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Ajg_50267.tex

PRACTICE GUIDELINES
Guidelines for the Management of DyspepsiaNicholas J. Talley, M.D., Ph.D., F.A.C.G.,1 Nimish Vakil, M.D., F.A.C.G.,2 and the Practice ParametersCommittee of the American College of Gastroenterology1Division of Gastroenterology and Hepatology, Mayo Clinic, Clinical Enteric Neuroscience Translational andEpidemiological Research Program, Mayo Clinic, Rochester, Minnesota; and 2University of Wisconsin MedicalSchool and Marquette University College of Health Sciences, Milwaukee, Wisconsin Dyspepsia is a chronic or recurrent pain or discomfort centered in the upper abdomen; patients with predominantor frequent (more than once a week) heartburn or acid regurgitation, should be considered to havegastroesophageal reflux disease (GERD) until proven otherwise. Dyspeptic patients over 55 yr of age, or those withalarm features should undergo prompt esophagogastroduodenoscopy (EGD). In all other patients, there are twoapproximately equivalent options: (i) test and treat for Helicobacter pylori (H. pylori) using a validated noninvasivetest and a trial of acid suppression if eradication is successful but symptoms do not resolve or (ii) an empiric trialof acid suppression with a proton pump inhibitor (PPI) for 4–8 wk. The test-and-treat option is preferable inpopulations with a moderate to high prevalence of H. pylori infection (≥10%); empirical PPI is an initial option inlow prevalence situations. If initial acid suppression fails after 2–4 wk, it is reasonable to consider changing drugclass or dosing. If the patient fails to respond or relapses rapidly on stopping antisecretory therapy, then thetest-and-treat strategy is best applied before consideration of referral for EGD. Prokinetics are not currentlyrecommended as first-line therapy for uninvestigated dyspepsia. EGD is not mandatory in those who remainsymptomatic as the yield is low; the decision to endoscope or not must be based on clinical judgement. In patientswho do respond to initial therapy, stop treatment after 4–8 wk; if symptoms recur, another course of the sametreatment is justified. The management of functional dyspepsia is challenging when initial antisecretory therapyand H. pylori eradication fails. There are very limited data to support the use of low-dose tricyclic antidepressantsor psychological treatments in functional dyspepsia.
(Am J Gastroenterol 2005;100:2324–2337) INTRODUCTION
as a subjective negative feeling that is nonpainful, and can
incorporate a variety of symptoms including early satiety

These and the previous guidelines were developed under or upper abdominal fullness. Patients presenting with pre-
the auspices of the American College of Gastroenterol- dominant or frequent (more than once a week) heartburn
ogy and its Practice Parameters Committee and approved or acid regurgitation should be considered to have gastro-
by the Board of Trustees. The world literature was re- esophageal reflux disease (GERD) until proven otherwise.
viewed extensively using the National Library of Medicine Dyspepsia is a common complaint in clinical practice; database. Appropriate studies were reviewed and any ad- therefore, its management should be based on the best ev- ditional studies found in the reference list of these papers idence. Dyspepsia has often been loosely defined; the most were obtained and reviewed. Evidence was evaluated along a widely applied definition of dyspepsia is the Rome Work- hierarchy, with randomized, controlled trials given the great- ing Teams formulation, namely chronic or recurrent pain or est weight. Abstracts presented at national and international discomfort centered in the upper abdomen (1). Predominant meetings were only used when unique data from ongoing epigastric pain or discomfort helps to distinguish dyspepsia trials were presented. When scientific data were lacking, from GERD; in the latter the dominant complaint is typically recommendations were based on expert consensus obtained heartburn or acid regurgitation but there may be a distinct from both the literature and the experience of the authors epigastric component that is confusing (2). Frequent reflux and the Practice Parameters Committee. Each guideline was symptoms (twice a week or more) probably impair quality evaluated by the committee and the strength of evidence to of life and are generally considered to identify GERD until guide clinical practice was assessed using established criteria proven otherwise (3–6). Clinical trials in dyspepsia have used various definitions and have often not distinguished obviousGERD from dyspepsia, making interpretation of treatment DEFINITIONS
Discomfort has been defined by the Rome Working Teams Dyspepsia is defined as chronic or recurrent pain or discom-
as a subjective negative feeling that is nonpainful, and fort centered in the upper abdomen. Discomfort is defined
has been considered to incorporate a variety of symptoms Guidelines for the Management of Dyspepsia
Table 1. Levels of Evidence
symptoms, explaining the observation that the prevalence re- Evidence from RCTs with low false positive rates (i.e., significant p values), adequate sample sizes (low likelihoodof type II errors) and appropriate methodology (low NATURAL HISTORY AND COSTS OF DYSPEPSIA
Evidence from RCTs with high false positive rates, Dyspepsia is usually a chronic condition in primary and sec- inadequate sample sizes, or inappropriate methodology ondary care. The costs in the United States remain poorly doc- III Evidence from nonrandomized trials using a umented, but in Sweden a total societal cost of $63 per adult was calculated for dyspepsia (including reflux disease) (11).
IV Evidence from nonrandomized trials using a historical cohort In another study, 288 adult primary care patients with dys- Evidence from case series without controls pepsia were followed up for 1 yr; dyspepsia patients tendedto remain symptomatic with 61% using drugs and 43% hav- Note: Adapted from Cook D et al. Chest 1992;102:305S.
ing gastrointestinal procedures, indicating intensive use ofmedical resources (12).
including early satiety, bloating, upper abdominal fullness, ornausea (1). However, bloating is most typically a symptom of DIAGNOSTIC TESTING
IBS and may not be located in the upper abdomen exclusively.
