable

schedules, and/or sleep disturbance. (Strong recommenda-

tion, low level o evidence)

7. Non-responders to PPI should be reerred or evaluation.

(Conditional recommendation, low level o evidence, see

reractory GERD section)

8. In patients with partial response to PPI therapy, increasingthe dose to twice daily therapy or switching to a different

PPI may provide additional symptom relie. (Conditional


9. Maintenance PPI therapy should be administered or GERD

patients who continue to have symptoms afer PPI is discon-

tinued and in patients with complications including erosive

esophagitis and Barretts esophagus. (Strong recommenda-

tion, moderate level o evidence). For patients who require

long-term PPI therapy, it should be administered in the lowest

effective dose, including on demand or intermittent therapy.

(Conditional recommendation, low level o evidence)

10. H2-receptor antagonist therapy can be used as a maintenanceoption in patients without erosive disease i patients experi-

ence heartburn relie. (Conditional recommendation,

moderate level o evidence). Bedtime H2RA therapy can be

added to daytime PPI therapy in selected patients with objec-

tive evidence o night-time reux i needed but may be

associated with the development o tachyphlaxis afer several

weeks o usage. (Conditional recommendation, low level

o evidence)

11. Terapy or GERD other than acid suppression, including

prokinetic therapy and/or bacloen, should not be used in

GERD patients without diagnostic evaluation. (Conditional

recommendation, moderate level o evidence)

12. Tere is no role or sucralate in the non-pregnant GERDpatient. (Conditional recommendation, moderate level o

evidence)

13. PPIs are sae in pregnant patients i clinically indicated.

(Conditional recommendation, moderate level o evidence)

SUMMARY OF THE EVIDENCE

Liestyle interventions are part o therapy or GERD. (Table 3)

Counseling is ofen provided regarding weight loss, head o bed

elevation, tobacco and alcohol cessation, avoidance o late-night

meals, and cessation o oods that can potentially aggravate reux


9/22


10/22


11/22



ambulatory pH studies with good symptom correlation (86). In

this patient cohort, long-term remission rates can be expected to

be comparable and in some cases statistically superior to medical

therapy. In a long-term ollow-up o a Veterans Affairs Coopera-

tive cooperative randomized controlled trial comparing medical

to surgical therapy or GERD, 92% o the patients in the medi-

cal arm were using medical therapy compared with 62% o the

surgical cohort at 10 years (87). In a 12-year long-term ollow-up

o patients randomized to undoplication compared with ome-

prazole, 53% o the surgery cohort were in remission compared

with 45% o the medically treated patients (P= 0.02), although

symptoms o gas-bloat syndrome remained more common in the

surgical cohort (88).

Patients choosing to undergo surgical therapy or GERD may

ace some additional risks including increased short-term risk

o mortality. Te most common adverse events associated with

undoplication include the gas-bloat syndrome in 1520% o

patients. A recent meta-analysis concluded that the prevalence

o postoperative dysphagia and inability to belch were signi-cantly lower in patients undergoing partial undoplication com-

pared with patients undergoing total undoplication (89). In a

Cochrane review, our randomized trials with over 1,200 subjects

randomized to medical or surgical therapy were included (90).

All our studies reported signicant improvements in GERD-

specic QOL afer surgery compared with medical therapy

although data were not combined. Tere was evidence to suggest

that symptoms o heartburn, reux, and bloating were improved

more afer surgery compared with medical therapy, but a small

proportion o participants reported persistent postoperative dys-

phagia. Overall rates o postoperative complications were low,

but undoplication was associated with a potential or adversepostoperative events.

Outcomes in patients with extraesophageal symptoms undergo-

ing Nissen undoplication have been less encouraging. In patients

enrolled in a VA Cooperative study, no signicant change in pulmo-

nary unction tests were demonstrated afer 1 year o surgery, even

in patients with abnormal baseline pulmonary unction tests (91).

A randomized controlled trial o cimetidine vs. undoplication and

placebo or asthma symptoms demonstrated equivalent effi cacy

or medical and surgical therapy compared with placebo but no

signicant change in FEV1 at 6 months (92). In a 2003 Cochrane

review, medical or surgical antireux therapy was not associated

with improvement in pulmonary unction, asthma symptoms, or

use o medication (93). Although surgery can be effective in care-ully selected patients with extraesophageal or atypical symptoms,

response rates are lower than in patients with heartburn (86). It is

particularly important to careully evaluate patients with so-called

laryngopharyngeal reux beore considering undoplication.

