ACG and CAG Clinical Guideline Management of Dyspe

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ACG and CAG Clinical Guideline: Management of Dyspepsia
Article in The American Journal of Gastroenterology · June 2017

DOI: 10.1038/ajg.2017.154
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988 CLINICAL GUIDELINES
CME
ACG and CAG Clinical Guideline: Management of

Dyspepsia
Paul M. Moayyedi, MB, ChB, PhD, MPH, FACG1, Brian E. Lacy, MD, PhD, FACG2, Christopher N. Andrews, MD3, Robert A. Enns, MD4,
Colin W. Howden, MD, FACG5 and Nimish Vakil, MD, FACG6
We have updated both the American College of Gastroenterology (ACG) and the Canadian Association of
Gastroenterology (CAG) guidelines on dyspepsia in a joint ACG/CAG dyspepsia guideline. We suggest that patients
≥60 years of age presenting with dyspepsia are investigated with upper gastrointestinal endoscopy to exclude organic
pathology. This is a conditional recommendation and patients at higher risk of malignancy (such as spending their
childhood in a high risk gastric cancer country or having a positive family history) could be offered an endoscopy
at a younger age. Alarm features should not automatically precipitate endoscopy in younger patients but this
should be considered on a case-by-case basis. We recommend patients <60 years of age have a non-invasive test
Helicobacter pylori and treatment if positive. Those that are negative or do not respond to this approach should
be given a trial of proton pump inhibitor (PPI) therapy. If these are ineffective tricyclic antidepressants (TCA) or
prokinetic therapies can be tried. Patients that have an endoscopy where no pathology is found are defined as
having functional dyspepsia (FD). H. pylori eradication should be offered in these patients if they are infected.
We recommend PPI, TCA and prokinetic therapy (in that order) in those that fail therapy or are H. pylori negative.
We do not recommend routine upper gastrointestinal (GI) motility testing but it may be useful in selected patients.
Am J Gastroenterol 2017; 112:988–1013; doi:10.1038/ajg.2017.154; published online 20 June 2017
INTRODUCTION review data (12) for a joint ACG and CAG guideline on dyspepsia
Descriptions of upper gastrointestinal symptoms date back thou- management.
sands of years (1). “Stomach disorders” became an obsession of
developed countries in the eighteenth century (2) when the term
dyspepsia was first coined (3). A systematic review (4) reported DEFINITION OF DYSPEPSIA AND SCOPE OF THE
that ~20% of the population has symptoms of dyspepsia glob- GUIDELINE
ally. Dyspepsia is more common in women, smokers, and those Dyspepsia was originally defined as any symptoms referable to
taking non-steroidal anti-inflammatory drugs (4). Patients with the upper gastrointestinal tract (13). The Rome committee has
dyspepsia have a normal life expectancy (5), however, symptoms developed iterative definitions of dyspepsia that have become
negatively impact on quality of life (6,7) and there is a significant more specific culminating in Rome IV (ref. 14). These definitions
economic impact to the health service and society (8). Dyspepsia have attempted to minimize the inclusion of gastro-esophageal
is estimated to cost the US health care service over $18 billion reflux disease in those with dyspepsia by excluding patients with
per annum (8) and societal costs are likely to be double this (9) heartburn and acid regurgitation (15). Rome definitions have
with 2–5% (refs 7,9) having time off work because of symptoms. been helpful in better-standardizing patients that are included
Cost-effective management of dyspepsia can reduce its health in studies of dyspepsia but are less relevant to clinical practice as
and economic burdens, but it is over 10 years since either the there is considerable overlap in symptom presentation (16) mak-
American College of Gastroenterology (ACG) (10) or Canadian ing classification difficult in many patients presenting in primary
Association of Gastroenterology (CAG) (11) published guidelines and secondary care. For this reason, we have used a clinically
on dyspepsia. We have therefore updated previous systematic relevant definition of dyspepsia as predominant epigastric pain
1
Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada; 2Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical
Center, Lebanon, New Hampshire, USA; 3Department of Medicine, University of Calgary, Calgary, Alberta, Canada; 4Division of Gastroenterology, St Paul’s
Hospital, University of British Columbia, Pacific Gastroenterology Associates, Vancouver, British Columbia, Canada; 5Division of Gastroenterology, University
of Tennessee Health Science Center, Memphis, Tennessee, USA; 6University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Correspondence: Dr Paul M. Moayyedi, MB, ChB, PhD, MPH, FACG, Division of Gastroenterology, McMaster University Medical Centre, 1200 Main Street West,
Hamilton, Ontario, HSC 4W8B, Canada. E-mail: [email protected]
Received 31 May 2016; accepted 28 March 2017
The American Journal of GASTROENTEROLOGY VOLUME 112 | JULY 2017 www.nature.com/ajg

ACG and CAG Clinical Guideline: Management of Dyspepsia 989
lasting at least 1 month. This can be associated with any other

Table 1. Summary and strength of recommendations
upper gastrointestinal symptom such as epigastric fullness, nausea,
vomiting, or heartburn, provided epigastric pain is the patient’s 1. We suggest dyspepsia patients aged 60 or over have an endoscopy to
primary concern. Although this definition may differ slightly from exclude upper gastrointestinal neoplasia. Conditional recommendation,
very low quality evidence.
those used in specific trials, we feel it best represents the clinical
problem and the breadth of trial definitions used across time, 2. We do not suggest endoscopy to investigate alarm features for dys-
pepsia patients under the age of 60 to exclude upper GI neoplasia.
location, and patient populations. Functional dyspepsia refers Conditional recommendation, moderate quality evidence.
to patients with dyspepsia where endoscopy (and other tests
3. We recommend dyspepsia patients under the age of 60 should have
where relevant) has ruled out organic pathology that explains the a non-invasive test for H. pylori, and therapy for H. pylori infection if
patient’s symptoms. positive. Strong recommendation, high quality evidence.
This guideline will focus on initial investigations for dyspep- 4. We recommend dyspepsia patients under the age of 60 should have
sia such as Helicobacter pylori (H. pylori) testing and endoscopy empirical PPI therapy if they are H. pylori-negative or who remain
symptomatic after H. pylori eradication therapy. Strong recommenda-
as well as pharmacological therapies such as H. pylori treatment,
tion, high quality evidence.
PPIs, and prokinetic therapy. We do not address the management
5. We suggest dyspepsia patients under the age of 60 not responding
of organic pathology that may present with dyspepsia identified to PPI or H. pylori eradication therapy should be offered prokinetic
at endoscopy, such as esophagitis or peptic ulcer disease as there therapy. Conditional recommendation very low quality evidence.
are other ACG guidelines for these specific diseases (17). Further, 6. We suggest dyspepsia patients under the age of 60 not responding to
when H. pylori testing or treatment is recommended we do not PPI or H. pylori eradication therapy should be offered TCA therapy.
specify which investigation or which therapy to use, as this will Conditional recommendation low quality evidence.
be addressed in an ACG guideline on H. pylori and other recent 7. We recommend FD patients that are H. pylori positive should be
guidelines have been published (18). The treatment sections war- prescribed therapy to treat the infection. Strong recommendation, high
quality evidence.
rant an important caveat. Recommendations are made based on
available data for patients who fail initial standard therapy such 8. We recommend FD patients who are H. pylori-negative or who remain
symptomatic despite eradication of the infection should be treated with
as H. pylori eradication, PPI therapy, and use of a TCA or pro- PPI therapy. Strong recommendation, moderate quality evidence.
kinetic agent. These recommendations are made in a sequential
9. We recommend FD patients not responding to PPI or H. pylori eradica-
manner recognizing that, with each therapeutic trial, there is tion therapy (if appropriate) should be offered TCA therapy. Conditional
significant time and expense involved in treating these patients, recommendation, moderate quality evidence.
and that there is little data available prospectively evaluating dys- 10. We suggest FD patients not responding to PPI, H. pylori eradication
peptic patients who fail consecutive therapies. However, since this therapy or tricyclic antidepressant therapy should be offered prokinetic
therapy. Conditional recommendation, very low quality evidence.
disorder is common, and since patients do not uniformly respond
to one medication, we believe it important to address key clinical 11. We suggest FD patients not responding to drug therapy should be
offered psychological therapies. Conditional recommendation, very low
treatment options, despite limited data. The assumption of this lat- quality evidence.
ter point is that patients that continue to consult due to persistent
12. We do not recommend the routine use of complementary and
symptoms desire further treatment. alternative medicines for FD. Conditional Recommendation, very low
The global literature was reviewed and this guideline takes an quality evidence.
international perspective. Nevertheless, the main viewpoint taken 13. We recommend against routine motility studies for patients with FD.
related to the US and Canada and our recommendations may not Conditional recommendation, very low quality evidence.
apply to other countries in some instances. We have indicated in 14. We suggest motility studies for selected patients with FD where
the text specific areas where local variations in incidence of disease gastroparesis is strongly suspected. Conditional recommendation,
or availability of medication may result in different approaches very low quality evidence.
being recommended in other countries. FD, functional dyspepsia; H. pylori, Helicobacter pylori; PPI, proton pump
inhibitor; TCA, tricyclic antidepressant.
All recommendations are listed in Table 1.
GUIDELINE METHODOLOGY and the Cochrane Controlled Trials Register and these databases
The group was chosen to represent a US and Canadian second- were searched from inception to December 2015 (Appendix 1).
ary and tertiary care perspective on managing dyspepsia with Two independent researchers (PMM and Cathy Yuan) assessed
experience in guideline methodology, motility, endoscopy, and eligibility and extracted data. We took the most stringent defini-
pharmacological therapies. The group formulated statements that tion of dyspepsia improvement as the outcome if more than one
followed the PICO (population, intervention, comparator, out- definition of improvement was given (i.e., the definition that
come) format to guide the search for evidence (Table 2). System- resulted in the lowest placebo response rate). Summary statistics
atic reviews were conducted for initial management strategies of were expressed as relative risk (RR) and number needed to treat
uninvestigated dyspepsia as well as for pharmacological therapies (NNT) with 95% confidence intervals (CI) and a random effects
for FD that supported the PICO statements. An experienced pro- model was used. We used the GRADE approach (19) to assess
fessional developed the search strategies for MEDLINE, EMBASE the quality of evidence and give strength of recommendation.
© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

