Managing Dyspepsia:What Do We Know and What Do We Need to Know?

Linda Rabeneck, M.D., M.P.H., Nelda P. Wray, M.D., M.P.H., and David Y. Graham, M.D.Department of Veterans Affairs Medical Center and Health Services Research and Development (HSR&D) Field Program,

and the Department of Medicine, Baylor College of Medicine, Houston, Texas

Objective: The conceptual revolution concerning therole of Helicobacter pyloriin the pathogenesis of pepticulcer disease has raised the larger question of how tointegrate this new information into the management ofpatients with dyspepsia. The aim of this research was tocritically evaluate current knowledge about dyspepsiaand its management.Methods:Relevant articles on dys-pepsia were identified from MEDLINE searches andfrom the bibliographies of identified articles. Studiesthat contained information on the prevalence of dyspep-sia, endoscopic findings, and evaluations of alternativemanagement strategies were reviewed.Results:By cou-pling H. pylori serological testing with clinical factorssuch as age and nonsteroidal antiinflammatory drug use,strategies have been developed that identify patientswith organic disease. Although the use of these strategiescan reduce the volume of endoscopies, their effects ondyspepsia symptoms are unknown. Computerized deci-sion analysis models have been used to evaluate thecost-effectiveness of alternative strategies. The indirectevidence obtained from these models suggests that em-piric therapy, guided by H. pylori testing, may be thepreferred approach. However, the models have beenhampered by the lack of information concerning dys-pepsia symptoms, the primary health outcome of themajority of patients seen in primary practice settings.Conclusions:Currently, the knowledge needed to inte-grate H. pylori tests and antimicrobial therapies into themanagement of patients with dyspepsia in primary prac-tice settings has not been developed. A pressing needexists for a randomized controlled trial to evaluate al-ternative management strategies. In conducting such atrial, valid, reliable instruments for measuring dyspepsiawill be needed. (Am J Gastroenterol 1998;93:920–924.© 1998 by Am. Coll. of Gastroenterology)

INTRODUCTION

In the past the prevailing concept of the pathogenesis ofpeptic ulcer was that of an imbalance between mucosal

integrity and the destructive effects of gastric acid secretion(1). According to this concept treatment with antisecretoryagents was the cornerstone of management. However, in1984 Helicobacter pylori infection was reported in thestomachs of patients with peptic ulcers (2). Since then, alarge body of evidence has accumulated that demonstratesan important role for this bacterial agent in the pathogenesisof peptic ulcer disease. Antimicrobial agents now have acentral role in the management of peptic ulcer disease. Inaddition, serological tests to detectH. pylori infection arereadily available. This conceptual revolution in the patho-genesis and treatment of peptic ulcer disease has raised thelarger question of how to integrate these new tests andtherapies into the management of patients with dyspepsia inprimary practice settings. The purposes of this paper are tocritically appraise what we know and to determine whatfurther information we need to appropriately manage pa-tients with dyspepsia in theH. pylori era.

MATERIALS AND METHODS

We identified articles by searching the MEDLINE data-base for the period from 1990 through 1997 using theMedical Subject Heading Terms “dyspepsia,” “Helicobac-ter pylori,” and “peptic ulcer.” We identified further articlesfrom the references cited in the articles obtained from thesearch. In selecting articles to include in this review, wegave preference to primary rather than secondary sources,such as review articles and book chapters. Abstracts, letters,editorials, articles not published in English, and those per-taining to children were excluded. For articles focusing onendoscopic findings, reports that contained fewer than 150patients and those that focused on inpatients were excluded.

RESULTS

Definition of dyspepsia and scope of the problem

Several working groups have set forth definitions of dys-pepsia for use in clinical research. The consensus is thatdyspepsia denotes episodic or persistent upper abdominalpain or discomfort that is thought by the physician to arisein the proximal or upper gastrointestinal tract (3–6). Thepain may be associated with other symptoms, and someReceived July 28, 1997; accepted Mar. 6, 1998.

THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 93, No. 6, 1998Copyright © 1998 by Am. Coll. of Gastroenterology ISSN 0002-9270/98/$19.00Published by Elsevier Science Inc. PII S0002-9270(98)00158-0

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relationship with food intake is often present, but this is notan essential feature.