A response to PPI is critical. In the absence o a PPI response,

surgery is unlikely to be effective even with an abnormal pH

study (94).

Given the increasing prevalence o obesity in the US, gastric

bypass has become a more common procedure compared

with Nissen undoplication. A 2009 review assessed the effi cacy

or surgical therapies or obesity on gastroesophageal reux (95).

In studies assessing Roux-en-Y gastric bypass surgery, GERD

symptoms improved when assessed postoperatively via question-

naire. Roux-en-Y was more effective compared with gastric band-

ing in one study. O the eight studies assessing vertical banded

gastroplasty, one study showed improvement in GERD symptoms,

but the other studies demonstrated no change or an increase in

reux symptoms. Te effects o gastric banding on GERD symp-

toms in eight studies were conicting.

Endoscopic therapies or GERD have been developed but have

not demonstrated long-term effi cacy. Tese therapies included

radiorequency augmentation to the lower esophageal sphincter,

silicone injection into the lower esophageal sphincter, and endo-

scopic suturing o the LES. None o these therapies demonstrated

long-term improvement in esophageal pH levels or the ability or

patients to stop antireux therapy and were subsequently removed

rom the US marketplace (96). Recent alternative approaches have

included transoral incisionless undoplication, a suturing device

designed to create a ull thickness gastroesophageal valve rom

inside the stomach. Unortunately long-term data regarding effi -cacy o this device are limited to a small number o subjects and

short duration o ollow-up (97). A recent study suggested that

at 36 months o ollow-up, the majority o patients had required

additional medical therapy or a revisional undoplication (98).

Sphincter augmentation using the LINX Reux system con-

structed o titanium beads has shown effi cacy up to 4 years in the

reduction o the amount o pathologic esophageal acid exposure

in a small number o subjects (99). Tis device has been approved

by the FDA based on a clinical study in 100 GERD patients. Tis

study ound that perormance o LINX resulted in consistent

symptom relie and pH control with markedly ewer side effects

than traditional laparoscopic undoplication in well-selectedpatients. More data are required beore widespread usage can be

recommended.

POTENTIAL RISKS ASSOCIATED WITH PPIs

Recommendations

1. Switching PPIs can be considered in the setting o side

effects. (Conditional recommendation, low level o evidence)

2. Patients with known osteoporosis can remain on PPI therapy.

Concern or hip ractures and osteoporosis should not affect

the decision to use PPI long-term except in patients with

other risk actors or hip racture. (Strong recommendation,

moderate level o evidence)3. PPI therapy can be a risk actor or Clostridium diffi cile

inection and should be used with care in patients at risk.


4. Short-term PPI usage may increase the risk o community-

acquired pneumonia. Te risk does not appear elevated in

long-term users. (Conditional recommendation, moderate

level o evidence)

5. PPI therapy does not need to be altered in concomitant clopi-

dogrel users as clinical data does not support an increased

risk or adverse cardiovascular events. (Strong recommenda-

tion, high level o evidence)


12/22


18 Katzet al.

1.111.46) and H2RAs (adjusted OR 1.22, 95% CI 1.091.36).

However, when the randomized controlled trial data were ana-

lyzed, only use o H2RAs was associated with an elevated risk

o hospital-acquired pneumonia (RR 1.22, 95% CI 1.011.48) A

more recent meta-analysis (six nested casecontrol studies) ound

an increased risk o community acquired pneumonia (CAP)

associated with PPI usage (OR 1.36, 95% CI 1.121.65), but the

results were conounded by signicant heterogeneity (104). In

exploratory subgroup analysis, short duration o use was asso-

ciated with an increased odds o CAP (OR 1.92 (95% CI 1.40

2.63), P= 0.003), whereas chronic use was not (OR 1.11 (95% CI

0.901.38), P< 0.001). Other studies have also demonstrated an

increased risk o CAP associated only with short-term PPI usage

(105,106). In summary, PPI therapy should not be withheld

in patients requiring therapy due to a potential risk o CAP;

however, the diagnosis o pneumonia and timing o initiation

o PPI therapy deserves urther study.