990 Moayyedi et al.
Table 2. PICO statements evaluated in the dyspepsia guideline
Informal Question PICO Question Method
Population Intervention(s) Comparator Outcome
What is the most appropriate Adult uninvestigated dys- Endoscopy Symptomatic 1. Upper GI cancers Observational data
initial evaluation for patients pepsia patients stratified management detected
≥60 years of age with by age 2. Early upper GI cancers
dyspepsia? detected
3. Rates of upper GI
malignancy by age
4. Adverse events
Are alarm features useful in Adult uninvestigated Patients with one or Patients with no Sensitivity, specificity, Observational data
identifying dyspepsia patients dyspepsia patients more alarm features alarm features positive and negative likeli- (cross-sectional,
with upper GI malignancy? hood ratios for identifying case–control and
upper GI malignancy and cohort studies)
all organic pathology
Is H. pylori test and treat the Adult uninvestigated H. pylori test and 1. Endoscopy 1. Dyspepsia resolution RCTs
most appropriate initial strategy dyspepsia patients treat 2. Empirical PPI 2. Dyspepsia improvement
for patients <60 years of age therapy 3. Quality of life
with dyspepsia? 4. Health-related
dyspepsia costs
5. Adverse events
Is empirical PPI therapy the Adult uninvestigated Empirical PPI 1. Placebo 1. Dyspepsia resolution RCTs
most appropriate strategy for dyspepsia patients therapy 2. Do nothing 2. Dyspepsia improvement
patients <60 years of age with 3. H2RA 3. Quality of life
dyspepsia that are H. pylori 4. Prokinetic 4. Health-related dyspep-
negative or remain symptomatic sia costs
after eradication therapy? 5. Adverse events
Is empirical prokinetic therapy Adult uninvestigated Prokinetic Placebo or do 1. Dyspepsia resolution RCTs
the most appropriate strategy for dyspepsia patients nothing/antacids 2. Dyspepsia improvement
patients <60 years of age with 3. Quality of life
dyspepsia that remain symp- 4. Adverse events
tomatic after H. pylori test and
treat and empirical PPI?
Is empirical antidepressant Adult uninvestigated Antidepressant Placebo or do 1. Dyspepsia resolution RCTs
therapy the most appropriate dyspepsia patients therapy nothing/antacids 2. Dyspepsia improvement
strategy for patients <60 years 3. Quality of life
of age with dyspepsia after 4. Adverse events
H. pylori test and treat and
empirical PPI therapy?
Is H. pylori eradication therapy Adult dyspepsia patients H. pylori eradica- Placebo antibiotics 1. Dyspepsia resolution RCTs
in H. pylori-positive patients with predominant epi- tion therapy 2. Dyspepsia improvement
effective in reducing symptoms gastric pain/discomfort 3. Quality of life
of FD? and a normal EGD that 4. Health-related
are H. pylori positive dyspepsia costs
5. Adverse events
Is PPI therapy effective in Adult dyspepsia patients PPI therapy 1. Placebo 1. Dyspepsia resolution RCTs
reducing symptoms of FD? with predominant epi- 2. H2RA 2. Dyspepsia improvement
gastric pain/discomfort 3. Prokinetic 3. Quality of life
and a normal EGD 4. Adverse events
Is antidepressant therapy Adult dyspepsia patients Antidepressant Placebo or do 1. Dyspepsia resolution RCTs
effective in reducing symptoms with predominant epigas- therapy nothing/antacids 2. Dyspepsia improvement
of FD? tric pain/discomfort and 3. Quality of life
a normal EGD 4. Adverse events
Is prokinetic therapy effective in Adult dyspepsia patients Prokinetic therapy Placebo or do 1. Dyspepsia resolution RCTs
reducing symptoms of FD? with predominant epi- nothing/antacids 2. Dyspepsia improvement
gastric pain/discomfort 3. Quality of life
Are psychological therapies Adult dyspepsia patients Psychological Usual care or sham 1. Dyspepsia resolution RCTs
effective in reducing symptoms with predominant epi- therapy therapy 2. Dyspepsia improvement
of FD? gastric pain/discomfort 3. Quality of life
EGD, upper GI endoscopy; FD, functional dyspepsia; GI, gastrointestinal; H. pylori, Helicobacter pylori; H2RA, H2-receptor antagonist; PICO, population, intervention,
comparator, outcome; PPI, proton pump inhibitor; RCT, randomized controlled trial.

The quality of evidence was expressed as high (estimate of effect early gastric cancer detection (23) and economic modeling (27).
is unlikely to change with new data), moderate, low, or very low These types of data are indirect and often overestimate the benefit
(estimate of effect is very uncertain) with objective reproducible of endoscopy, so clinicians may treat a minority of patients over
criteria that determine how this is assessed that involves the risk the age of 60 with empirical therapy provided they feel the risk of
of bias of the studies, evidence of publication bias, unexplained upper GI cancer malignancy is low. On the other hand, the risk of
heterogeneity among studies, directness of the evidence and pre- upper GI malignancy increases in those who were born and spent
cision of the estimate of effect (20). A summary of the quality of their childhood in certain geographical regions such as South East
evidence for the statements is given in Tables 3–5. The strength of Asia and some countries in South America (31). In light of the
recommendation was given as either strong (most patients should conditional recommendation with the quality of evidence being
receive the recommended course of action) or conditional (many low, the age threshold for endoscopy should be lowered in these
patients will have this recommended course of action but differ- patients, and possibly others, according to clinical judgment. In
ent choices may be appropriate for some patients and a greater borderline cases the sex of the patient may be taken into considera-
discussion is warranted so each patient can arrive at a decision tion as age-adjusted upper GI cancer risk is about twice as high in
based on their values and preferences). The strength of recom- men as it is in women (31). As with all guidelines, clinical decisions
mendation is based on the quality of evidence, risks vs. benefits, should be based on symptoms, patient concerns, physical exami-
patients’ values and preferences, as well as costs (21). We used a nation findings, laboratory and radiologic studies, and data from
modified Delphi approach to developing consensus based on the the literature, when available.
evidence with iterative discussion on the evidence for each state-
ment by e-mail and phone calls with one face-to-face meeting.
Voting on all statements was unanimous, including the strength STATEMENT 2. WE DO NOT SUGGEST ENDOSCOPY
or recommendation and quality of evidence. A summary of the TO INVESTIGATE ALARM FEATURES FOR DYSPEPSIA
recommendations is given in Table 1. Algorithms for suggested PATIENTS UNDER THE AGE OF 60 TO EXCLUDE
management of patients with undiagnosed dyspepsia and FD are UPPER GI NEOPLASIA
given in Figure 1 and Figure 2, respectively. Conditional recommendation, moderate quality evidence
Previous guidelines (10–12) have typically recommended upper
GI endoscopy at any age when alarm features (e.g., weight loss,
STATEMENT 1. WE SUGGEST DYSPEPSIA PATIENTS anemia, dysphagia, persistent vomiting) are present. However,
AGED 60 OR OVER HAVE AN ENDOSCOPY TO a systematic review of seven studies evaluating over 46,000 dys-
EXCLUDE UPPER GASTROINTESTINAL NEOPLASIA pepsia patients undergoing upper GI endoscopy found that alarm
Conditional recommendation, very low quality evidence features had limited value (32). Alarm features also had limited
Gastric cancer is the third commonest cause of cancer mortality utility in detecting any organic pathology (malignancy, pep-
worldwide with nearly a million cases annually (22) and often tic ulcer disease, or esophagitis) (33). Individual alarm features
presents with dyspepsia. Endoscopy can detect gastric cancer at such as weight loss, anemia, or dysphagia had sensitivities and
an earlier stage (23) and therefore is advisable in patients at sig- specificities of ~66% with a positive likelihood ratio of 2.74 (95%
nificant risk of this disease. Endoscopy can also diagnose esopha- CI=1.47–5.24) (31). This means that if a dyspepsia patient has an
geal adenocarcinoma, which has been increasing rapidly in North alarm feature they have a 2–3-fold risk of having underlying upper
America although there is now evidence that the rising incidence GI malignancy. However, the risk of a person<60 years old having
is reaching a plateau (24). While endoscopy is the gold stand- malignancy is typically very low so, even with an alarm feature,
ard test for diagnosing malignancy, it is expensive and invasive the risk is still much <1% and it is very unlikely that endoscopy
with a small risk of serious morbidity and mortality (25,26). All of all young patients with alarm features would be cost-effective.
guidelines have therefore recommended alternative approaches Data published since this systematic review have been adminis-
for management of dyspepsia in patients with low risk of malig- trative database studies that have confirmed that alarm features
nancy. The risk of malignancy is predominantly related to age have a low positive predictive value and so are of limited value
and so previous ACG guidelines (10) have suggested that routine in stratifying patients for endoscopy (34–37). It should be noted
endoscopy to investigate dyspepsia should only be performed in that this guideline does not cover patients presenting with alarm
patients’ aged 55 and over. We have raised this threshold further features such as progressive dysphagia and/or weight loss in the
to >60 years of age as evidence that endoscopy was cost-effective absence of epigastric pain. Such patients do not meet definitions
at the 55-year-old threshold at that time was borderline in eco- for dyspepsia and are out of the scope of this guideline. Similarly,
nomic analyses (27). Furthermore, in the 10 years since then the this guideline does not cover epigastric pain presentations which
age-specific incidence of gastric cancer has fallen further in the suggest a pancreatic or biliary source (e.g., pain radiating to the
US and Canada (28,29) and studies have shown that the cost of back), which should generally prompt appropriate imaging such
endoscopy per case of upper GI cancer detected is prohibitive(30). as ultrasound or CT. Further, alarm features not discussed above
We have given this statement a conditional recommendation, (e.g., jaundice) would clearly need to be investigated with tests
as the quality of evidence is very low. The data mainly relate to other than endoscopy. Pancreatic cancer can present as epigastric
national databases of upper GI cancer risk (28,29), case series on pain and it would be sensible to exclude this diagnosis in patients