Nausea can be secondary to a variety of nonabdominal con- Dyspeptic patients more than 55 yr old, or those with
ditions. Hence, neither bloating nor nausea alone should be alarm features (bleeding, anemia, early satiety, unexplained
considered to identify dyspepsia. Belching alone is also an weight loss (>10% body weight), progressive dysphagia,
insufficient symptom to identify dyspepsia and can be sec- odynophagia, persistent vomiting, a family history of gas-
ondary to air swallowing, although it is commonly present trointestinal cancer, previous esophagogastric malignancy,
with epigastric pain or discomfort. Acute self-limited dys- previous documented peptic ulcer, lymphadenopathy, or an
pepsia generally requires no investigation and will not be abdominal mass) should undergo prompt endoscopy to rule
further considered here in these management guidelines.
out peptic ulcer disease, esophagogastric malignancy, and
other rare upper gastrointestinal tract disease.

In patients aged 55 yr or younger with no alarm features,
the clinician may consider two approximately equivalent
EPIDEMIOLOGY OF DYSPEPSIA
management options: (i) test and treat for H. pylori using
a validated noninvasive test and a trial of acid suppression

It is established that dyspepsia is a common problem world- if eradication is successful but symptoms do not resolve
wide. In the United States, the point prevalence is approxi- or (ii) an empiric trial of acid suppression with a proton
mately 25%, excluding those people who have typical GERD pump inhibitor (PPI) for 4–8 wk. The test-and-treat option
symptoms (7). The prevalence is lower if patients with any is preferable in populations with a moderate to high preva-
symptoms of heartburn and regurgitation are excluded (8).
lence of H. pylori infection (≥10%), whereas the empirical
The incidence is more poorly documented. In the United PPI strategy is preferable in low prevalence situations.
States, approximately 9% of people who had no symptoms of Some anxious patients may need the reassurance af-
dyspepsia anually in the prior year reported new symptoms forded by endoscopy. On the other hand, repeat EGD is
on follow-up; however, those with a past history of dyspepsia not recommended once a firm diagnosis of functional dys-
or peptic ulcer were not excluded and hence the onset-rate pepsia has been made, unless completely new symptoms or
may be exaggerated (9). In Scandinavia, an incidence rate of alarm features develop. Repeat EGD is otherwise unlikely
less than 1% over 3 months has been reported (10). Whatever to ever be cost-effective.
the incidence, the number of subjects who develop dyspepsia Grades of evidence:
is matched by a similar number of subjects who lose their Early endoscopy for alarm symptoms: C
Test-and-treat strategy for H. pylori: A
Acid suppression therapy: A

Table 2. Graded Recommendations for Clinical Practice
Reassurance after endoscopy: C
Strength of Evidence to Guide Clinical Practice Very few studies have investigated dyspepsia subjects from Supported by two or more level I studies without the community by esophagogastroduodenoscopy (EGD) and conflicting evidence from other level I studies other tests, to determine the underlying causes of the symp- Supported by two or more level I studies with conflicting toms. In a population-based study from northern Norway, evidence from other level I studies or supported by onlyone level I or two or more level II studies amongst those with epigastric pain only 9% had a peptic ulcer and 14% had reflux esophagitis, but how many had en-doscopy negative reflux disease is uncertain (13). In a com- Note: Adapted from Guyatt GH et al. JAMA 1995;274:1800–1804; Users Guides tothe Medical Literature, JAMA Press 2001; and Cook D et al. Chest 1992;102:305S.
parable study from northern Sweden, a similar proportion of Talley et al.
uncertain; hence, these patients are not excluded from the functional dyspepsia diagnosis category (26).
PATHOPHYSIOLOGICAL DISTURBANCES IN
ENDOSCOPY-NEGATIVE (FUNCTIONAL) DYSPEPSIA
Approximately 40% of patients with functional dyspepsia have delayed gastric emptying (27). However, it is controver- sial whether a specific symptom profile is associated with delayed gastric emptying, and whether changes in gastric emptying can predict symptom improvement in functional dyspepsia. Stanghellini et al. in 343 Italian patients reported that delayed gastric emptying was significantly more frequent in patients characterized by female sex, low body weight, presence of relevant and severe postprandial fullness, nausea,vomiting, and absence of severe epigastric pain; female sex, Figure 1. Algorithm for the management of uninvestigated
dyspepsia
relevant and severe postprandial fullness, and severe vomitingwere independently associated with delayed gastric emptyingof solids (28). In a separate study of 483 patients, the same subjects had peptic ulcer or esophagitis, although 32% with Italian group identified distinct subgroups based on predom- esophagitis were asymptomatic (14). Many people with dys- inant symptoms and gastric emptying; one was character- pepsia presenting to primary care have no obvious cause for ized by predominant epigastric pain, male gender and normal their symptoms based on EGD. The most common finding in gastric emptying, and a second by predominant nonpainful North America is probably esophagitis; in a Canadian study symptoms, female gender, and a high frequency of associ- of uninvestigated dyspepsia in primary care, 43% of 1,040 pa- ated irritable bowel syndrome and delayed gastric emptying tients had erosive esophagitis and only 5% a peptic ulcer, but (29). Sarnelli et al. also reported that delayed gastric empty- this study did include patients with heartburn (15). Studies ing was associated with postprandial fullness and vomiting from open-access endoscopy practices and outpatient series (30). Other studies, however, have failed to identify a definite support the view that only a minority of patients presenting symptom profile associated with delayed gastric emptying with dyspepsia have peptic ulcer disease or reflux esophagi- suggesting there is not a simple association (31). Moreover, tis, and gastric cancer is relatively rare in western populations evidence that a gastric emptying test cost-effectively alters Additional diagnostic testing over and above EGD has a There is evidence that the stomach and other regions of low yield in dyspepsia, at least in primary care. Studies apply- the gut including the duodenum and esophagus are hyper- ing abdominal ultrasonography in dyspepsia have reported sensitive to distention in functional dyspepsia, although this few abnormalities aside from asymptomatic cholelithiasis applies only in a subgroup (32–36). Tack et al. recently re- that needs no intervention (18, 