Reduction in gastric acid has been associated with decreased

release o ionized calcium rom calcium salts and protein-boundcalcium. Although some physiologic data have suggested that

PPIs might inhibit osteoclast-mediated bone resorption, clini-

cal studies have rendered mixed results. In the Manitoba Bone

Mineral Density Database, the study with the longest ollow-up

to date (107), cases with osteoporosis at the hip or lumbar verte-

brae were matched to three controls with normal bone mineral

density. PPI use over the previous 5 years was not associated with

having osteoporosis at either the hip (OR 0.84; 95% CI, 0.55

1.34) or the lumbar spine (OR 0.79; 95% CI, 0.591.06), and it

was concluded that the association between PPI use and hip rac-

ture was probably related to actors independent o osteoporo-

sis. A 2010 casecontrol study demonstrated that the excess hipracture risk among PPI users was only present in persons with

at least one other risk actor (108). wo meta-analyses published

in 2011 demonstrated small increases in risk o hip racture (OR

1.2) but were limited by substantial heterogeneity among studies

included (109,110).

In 2009, the FDA issued a warning regarding the potential or

increased adverse cardiovascular events in concomitant users o

PPI and clopidogrel therapy, particularly among users o omepra-

zole, lansoprazole, and esomeprazole. Te concern arises rom

the act that the antiplatelet activity o clopidogrel requires activa-

tion by CYP 2C19, the same pathway required or metabolism o

some PPIs. Initial studies raised concern or a potential interac-

tion based on in vitrotests demonstrating that clopidogrels abilityto inhibit platelet aggregation was decreased in the presence o

PPIs (111,112). Subsequent retrospective studies yielded conict-

ing results with some publications suggesting an increased risk

or cardiovascular events (113115) and others showing lack o

effect (116,117). In two randomized controlled trials, PPIs did not

increase the risk o adverse events in patients receiving clopidog-

rel (118,119). Meta-analyses have demonstrated that the strength

o potential interactions is dependent upon the assessment o

clinical outcomes, adjustment or conounders, and data quality.

For example, in a meta-analysis including 26 studies (16 published

articles, 10 abstracts), the authors divided the analyses between


Potential adverse events associated with PPI therapy have

included headache, diarrhea, and dyspepsia in < 2% o users.

Switching to another PPI can be attempted in these patients or

in patients who ail to respond to an initial PPI, although data

supporting this practice are limited. Other potential adverse

associations have included vitamin and mineral deciencies,

association with community-acquired inections including

pneumonia and diarrhea, hip ractures and osteoporosis, and

increased cardiovascular events in patients using concomitant

clopidogrel therapy. Te FDA issued warnings regarding the

potential or wrist, hip, and spine ractures among PPI users

in 2010 and warnings regarding potential or adverse cardio-

vascular events among clopidogrel users taking PPI therapy in

2009. Because o these concerns, multiple meta-analyses and

systematic reviews have been published.

Te reason or concern regarding potential vitamin B12 de-

ciency in PPI users derives rom the act that the rst step in cobala-

min absorption requires gastric acid and pepsin in order to releasecobalamin rom dietary proteins. In two recent reviews, there was

no supporting clinical evidence to document the development

o B12 deciency in chronic PPI users (100,101). However, recent

studies have suggested that in elderly institutionalized long-term

PPI users, B12 deciency is more likely to develop and should be

considered in this cohort.

Gastric acid is necessary to allow absorption o non-heme

iron and also enhances iron salt dissociation rom ingested

ood. Iron deciency anemia has been reported in patients with

atrophic gastritis, gastric resection, or vagotomy. Tere currently is

no data demonstrating the development o iron deciency anemia

in normal subjects on PPI therapy (100).By their effects in increasing gastric pH levels, the usage o

PPIs may encourage growth o gut microora and increase sus-

ceptibility to organisms including Salmonella, Campylobacter

jejuni, Escherichia coli, Clostridium diffi cile, Vibrio cholerae,

and Listeria. A systematic review published in 2011 ound an

increased susceptibility in PPI users or Salmonella inections

(adjusted RR ranging rom 4.28.3 in two studies), Campylo-

bacter (RR 3.511.7 in our studies) and C. diffi cile inections

(RR 1.25.0 in 17 out o 27 studies demonstrating a positive

association) (102). Te studies ailing to demonstrate an asso-

ciation were predominantly in older patients > 65 years o age

where because o the presence o co-morbid conditions and

associated hypochlorhydria, the addition o PPI therapy did notraise the risk o inection. On the basis o the available evidence,

PPI usage can be a risk actor or Clostridium diffi cile and other

enteric inections and should be used with care in patients at

risk.