992 Moayyedi et al.
over the age of 60 presenting with new onset dyspepsia by com- The other main comparator to H. pylori test and treat was empirical
bining endoscopy with an imagining modality that evaluates the PPI therapy. There were four trials (43,47–49) involving 1,608 dys-
pancreas such as abdominal ultrasound. In patients <60 years pepsia patients that compared these strategies with 1-year follow up.
of age pancreatic cancer is rare and it is important to note that a Overall 73% of patients had dyspepsia at the end of 1-year follow up
systematic review of >57,000 dyspepsia patients <0.01% had pan- in the H. pylori test and treat group vs. 78% in the PPI group. There
creatic cancer (32). This is consistent with the low incidence of was no statistically significant difference between the two strategies
pancreatic cancer in the US population <60 years of age. The pre- (RR=0.89; 95% CI=0.77–1.04) (Appendix 2; Appendix Figure 5). A
test probability of pancreatic cancer, even in those presenting with systematic review (50) found there was a trend towards a reduction
dyspepsia, is likely to be very low in this population, and therefore in cost for H. pylori test and treat compared to empirical PPI therapy,
we do not recommend routinely imaging the pancreas in younger but this was not statistically significant. The trend for both benefit
patients with dyspepsia. and costs favored H. pylori test and treat compared to empirical PPI
The quality of evidence is moderate as it is based on cross- and, therefore, the group felt this was the preferred initial strategy
sectional studies and there is some unexplained heterogeneity with acid suppression reserved for those who were H. pylori negative
among studies. The recommendation is conditional as the group or who continued to have symptoms despite eradication therapy.
felt that a minority of patients <60 years of age with alarm features The quality of evidence was high as the findings were robust
would warrant endoscopy, particularly if the feature was promi- with narrow CIs. All trials were high risk of bias as blinding was
nent (e.g., weight loss >20 lb or rapidly progressive dysphagia) or not possible with this type of comparison. The impact of reduc-
if a combination of features were present. Current data have not tion of costs and endoscopy was very strong and there was little
evaluated severe symptoms or combinations of features, so the clinically important heterogeneity among studies. The randomized
need for endoscopy needs to be evaluated on a case-by-case basis trials that have evaluated H. pylori test and treat all reported
in these circumstances using clinical judgment. Risk also increases H. pylori infection rates that were between 20 and 30% (refs
with age so the threshold to refer for upper GI endoscopy would be 38–44,47–49). A previous guideline (12) suggested that PPI
lower in a 58-year-old compared to a 28-year-old with dyspepsia therapy might be the appropriate first line approach when H. pylori
and alarm features. Family history of upper GI malignancy would prevalence rates are <15% in the population being tested. We felt
also factor into any endoscopy decision. that it is often difficult to know what the H. pylori prevalence is in
the local population and even with very low rates of infection test
and treat is likely to be the most cost-effective first line strategy
STATEMENT 3. WE RECOMMEND DYSPEPSIA as randomized trials data suggests that this approach will reduce
PATIENTS UNDER THE AGE OF 60 SHOULD HAVE A gastric cancer rates in those infected (51,52).
NON-INVASIVE TEST FOR H. PYLORI, AND THERAPY
FOR H. PYLORI INFECTION IF POSITIVE
Strong recommendation, high quality evidence STATEMENT 4. WE RECOMMEND DYSPEPSIA
Six trials (38–43) compared H. pylori test and treat with prompt PATIENTS UNDER THE AGE OF 60 SHOULD
upper GI endoscopy in 2,399 undiagnosed dyspepsia patients. HAVE EMPIRICAL PPI THERAPY IF THEY ARE
Most trials followed patients for 1 year and there was no H. PYLORI-NEGATIVE OR WHO REMAIN
difference in terms of global dyspepsia symptoms at the end of SYMPTOMATIC AFTER H. PYLORI ERADICATION
follow up between H. pylori test and treat and prompt endoscopy THERAPY
(74 vs. 77%, respectively, continued to have symptoms) with a RR Strong recommendation, high quality evidence
of remaining dyspeptic in the H. pylori test and treat compared to There were six randomized controlled trials (RCTs) (53–58)
the endoscopy group of 0.94 (95% CI=0.84–1.04) (Appendix 2: evaluating 2,709 dyspepsia patients that compared PPI therapy
Appendix Figure 1). Twenty-five percent of patients in the with placebo or antacid therapy. Overall dyspepsia symptoms
H. pylori test and treat arm had an upper GI endoscopy over a 1-year were present in 50% of the PPI group vs. 73% of the placebo group
period compared with nearly all patients in the prompt endoscopy (RR remaining dyspeptic on PPI=0.75; 95% CI=0.64–0.88)
arm (Appendix 2: Appendix Figure 2). This was the main driver in (Appendix 2: Appendix Figure 6) with an NNT of six (95% CI=
the statistically significant cost saving in the H. pylori test and treat 4–11). The quality of evidence was high as, although some trials
group (mean saving=$402; 95% CI=$329–$475) (Appendix 2: had an unclear risk of bias, the effect was strong and most studies
Appendix Figure 3) (39–41,43,44). We suggest that clinicians reported a statistically significant effect of PPI therapy on symptoms.
allow at least 4 weeks before reassessing symptomatic response to The alternative approach to PPI therapy is to reduce acid produc-
H. pylori eradication therapy. tion with an H2-receptor antagonist (H2RA). There were 7 RCTs
Two trials (45,46) involving 563 H. pylori-infected dyspepsia (53,57,59–63) evaluating 2,456 dyspepsia patients comparing these
patients randomized participants to eradication therapy or two approaches. There was no statistically significant difference
placebo. There was a statistically significant benefit of H. pylori between PPI and H2RA in providing symptom relief (RR=0.93;
eradication therapy (RR remaining dyspeptic=0.81; 95% CI= 95% CI=0.76–1.16) with a large amount of heterogeneity among
0.70–0.94) with a NNT of seven (95% CI=5–14) (Appendix 2: studies (I2=91% (Appendix 2: Appendix Figure 7). Four trials
Appendix Figure 4). (53,59,60,62) had a significant effect in favor of PPI, two trials

(57,63) showed no significant difference between both groups

Test accu-
Moderate
Moderate
racy QoE
and one trial showed a benefit of H2RA (ref. 61). This trial (61)
°
⊕⊕⊕
⊕⊕⊕
–
–
evaluated an H2RA not available in the West. It is not biologically
plausible that H2RA would be more effective than PPI therapy; if
this trial is excluded there is a significant benefit of PPI over H2RA
Pre-test probability
Effect per 1,000
patients tested
658 (548–788)
339 (209–449)
(RR remaining dyspeptic=0.81; 95% CI=0.72–0.91). There is not
of 0.3%
a major difference in cost between H2RA and PPI therapy and the
2 (2–2)
1 (1–1)
group felt the balance of evidence supported empirical PPI over

H2RA therapy.
There were five RCTs (43,64–67) involving 1,752 dyspepsia
patients that found no significant difference in dyspepsia symp-
Publication
toms between prompt endoscopy and empirical acid suppres-

sion with PPI or H2RA therapy (RR=1.00; 95% CI=0.94–1.05)
None
None
bias
(Appendix 2: Appendix Figure 8).

The evidence was graded as high as there were no concerns
Factors that may decrease quality of evidence
Imprecision
regarding heterogeneity, publication bias, imprecision, or risk

Not serious
Not serious
of bias in the estimate of effect. The evidence is somewhat indi-

rect as we are recommending this for dyspepsia patients who are
H. pylori-negative or are symptomatic after eradication therapy.
The trials were from an unselected group of dyspepsia patients but
Inconsistency
most were H. pylori-negative and we felt this minor degree of indi-

Seriousa
Seriousa
rectness of the evidence was insufficient to reduce the quality of

the trials. It should also be noted that the PPI trials used once-daily
standard dosing. It is unlikely that higher doses of PPI will increase
benefit in dyspepsia.
Indirectness
Not serious
Not serious
STATEMENT 5. WE SUGGEST DYSPEPSIA PATIENTS

UNDER THE AGE OF 60 NOT RESPONDING TO PPI
Risk of bias
Not serious
Not serious
OR H. PYLORI ERADICATION THERAPY SHOULD BE

OFFERED PROKINETIC THERAPY
Conditional recommendation very low quality evidence
There is a relative paucity of data evaluating prokinetic therapy
Cross-sectional (cohort
Cross-sectional (cohort
in the treatment of undiagnosed dyspepsia. There were no rand-

type accuracy study)
type accuracy study)
omized studies comparing prokinetic therapy with placebo. There

were three trials (57,62,66) that compared PPI with prokinetic
Table 3. Summary or findings of studies evaluating alarm features
Study design
therapy in 680 dyspepsia patients. Follow up was from 4 to 52

weeks and there was a trend towards PPI being more effective than
prokinetic therapy (RR=0.78; 0.60–1.02, P=0.06) (Appendix 2:
Appendix Figure 9) but this did not achieve statistical signifi-
7 studies 46,011
(No of patients)
cance. Two trials (57,62) showed PPI therapy was superior and
7 studies 150
No of studies
one (66) reported no difference.

Significant unexplained heterogeneity between studies.
All trials were high risk of bias and the effect was uncertain so
patients
patients
the quality of the evidence was rated very low. We felt that proki-
netic therapy should be offered after H. pylori test and treat and/
CI, confidence interval; GI, gastrointestinal.
or PPI therapy has failed as PPI therapy is more effective in gastro-

classified as having upper GI cancer)
True negatives (patients without up-
False negatives (patients incorrectly
Specificity: 0.66 (95% CI: 0.55–0.79).

Sensitivity: 0.67 (95% CI: 0.54–0.83).
False positives (patients incorrectly
True positives (patients with upper
esophageal reflux disease (68) and peptic ulcer disease (69) and has
classified as not having upper GI
greater efficacy in FD using indirect comparisons of randomized

data (see below). Furthermore, the prokinetics that were evaluated
in randomized trials (cisapride and mosapride) are not available
in most countries worldwide. Given risks of potential side effects
Prevalence: 0.3%.
with prokinetics, they should be used at the lowest effective dose

per GI cancer)
and consistent with country specific safety recommendations (e.g.,

GI cancer)
Outcome
cancer)
metoclopramide use less than 12 weeks (70), domperidone dose

30 mg daily or less (71)).
a

994
Moayyedi et al.
Table 4. Summary of findings table for management strategies in uninvestigated dyspepsia
Quality assessment No of patients Effect Quality Importance
No of Study design Risk of bias Inconsistency Indirectness Imprecision Other Intervention Control Relative Absolute
studies considerations (95% CI) (95% CI)
H. pylori test and treat vs. endoscopy: dyspepsia outcome (follow up: median 1 years; assessed with: questionnaire)
The American Journal of GASTROENTEROLOGY

6 Randomized Seriousa Not serious Not serious Not serious None 896/1,219 904/1,180 RR 0.94 46 fewer per 1,000 ⊕⊕⊕ Critical
trials (73.5%) (76.6%) (0.84–1.04) (from 31 more to Moderate
°
123 fewer)
H. pylori test and treat vs. endoscopy: health-related dyspepsia costs (US $) (follow up: median 1 years; assessed with: questionnaire)
5 Randomized Seriousa Not serious Not serious Not serious Strong associa- 893 878 – MD 402 s.d. more ⊕⊕⊕⊕ Critical
trials tion (329 more to 475 High
more)
PPI therapy vs. placebo: dyspepsia outcome (follow up: range 2–8 weeks)
6 Randomized Not serious Seriousb Not serious Not serious Strong associa- 743/1,500 877/1,209 RR 0.75 181 fewer per ⊕⊕⊕⊕ Critical
trials tion (49.5%) (72.5%) (0.64–0.88) 1,000 (from 87 High
fewer to 261 fewer)
PPI vs. prokinetic therapy: dyspepsia outcome (follow up: range 2–8 weeks)
3 Randomized Not serious Seriousb Not serious Very serious None 250/366 314/279 RR 0.78 248 fewer per ⊕ Critical
trials (68.3%) (112.5%) (0.60–1.02) 1,000 (from 23 Very low
°°°
more to 450 fewer)
TCA therapy: dyspepsia outcome (follow up: range 2–8 weeks)
3 Randomized Not serious Not serious Seriousc Seriousd None 77/170 104/169 RR 0.74 160 fewer per ⊕⊕ Critical
trials (45.3%) (61.5%) (0.61–0.91) 1,000 (from 55 °°
Low
fewer to 240 fewer)
CI, confidence interval; FD, functional dyspepsia; MD, mean difference; PPI, proton pump inhibitor; RR, risk ratio; TCA, tricyclic antidepressant.
a
All trials high risk of bias as blinding not possible.
b
Significant unexplained heterogeneity with I2>50%.
c
Patients had FD and not uninvestigated dyspepsia. We are assuming most patients will have FD.
d
95% CI are relatively wide as only based on three studies.
VOLUME 112 | JULY 2017 www.nature.com/ajg

Table 5. Summary of findings table for interventions for FD
Quality assessment No of patients Effect Quality Importance
No of Study design Risk of bias Inconsistency Indirectness Imprecision Other Intervention Control Relative Absolute
studies considerations (95% CI) (95% CI)
© 2017 by the American College of Gastroenterology