19). Endoscopic ultrasonog- ported in 160 patients with functional dyspepsia that one third raphy (EUS) has been reported to have a higher yield of had gastric hypersensitivity and this abnormality was associ- identifying pancreatico-biliary pathology but selection bias ated with increased postprandial pain as well as belching and may explain the observation and much of the pathology iden- weight loss, but confirmatory data are needed on the symptom tified is of questionable significance (20, 21). Twenty-four hour esophageal pH testing can identify pathological acid In a barostat study, Tack et al. studied patients with func- reflux in approximately 20% of patients with a clinical and tional dyspepsia; impaired gastric accommodation to a meal endoscopic diagnosis of functional dyspepsia (22–25). How- (a “stiff fundus”) was found in 40%, and this abnormality ever, the symptom criteria used to define functional dyspep- was associated with early satiety and weight loss but not with sia in these studies have generally been broader than recom- hypersensitivity to gastric distention, presence of H. pylori, mended by the Rome Committees, and hence patients with or delayed gastric emptying (37). However, Boeckxstaens typical reflux symptoms contaminated the studies. Klauser et et al. failed to replicate these findings; while postprandial al. extensively evaluated a group of patients with functional symptoms were more often evoked with a meal in functional dyspepsia; they reported that 47% had abnormal findings on dyspepsia, there was no clear symptom profile that was asso- additional testing but the significance of the various abnor- ciated with a failure of fundic relaxation (38). Noninvasive malities identified, including minor delays in gastric empty- testing is available to assess abnormal fundic accommoda- ing and lactose intolerance remains questionable (22). De- tion including gastric ultrasound, SPECT, and MRI, but the pending on the background prevalence of H. pylori, this in- clinical relevance of identifying this abnormality remains in fection will be identified in 20–60% of patients with func- some dispute in terms of defining therapeutic interventions tional dyspepsia, but the clinical relevance in most cases is Guidelines for the Management of Dyspepsia
New clinical tests of gastric function are under evaluation.
abnormalities, but the results have been inconsistent (45, 46).
The water-load test and nutrient-load test may help identify The optimal age threshold for endoscopy is unclear but 55 yr gastric dysfunction in clinical practice (40, 41). These rep- (rather than 45 yr) seems a reasonable cut-off because cancer resent simple tests of the ability of a patient to drink water is rare in younger patients in the United States, but no age or a nutrient load such as Ensure until they feel completely full. Dyspepsia patients tolerate lower volumes than controls Several other alarm features have been traditionally ap- for example, and have more symptoms 30 min after reach- plied to try and identify serious underlying disease in dyspep- ing satiation. Hence, this is a stomach “stress test” and can sia, especially malignancy. These include unexplained weight objectively quantify postprandial distress. However, normal loss, anorexia, early satiety, vomiting, progressive dyspha- cutoffs vary by laboratory (as do test protocols), and the rate gia, odynophagia, bleeding, anemia, jaundice, an abdominal of gastric emptying of the nutrient meal as well as relaxation mass, lymphadenopathy, a family history of upper gastroin- of the fundus secondary to meal ingestion can potentially testinal tract cancer, or a history of peptic ulcer, previous modulate the test results. Some have found that the drink gastric surgery or malignancy. Upper gastrointestinal ma- tests correlate with fundic dysaccommodation rather than lignancy is rarely present in young patients without alarm visceral hypersensitivity (42). Others have failed to demon- features, but the positive predictive value of alarm features strate a relationship to gastric dysfunction while some data remains very poor (47, 48). A long history of symptoms in suggest these tests correlate with psychological disturbances patients should make cancer unlikely but a symptom dura- (40, 41). Currently, patients with gastroduodenal motility dis- tion threshold has not been defined in the literature. Use of turbances, gastroduodenal hypersensitivity, or other patho- antisecretory therapy can mask a cancer at endoscopy (49) physiological abnormalities of uncertain relevance are not but does not appear to alter the outcome (50).
excluded from the functional dyspepsia umbrella.
Although alarm symptoms are not specific for a serious underlying disorder, few patients younger than 55 yr of age SYMPTOMS AND SYMPTOM SUBGROUPS
with an upper gastrointestinal malignancy present withoutalarm symptoms. In patients with alarm features, and in older There is convincing evidence that a patients symptoms cannot patients >55 yr of age with new symptoms, prompt EGD is be used to identify structural disease in uninvestigated dys- considered the gold standard to ensure that malignancy has pepsia (15, 43). Working teams have suggested subdividing not been missed. There are regions in the United States of dyspepsia into ulcer-like or dysmotility-like dyspepsia based high cancer incidence where lower age thresholds may need on symptom patterns or predominance; it was postulated that to be considered such as Alaska (51). On the basis of expert symptom subgroups could identify more homogenous pop- opinion, if an EGD has already been done recently, repeating ulations that would respond to targeted medical therapy (1, this test is highly unlikely to alter management.
7). However, individual symptoms, symptom subgroups, and The patient who presents with new onset dyspepsia or be- scoring systems have all failed to be useful in identifying un- cause of chronic symptoms needs an appropriate, evidence- derlying peptic ulcer disease, or distinguishing organic from based clinical evaluation. The physician generally wishes to functional dyspepsia. A study from Canada reported that the ascertain the likely cause of the symptoms and exclude under- patient’s dominant symptom (including heartburn) failed to lying serious structural disease. However, the patient may ac- predict endoscopic findings in a primary care population (15).
tually be presenting not necessarily because of the symptoms It is thus controversial whether subdividing dyspepsia into per se but because of a fear of serious disease or recent psy- symptom subgroups aids management in documented func- chological distress. It is reasonable that the physician identify and address such issues as fear of cancer or underlying heartdisease in order to optimize management (52).