An increased risk or community-acquired pneumonia

cannot be clearly documented in association with PPI therapy.

A systematic review identied 31 studies (ve casecontrol

studies, three cohort studies, and 23 randomized controlled

trials) (103). A meta-analysis o the eight observational studies

showed that the overall risk o pneumonia was higher among

patients using PPIs (adjusted odds ratio (OR) 1.27, 95% CI


13/22



primary outcomes (myocardial inarction, stroke, stent occlusion,

or death) and secondary outcomes (re-hospitalization or car-

diac symptoms or revascularization procedures) (120). Clinical

data rom the two randomized controlled trials which included

usage o all PPIs except or dexlansoprazole did not show an

increased risk or adverse cardiovascular events (risk difference,

RD 0.0, 95% CI 0.01, 0.01). Te meta-analysis o primary out-

comes showed a RD o 0.02 (95% CI 0.01, 0.03) or all studies.

Te meta-analysis or secondary outcomes yielded a RD o 0.02

(95% CI 0.010.04) based on 19 published papers and abstracts.

When primary and secondary outcomes were combined, the

meta-analysis or published papers yielded an overall RD o

0.05 (95% CI 0.030.06). Te authors concluded that in patients

using concomitant clopidogrel and PPI therapy, the risk o adverse

cardiac outcomes was 0% based on data rom well-controlled

randomized trials. Data rom retrospective studies and the addi-

tion o probable vascular events signicantly increased the RD

estimates, likely due to lack o adjustment or potential conound-

ers (76). Subsequent meta-analyses have concluded that the datarom two randomized trials did not support an adverse effect,

and that analysis o cardiovascular events rom the remainder

o the studies was limited by moderate-substantial heterogeneity

(121,122).

EXTRAESOPHAGEAL PRESENTATIONS OF GERD:

ASTHMA, CHRONIC COUGH, AND LARYNGITIS

Recommendations

1. GERD can be considered as a potential co-actor in patients

with asthma, chronic cough, or laryngitis. Careul evalua-

tion or non-GERD causes should be undertaken in all othese patients. (Strong recommendation, moderate level o

evidence).

2. A diagnosis o reux laryngitis should not be made based

solely upon laryngoscopy ndings (Strong recommendation,

moderate level o evidence).

3. A PPI trial is recommended to treat extraesophageal

symptoms in patients who also have typical symptoms o

GERD. (Strong recommendation, low level o evidence)

4. Upper endoscopy is not recommended as a means to

establish a diagnosis o GERD-related asthma, chronic

cough, or laryngitis. (Strong recommendation, low level o

evidence)

5. Reux monitoring should be considered beore a PPI trialin patients with extraesophageal symptoms who do not have

typical symptoms o GERD. (Conditional recommendation,

low level o evidence).

6. Non-responders to a PPI trial should be considered or

urther diagnostic testing, and are addressed in the reractory

GERD section below. (Conditional recommendation, low

level o evidence)

7. Surgery should generally not be perormed to treat

extraesophageal symptoms o GERD in patients who do not

respond to acid suppression with a PPI. (Strong recommen-

dation, moderate level o evidence)


Te spectrum o clinical presentations attributed to GERD has

expanded rom typical esophageal symptoms o heartburn and

regurgitation, to an assortment o extraesophageal maniestations

including respiratory and laryngeal symptoms. Several epidemio-

logical studies have identied an association between GERD and

these extraesophageal symptoms, but causality cannot be inerred

rom these studies. A systematic review o 28 studies ound that

symptoms o GERD and abnormal 24-h pH monitoring were

present in 59% and 51% o asthma patients, but concluded that

there was little data to clariy the direction o causality in this asso-

ciation (123). Cohort studies suggest that GERD may be the cause

in 2141% o chronic nonspecic cough (124). A large VA popula-

tion casecontrol study ound increased odds ratios or pharyngi-

tis (OR 1.60), aphonia (OR 1.81), and chronic laryngitis (OR 2.01)

in cases with esophagitis or esophageal stricture compared with

controls (125). Te Montreal Consensus recognized established

associations between GERD and asthma, chronic cough, and

laryngitis, while acknowledging that these disorders requentlyhave a multi-actorial etiology and that gastro-esophageal reux

may be a co-actor rather than a cause. Te Montreal consensus

also recognized the rarity o extraesophageal syndromes occur-

ring in isolation without concomitant typical symptoms o GERD

(3). Currently available diagnostic tools to establish GERD as the

cause o extraesophageal symptoms have serious limitations, and

recent placebo-controlled trials have ailed to show a clear thera-

peutic benet o PPIs in treating all-comers with extraesophageal

symptoms. Tereore, patients with asthma, chronic cough, or

laryngitis should have careul evaluation or non-GERD causes.