H. pylori eradication vs. placebo antibiotics in H. pylori +ve FD (follow up: range 3–12 months)
22 Randomized Not serious Not serious Not serious Not serious None 1,767/2,604 1,751/2,292 RR 0.91 69 fewer per ⊕⊕⊕⊕ Critical
trials (67.9%) (76.4%) (0.88–0.94) 1,000 (from 46 High
fewer to 92 fewer)
PPI therapy vs. placebo (follow up: range 2–4 weeks)
15 Randomized Not serious Seriousa Not serious Not serious None 2,332/3,621 1,293/1,777 RR 0.83 124 fewer per 1,000 ⊕⊕⊕ Critical
trials (64.4%) (72.8%) (0.77–0.89) (from 80 fewer to Moderate
°
167 fewer)
TCA therapy vs. placebo (follow up: range 2–12 weeks)
3 Randomized Not serious Not serious Not serious Seriousb None 77/170 104/169 RR 0.74 160 fewer per 1,000 ⊕⊕⊕ Critical
trials (45.3%) (61.5%) (0.61–0.91) (from 55 fewer to Moderate
°
240 fewer)
Prokinetic therapy vs. placebo (follow up: range 2–8 weeks)
26 Randomized Not serious Seriousa Not serious Seriousc Publication 3,430/5,123 2,815/3,665 RR 0.92 61 fewer per 1,000 ⊕ Critical
trials bias strongly (67.0%) (76.8%) (0.88–0.97) (from 23 fewer to Very low
°°°
suspectedd 92 fewer)
Psychological therapies vs. usual care (follow up: range 4–12 weeks)
4 Randomized Very seriouse Seriousa Not serious Seriousf Strong treat- 125/394 243/395 RR 0.53 283 fewer per 1,000 ⊕ Critical
trials ment effect (31.7%) (61.5%) (0.44–0.65) (from 203 fewer Very low
°°°
to 345 fewer)
CI,Confidence interval; FD, functional dyspepsia; PPI, proton pump inhibitor; RR, risk ratio; TCA, tricyclic antidepressant.
a
Unexplained heterogeneity with I2>50%.
b
Wide 95% CI as based on three trials.
c
Various prokinetics evaluated and none available in US or Canada—those that have a statistically significant effect show very modest efficacy with 95% CI close to 1.0.
d
Strong funnel plot asymmetry with small trials showing large effect and many large trials negative.
e
Studies not blinded and outcome subjective.
f
Wide 95% CI and only two RCTs for any type of intervention.

995
996 Moayyedi et al.
Adult dyspepsia patient

≥ 60 years of age < 60 years of age
H. pylori
Endoscopy test and treat
Organic Normal Positive

pathology Negative
No response
H. pylori PPI
Manage according Manage according to eradication
to relevant guideline Figure 2
Response Response No
Response
Response TCA
Success or prokinetic
Response No
Response
Consider
psychotherapy
Figure 1. Algorithm for the management of undiagnosed dyspepsia.
Functional dyspepsia patient

H. pylori positive H. pylori negative
H. pylori
PPI
eradication No response
Response
Response TCA
Response
Success No
Response
Response
Prokinetic
Response
No
Response
Consider
psychotherapy
Figure 2. Algorithm for the treatment of functional dyspepsia.

STATEMENT 6. WE SUGGEST DYSPEPSIA PATIENTS unexplained heterogeneity among studies and no evidence of pub-
UNDER THE AGE OF 60 NOT RESPONDING TO PPI lication bias. The recommendation is strong as the approach is
OR H. PYLORI ERADICATION THERAPY SHOULD BE cost-effective (97) and adverse events associated with antibiotics
OFFERED TRICYCLIC ANTIDEPRESSANT THERAPY are usually mild. Although the impact on dyspepsia symptoms is
Conditional recommendation low quality evidence modest, H. pylori eradication may also reduce future risk of gastric
There are no randomized trials of antidepressant therapies in undi- cancer and peptic ulcer disease and the benefits of this approach
agnosed dyspepsia. A systematic review (72) identified 13 trials clearly outweigh the harms of antibiotic prescribing. It is worth
involving 1,241 patients with FD that evaluated psychotropic noting that the evidence suggests that antibiotics reduce dyspep-
drugs compared to placebo. The review identified three trials that sia symptoms and the assumption is that this is due to eradicating
evaluated TCA therapy and these drugs had a significant effect H. pylori infection. It is possible that the efficacy relates to treating
in reducing dyspepsia symptoms (RR=0.74; 95% CI=0.61–0.91). other infectious agents (98) that might cause dyspepsia but this
No effect was seen with serotonin reuptake inhibitor therapy. The nuance does not change the recommendation that H. pylori-posi-
quality of evidence is low as there is no study evaluating undi- tive FD patients should be offered eradication therapy.
agnosed dyspepsia. The results are therefore indirectly applied to
this population with the assumption that most dyspepsia patients
in North America will have FD (73). TCAs are unlikely to have a STATEMENT 8. WE RECOMMEND FUNCTIONAL
major impact on peptic ulcer disease or gastro-esophageal reflux DYSPEPSIA PATIENTS WHO ARE H. PYLORI-
disease and so their efficacy in the general dyspepsia population NEGATIVE OR WHO REMAIN SYMPTOMATIC DESPITE
is likely to be lower than estimated in the systematic review. The ERADICATION OF THE INFECTION SHOULD BE
recommendation is conditional based on the low quality of evi- TREATED WITH PPI THERAPY
dence, the adverse events associated with TCAs (72) and con- Strong recommendation, moderate quality evidence
siderations that some patients will not like the perceived stigma There is some evidence that a subset of FD may relate to height-
of taking an antidepressant. The decision to use TCAs will there- ened sensitivity to acid (99). We identified 15 RCTs in 14 papers
fore be made on a case-by-case basis and the group did not find (100–113) evaluating 5,853 FD patients that compared PPI
a preference in the order in which prokinetic or TCA therapy is therapy at standard and/or low dose with placebo. Follow up
prescribed. was for 2–8 weeks and all reported outcome in terms of global
improvement in dyspepsia symptoms. We combined low and
standard dose PPI arms as the comparison between the two
STATEMENT 7. WE RECOMMEND FUNCTIONAL revealed no significant difference. Overall 2,724/3,916 (69.6%)
DYSPEPSIA PATIENTS THAT ARE H. PYLORI POSITIVE patients in the PPI group had persistence of dyspepsia symptoms
SHOULD BE PRESCRIBED THERAPY TO TREAT THE compared with 1,457/1,937 (75.2%) in the control group. There
INFECTION was a statistically significant impact of PPI therapy on dyspep-
Strong recommendation, high quality evidence sia symptoms (RR dyspepsia remaining=0.87; 95% CI=0.82–0.94;
Patients who have an endoscopy with normal findings and pre- P<0.00001) (Appendix 2: Appendix Figure 11) with a NNT of 10
dominant epigastric pain are considered to have FD. A posi- (95% CI=7–20).
tive diagnosis of FD can also be made without endoscopy using Randomized trials comparing alternatives to PPI therapy were
clinical symptoms and history (14). Patients with a normal considered. There were two RCTs (100,114) comparing PPI
endoscopy should have gastric biopsies to assess for the presence to H2RA in 740 FD patients with no significant difference between
of H. pylori infection if prior non-invasive testing has not been the two therapies (RR=1.27; 95% CI=0.83–1.94). There is insuf-
performed. There are a number of biologically plausible reasons ficient data to have confidence that H2RA is not inferior to PPI
why H. pylori infection may lead to dyspepsia symptoms in FD therapy and PPI therapy results in more profound acid sup-
(74). We identified 22 RCTs (75–96) evaluating 4,896 H. pylori- pression. There were four RCTs (115–118) involving 892 FD
positive FD patients that compared eradication therapy with patients comparing PPI with prokinetics. There was a statistically
placebo antibiotics. Follow up was for 3–12 months and all gave significant difference between the two therapies in favor of PPI
outcome in terms of global improvement in dyspepsia symptoms. therapy (RR dyspepsia remaining=0.90; 95% CI=0.81–1.00,
Overall 1,767/2,604 (67.9%) patients in the H. pylori eradication P=0.04) (Appendix 2: Appendix Figure 12).
therapy group had persistence of dyspepsia symptoms compared Data suggest that there is no value in doubling the dose of
with 1,751/2,292 (76.4%) in the control group. There was a sta- PPI therapy so the drug should be discontinued if the patient
tistically significant impact of H. pylori eradication on dyspepsia does not respond after 8 weeks of standard dose, once-daily
symptoms (RR dyspepsia remaining=0.91; 95% CI=0.88–0.94; therapy. Subgroup analysis suggests that those patients who have
P<0.00001) with no significant heterogeneity (χ2=20.5, P=0.49, more prominent heartburn-related symptoms respond better
I2=0%) (Appendix 2: Appendix Figure 10). There was no funnel to PPI therapy (119) but there is no evidence that epigastric pain
plot asymmetry and the NNT was 12.5 (95% CI=10–20). syndrome responds better than postprandial distress syndrome
The quality of evidence is high as the subset of low risk of bias type dyspepsia (115). We therefore do not recommend using the
trials gave a similar statistically significant result and there is no type of symptom in FD to guide treatment choice. The quality