Table 1 summarizes the population-based estimates of theperiod prevalence of dyspepsia, which range from 13% to41% (7–16). This variation is largely accounted for bydifferences in research methods, which include the spectrumof symptoms encompassed, the duration of symptoms re-quired for inclusion in the study, and the time period overwhich the prevalence was estimated. Regardless of thesemethodological differences, it is clear that dyspepsia is avery common symptom in the general population.

Approximately 25% of individuals with dyspepsia in thegeneral population seek health care (9), the provision ofwhich accounts for substantial resource use and costs. Forexample, in the U.S., it is estimated that in 1985 gastritis anddyspepsia accounted for $1.1 billion in direct costs (17).

Findings on diagnostic work-up

Table 2 summarizes reports of the main endoscopic find-ings in patients with dyspepsia (12, 18–30). Two majormethodological differences among the studies should benoted. First, differences exist in the sampling frame,i.e.,how the subjects were recruited. In the majority of studies,subjects were referred for endoscopy by their primary carephysicians (referral-based) (18, 19, 21, 22, 25, 27–30).However, in three studies subjects were recruited by offer-ing endoscopy to all patients with dyspepsia presenting forcare to their primary care physicians (primary-care based)(20, 23, 24). In two studies all patients who reported dys-pepsia on a mailed questionnaire were offered endoscopy(population-based) (12, 26). Second, the inclusion/exclusioncriteria differed. In half the studies patients with complicat-ing features, such as previous gastric surgery (25, 27, 29),

TABLE 1Period Prevalence of Dyspepsia

ReferenceNo.

Country Year N Prevalence* Study Sample

(7) UK 1951 5951 31% (5 yr) $ 14 yr(8) UK 1968 1487 20% (3 months) Men;$ 15 yr(9) UK 1989 2066 38% (6 months) $ 20 yr

(10) UK 1989 1085 16% (NR) Men; 50–75 yr(11) UK 1990 7428 41% (6 months) $ 20 yr(12) Norway 1990 1802 28% (ever) 20–69 yr(13) USA 1992 835 26% (1 yr) 30–64 yr(14) USA 1993 5430 13% (3 months) $ 15 yr(15) Denmark 1994 3606 19% (1 yr) 30–60 yr(16) Sweden 1995 1156 32% (3 months) 19–79 yr

* Figures in parentheses indicate time period over which prevalence was reported.Year 5 year published; N5 number in study sample; NR5 not reported.

TABLE 2Endoscopic Findings (%) in Individuals With Dyspepsia

Reference Country Year N GU DU Esoph Cancer Sample

(18) UK 1979 187 5.9 5.3 (25)* 17.6 1.1 R(19) UK 1980 346 6.4 12.1 (24) NR 1.2 R(20) Sweden 1985 165 4.2 10.3 0 1.2 PC(21) Norway 1986 676 NR NR NR 1.3 R(22) UK 1988 686 7.9 12.1 14.1 1.6 R(23) Sweden 1989 172 4.1 9.3 (13) 10.5 1.2 PC(12) Norway 1990 309 1.6 2.3 (8) NR 0 P(24) UK 1990 2585 6.5 10.2 NR 2.2 PC†(25) Norway 1990 930 4.7 12.7 14.1 1.0 R(26) Norway 1991 273 8.4‡ 12.1 0 P(27) USA 1993 820 8.2 3.5 14.3 3.4 R(28) Germany 1993 220 5.0 10.0 16.8 1.8 R(29) Italy 1993 2253 1.6 5.0 (6) 5.3 2.0 R(30) UK 1994 1540 6.8 (26) NR 3.2 R

* Figures in parentheses denote number of patients with active ulcer or scarred duodenal cap.† 5 patients, 40 yr excluded.‡ 8.4% of study sample had DU or GU.Year5 year published; N5 number in study sample; GU5 gastric ulcer; DU5 duodenal ulcer; esoph5 erosive esophagitis; cancer5 gastric cancer;

R 5 study sample obtained from patients referred for endoscopy; PC5 study sample obtained by offering endoscopy to all patients with dyspepsia presentingin primary care settings; P5 study sample obtained by offering endoscopy to all individuals who reported dyspepsia in population-based survey questionnaire.