ALARM FEATURES AND IDENTIFICATION OF STRUCTURAL
The patient requiring major reassurance needs to be dif- ferently managed than one who does not have such concerns, DISEASE IN UNINVESTIGATED DYSPEPSIA
but fear of serious disease probably explains only some health The risk of malignancy increases with age and therefore
care seeking behavior (53). The physician also needs to de- empirical therapy is not currently recommended in individ-
cide whether pharmacological therapy is required, includ- uals over 55 yr of age who develop new dyspeptic symptoms.
ing which drug and for how long. This in turn depends on Grade of evidence: C
the underlying provisional diagnosis, which may need to be New-onset dyspepsia in older age is an alarm feature or red refined after the patient has initially had a trial of therapy.
flag. The American College of Physicians in 1985 publisheda guideline recommending that patients who were over the MANAGEMENT OPTIONS IN YOUNGER PATIENTS WITH NO
age of 45 deserved referral for prompt endoscopy to rule ALARM FEATURES
out underlying malignancy, as gastric cancer is very rare inthe United States below the age of 45 yr although it increases A number of management options are available to the clin- thereafter (44). Some studies have reported that older age is an ician in younger patients with no alarm features with un- independent risk factor for identifying underlying structural investigated dyspepsia. A wait-and-see strategy of patient Talley et al.
reassurance and education, with use of over-the-counter gastric ulcer (GU) in 13%; those who were breath test nega- antacids, H2-blockers, or PPIs and reevaluation can be con- tive had a DU in 2% and GU in 3% (56). Other studies suggest sidered, particularly in primary care. Another strategy worth that between 20% and 60% of patients with dyspepsia who considering is prescription of empirical full-dose or high- are H. pylori infected will have underlying peptic ulcer dis- dose antisecretory therapy, reserving further evaluation for ease, but this varies widely depending upon the background those who are either unresponsive or have an early symp- incidence of peptic ulcer (57, 58). Cost-effectiveness stud- tomatic relapse after ceasing medication. Empiric antisecre- ies in the United States suggest that when the prevalence of tory therapy was the backbone of the guideline proposed by H. pylori infection in patients with functional dyspepsia is the American College of Physicians and is still widely ap- less than 12% or when the prevalence of H. pylori infection plied in practice (44). A third approach applies H. pylori test- in patients with peptic ulcer disease is less than 48%, ini- and-treat as the initial strategy, currently most widely rec- tial empirical treatment with a PPI is preferable (59). Others ommended around the world (54, 55). Here, young patients have suggested that when H. pylori infection decreases below without alarm features are tested for H. pylori infection. If 20%, empiric PPI therapy starts to dominate test-and-treat in H. pylori is detected, empiric antibiotic therapy is prescribed in an attempt to eradicate the infection; H. pylori-negativepatients are treated with empiric antisecretory therapy ini- Test-and-Treat H. pylori Versus Placebo in Dyspepsia in
tially. A modification of the H. pylori test-and-treat strategy the Community
is to either prescribe empiric antisecretory therapy first and There are data indicating a small benefit for treating H. pylori reserve H. pylori testing later for failures, or apply empiric empirically in those with the infection in the community antisecretory therapy after H. pylori eradication fails to re- (nonpatients). In a U.K. community trial, 32,929 individu- lieve symptoms. A final approach is to perform prompt EGD als were invited and 8,455 attended and were eligible; 2,329 for all patients with dyspepsia. The best option remains un- were positive for H. pylori and were assigned active treatment der debate, but new data are available to help guide a rational or placebo, with 1,773 (76%) returning at 2 yr (61). There was an absolute risk reduction of 5% for upper GI symptomson active therapy versus placebo, although quality of life wasunchanged. Presumably much of this benefit is explained bythe treatment of undiagnosed peptic ulcer disease.
TEST-AND-TREAT H. pylori
The application of a test-and-treat strategy for H. pylori
Test-and-Treat H. pylori Versus Usual Management of
should be based on the practice setting (Fig. 1). High-
Uninvestigated Dyspepsia in Primary Care
prevalence populations in the United States (e.g., recent
Chiba et al. conducted a randomized placebo-controlled trial immigrants from developing countries) should undergo
in 36 family practices in Canada; they randomized 294 test-and-treat as the preferable nonendoscopic strategy.
H. pylori-positive patients to omeprazole plus antibiotics or Conversely, in communities where gastric or esophageal
omeprazole plus placebo for 1 wk, and then arranged follow- cancer has a high incidence, prompt endoscopy should be
up by family physicians for usual care (62). They found eradi- considered early but this would not apply to most of the
cation resulted in no or minimal symptoms in 50% of patients country. In low-prevalence populations (e.g., high socioe-
compared to 36% in the placebo-therapy arm at the end of 12 conomic areas, where the background prevalence of ulcer
months. It is of interest that this benefit was observed despite or H. pylori infection is low), an alternative strategy is to
including some GERD patients in this trial. The eradication prescribe first a course of antisecretory therapy empirically
therapy arm also reduced costs by Can$53 per patient. Al- for 4–8 wk. If the patient fails to respond or relapses rapidly
lison et al. in a study in primary care in the United States on stopping antisecretory therapy, then the test-and-treat
observed no cost benefit of test-and-treat over usual care al- strategy is best applied before consideration of referral for
though symptoms were significantly reduced in the test-and- EGD. EGD is not mandatory in those who remain symp-
treat arm (63). An underpowered U.S. study failed to detect tomatic as the yield is low; the decision to endoscope or not
a difference between test-and-treat and usual care (64).
must be based on clinical judgement.