998 Moayyedi et al.
of the evidence was moderate as there was some unexplained sively in FD and we identified 26 randomized trials in 23 papers
heterogeneity in the data. The recommendation was strong as PPI (132–154) involving 8,788 FD patients. There was a statistically
therapy is well tolerated and inexpensive. significant effect of prokinetic therapy in reducing global symp-
We evaluated recent concerns regarding the long-term risk of toms of FD with a RR of remaining dyspeptic in the prokinetic
PPI therapy, among which hip fracture, community-acquired group of 0.92 (95% CI=0.88–0.97) (Appendix 2: Appendix
pneumonia, C. difficile infection, electrolyte disturbances, and Figure 13) with a NNT of 12.5 (95% CI=8–25). None of the pro-
dementia have been hypothesized (120). However, we feel the kinetic therapies that were eligible to review for this guideline is
most likely explanation for these associations is residual confound- available in US, Canada, or Europe. There are no clinical trials
ing (121) and even if the associations were causal, the number with metoclopramide in FD.
needed to harm was >1,000 in most cases (122) and the benefits There were seven trials (155–161) involving 263 patients with
outweighed any known harms. However, PPI therapy should be upper GI symptoms that evaluated domperidone. These were all
stopped if it is no longer providing benefit and patients should not excluded, as they did not meet a priori eligibility criteria. The usual
have long-term PPI therapy without attempts to withdraw it every reason was that patients had a barium meal rather than endoscopy
6–12 months, consistent with US FDA guidance (123) and/or a non-standard definition of dyspepsia was used. Never-
theless we synthesized these data, as domperidone is available in
Canada and some other countries although not in the US. Overall
STATEMENT 9. WE RECOMMEND FUNCTIONAL there was a statistically significant effect on symptoms (RR remain-
DYSPEPSIA PATIENTS NOT RESPONDING TO PPI ing symptomatic with domperidone=0.71; 95% CI=0.53–0.97)
OR H. PYLORI ERADICATION THERAPY (Appendix 2: Appendix Figure 14) with a NNT of 3 (95% CI=2–8).
(IF APPROPRIATE) SHOULD BE OFFERED TRICYCLIC The quality of evidence was graded as very low as all of the dom-
ANTIDEPRESSANT THERAPY peridone data had unclear or high risk of bias and none met eligi-
Conditional recommendation, moderate quality evidence bility criteria. All other prokinetic data had significant unexplained
Antidepressant therapies have been shown in randomized trials heterogeneity and there was evidence of publication bias, small
to reduce symptoms in irritable bowel syndrome (124). There is positive studies driving the result and larger trials showing little or
a large overlap between irritable bowel syndrome and FD (125) no treatment effect (Egger test for bias—P=0.004). Furthermore
so it is plausible that antidepressants will also be effective for dys- some prokinetics have significant risk of adverse events (131) with
pepsia symptoms. A systematic review (72) identified 13 RCTs metoclopramide being associated with dystonia, parkinsonism-
evaluating psychotropic drugs in FD. There were three trials type movements, and/or tardive dyskinesia while domperidone
(126–128) involving 339 FD patients comparing TCAs with pla- may cause QT prolongation which in turn could increase the risk of
cebo. There was a statistically significant effect in reducing dys- serious arrhythmias in those with pre-existing cardiac conditions.
pepsia symptoms (RR=0.74; 95% CI=0.61–0.91) with an NNT of
six (95% CI=6–18). There were two trials (128,129) involving 388
FD patients comparing SSRIs with placebo. There was no statis- STATEMENT 11. WE SUGGEST FUNCTIONAL
tically significant effect of SSRI therapy on dyspepsia symptoms DYSPEPSIA PATIENTS NOT RESPONDING TO DRUG
(RR=1.01; 95% CI=0.89–1.15) (72). THERAPY SHOULD BE OFFERED PSYCHOLOGICAL
The quality of evidence was moderate as there was some uncer- THERAPIES
tainty around the estimate of effect of TCAs as the 95% CI were Conditional recommendation, very low quality evidence
wide. The recommendation was conditional as TCAs are associ- There are a large number of trials suggesting psychological thera-
ated with adverse events (which include constipation, dry mouth, pies are effective in irritable bowel syndrome (124) although the
urinary retention, and somnolence) (72) and a significant propor- quality of these data is very low. A previous systematic review
tion of patients might prefer not to take antidepressant medication. (162) of psychological therapies in FD suggested the number of
In contrast to Statements 5 and 6 above, it should be noted that we trials were limited so no firm conclusions could be made. We have
recommend TCA before prokinetic for treatment of FD based on updated this review and have now identified a total of 12 RCTs
the superior evidence for TCA in this indication. (163–174) involving 1,563 FD patients. All trials reported a sta-
tistically significant benefit of psychological therapies over con-
trol, which was most commonly usual management. These studies
STATEMENT 10. WE SUGGEST FUNCTIONAL reported a variety of psychological interventions; the common-
DYSPEPSIA PATIENTS NOT RESPONDING TO PPI, est approaches were cognitive behavioral therapy or other vari-
H. PYLORI ERADICATION THERAPY OR TRICYCLIC ous forms of psychotherapy. Only four papers (165,169,172,174)
ANTIDEPRESSANT THERAPY SHOULD BE OFFERED described the outcome in terms of a dichotomous improvement in
PROKINETIC THERAPY dyspepsia symptoms in 789 FD patients. These studies suggested
Conditional recommendation, very low quality evidence that there was a significant benefit of psychological therapies in
Patients with FD often have disorders of gastric motility (130) and reducing dyspepsia symptoms (RR=0.53; 95% CI=0.44–0.65)
many pharmacological agents have been developed to improve (Appendix 2: Appendix Figure 15) with a NNT of three
gastric emptying (131). Prokinetics have been studied exten- (95% CI=3–4).

The quality of the data is very low despite a reasonably dramatic been identified in up to 40% of patients with FD (12,180). How-
effect on reducing dyspepsia symptoms. The studies were all high ever, this can be accurately identified with only two specialized
risk of bias as there was no blinding and this is important given motility studies (i.e., gastric barostat or single-photon emission
the outcome of dyspepsia improvement is subjective. There was computed tomography), neither of which is readily available
unexplained heterogeneity among studies and many used differ- (183). Delayed gastric emptying, using either scintigraphic tests
ent forms of psychological therapy so there is a lack of precision or breath tests, has been identified in up to 30% of patients with
around the estimate of effect for any given type of psychological FD, although the extent of this delay is usually mild (12,180,182).
intervention. The recommendation was conditional as the quality A recent, large-multicenter trial, using a validated 4-h solid
of the data was very low, may be expensive, and requires significant phase gastric-emptying scan protocol with all studies read at one
time and motivation from the patient. center, found that 21% of patients meeting Rome II criteria for
FD had delayed gastric emptying (128). Symptoms of FD may
also arise due to a prior infection (viral, bacterial, protozoal),
STATEMENT 12. WE DO NOT RECOMMEND visceral hypersensitivity, medications, duodenal eosinophilia,
THE ROUTINE USE OF COMPLEMENTARY AND and abnormal or excess feedback from the upper small intestine
ALTERNATIVE MEDICINES FOR FUNCTIONAL (180,181,184). Unfortunately, however, identifying the abnormal
DYSPEPSIA pathophysiologic mechanisms that underlie the development of
Conditional recommendation, very low quality evidence FD symptoms has not directly altered treatment strategies. For
Complementary and alternative medicines (CAM) are used by example, several studies have demonstrated a lack of relationship
about 20% of the general population for gastrointestinal symptoms between FD symptoms and gastric emptying (149,185,186). Since
(175). The proportion of secondary and tertiary care patients with tests to measure gastric accommodation are not readily available
FD taking CAM may be even higher. These interventions have (barostat and single-photon emission computed tomography) or
been reviewed (131) and there are numerous proposed herbal expensive, invasive and uncomfortable (barostat), and because
remedies as well as other approaches. Many of these have been delays in gastric emptying are not accurately related to symptoms,
subject to randomized trials but the approaches are too diverse routine motility tests for patients with FD are not recommended.
to draw any definitive conclusions. For example, one qualitative
review (176) identified 26 CAM methods for treating FD. One
of the largest single trials relates to STW 5, a herbal preparation STATEMENT 14. WE SUGGEST MOTILITY STUDIES
containing extracts of bitter candy tuft, matricaria flower, pepper- FOR SELECTED PATIENTS WITH FUNCTIONAL
mint leaves, caraway, licorice root, and lemon balm. 315 patients DYSPEPSIA WHERE GASTROPARESIS IS STRONGLY
with FD were randomized to STW 5 or placebo for 8 weeks (177) SUSPECTED
and there was a statistically significant benefit for the active treat- Conditional recommendation, very low quality evidence
ment but this was only marginal (Gastrointestinal Symptoms Gastroparesis can be diagnosed using a combination of symp-
Score improved by 6.9±4.8 in the STW 5 group compared with toms (e.g., nausea, vomiting, abdominal pain, early satiety, bloat-
5.9±4.3, P=0.04) and it is unclear whether this difference was clin- ing), an upper endoscopy not showing evidence of mechanical
ically meaningful. A systematic review (178) of Chinese herbal obstruction, and a delay in gastric emptying using a 4-h solid
medicine in FD identified 13 trials involving 1,153 patients. The phase gastric-emptying scan (187). FD can be diagnosed using
review concluded that there was a signal that Chinese herbal a combination of symptoms (e.g., upper abdominal pain, nausea,
medicine may improve FD symptoms but the trials were of very vomiting, early satiety, bloating) and a normal upper endoscopy
poor methodological quality. Similarly, a Cochrane review (179) (14). Although generally thought of as distinct, there is signifi-
of acupuncture in FD identified seven studies involving 542 FD cant overlap in these two disorders and they likely represent part
patients. Again the authors felt that the data were of very low of a spectrum of gastric sensorimotor disorders (182). As noted,
quality and concluded it was unclear whether acupuncture was most patients (70–80%) with FD have normal gastric empty-
effective in FD. CAM may be appropriate for individual patients ing; thus, routine motility testing is not required. In FD patients
interested in exploring these approaches provided they are aware with delayed gastric emptying, the degree of delay is usually mild
that there is insufficient evidence to determine the benefit or risk (10–20% of material remaining at 4 h) (128). The occasional FD
of these interventions. patient with persistent symptoms of nausea and vomiting may
have a marked delay in gastric emptying (188,189), and identify-
ing this could potentially lead to a change in therapy. Unfortu-
STATEMENT 13. WE RECOMMEND AGAINST nately, there is no data from RCTs to answer the question of how
ROUTINE MOTILITY STUDIES FOR PATIENTS WITH medical management changes if a marked delay in gastric empty-
FUNCTIONAL DYSPEPSIA ing is identified. The patient with daily or intractable vomiting
Conditional recommendation, very low quality evidence may have gastroparesis rather than FD and should be investigated
The diagnosis and treatment of FD can be challenging because appropriately. We felt that a 4-h solid phase gastric-emptying scan
symptoms develop due to a number of different pathophysiologic should be performed in FD patients with predominant symptoms
processes (12,180–182). Abnormal gastric accommodation has of severe nausea and vomiting who fail empiric therapy.