GERD should be viewed as a possible contributing actor in some

but not all patients presenting with these clinical entities.Diagnosing GERD as the cause o extraesophageal symp-

toms has proven to be very challenging. Upper endoscopy can

document the presence o GERD when erosive esophagitis is

present, but it is ound in only one third o patients with GERD

symptoms (126) and is even rarer afer treatment with PPIs (59).

Even when present, nding erosive esophagitis does not establish a

diagnosis o GERD-related asthma, chronic cough, or laryngitis.

Ambulatory reux monitoring can conrm the presence o

GERD by documenting a pathological amount o gastroesopha-

geal reux. Current consensus is that the total percentage o time

the pH is < 4 is the most useul single discriminator between phys-

iologic and pathologic reux (127). Tere is great variability in the

reported prevalence o abnormal pH monitoring in patients withasthma (123), chronic cough (128), and laryngitis (129). Similar to

the nding o erosive esophagitis on endoscopy, documentation o

pathological reux on ambulatory monitoring does not establish

GERD as the cause o the extraesophageal symptoms. On the other

hand, a negative reux monitoring test should direct the diagnos-

tic effort toward non-GERD etiologies. Beyond establishing the

presence o pathological reux, ambulatory reux monitoring

may be used to determine whether the patients symptoms are due

to reux. Te two most commonly used methods to evaluate

the temporal association between reux episodes and symptoms

are the symptom index (SI) (130) and the symptom-association


14/22


20 Katzet al.

signicant improvement in cough scores in those receiving PPI

(standardized mean difference 0.41, 95% CI 0.75 to 0.07)

(140). Te experience with treating laryngeal symptoms attributed

to reux disease is comparable. A meta-analysis o eight rand-

omized controlled trials ound that PPI therapy had no signicant

advantage over placebo in achieving improvement o symptoms o

suspected GERD-related chronic laryngitis (RR 1.28, 95% CI 0.94

to 1.74) (141).

Tere are no high-quality randomized controlled trials evaluat-

ing the effectiveness o laparoscopic undoplication or the treat-

ment o extraesophageal symptoms o GERD. A recent Agency

or Healthcare Research and Quality review on the compara-

tive effectiveness o GERD treatments summarized the available

data on undoplication or asthma, cough, and laryngitis (142).

As explained in detail in this review, all the data on surgery or

extraesophageal GERD come rom surgical cohort studies with

wide variation in population treated, severity o symptoms, out-

come measures, surgical intervention, and duration o ollow-up.

Although some o these studies may show benet, the conclusiono the review was that the strength o the evidence was insuffi cient,

and no consistent benet could be attributed to surgery.

On the basis o the inormation summarized above, PPI therapy

seems reasonable in patients with asthma, chronic cough, and

laryngitis who also have typical symptoms o GERD or objective

evidence o GERD by endoscopy or reux monitoring. In these

patients, acid suppression with PPIs has proven to be bene-

cial to heal esophagitis and treat typical symptoms; whether the

extraesophageal symptoms will improve is less predictable. We have

ew well-dened markers to predict which patients will respond

to therapy. Empirical treatment or patients without typical symp-

toms or objective evidence o GERD thus cannot be routinely rec-ommended. Te historic recommendation is to treat patients with

higher dose PPI (twice daily) than patients with typical GERD

symptoms; however, this is based on uncontrolled and observa-

tional data only (143,144). Patients who are treated with PPI and

who do not respond to a 23 month course o acid suppression can

be evaluated and managed as proposed in the reractory GERD

section. Te importance o pursuing non-GERD etiologies in this

group o patients is critical.