Grade of evidence for test-and-treat or acid suppr-
Test-and-Treat H. pylori Versus Prompt EGD in Primary
ession: A
and Secondary Care
Grade of evidence for a H. pylori prevalence of less than
There is consistent empiric evidence that a test-and-treat strat- 10% in the local community as the cutoff for deciding to
egy is at least equivalent to prompt endoscopy in terms of use empiric acid suppression rather than test-and-treat: C
outcomes. Lassen et al. randomized 500 patients (including The rationale for noninvasive H. pylori testing is the iden- older patients) in primary care with dyspepsia to either H. tification of underlying peptic ulcer disease. For example, in pylori test-and-treat or prompt endoscopy (65). They found Scotland where the incidence of peptic ulcer is high, McColl that there were no differences in symptomatic outcomes or et al. showed that in patients with dyspepsia and a positive quality of life between the groups at 1 yr, although the en- C13 urea breath test had a duodenal ulcer (DU) in 40% and doscopy group had a slightly higher patient satisfaction score Guidelines for the Management of Dyspepsia
of questionable clinical significance. The authors also iden- lori is very uncommon, a positive test is more likely to be a tified a reduction in the number of endoscopic procedures false positive. Where H. pylori infection is highly prevalent, performed in the test-and-treat arm. Heaney et al. in Ireland a negative result is more likely to be a false negative (77).
evaluated dyspepsia patients less than 45 yr old referred to Cost-effectiveness studies suggest that the stool test and the an open-access endoscopy unit who were H. pylori-positive urea breath test that detect active infection are preferable to on noninvasive testing (66). Patients here were randomized serological tests in the United States (78, 79).
to either empiric H. pylori therapy or immediate EGD. They The current treatment of choice for H. pylori infected pa- found that more patients became symptom free in the H. tients is a combination of PPI (standard dose twice daily) pylori eradication arm than in the prompt endoscopy arm.
with amoxicillin (1 g twice daily) and clarithromycin (500 McColl et al. evaluated 708 patients under age 55 yr referred mg twice daily) administered for 7–10 days (7-day therapy for endoscopy; these patients were randomized to either H. is approved with rabeprazole; 10-day therapy is approved pylori test-and-treat or endoscopy including H. pylori testing with lansoprazole, omeprazole, pantoprazole, and esomepra- (67). They found no significant difference in dyspepsia score zole). Metronidazole (400 mg twice daily) may be substi- at the 12 months follow-up in the two groups. Furthermore, tuted for amoxicillin in this regimen if the patient is allergic only 8% of patients who had testing and treatment eventually to penicillin. An alternative strategy is the combination of underwent endoscopy; overall patient satisfaction and quality Bismuth, metronidazole, and tetracycline (Bismuth subsal- of life was similar in both groups. Jones et al. evaluated 232 icylate [Pepto Bismol ] 525 mg QID + metronidazole 250 patients in primary care, of whom 141 underwent testing and mg QID + tetracycline 500 mg QID) combined with a PPI treatment for H. pylori; 91 who had previously undergone endoscopy comprised the control group (68). Although not A final issue relates to potential complications of therapy.
a randomized controlled trial, they identified similar clini- Antibiotic allergies and super-infection can occur. It is con- cal outcomes but lower costs in the test-and-treat group at troversial whether eradication of H. pylori infection increases 1 yr. Because this was a retrospective, unmatched noncon- the risk of development of reflux esophagitis or reflux symp- secutive controlled study, the results are difficult to interpret.
toms (82, 83). However, it appears likely that this risk is Additional randomized trial data (69) and a Cochrane meta- only present in those with a predisposition to GERD who analysis (70) suggest overall that prompt EGD and test-and- also have severe gastritis in the body or fundus that impairs acid secretion, which is reversed with H. pylori eradication; Other evidence supports the view that H. pylori testing this is likely to be uncommon in most of the United States may provide adequate patient reassurance. Patel et al. eval- (84). Hence, this issue while much discussed should not be uated 193 dyspepsia patients under the age of 45 yr (71).
a major clinical concern when contemplating test-and-treat, Seventy of these patients were H. pylori-seronegative with- unless convincing data to the contrary arise. Progression of out alarm features, 90 were seropositive for H. pylori and 23 H. pylori gastritis may occur on acid suppression, and some had alarm features; the H. pylori-positive patients and those have suggested H. pylori eradication should be considered with alarm features underwent prompt endoscopy. No dif- for all patients requiring long-term acid suppression, which ference in outcome or satisfaction was detected between the seems reasonable (85, 86). An unresolved issue is whether groups in follow up after referral back to their primary care test-and-treat will widen the problem of community acquired Disadvantages of Test-and-Treat
PROMPT ENDOSCOPY
A notable disadvantage of test-and-treat is that cure of H.
pylori
infection will only lead to a minority reporting symp- Advantages of Prompt Endoscopy
tom improvement, as demonstrated in the above management There is empiric evidence from a management trial of prompt trials, and this can be confusing to the clinician (60–65). How- endoscopy in older patients that this is the strategy of first ever, endoscopy and targeted medical therapy does no better.
choice. Delaney et al. evaluated the cost-effectiveness of an Indeed, eradication of H. pylori infection does not relieve initial endoscopy compared with usual management in pa- symptoms in all patients with peptic ulcer disease, with at tients with dyspepsia over the age of 50 presenting in primary least one third continuing to be symptomatic (72, 73).
care (87). A total of 422 patients were randomly assigned to The choice of the H. pylori test is critical. Many serologi- either usual care or initial endoscopy; the initial endoscopy cal tests have not been locally validated, and have suboptimal arm showed significant improvement in symptom scores and sensitivity and specificity in practice (74). The urea breath test quality of life as well as a 48% reduction in the use of PPIs.