1000 Moayyedi et al.
ACKNOWLEDGMENTS 15. Tack J, Talley NJ, Camilleri M et al. Functional gastroduodenal disorders.
Gastroenterology 2006;130:1466–79.
We are grateful to Cathy Yuan and Maria Ines Pinto-Sanchez for
16. Vakil N, Halling K, Ohlsson L et al. Symptom overlap between post-
conducting systematic reviews that support this guideline. We are prandial distress and epigastric pain syndromes of the Rome III dyspepsia
also thankful to Grigoris Leontiaidis, Joseph Ahn and Lauren classification. Am J Gastroenterol 2013;108:767–74.
17. Katz PO, Gerson LB, Vela MF. Diagnosis and management of gastro-
Gerson for providing leadership in the process that supported this
esophageal reflux disease. Am J Gastroenterol 2013;108:308–28.
joint ACG/CAG guideline. 18. Fallone CA, Chiba N, van Zanten SV et al. The Toronto consensus for
the treatment of Helicobacter pylori infection in adults. Gastroenterology
2016;151:51–69.
CONFLICT OF INTEREST
19. Guyatt GH, Oxman AD, Vist G et al. Rating quality of evidence and
Guarantor: Paul Moayyedi, MB, ChB, PhD, MPH, FACG. strength of recommendations GRADE: an emerging consensus on
Specific author contributions: All authors contributed to the rating quality of evidence and strength of recommendations. BMJ 2008;
336:924–6.
development of the guideline statements, interpretation of the
20. Guyatt GH, Oxman AD, Kunz R et al. Rating quality of evidence and
evidence for each statement and the writing of the article. strength of recommendations: What is "quality of evidence" and why is it
Financial support: None. important to clinicians? BMJ 2008;336:995–8.
21. Guyatt GH, Oxman AD, Kunz R et al. Rating quality of evidence and
Potential competing interests: Paul Moayyedi has accepted speaker
strength of recommendations: going from evidence to recommendations.
fees from Allergan and Abbvie. He has been on advisory boards for BMJ 2008;336:1049–51.
Allergan, Shire and Salix pharmaceuticals. He has received research 22. GLOBCAN project, International Agency for Research on Cancer. http://
globocan.iarc.fr/old/FactSheets/cancers/stomach-new.asp. Accessed on 11
funds from Allergan and Takeda. Colin Howden is a consultant for
May 2016.
Allergan, Aralez, Ironwood, Otsuka, SynteractHCR, Takeda and US 23. Spahos T, Hindermarsh A, Cameron E et al. Endoscopy waiting times and
World Meds. Christopher N. Andrews has honoraria from Allergan, impact of the two week wait scheme on diagnosis and outcome of upper
gastrointestinal cancer. Postgrad Med J 2005;81:728–30.
Abbvie, Pendopharm, Lupin, and Medtronic; research support from
24. Pohl H, Sirovich B, Welch HG. Esophageal adenocarcinoma incidence: are
Janssen and HPI Pharma; and is Director of Callitas Pharma. Robert we reaching the peak? Cancer Epidemiol Biomarkers Prev 2010;19:1468–70.
Enns has no conflicts. Nimish Vakil is a consultant for AstraZeneca, 25. Quine MA, Bell GD, McCloy RF et al. Prospective audit of upper gastroin-
testinal endoscopy in two regions of England: safety, staffing and sedation
Ironwood, Restech, Yuhan, Allergan, Otsuka, US World Meds and
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Actavis. Brian E. Lacy is on the advisory board for Ironwood, Covi- 26. Ben-Menachem T, Decker A, Early DS et al. Adverse events of upper GI
dien, and Salix, and has received research support from Covidien. endoscopy. Gastrointest Endosc 2012;76:707–18.
27. Barton PM, Moayyedi P, Talley NJ et al. Cost effectiveness analysis: applica-
tions. Med Decision Making 2008;28:33–43.
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patients with and without delayed gastric emptying: a randomized double- 176. Stake-Nilsson K, Soderlund M, Hultcrantz R et al. A qualitative study of
blind placebo-controlled trial. Aliment Pharmacol Ther 2000;14:1653–61. complementary and alternative medicine use in persons with uninvestigated
150. Talley NJ, Van Zanten SV, Saez LR et al. A dose-ranging, placebo-controlled, dyspepsia. Gastroenterol Nurs 2008;32:107–14.
randomized trial of alosetron in patients with functional dyspepsia. Aliment 177. von Arnim U, Peitz U, Vinson B et al. STW 5, a phytopharmacon for
Pharmacol Ther 2001;15:525–37. patients with functional dyspepsia: results of a multicenter, placebo-
151. Talley NJ, Tack J, Ptak T et al. Itopride in functional dyspepsia: results of controlled double-blind study. Am J Gastroenterol 2007;102:1268–75.
two phase III multicentre, randomised, double-blind, placebo-controlled 178. Wang C, Zhu M, Xia W et al. Meta-analysis of traditional Chinese
trials. Gut 2008;57:740–6. medicine in treating functional dyspepsia of liver-stomach disharmony
152. Vakil N, Laine L, Talley NJ et al. Tegaserod treatment for dysmotility-like syndrome. J Tradit Chin Med 2012;32:515–22.
functional dyspepsia: results of two randomized, controlled trials. 179. Lan L, Zeng F, Liu GJ et al. Acupuncture for functional dyspepsia.
Am J Gastroenterol 2008;103:1906–19. Cochrane Database System Rev 2014, Issue 10. Art. No.: CD008487
153. Wood SF, Penney SC, Cochran KM. Cisapride in functional dyspepsia: 10.1002/14651858.CD008487.pub2.
a double-blind, placebo-controlled randomized trial in general practice 180. Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of
patients. Scand J Gastroenterol Suppl 1993;195:5–10. functional dyspepsia. Gastroenterology 2004;127:1239–55.
154. Yeoh KG, Kang JY, Tay HH et al. Effect of cisapride on functional dyspepsia 181. Lacy BE, Cash BD. A 32-year-old woman with chronic abdominal pain.
in patients with and without histological gastritis: a double-blind placebo- JAMA 2008;299:555–65.
controlled trial. J Gastroenterol Hepatol 1997;12:13–8. 182. Lacy BE. Functional dyspepsia and gastroparesis: One disease or two?
155. Bekhti A, Rutgeerts L. Domperidone in the treatment of functional Am J Gastroenterol 2012;107:1615–20.
dyspepsia in patients with delayed gastric emptying. Postgrad Med J 183. Ang D. Measurement of gastric accommodation: a reappraisal of conven-
1979;55(Suppl 1):30–2. tional and emerging modalities. Neurogastroenterol Motil 2011;23:287–91.
156. Chey WY, You CH, Ange DA. Open and double blind clinical trials of 184. Talley NJ, Walker MM, Aro P et al. Non-ulcer dyspepsia and duodenal
domperidone in patients with unexplained nausea, vomiting, abdominal eosinophilia: an adult endoscopic population-based case-control study.
bloating and early satiety. Gastroenterology 1982;82(Suppl 1):1033. Clin Gastroenterol Hepatol 2007;5:1175–83.
157. Davis RH, Clench MH, Mathias JR. Effects of domperidone in patients 185. van Lelyveld N, Schipper M, Samsom M. Lack of relationship between
with chronic unexplained upper gastrointestinal symptoms: a double- chronic upper abdominal symptoms and gastric function in functional
blind placebo- controlled study. Dig Dis Sci 1988;33:1505–11. dyspepsia. Dig Dis Sci 2008;53:1223–30.
158. Haarmann K, Lebkuchner F, Widmann A et al. A double-blind study 186. Cassilly DW, Wang YR, Friedenberg FK et al. Symptoms of gastroparesis:
of domperidone in the symptomatic treatment of chronic post-prandial use of the gastroparesis cardinal symptom index in symptomatic patients
upper gastrointestinal distress. Postgrad Med J 1979;55(suppl 1):24–7. referred for gastric emptying scintigraphy. Digestion 2008;78:144–51.
159. Van de Mierop L, Rutgeerts L, Van den Langenbergh B et al. Oral domperi- 187. Camilleri M, Parkman HP, Shafi MA et al. Clinical guideline: management
done in chronic postprandial dyspepsia. Digestion 1979;19:244–50. of gastroparesis. Am J Gastroenterol 2013;108:18–37.
160. Van Ganse W, Van Damme L, Van de Mierop L et al. Chronic dyspepsia: 188. Stanghellini V, Tosetti C, Paternico A et al. Risk indicators of delayed
double-blind treatment with domperidone (R 33 812) or a placebo. A gastric emptying of solids in patients with functional dyspepsia. Gastro-
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161. Van Outryve M, Lauwers W, Verbeke S. Domperidone for the sympto- 189. Sarnelli G, Caenepeel P, Geypens B et al. Symptoms associated with impaired
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Med J 1979;55(suppl 1):33–5. enterol 2003;98:783–8.

1004
APPENDIX 1
SEARCH STRATEGIES USED FOR THE DYSPEPSIA GUIDELINE
Topic Medline (Database: Epub Ahead of Print, In-Process & Other Non-Indexed Embase <1974 to present
Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present>
Moayyedi et al.
Psychological therapy, from 1 exp Dyspepsia/ (7,888) 1 exp Dyspepsia/ (28,265)

2005 to 12 May 2016, Multi-file 2 eructation/ (328) 2 eructation/ (983)
search, n=745 3 flatulence/ (1,301) 3 flatulence/ (9,815)
4 (dyspep* or "NUD" or "FD").mp. (20,895) 4 (dyspep* or "NUD" or "FD").mp. (42,121)
5 (indigestion or indigestive).tw,kw. (799) 5 (indigestion or indigestive).tw,kw. (1,203)
6 1 or 2 or 3 or 4 or 5 (22,982) 6 1 or 2 or 3 or 4 or 5 (52,030)
7 exp Psychotherapy/(167,526) 7 exp Psychotherapy/(209,526)
8 psychotherap*.af. (103,197) 8 psychotherap*.af. (139,519)
9 ((animal assisted or aromatherapy or art or behavior or behaviour or color or colour 9 ((animal assisted or aromatherapy or art or behavior or behaviour or color or colour or dance or
or dance or feedback or music or narrative or person-centered or play or psychoana- feedback or music or narrative or person-centered or play or psychoanalytic* or psycholog*) adj5
lytic* or psycholog*) adj5 (therap* or treat* or manag* or strategy*)).tw,kw. (67,724) (therap* or treat* or manag* or strategy*)).tw,kw. (95,906)
10 ((horticultural or socioenvironmental or social environment or socio* environ- 10 ((horticultural or socioenvironmental or social environment or socio* environment or logotherap*

ment or logotherap* or reality or gestalt) adj5 (therap* or treat* or manag* or or reality or gestalt) adj5 (therap* or treat* or manag* or strategy*)).tw,kw. (3,158)
strategy*)).tw,kw. (2,178)
11 (autogenic training or (relaxation adj2 progressive) or bibliotherap* or 11 (autogenic training or (relaxation adj2 progressive) or bibliotherap* or hypnosis or hypnoses or
hypnosis or hypnoses or hypnotherap* or hypnotism or mesmerism or hypnotherap* or hypnotism or mesmerism or abreaction or catharsis).tw,kw. (12,483)
abreaction or catharsis).tw,kw. (9,967) 12 or/7–11 (332,259)
12 or/7–11 (254,628) 13 6 and 12 (1,203)
13 6 and 12 (253)
14 randomized controlled trial.pt. (416,221) 14 random*.mp. (1,250,429)
15 controlled clinical trial.pt. (90,701) 15 clinical trial:.mp. (1,213,928)
16 random*.mp. (1,046,809) 16 exp health care quality/ (2,307,441)
17 placebo.ab. (171,882) 17 double-blind:.mp. or placebo:.tw. or blind:.tw. (462,289)
18 trial.ab. (364,897) 18 or/14–17 (4,013,838)
19 groups.ab. (1,579,013)
20 or/14–19 (2,535,619) 19 13 and 18 (766)
21 13 and 20 (78) 20 limit 19 to yr="2005 -Current" (602)
22 limit 21 to yr="2005 -Current" (42)
Prokinectis and FD from 2010 to 1 exp Dyspepsia/7,859 1 exp dyspepsia/28,132
12 April 2016, Multi-file search, 2 (dyspep* or "NUD" or "FD").tw,kw. 18,461 2 (dyspep* or "NUD" or "FD").tw,kw. 26,029
n=1,026 3 (indigestion or indigestive).tw. 783 3 (indigestion or indigestive).tw. 1,188
4 or/1–3 20,884 4 or/1–3 42,564
5 (prokinetic* or gastroprokinetic* or gastrokinetic* or gastro-kinetic*).tw,kw. 2,687 5 (prokinetic* or gastroprokinetic* or gastrokinetic* or gastro-kinetic*).tw,kw. 4,035
6 (antiemetic* or anti-emetic).tw,kw. 7,327 6 (antiemetic* or anti-emetic).tw,kw. 10,216
7 exp Benzamides/46,246 7 exp benzamide derivative/54,971
8 (Benzoic Acid Amide or Amides or Phenyl Carboxyamide or Benzamide* or 8 (Benzoic Acid Amide or Amides or Phenyl Carboxyamide or Benzamide* or Benzoylamide or
Benzoylamide or benzoates).tw,kw. 13,430 benzoates).tw,kw. 16,902
9 (Phenylcarboxyamide or Phenylcarboxamide or Benzenecarboxamide or Amid 9 (Phenylcarboxyamide or Phenylcarboxamide or Benzenecarboxamide or Amid kyseliny benzoove).
kyseliny benzoove).tw,kw. 12 tw,kw. 13
10 exp Domperidone/1,623 10 exp domperidone/7,795
11 (domperidon* or domidon or Domperi or Domstal or evoxin or gastrocure or 11 (domperidon* or domidon or Domperi or Domstal or evoxin or gastrocure or motilium or mo-
motilium or motilium).tw,kw. 2,103 tilium).tw,kw. 3,417
12 (motis or nauzelin or Motinorm Costi or Nomit or Brulium or Molax).tw,kw. 4 12 (motis or nauzelin or Motinorm Costi or Nomit or Brulium or Molax).tw,kw. 16
13 exp Antiemetics/133,454 13 exp antiemetic agent/168,619
14 exp Metoclopramide/4,630 14 exp metoclopramide/22,515
15 (Metoclopramide or cerucal or clopra or gastrese or gastrobid or gastroflux or 15 (Metoclopramide or cerucal or clopra or gastrese or gastrobid or gastroflux or gastromax or
gastromax or maxolon).tw,kw. 5,414 maxolon).tw,kw. 7,192
16 (metaclopramide or metozolv or metramid or migravess or mygdalon or 16 (metaclopramide or metozolv or metramid or migravess or mygdalon or octamide or parmid).
octamide or parmid).tw,kw. 45 tw,kw. 114
17 (primperan or reglan or reliveran or rimetin or Degan or Maxeran or Pylomid or 17 (primperan or reglan or reliveran or rimetin or Degan or Maxeran or Pylomid or Pramin).tw,kw.
Pramin).tw,kw. 115 1,692
18 exp Cisapride/1,444 18 exp cisapride/7,296
19 (Cisapride or alimix or Prepulsid or Propulsid).tw,kw. 1,675 19 (Cisapride or alimix or Prepulsid or Propulsid).tw,kw. 2,729
20 exp Cholinesterase Inhibitors/44,836 20 exp cholinesterase inhibitor/77,946