GERD REFRACTORY TO TREATMENT WITH PPIs

Recommendations

1. Te rst step in management o reractory GERD is optimi-zation o PPI therapy. (Strong recommendation, low level o

evidence)

2. Upper endoscopy should be perormed in reractory patients

with typical or dyspeptic symptoms principally to exclude

non-GERD etiologies. (Conditional recommendation, low

level o evidence)

3. In patients in whom extraesophageal symptoms o GERD

persist despite PPI optimization, assessment or other etio-

logies should be pursued through concomitant evaluation by

EN, pulmonary, and allergy specialists (Strong recommen-

dation, low level o evidence)

probability (SAP) (131). Both methods rely on precise and timely

symptom recording by the patient, along with accurate reux

detection by the testing device. Symptom association analysis

perormed during reux monitoring may document a temporal

association between reux episodes and asthma attacks or cough

events. Te sensitivity and specicity o symptom association ana-

lysis tools is limited and there are no outcome studies to support

treatment o extraesophageal GERD based on this parameter alone

(127). A recent study o 237 patients with extraesophageal reux

symptoms that were reractory to PPI, ound that the presence o

heartburn or abnormal acid exposure on pH monitoring predicted

response to escalation o therapy, but the SI, SAP, or impedance

variables did not (132). Te recent development o ambulatory

reux-cough monitoring by combining impedance-pH to measure

reux (acid or nonacid) along with acoustic detection o cough,

which eliminates the subjectivity o patient-reported cough, has

enabled a more accurate assessment o the relationship between

reux and cough; a recent study using this approach was able to

document reux-induced cough as well as cough-induced reux(133). Whether these technical improvements increase the yield o

symptom association analysis in patients with cough attributed to

reux requires urther studies.

Laryngoscopic ndings, especially edema and erythema, are

ofen used to diagnose reux-induced laryngitis (134). It should

be pointed out that laryngoscopy revealed one or more signs o

laryngeal irritation in over 80% o healthy controls in a well-done

prospective study (135). Moreover, in a study o ve EN (ear,

nose, and throat) physicians who blindly evaluated 120 video

recordings o laryngoscopy exams, concordance among physicians

was low or edema, erythema, as well as likelihood and severity

o laryngopharyngeal reux; similarly, intra-rater reliability wasextremely variable or these ndings (136). It is important to

keep in mind that signs o laryngeal irritation may also be the

result o non-GERD etiologies such as allergy, smoking, or voice

abuse. Tereore, it is recommended that a diagnosis o reux-

induced laryngitis not be made based on laryngoscopy ndings

alone.

A course o action that is ofen pursued in clinical practice is

to empirically prescribe acid suppression with PPIs, especially

in patients with concomitant typical symptoms o GERD. wo

randomized controlled trials have shown that PPIs result in

improvement o various asthma outcomes (137,138). However, a

meta-analysis o 11 randomized controlled trials concluded that

PPI therapy in adults with asthma results in a statistically signi-cant but overall only a small improvement in peak expiratory

ow rate, that is unlikely to be o meaningul clinical signicance.

Tus, there is insuffi cient evidence to recommend PPIs or rou-

tine asthma treatment when other GERD symptoms are absent

(139). Improvement in peak expiratory ow was greater, though

still modest, in the eight studies that required evidence o GERD

(by symptoms, endoscopy, or reux monitoring) compared with

the three studies that did not require evidence o GERD. A meta-

analysis o nine randomized controlled trials ound no advantage

or PPI compared with placebo or total resolution o cough (OR

0.46, 95% CI 0.19 to 1.15), although sensitivity analysis ound


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4. Patients with reractory GERD and negative evaluation

by endoscopy (typical symptoms) or evaluation by EN,

pulmonary, and allergy specialists (extraesophageal

symptoms), should undergo ambulatory reux monitoring

(Strong recommendation, low level o evidence)

5. Reux monitoring offmedication can be perormed by any

available modality (pH or impedance-pH) (Conditional

recommendation, moderate level o evidence). esting on

medication should be perormed with impedance-pH moni-

toring in order to enable measurement o nonacid reux.


6. Reractory patients with objective evidence o ongoing

reux as the cause o symptoms should be considered or

additional antireux therapies that may include surgery

or LESR inhibitors. (Conditional recommendation, low

level o evidence). Patients with negative testing are unlikely

to have GERD and PPI therapy should be discontinued.