and stool antigen test are currently the most accurate nonin- Hence, initial endoscopy in older patients with dyspepsia at vasive diagnostic tools and can be used with confidence (75, least in this U.K. study was potentially cost-effective provided 76). The value of noninvasive H. pylori testing, even if a the cost of EGD was low. The cost-effectiveness of endoscopy local evaluated test is applied, still depends on the positive in older people in the U.S. setting needs investigation.
and negative predictive value, which in turn is related to the There is only limited and unconvincing evidence that background prevalence of H. pylori infection. When H. py- endoscopy leads to improved patient satisfaction scores in Talley et al.
dyspepsia. Bytzer el al. conducted a randomized trial com- EMPIRIC ANTISECRETORY THERAPY IN UNINVESTIGATED
paring prompt endoscopy with empiric H2-receptive blocker DYSPEPSIA
therapy in dyspepsia (88). They found there was significantimprovement in satisfaction scores at one month after en- In H. pylori-negative cases with uninvestigated dyspepsia
doscopy compared to the empiric antisecretory therapy arm.
and no alarm features, an empiric trial of acid suppression
In addition, 66% of the patients in the empiric therapy arm for 4–8 wk is recommended first-line therapy (Fig. 1).
eventually underwent endoscopy during the 12 months of Grade of evidence: A
follow-up. However, this unblinded study may have been bi- If initial acid suppression fails after 2–4 wk, it is rea-
ased by patient and physician expectation that endoscopy is sonable to step up therapy, although this is based on ex-
the preferred management strategy, and H. pylori status was pert opinion only; this may require changing drug class or
not considered. Other studies have suggested that patients dosing. In the absence of established prokinetic drugs for
with dyspepsia are reassured by EGD and may require fewer dyspepsia in the United States, this drug class is not cur-
prescriptions, although the duration of reassurance is not es- rently recommended as first-line therapy for dyspepsia in
the United States.
Dyspeptic patients who seek medical attention are more Grade of evidence: C
concerned about the possible seriousness of their symptoms In patients who do respond to initial therapy, it is recom-
and are more likely to be concerned about underlying cancer mended that treatment be stopped after 4–8 wk and if symp-
(92). Health anxiety has been shown to lead to a cycle of toms recur, another course of the same treatment is justified.
repeated medical consultations. In a study of primary care There are no data on long-term self-directed therapy in this
patients undergoing open-access endoscopy, Hungin et al. condition, although this may be worth considering in some
demonstrated that consultations for dyspepsia fell by 57% patients.
in patients with normal endoscopy and by 37% in patients Grade of evidence: C
with minor abnormalities at endoscopy. In 60% of patients The American College of Physicians in 1985 recom- with normal endoscopy, medication use was terminated or mended an empiric trial of an H2 receptor antagonist for 6–8 decreased (93). Quadri and Vakil demonstrated that one third wk; those who relapsed after therapy or those who failed of patients referred for open-access endoscopy for dyspepsia to respond to therapy in 7–10 days were to be referred for in the United States had high levels of health related anxiety; endoscopy (44). The widespread availability of PPIs has re- following a normal endoscopy or the demonstration of mi- sulted in this class of agents frequently being prescribed as nor abnormalities, and reassurance by the endoscopist, scales initial empiric therapy in uninvestigated dyspepsia in place for preoccupation with health and fear of illness and death showed significant improvement after endoscopy, and the ef- A meta-analysis of several large studies has demonstrated fects were preserved for 6 months (86).
a short course of PPI therapy compared with a H2-receptorantagonist, alginate, or placebo in primary care providesbetter symptomatic outcomes (70). However, these stud- Disadvantages of Endoscopy
ies frequently included patients with symptomatic reflux There are several potential disadvantages of prompt en- disease and did not exclude peptic ulcer. It is unknown doscopy for all dyspeptic patients that need to be carefully whether GERD or ulcer disease, or both, accounts for the considered. Endoscopy is invasive and although the risks of apparent short-term benefits of empiric therapy in these this procedure in relatively healthy patients are very low, the issue of the risk-benefit ratio needs careful weighing, par- There are limited data that prokinetic therapy employed as ticularly as the procedure is very unlikely to identify an un- an empiric strategy may be efficacious in uninvestigated dys- expected structural cause in a young patient with no alarm pepsia. Kearney et al. noted no significant difference in the features. Finding esophagitis, the most likely structural ab- severity of dyspeptic symptoms among 60 patients random- normality, may often not lead to a change in management ized to receive cisapride as compared to placebo in the setting (94, 95). Moreover, the high prevalence of dyspepsia means of uninvestigated dyspepsia and negative H. pylori-serology that a general recommendation to perform endoscopies on (99). Quartero et al. conducted a trial in primary care of all patients would be very costly and would overwhelm en- 563 patients who were randomized to ranitidine or cisapride; doscopy services. Furthermore, it is contentious that prompt treatment success was similar in both groups but was un- EGD provides any direct benefits despite some positive stud- der 50%, and the relapse-free periods were also similar with ies quoted above. One study evaluated management strategies both drugs (100). A randomized trial in H. pylori-negative in 326 primary care patients with dyspepsia; endoscopy was dyspepsia from Canada demonstrated that cisapride had low not superior to any of the empirical treatment strategies uti- efficacy and was inferior to acid suppression (101). More- lized in this study (96). A systematic review concluded that over, cisapride is no longer available because of rare toxicity most data failed to support the view that endoscopy alone from QTC prolongation and sudden death. There have been improves patient outcome in dyspepsia compared with other no trials of metoclopramide, tegaserod or domperidone in the management of uninvestigated dyspepsia.