Appendix Table 1 continued on following page
21 (Itopride or ganaton).tw,kw. 102 21 (Itopride or ganaton).tw,kw. 226
22 Mosapride.tw,kw. 262 22 exp mosapride/380
23 exp Erythromycin/22,427 23 Mosapride.tw,kw. 469
24 (erythromycin or aknemycin or emcin or emgel or emycin or eryderm or erygel 24 exp erythromycin/66,403
or erymax).tw,kw. 18,745 25 (erythromycin or aknemycin or emcin or emgel or emycin or eryderm or erygel or erymax).tw,kw.
25 (erymin or eryped or gallimycin or ilosene or ilosone or ilotycin or lauromicina 22,087
or maracyn).tw,kw. 60
26 (monomycin or ornacyn or retcin or rommix or romycin or roymicin or staticin 26 (erymin or eryped or gallimycin or ilosene or ilosone or ilotycin or lauromicina or maracyn).tw,kw.
or stiemycin or theramycin or tiloryth or wyamycin).tw,kw. 275 275
27 (Motilin adj3 (receptor* or agonist*)).tw,kw. 369 27 (monomycin or ornacyn or retcin or rommix or romycin or roymicin or staticin or stiemycin or
28 ((5HT3 or 5HT 3 or 5-HT3 or 5-HT 3) adj3 antagonist*).tw,kw. 3,638 theramycin or tiloryth or wyamycin).tw,kw. 271
29 ((5HT or 5-HT or 5-hydroxytryptamine*) adj3 (agonist* or antagonist*)).tw,kw. 28 exp motilin receptor agonist/69,135
8,795 29 (Motilin adj3 (receptor* or agonist*)).tw,kw. 458
30 ((5-HT1A or 5HT1A or 5-HT 1A or 5HT 1A) adj3 agonist*).tw,kw. 4,069 30 ((5HT3 or 5HT 3 or 5-HT3 or 5-HT 3) adj3 antagonist*).tw,kw. 4,824

31 exp Serotonin Antagonists/47,240
32 exp Serotonin 5-HT3 Receptor Antagonists/612 31 ((5HT or 5-HT or 5-hydroxytryptamine*) adj3 (agonist* or antagonist*)).tw,kw. 9,448
33 exp Serotonin 5-HT4 Receptor Agonists/224
34 exp Serotonin 5-HT1 Receptor Agonists/2,887 32 ((5-HT1A or 5HT1A or 5-HT 1A or 5HT 1A) adj3 agonist*).tw,kw. 4,827
35 (serotonin adj3 receptor adj3 (agonist* or antagonist* or block*)).tw,kw. 2,068 33 exp serotonin antagonist/120,230
36 (tegaserod or Zelnorm or Zelmac).tw,kw. 388 34 exp serotonin 3 antagonist/3,440
37 ABT-229.tw,kw. 22 35 exp serotonin 4 agonist/802
38 (Tandospirone or Sediel or metanopirone or buspirone).tw,kw. 2,603 36 exp serotonin 1 agonist/610
39 (alosetron or Lotronex).tw,kw. 245 37 (serotonin adj3 receptor adj3 (agonist* or antagonist* or block*)).tw,kw. 2,790
40 (Acotiamide or YM-443 or Z-338D).tw,kw. 40 38 exp tegaserod/ 1,705
39 (tegaserod or Zelnorm or Zelmac).tw,kw. 737
41 (acetylcholinesterase inhibitor* or cholinesterase Inhibitor* or anti-cholinesterase* 40 ABT-229.tw,kw. 98
or anticholinesterase*).tw,kw. 10,393 41 exp tandospirone/519
42 ((5HT-4 or 5HT4 or 5-HT 4 or 5-HT4) adj3 agonist*).tw,kw. 740 42 (Tandospirone or Sediel or metanopirone or buspirone).tw,kw. 3,272
43 or/5–42 316,333 43 exp alosetron/1,233
44 (alosetron or Lotronex).tw,kw. 541
44 4 and 43 1,331 45 exp acotiamide/105
45 randomized controlled trial.pt. 412,566 46 (Acotiamide or YM-443 or Z-338D).tw,kw. 77
46 controlled clinical trial.pt. 90,495 47 (acetylcholinesterase inhibitor* or cholinesterase Inhibitor* or anti-cholinesterase* or
47 random*.mp. 1,019,981 anticholinesterase*).tw,kw. 13,960
48 placebo.ab. 168,576 48 ((5HT-4 or 5HT4 or 5-HT 4 or 5-HT4) adj3 agonist*).tw,kw. 1,013
49 drug therapy.fs. 1,841,827 49 or/5–48 452,852
50 trial.ab. 354,331 50 4 and 49 3,919
51 groups.ab. 1,539,040
52 or/45–51 3,918,006 51 random*.mp. 1,239,350
53 exp animals/ not humans.sh. 4,221,321 52 placebo:.mp. 372,038
54 52 not 53 3,364,132 53 clinical trial:.mp. 1,207,584
55 44 and 54 1,058 54 double-blind:.mp. or blind:.tw. 354,000
56 limit 55 to yr="2010 -Current" 221 55 or/51–54 2,210,439
56 exp animal/ not human/4,594,892
57 55 not 56 2,042,185
58 50 and 57 2,204
59 remove duplicates from 58 2,189
60 limit 59 to yr="2010 -Current" 639
HP eradication and HP from 1 randomized controlled trial.pt. (338,380) 1 clinical trial/ or (clin$ adj2 (trial$ or stud$)).tw.
2006 to 4 April 2016, 2 controlled clinical trial.pt. (85,027) 2 exp Randomized controlled trial/
Multi-file search, n=1,170 3 random*.mp. (793,630) 3 exp Randomization/
4 placebo.ab. (139,962) 4 Single-Blind Method/
5 drug therapy.fs. (1,570,375) 5 Double-Blind Method/
6 trial.ab. (263,685) 6 Cross-Over Studies/ or (crossover$ or cross-over$).tw.
7 groups.ab. (1,213,517) 7 exp Random Allocation/
8 1 or 2 or 3 or 4 or 5 or 6 or 7 (3,196,892) 8 RCT.tw.
9 exp animals/ not exp humans/(3,749,652) 9 ((single or double or treble or triple) adj3 (blind$ or mask$)).tw.


1005
1006
10 8 not 9 (2,726,261) 10 comparative study/
11 exp Dyspepsia/ (6,867) 11 controlled study/
12 eructation/ (276) 12 Prospective study/
Moayyedi et al.
13 flatulence/ (1,134) 13 evaluation studies/

14 (dyspep$ or NUD or FD).mp. (17,100) 14 random$.mp.
15 (indigestion or indigestive).tw. (626) 15 placebo/ or placebo:.mp.
16 11 or 12 or 13 or 14 or 15 (18,878) 16 (control$ or prospective$ or volunteer$).tw.
17 exp helicobacter/(27,791) 17 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 14 or 16
18 exp helicobacter infections/(23,015) 18 exp animal/not exp human/
19 exp helicobacter pylori/(26,780) 19 17 not 18
20 (helicobacter or pylori or pyloridis or HP or Campylobacter).mp. (57,996) 20 exp dyspepsia/
21 17 or 18 or 19 or 20 (57,996) 21 eructation/
22 16 and 21 (3,975) 22 flatulence/
23 (dyspepsia or dyspeptic or NUD or FD).mp.
24 (indigestion or indigestive).tw.
23 10 and 22 (2,030) 25 20 or 21 or 22 or 23 or 24

24 limit 23 to yr="2006 -Current" (500) 26 exp Helicobacter/
27 exp Helicobacter pylori/
28 exp Helicobacter infection/
29 (helicobacter or pylori or pyloridis or HP or Campylobacter).mp.
30 26 or 27 or 28 or 29
31 25 and 30
32 19 and 31 (3,551)
33 limit 32 to yr="2006 -Current" (1,237)
PPI and FD from 2002 to 25 Feb 1. exp dyspepsia/ 1. exp dyspepsia/
2016, Multi-file search, n=2,670 2. (Dyspepsia or dyspeptic or NUD or FD).mp. 2. (Dyspepsia or dyspeptic or NUD or FD).mp.
search in 11 April 2013, n=527 3. (indigestion or indigestive).tw. 3. (indigestion or indigestive).tw.
update search in 2016
4. or/1–3 4. or/1–3
5. exp Proton Pump Inhibitors/ 5. exp proton pump inhibitor/
6. ((proton adj2 pump adj2 inhibitor$) or PPI or PPIs).tw. 6. ((proton adj2 pump adj2 inhibitor$) or PPI or PPIs).tw.
7. Esomeprazole Sodium/ 7. esomeprazole/
8. (Esomeprazole or Nexium or Esotrex or Alenia or Escz or Esofag or Nexiam).tw. 8. (Esomeprazole or Nexium or Esotrex or Alenia or Escz or Esofag or Nexiam).tw.
9. Omeprazole/ 9. omeprazole/
10. (omeprazole or losec or nexium or prilosec or rapinex or zegerid or ocid or 10. (omeprazole or losec or nexium or prilosec or rapinex or zegerid or lomac or ocid or Lomac or
Lomac or Omepral or Omez).tw. Omepral or Omez).tw.
11. (pantoprazole or protium or protonix or Pantotab or Pantopan or Pantozol or 11. pantoprazole/
Pantor or Pantoloc or Astropan or Controloc or Pantecta or Inipomp or Somac or 12. (pantoprazole or protium or protonix or Pantotab or Pantopan or Pantozol or Pantor or Pantoloc or
Pantodac or Zurcal or Zentro).tw. Astropan or Controloc or Pantecta or Inipomp or Somac or Pantodac or Zurcal or Zentro).tw.
12. (rabeprazole or aciphex or dexrabeprazole or pariet or Zechin or Rabecid or 13. rabeprazole/
Nzole-D or Rabeloc).tw. 14. (rabeprazole or aciphex or dexrabeprazole or pariet or Zechin or Rabecid or Nzole-D or Rabeloc).tw.
13. (Dexlansoprazole or Kapidex or Dexilant).tw. 15. lansoprazole/
14. (lansoprazole or lanzoprazole or agopton or bamalite or Inhibitol or Levant or 16. (lansoprazole or lanzoprazole or agopton or bamalite or Inhibitol or Levant or Lupizole or lanzor or
Lupizole or lanzor or monolitum or ogast or ogastro or opiren or prevacid or prezal monolitum or ogast or ogastro or opiren or prevacid or prezal or pro ulco or promeco or takepron or
or pro ulco or promeco or takepron or ulpax or zoton).tw. ulpax or zoton).tw.
15. or/5–14 17. (Dexlansoprazole or Kapidex or Dexilant).tw.
16. 4 and 15 18. or/5–17
17. randomized controlled trial.pt. 19. 4 and 18
18. controlled clinical trial.pt.
19. randomized.ab. 20. random:.tw. or placebo:.mp. or double-blind:.tw.
20. placebo.ab. 21. 19 and 20
21. drug therapy.fs.
22. randomly.ab.
23. trial.ab.
24. groups.ab.
25. or/17–24
26. 16 and 25
27. exp animals/ not humans.sh.
28. 26 not 27