(Strong recommendation, low level o evidence)


We are seeing increasing numbers o patients treated empirically

with PPIs or symptoms that are suspected to be due to GERD who

do not respond to these medications. Te term reractory GERD

encompasses a heterogeneous group o patients that may differ

in symptom requency and severity, PPI dosing regimen (once

or twice daily), and response to therapy (rom partial to absent).

Although there is no established consensus regarding the deni-

tion o reractory GERD in terms o symptom burden, degree o

therapeutic response, and PPI dose at which ailure occurs, we

should accept that reractory GERD is a patient-driven phenom-enon (145). Not surprisingly, reractory GERD has a signicant

impact on QOL. A recent systematic review o nine studies ound

that persistent reux symptoms on PPI therapy are associated with

reduced physical and mental health-related QOL (10). Tereore,

any patient who seeks consultation or bothersome symptoms

that are attributable to GERD and that persist despite treatment

with a PPI merits evaluation and management. As not all patients

who ail to respond to PPIs will have GERD, the most important

goal o the diagnostic evaluation in these patients is to differenti-

ate those with persistent reux as the cause o the ongoing symp-

toms, rom those with non-GERD etiologies.

Te reported proportion o patients with heartburn who do not

respond to PPIs varies among studies, likely due to differing de-nitions o ailure, dissimilar patient groups, and different medica-

tion dosing. It has been estimated that ailure to control symptoms

occurs in up to 40% o patients treated with a PPI (146). A recent

systematic review ound persistent, troublesome typical symptoms

o GERD (heartburn and regurgitation) in 32% o patients in ran-

domized primary care trials and 45% o patients in observational

studies (147). Te proportion o patients with extraesophageal

presentations o GERD that do not respond to medication is less

well documented, but the success rate o treating extraesopha-

geal reux symptoms is lower than that or typical symptoms

(139141). A recent comparison o PPI responders and non-

responders ound that PPI ailure appears to be signicantly more

common in those with atypical symptoms. Additional actors

associated with PPI ailure were longer duration o disease, poor

compliance, and obesity (63).

Te rst step in the management o reractory GERD is to

optimize PPI therapy by conrming compliance and ensuring

appropriate dosing. Poor compliance is associated with lack o

response to PPI (63). Furthermore, adherence to PPI therapy was

ound in only 60% o patients with GERD in a large population-

based VA study (148). Te effi cacy o PPIs (as discussed above)

is generally maximized when PPIs are taken beore a meal (149).

Optimal PPI dosing (beore meals) was seen in only 46% o

100 patients who were reerred or persistent GERD symptoms

despite treatment (66). A survey o 491 physicians ound that

nearly 70% o primary care physicians and 20% o gastroenterol-

ogists in the US advised patients to take the PPI dose at bedtime

or did not believe that the relationship to meals was important

(150). Tereore, any patient with reractory symptoms should

be instructed regarding optimal dosing o the PPI being used.Once compliance and appropriate dosing are ensured, a single

trial o a different PPI can be considered. Recent evidence rom

a multicenter randomized trial showed this strategy to be helpul

in some patients (67). A randomized controlled trial in patients

with persistent GERD symptoms despite a single daily dose

o PPI, showed that increasing PPI to twice daily or switching

to another PPI both resulted in symptomatic improvement in

roughly 20% o patients, without a clear advantage or either

strategy (151).

Patients with persistent symptoms despite optimization o PPI

therapy require urther work-up (Figure 1). Tose with typical,

esophageal symptoms should undergo endoscopy principally toexclude non-reux esophageal disorders such as EoE, which can

present with esophageal symptoms reractory to PPI and to look

or the rare patient with erosive esophagitis, a nding that provides

evidence o ongoing acid reux. Although the prevalence o EoE

in patients with reractory GERD in the US has not been studied,

a recent Markov model ound that obtaining esophageal biopsies

to diagnose EoE in reractory GERD patients is cost-effective only

when the prevalence o EoE is 8% or greater (152). I endoscopy

is negative, as is requently the case, the next step is to perorm

reux monitoring to quantiy reux and assess the relationship

between reux episodes and the patients symptoms. Reux moni-

toring should also be considered in patients with extraesophageal

symptoms that persist despite PPI optimization and in whom non-GERD etiologies have been ruled out through pulmonary, EN,

and allergy evaluation.