Guidelines for the Management of Dyspepsia
Obvious disadvantages of empiric antisecretory therapy this model, the most costly approach was test-and-treat fol- include the concern that peptic ulcer disease will be inappro- lowed by endoscopy for failures. This model also suggested priately and inadequately treated, and patients subsequently that empirical PPI therapy became cost-effective if the preva- may present with complicated ulcer disease if for any reason lence of H. pylori infection was 12% or less in the dyspeptic the therapy is ceased. Antisecretory therapy can also lead to population. Ladabaum et al. observed that as the likelihood misdiagnosis of peptic ulcer disease at subsequent endoscopy, of H. pylori (and ulcer disease) decreases below 20%, em- as the ulcer will more likely heal and be missed. The impact piric PPI therapy starts to dominate test-and-treat in unin- of acid rebound in dyspepsia remains unclear (102). Em- vestigated dyspepsia (60). Therefore, recommendations for piric antisecretory therapy may lead to long-term inappropri- the test-and-treat strategy may need to be modified when the ate maintenance therapy that the patient does not require. It prevalence of H. pylori infection is low, and we recommend is unclear whether antisecretory therapy postpones eventual on the basis of expert opinion considering a PPI in the setting investigation or not, which in turn impacts on its potential of a H. pylori prevalence below 10% in the local commu- nity. A recent systematic review and economic analysis usinggeneric/over-the-counter costs for PPIs found that they were H. pylori TEST-AND-TREAT VERSUS EMPIRIC
cost-effective in the United States provided generic costs of a ANTISECRETORY THERAPY
PPI were used in the analysis (108). Upper GI radiology wasnot a cost-effective alternative to H. pylori test-and-treat in There are only very limited data comparing empiric H. pylori treatment versus empiric PPI therapy. Manes et al. comparedtest-and-treat with PPI therapy for a month with 12 monthsof follow-up in a secondary care setting in Italy (103). In the WEIGHING THE OPTIONS
test-and-treat arm, 56% were eventually endoscoped because A Cochrane review has been conducted of available manage- of poor symptom control, but none had a peptic ulcer; in ment strategies for dyspepsia (70). They identified 18 pub- the PPI arm, 88% were endoscoped and 17% had a peptic lished papers that had 20 comparisons included. In a pooled ulcer, but most (88%) were infected with H. pylori. More analysis, PPIs were significantly more effective than both studies are needed, but these data suggest that in H. pylori- positive dyspeptic patients, empiric PPI therapy is not the 2 receptor antagonists and antacids in uninvestigated dys- pepsia. A significant limitation of the studies is that they management option of choice in areas where the prevalence included broad groups of patients including those with obvi- ous reflux disease. There was insufficient data to determine ECONOMIC MODELS OF DYSPEPSIA MANAGEMENT
whether empiric prokinetic therapy was beneficial. They alsoconcluded a H. pylori test-and-treat strategy may be as effec- Fendrick et al. undertook economic modeling of manage- tive as endoscopy-based management with reduced costs be- ment strategies in patient with suspected peptic ulcer disease, cause of the decreased numbers of patients that subsequently which presumably applies to the majority of patients with require EGD, but it was unclear whether test-and-treat com- uninvestigated dyspepsia (104). They found that an initial pared to empirical acid suppression was equivalent or not strategy of H. pylori testing and treatment was cost-effective, unless the cost of endoscopy fell to less than $500 whenprompt endoscopy became more cost-effective. Sonnenberg ENDOSCOPY-NEGATIVE DYSPEPSIA (FUNCTIONAL
noted that if the ulcer disease prevalence rate exceeded 10% DYSPEPSIA, NONULCER DYSPEPSIA)
in H. pylori-infected subjects, then a noninvasive strategybased on serological testing became cost-effective (105). Sil- The management of endoscopy-proven functional dyspep-
verstein el al. concluded that there was a toss up between sia is particularly challenging when initial antisecretory
H. pylori test-and-treat compared with other strategies, but therapy and H. pylori eradication fails. Patients who fail
reevaluation of this model applying the assumptions made by to respond to simple measures need to have their diagnosis
Fendrick et al. confirmed their results, supporting test-and- reconsidered. Dietary therapy has no established efficacy
treat (106). Ofman et al. concluded that test-and-treat was but may help some individuals. There are very limited data
cost-saving; the cost of endoscopy would need to drop from to support the use of herbal preparations, simethicone, and
$740 by 96% for an initial endoscopy strategy to become low-dose tricyclic antidepressants in functional dyspepsia.
equally cost-effective in their model (107).
Bismuth, sucralfate, and antispasmodics are not established
Spiegel et al. tested four different management strategies in to be of benefit over placebo in functional dyspepsia. Hyp-
decision analysis (59). This analysis was confined to patients notherapy, psychotherapy, and cognitive-behavioral ther-
younger than 45 yr of age presenting in primary care. They apy are supported by limited studies but cannot be generally
identified initial antisecretory therapy followed by endoscopy recommended at the present time.
as the least costly therapy per patient treated. However, this Grades of evidence:
rendered fewer patients symptom-free at 1 yr than strategies Dietary modification: C
which combined empiric PPI therapy with test-and-treat. In Simethicone: B
Talley et al.