Initial management strategies 1 exp dyspepsia/ (7,282) 1 exp dyspepsia/ (25,632)

for undiagnostic dyspepsia from 2 (dyspep* or FD or NUD).ti,ab,kw. (10,750) 2 (dyspep* or FD or NUD).ti,ab,kw. (14,899)
2004 to February 2016 Multi-file 3 1 or 2 (12,551) 3 1 or 2 (29,332)
search, n=1,989 in 06 August 4 exp Proton Pump Inhibitors/ (14,111) 4 exp proton pump inhibitor/ (52,191)
2014, update search n=414 in 5 exp omeprazole/ (8,570) 5 exp omeprazole/ (26,121)
09 February 2016
6 exp esomeprazole/(691) 6 exp esomeprazole/(5,198)
7 exp lansoprazole/(1,848) 7 exp lansoprazole/(8,781)
8 exp rabeprazole/(795) 8 exp pantoprazole/(6,458)
9 (proton pump inhibitor* or PPI or PPIs or omeprazole or esomeprazole or lanso- 9 exp rabeprazole/ (3,819)
prazole or pantoprazole or rabeprazole).ti,ab,kw. (22,117) 10 (proton pump inhibitor* or PPI or PPIs or omeprazole or esomeprazole or lansoprazole or panto-
10 or/4–9 (25,881) prazole or rabeprazole).ti,ab,kw. (31,909)
11 or/4–10 (62,185)

11 exp Histamine H2 Antagonists/(18,410)
12 exp ranitidine/(4,990) 12 exp histamine H2-receptor antagonist/(61,484)
13 exp cimetidine/(9,164) 13 exp ranitidine/(21,483)
14 exp famotidine/(1,480) 14 exp cimetidine/(30,685)
15 exp nizatidine/(300) 15 exp famotidine/(7,264)
16 ((histamine H2 adj5 antagonist*) or H2-receptor antagonist* or H2RA or H2RAs 16 exp nizatidine/ (1,928)
or H2-RA or H2-RAs or cimetidine or ranitidine or famotidine or nizatidine or roxati- 17 ((histamine H2 adj5 antagonist*) or H2-receptor antagonist* or H2RA or H2RAs or H2-RA or H2-
dine).ti,ab,kw. (18,135) RAs or cimetidine or ranitidine or famotidine or nizatidine or roxatidine).ti,ab,kw. (23,645)
17 or/11–16 (23,248) 18 or/12–17 (63,515)
18 exp Helicobacter/ or exp Helicobacter pylori/ or exp Helicobacter infection/ 19 exp Helicobacter/ or exp Helicobacter pylori/ or exp Helicobacter infection/ (50,719)
(31,400) 20 (helicobacter or pylori or pyloridis or "HP" or Campylobacter).ti,ab,kw. (74,711)
19 (helicobacter or pylori or pyloridis or "HP" or Campylobacter).ti,ab,kw. (59,887)
20 18 or 19 (62,395) 21 (test* adj3 (treat or manage* or therapy*)).ti,ab,kw. (13,763)

21 (test* adj3 (treat or manage* or therapy*)).ti,ab,kw. (10,129) 22 (19 or 20) and 21 (471)
22 20 and 21 (369) 23 exp endoscopy/ (413,319)
23 exp Endoscopy/(261,964) 24 (endoscop* or Gastroscop* or Duodenoscop*).).ti,ab,kw. (88,994)
24 (endoscop* or Gastroscop* or Duodenoscop*).ti,ab,kw. (59,007) 25 23 or 24 (436,324)
25 23 or 24 (286,034) 26 (initial adj3 (investigat* or manage* or procedure or strateg*)).ti,ab,kw. (12,734)
26 (initial adj3 (investigat* or manage* or procedure or strateg*)).ti,ab,kw. (9,656)
27 (empirical adj3 treat* or therap* or manage* or strateg*)).ti,ab,kw. (5,343) 27 (empirical adj3 treat* or therap* or manage* or strateg*)).ti,ab,kw. (7,204)
28 10 or 17 or 22 or 25 or 26 or 27 (340,111) 28 11 or 18 or 22 or 25 or 26 or 27 (550,017)
29 3 and 28 (4,280) 29 3 and 28 (9,263)
30 randomized controlled trial.pt. (379,756) 30 random$.mp. (1,036,938)
31 controlled clinical trial.pt. (889,20) 31 double-blind:.mp. or placebo:.tw. or blind:.tw. (399,530)
32 random$.mp. (913,711) 32 30 or 31 (1,218,944)
33 placebo.ab. (156,611) 33 29 and 32 (1,833)
34 drug therapy.fs. (1,719,987) 34 exp animal/ not human/ (4,408,333)
35 trial.ab. (312,630) 35 33 not 34 (1,831)
36 groups.ab. (1,379,836) 36 limit 35 to yr="2004 -Current" (1,048)
37 or/30–36 (3,579,084)
38 29 and 37 (2,297)
39 exp animals/not humans/(3,972,902)
40 38 not 39 (2,292)
41 limit 40 to yr="2004 -Current" (955)

1007
APPENDIX 2
Forest plots of meta-analyses that support the dyspepsia guideline.
Figure 1. Forest plot of randomized controlled trials comparing H. pylori test and treat with early endoscopy with continued dyspepsia
as the outcome.
Figure 2. Forest plot of randomized controlled trials comparing H. pylori test and treat with early endoscopy with proportion having
endoscopy as the outcome.
Figure 3. Forest plot of randomized controlled trials comparing H. pylori test and treat with early endoscopy with dyspepsia health
service costs as the outcome.
Figure 4. Forest plot of randomized controlled trials comparing H. pylori eradication with placebo antibiotics in infected dyspepsia
patients.

Figure 5. Forest plot of randomized controlled trials comparing H. pylori test and treat with empirical PPI therapy with continued dys-
pepsia as the outcome.
Figure 6. Forest plot of randomized controlled trials comparing empirical PPI therapy with placebo with continued dyspepsia as the
outcome.
Figure 7. Forest plot of randomized controlled trials comparing empirical PPI therapy with H2-receptor antagonists with continued
dyspepsia as the outcome.
Figure 8. Forest plot of randomized controlled trials comparing empirical acid suppression therapy with early endoscopy with continued
dyspepsia as the outcome.

Figure 9. Forest plot of randomized controlled trials comparing empirical PPI therapy with prokinetic therapy with continued dyspepsia
as the outcome.
Figure 10. Forest plot of randomized controlled trials comparing H. pylori eradication with placebo antibiotics in H. pylori-infected
patients with functional dyspepsia.

Figure 11. Forest plot of randomized controlled trials comparing proton pump inhibitors with placebo in functional dyspepsia
patients.
Figure 12. Forest plot of randomized controlled trials comparing proton pump inhibitors with prokinetics in functional dyspepsia
patients.

Figure 13. Forest plot of randomized controlled trials comparing motility modifying drugs with placebo in functional dyspepsia
patients.

Figure 14. Forest plot of randomized controlled trials comparing domperidone with placebo in patients with upper GI symptoms.
Figure 15. Forest plot of randomized controlled trials comparing psychological therapies with controls in functional dyspepsia
patients.
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ACG and CAG Clinical Guideline: Management of Dyspepsia

Article in The American Journal of Gastroenterology · June 2017

Paul Moayyedi Colin W. Howden

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ACG and CAG Clinical Guideline: Management of

Am J Gastroenterol 2017; 112:988–1013; doi:10.1038/ajg.2017.154; published online 20 June 2017

The American Journal of GASTROENTEROLOGY VOLUME 112 | JULY 2017 www.nature.com/ajg

lasting at least 1 month. This can be associated with any other

© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

Table 2. PICO statements evaluated in the dyspepsia guideline

Informal Question PICO Question Method

Population Intervention(s) Comparator Outcome

The American Journal of GASTROENTEROLOGY VOLUME 112 | JULY 2017 www.nature.com/ajg

© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

The American Journal of GASTROENTEROLOGY VOLUME 112 | JULY 2017 www.nature.com/ajg

(57,63) showed no significant difference between both groups

group felt the balance of evidence supported empirical PPI over

toms between prompt endoscopy and empirical acid suppres-

(Appendix 2: Appendix Figure 8).

regarding heterogeneity, publication bias, imprecision, or risk

of bias in the estimate of effect. The evidence is somewhat indi-

most were H. pylori-negative and we felt this minor degree of indi-

rectness of the evidence was insufficient to reduce the quality of

STATEMENT 5. WE SUGGEST DYSPEPSIA PATIENTS

OR H. PYLORI ERADICATION THERAPY SHOULD BE

in the treatment of undiagnosed dyspepsia. There were no rand-

type accuracy study)

omized studies comparing prokinetic therapy with placebo. There

therapy in 680 dyspepsia patients. Follow up was from 4 to 52

one (66) reported no difference.

or PPI therapy has failed as PPI therapy is more effective in gastro-

Speciﬁcity: 0.66 (95% CI: 0.55–0.79).

greater efficacy in FD using indirect comparisons of randomized

with prokinetics, they should be used at the lowest effective dose

and consistent with country specific safety recommendations (e.g.,

metoclopramide use less than 12 weeks (70), domperidone dose

© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

Table 4. Summary of ﬁndings table for management strategies in uninvestigated dyspepsia

Quality assessment No of patients Effect Quality Importance

The American Journal of GASTROENTEROLOGY

VOLUME 112 | JULY 2017 www.nature.com/ajg

Quality assessment No of patients Effect Quality Importance

© 2017 by the American College of Gastroenterology

The American Journal of GASTROENTEROLOGY

Adult dyspepsia patient

Organic Normal Positive

Figure 1. Algorithm for the management of undiagnosed dyspepsia.

Functional dyspepsia patient

Figure 2. Algorithm for the treatment of functional dyspepsia.

The American Journal of GASTROENTEROLOGY VOLUME 112 | JULY 2017 www.nature.com/ajg

© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

The American Journal of GASTROENTEROLOGY VOLUME 112 | JULY 2017 www.nature.com/ajg

© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

The American Journal of GASTROENTEROLOGY VOLUME 112 | JULY 2017 www.nature.com/ajg

© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

The American Journal of GASTROENTEROLOGY VOLUME 112 | JULY 2017 www.nature.com/ajg

© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

Psychological therapy, from 1 exp Dyspepsia/ (7,888) 1 exp Dyspepsia/ (28,265)