AJG – June 1998 DYSPEPSIA MANAGEMENT 921

were excluded. In one study patients, 40 yr of age wereexcluded (24).

The distribution of endoscopic findings varied across thestudy populations, reflecting these methodological differ-ences. The four major findings were gastric ulcer (1.6–8.2%), duodenal ulcer (2.3–12.7%), erosive esophagitis (0–17.6%), and gastric cancer (0–3.4%). The higher rates ofgastric cancer ($ 2%) were obtained in the referral-basedstudies (27, 29, 30) and the study that excluded patients,40 yr of age (24). A variable proportion of patients hadgastric or duodenal erosions of uncertain relationship totheir symptoms. Some patients with normal upper endos-copy undoubtedly had gastroesophageal reflux disease, al-though this was not consistently reported. Regardless ofthese methodological differences, clearly, a substantial pro-portion of patients with dyspepsia, from 50% (19) to 70%(25), have no detectable organic disease.

Factors that predict findings on diagnostic work-up

Because at least half the individuals with dyspepsia havea negative diagnostic work-up, efforts have been made toidentify clinical factors that are associated with the presenceof organic disease. The underlying hypothesis is that thesefactors could be used to identify those with organic diseaseso that the remaining patients could be managed withoutbarium x-rays or endoscopy.

In a study of 483 patients referred for upper gastrointes-tinal (UGI) barium series, 95% of those with an abnormalradiograph had at least one of the following: age. 50 yr,previous history of peptic ulcer, relief of pain by food, andpain that occurred within an hour of eating (31). However,despite their high sensitivity, the specificity of these factorswas poor. Approximately 70% of individuals without or-ganic disease had one or more positive factors.

Subsequent studies focusing on patients referred for up-per endoscopy found similar results. From these studies it isclear that organic disease is more common in patientsaged. 40 yr (22, 25, 32). In particular, gastric cancer isvery uncommon in patients aged, 45 yr (22). In additionto age, other clinical factors reported to be associated withpeptic ulcer disease are night pain (20), relief of pain withfood or antacids (20, 32), previous history of peptic ulcerdisease (20, 32), family history of peptic ulcer disease (32),a long history (at least 4 yr) (32), male gender (25), andsmoking (32). Although it is well established that the use ofnonsteroidal antiinflammatory drugs (NSAIDS) is associ-ated with an increased risk for peptic ulcer disease (33, 34),NSAID ingestion was not evaluated in these studies.

Based on clinical factors, several scoring systems havebeen developed to identify patients with organic disease(35–38). However, these scoring systems have not met withwidespread acceptance because their generalizability hasbeen questioned (39) and some are based on computermodels that are not widely available (37, 38).

Clinical features have been used to categorize patientsinto subgroups that might reflect differences in underlying

pathophysiology (3). These subgroups are ulcer-like, dys-motility-like, reflux-like, and nonspecific. However, theusefulness of this approach is doubtful because considerableoverlap exists among the subgroups (13, 16), which do notdiscriminate well between patients with and without organicdisease (27).

Strategies for managing patients with dyspepsia

Before theH. pylori era. Before theH. pylori era, thequestion was whether patients should undergo prompt di-agnostic work-up (UGI series or endoscopy) to establish afirm diagnosis, or whether a course of empiric therapyshould be given with endoscopy reserved for nonresponders.In 1985 the Health and Public Policy Committee of theAmerican College of Physicians (ACP) recommended ini-tial empiric therapy with antacids or H2-blockers for patientswith uncomplicated dyspepsia, with endoscopy reserved forthose with no or minimal response to therapy after 7 to 10days, and those with persisting symptoms after a 6- to 8-wkperiod (40). This approach, which was based on a criticalreview of the published evidence (41), has been the standardof care in primary practice settings. Subsequently, a ran-domized clinical trial reported that prompt endoscopy wasmore cost-effective than empiric H2-blocker therapy (42).Regardless of the strengths and weaknesses of this trial, thequestion must now be revisited becauseH. pylori infectionwas not taken into account.