Reux monitoring enables urther characterization o the

reractory patient, as the study may reveal: (a) PPI ailure with

ongoing acid reux, which will require escalation o therapy to

control acid reux (b) adequate acid control but ongoing sympto-

matic non-acid reux, which may respond to specic therapy or

(c) no reux. Among reractory GERD patients with a negative

reux monitoring study, those with heartburn may be classied

as having unctional heartburn while those with extraesopha-

geal symptoms (asthma, cough, laryngitis) will need additional


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22 Katzet al.

acid exposure in 96% o patients with reractory GERD that were

tested on twice daily PPI (154). Although rare, an abnormal pH test

in a patient taking a PPI (i.e. ongoing acid reux despite treatment)is evidence o therapeutic ailure or noncompliance. A negative pH

test in treated patients makes ongoing acid reux as the cause o

their symptoms very unlikely, but it cannot account or the possi-

bility o nonacid reux, which can be measured using impedance-

pH monitoring. A study that used the SI to evaluate 144 patients

reractory to twice daily PPI therapy ound that ongoing symp-

toms were related to non-acid reux in 37% and acid reux in 11%

(155). In the remaining 52% o patients, there was no association

between reux (either acid or non-acid) and symptoms. A positive

SI was more common in patients with typical symptoms (heart-

burn, regurgitation, and chest pain) compared with those with an

atypical presentation (55% vs. 25%). A different study using the

SAP in patients who were symptomatic despite PPI therapy oundan association between reux and symptoms in 37% o 60 patients;

the SAP was positive due to nonacid reux in 17 %, acid reux in

5%, and acid plus nonacid reux in 15% (156). As demonstrated by

these studies, impedance-pH testing covers all possible scenarios

or persistent symptoms in a treated patient: ongoing acid reux,

ongoing non-acid reux, or no reux. Furthermore, a systematic

review that quantied acid and nonacid (both weakly acidic and

weakly alkaline) reux in studies o GERD patients taking a PPI,

ound that weakly acidic reux underlies the majority o reux

episodes in these patients and is the main cause o persistent

symptoms despite PPI therapy (157). Finally, a negative imped-

or repeat work-up or non-GERD (pulmonary, allergic, EN)

etiologies.

wo key issues to consider are whether reux monitoringshould be perormed afer stopping PPI therapy or while onmed-

ication, and what technique to use (catheter-based pH, wireless

pH, or impedance-pH). At the present time there are limited data

and no clear consensus regarding the optimal testing methodo-

logy or reractory GERD. Te approach to testing may be chosen

based on the patients clinical presentation and pretest likelihood

o GERD, as well as on the available technology and expertise.

Reux monitoring both off as well as on PPI offers important and

clinically useul inormation as outlined below.

Reux monitoring off PPI(7 days afer cessation o PPI) can be

perormed with any o the available techniques (catheter or wire-

less pH, or impedance-pH). I reux monitoring offmedication is

negative (normal distal esophageal acid exposure and a negativesymptom-reux association), GERD is very unlikely. In a patient

with a negative test offtherapy, PPIs can be stopped and the diag-

nostic effort should be steered toward non-GERD etiologies. On

the other hand, a positive test afer PPI cessation offers objective

evidence o GERD but it does not provide insight regarding the

reason or the ailure to respond to treatment.

Reux monitoring on PPIshould be perormed with impedance-

pH monitoring to enable measurement o nonacid reux.Te yield

o pH monitoring without impedance in a patient taking a PPI is

very low because in acid-suppressed patients reux becomes pre-

dominantly nonacid (153). In act, pH monitoring revealed normal

REFRACTORY GERD

Optimize PPI therapy

Exclude other etiologies

Atypical symptomsTypical symptoms

Upper Endoscopy Referral to ENT, pulmonary, allergy

Specific treatment Specific treatment

Normal

REFLUX MONITORING

Low pre test

probability of GERD

Test off medication with pH orimpedance-pH

Test on medication withimpedance-pH

High pre test

probability of GERD

Abnormal (eosinophilicesophagitis, erosive

esophagitis, other)

Abnormal (ENT,pulmonary, or allergic

disorder)

No response

Figure 1. Algorithm for the evaluation of refractory gastroesophageal reflux disease (GERD). ENT, ear, nose, and throat; PPI, proton pump inhibitor.


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incisionless undoplication

Documents

ACG Guideline GERD March 2013 Plus Corrigendum