Hypnotherapy,
Psychotherapy,
Cognitive-behavioral
ication in functional dyspepsia, with the number needed to therapy: B
treat being 15 (118). While longer than 1-yr follow-up dataare generally lacking, one 5-yr study suggests any benefit MANAGEMENT OF DOCUMENTED
will persist (119). On the basis of the evidence, it is accept-able to offer H. pylori eradication therapy to infected pa- FUNCTIONAL DYSPEPSIA
tients with functional dyspepsia. The results also imply that Once a diagnosis of functional dyspepsia is confirmed by a offering H. pylori eradication therapy empirically to those negative endoscopy, an empiric trial of therapy is commonly with otherwise uninvestigated dyspepsia who are infected prescribed. However, the benefits of all therapies in this con- is reasonable even if ulcer disease is unlikely. Moreover, H. pylori eradication in those with documented functional Many patients do not require medication for dyspepsia dyspepsia may help prevent ulcer disease, although convinc- after they have had reassurance and education. It is there- ing evidence is not available. Hsu et al. observed during 1 fore important for the clinician to explain the meaning of yr of follow-up in a randomized controlled trial compris- the symptoms and their benign nature. Ascertaining why a ing 161 patients with functional dyspepsia, 2 patients in the patient with long-standing symptoms has presented on this H. pylori eradication treatment group (3%) and 6 patients occasion for care can be helpful, as this may identify those in the placebo group (8%) developed peptic ulcers at repeat who have fears of an underlying serious disease or specific psychological distress that can be addressed. Potential precip- The benefit of other treatments remains uncertain. A itating factors in dyspepsia remain poorly defined. High-fat Cochrane review included 12 trials with prokinetics com- meals should be avoided; eating frequent and smaller meals prising 829 patients and showed that there was a relative throughout the day can sometimes be helpful. Specific foods risk reduction of 50%, compared with placebo, but most of that precipitate symptoms can be avoided. Food intolerance is the studies were with cisapride (98). Moreover, analysis of uncommon, however, and food allergy very rare. Follow-up the studies suggested that publication bias at least partly ex- of the patient helps determine the natural history and allows plains the apparent benefits of prokinetic therapy. Prokinetics further correction of faulty ideas and provides reassurance should be reserved for difficult cases as options in the United that can be very helpful in long-term management.
States are few and current agents (e.g., metoclopramide, ery- Antacids and sucralfate were not superior to placebo in thromycin, tegaserod) have limited or poorly established ef- functional dyspepsia based on a Cochrane review (98). How- ficacy, or side-effects are common (121). Routine use of gas- ever, a recent trial of simethicone has suggested potential tric emptying studies is not recommended as improvements benefit compared with placebo, and in another study equiv- in gastric emptying do not correlate well with symptom im- alence with cisapride (110, 111). A Cochrane review of 8 provement (31, 122). Drugs that relax the gastric fundus (e.g., trials of H2 receptor antagonists with 1,125 patients showed tegaserod, cisapride, sumatriptan, buspirone, clonidine, some a relative risk reduction of 30% but the quality of the trials SSRIs, nitric oxide donors) may theoretically improve some was generally poor (98). PPIs in this review also produced a dysmotility-like dyspepsia (e.g., early satiety) but adequate relative risk reduction of approximately 30% and the quality randomized controlled trials are lacking (123). Antidepres- of the trials was better (98). An economic model suggested sants are also of uncertain efficacy in functional dyspepsia but that PPI therapy was cost-effective for functional dyspepsia in are often prescribed (121, 124). There are insufficient data on the United States (108). However, in a recent randomized trial the use of tricyclic antidepressants such as amitryptyline in of 453 patients from Hong Kong, the proportion of patients dyspepsia, but small studies have suggested benefit; how- achieving complete relief of dyspepsia with lansoprazole 30 ever, the beneficial effect of low-dose amitryptyline seen in and 60 mg was 23% and 23%, respectively, compared with functional dyspepsia was not related to changes in perception 30% on placebo (112). In contrast, another recent trial re- of gastric distension (125). An increased tolerance to aver- ported significant benefit with lansoprazole in a U.S. popula- sive visceral sensations may play a role in the therapeutic tion (113). H. pylori status is unlikely to affect the therapeutic effect. There are limited data with the SSRIs. Psychological outcome of acid suppression therapy in functional dyspepsia therapies are promising, particularly hypnotherapy, but more (108). Large trials have failed to identify any difference in data are needed in larger patient populations before these can therapeutic outcome in H. pylori-positive versus negative pa- be recommended for routine use (126, 127). Other alterna- tients, although Blum et al. did identify a superior response tive therapies such as herbal preparations remain of unproven to PPI therapy in H. pylori-positive patients (114, 115).
Eradication of H. pylori in functional dyspepsia is contro- versial. Two high-quality meta-analyses have reached differ-ent conclusions but this may be likely explained by which ADDITIONAL DIAGNOSES AND TESTING
trials were included and excluded in each systematic review IN REFRACTORY CASES
(116, 117). Updating these meta-analyses now suggests thatwhen all appropriate trials are considered, there is a small In patients with resistant symptoms, it is worth reevaluating
but significant therapeutic gain achieved with H. pylori erad- the diagnosis.
Guidelines for the Management of Dyspepsia
Grade of evidence: C
Abdominal wall pain can be confused with functional dys-
pepsia; physical examination here is diagnostic (increased rather than reduced tenderness on tensing the abdominal wall muscles) (130). Biliary pain is characteristic and different from dyspepsia; ultrasound usually is unhelpful in the ab- sence of typical biliary pain. Exclusion of atypical GERD with esophageal pH testing may alter management; at least 20% of patients with diagnosed functional dyspepsia clini-cally turn out to have GERD on esophageal pH studies (23–25, 131). Thus, even if a trial of PPI therapy has failed, pH Reprint requests and correspondence: Nicholas J. Talley, M.D.,
Ph.D., Mayo Clinic College of Medicine, 200 First Street S.W., PL-
testing may be considered off therapy, although the yield in this particular setting is not defined. Abdominal imaging to Received February 18, 2005; accepted May 23, 2005. rule out chronic pancreatitis or small bowel pathology maybe worth considering too but usually has a low yield; cap-sule endoscopy does not yet have an established role here.
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