During the H. pylori era. In 1994 an NIH ConsensusDevelopment Panel stated thatH. pylori-infected patientswith gastric or duodenal ulcers should be treated with an-timicrobials (43). What the NIH Panel did not address wasthe question of how to incorporate the new informationconcerningH. pylori into the management of patients withdyspepsia.

H. pylori infection is extraordinarily common in asymp-tomatic individuals; its prevalence increases with age andreaches approximately 50% by age 50 yr (44). Although themajority of infected individuals have asymptomatic chronicsuperficial gastritis,H. pylori infection is strongly associ-ated with peptic ulcer disease, which in turn is present in upto 20% of patients with dyspepsia. These links betweenH.pylori infection, peptic ulcer disease, and dyspepsia providethe impetus for evaluatingH. pylori-based patient manage-ment strategies.

Algorithms based onH. pylori serological testing andclinical factors (age, NSAID use) have been used to identifypatients with organic disease (45, 46). Although the use ofthese algorithms can reduce the volume of endoscopies,their effects on dyspepsia symptoms are unknown, and theydo not provide guidance to primary care physicians in theuse of noninvasive tests and antimicrobial therapies.

Computerized decision analysis models have been used tocompare the cost-effectiveness of alternative managementstrategies. Using this approach, the alternative strategies andthe outcomes to be compared are depicted in a decision treestructure. The data used to estimate the model parameters

922 RABENECK et al. AJG – Vol. 93, No. 6, 1998

(e.g., rate of recurrent dyspepsia symptoms) are obtainedfrom the published literature. To judge the relevance of amodel to clinical practice, one can ask the following: 1) Isthe structure clinically sensible? In other words, is the se-quence of decisions depicted by the decision tree what onewould do in practice? 2) Are the parameter estimates basedon valid data? 3) Are the outcomes clinically relevant?

The first model compared two invasive strategies (promptendoscopy with or without biopsies to detectH. pylori)versusthree noninvasive strategies (serologicalH. pyloritesting and treatment of those infected; empiric antisecre-tory agents with or without antimicrobial therapy) and foundthat the noninvasive strategies were associated with lowercosts per ulcer cured and costs per patient at 1 yr (47). Thesecond model compared prompt endoscopyversusempirictherapy guided by serologicalH. pylori testing and found nodifference in costs per patient at 1 yr (48). The structures ofthe two models are clinically sensible. However, lackingvalid data for several parameters, the two groups of inves-tigators used different estimates, leading to discrepant re-sults. In addition, neither model addresses a key clinicaloutcome, relief of dyspepsia symptoms. The third modelcompared empiric antisecretory therapyversusserologicalH. pylori testing coupled with prompt endoscopy in theinfected patients and found that empiric therapy was asso-ciated with lower costs per patient at 1 yr (49). Cost savingsfor the testing strategy did not begin to accrue for at least 8yr. Here again, the model did not address dyspepsia symp-toms. The fourth model compared prompt endoscopyversusempiric antisecretory and antimicrobial therapy in patientswith dyspepsia known to be infected withH. pylori based onserological testing. Empiric therapy was associated withlower costs per patient at 1 yr (50). The structure of themodel is clinically sensible, and complications of both en-doscopy and antimicrobial therapy were taken into account.However, largely to cope with existing data gaps, the in-vestigators assumed that the clinical outcomes for the twostrategies were the same, and conducted a cost comparison.

Taken together, the central finding of these four decisionanalysis models is that at 1 yr, compared with strategiesbased on prompt endoscopy, costs are the same or lower forthe empiric antimicrobial strategies. From a payor’s per-spective, this finding is of major importance. However,patients and their physicians need to be able to weigh thesecosts against relief of dyspepsia symptoms. Here the deci-sion analysis models fall short, in large part because validdata for key parameters are lacking. Thus, the question ofthe most cost-effective approach for managing patients withdyspepsia in primary care practice remains unresolved.

DISCUSSION

Before theH. pylori era the central question in the initialmanagement of patients with dyspepsia was whether toprescribe empiric antisecretory therapy or to performprompt endoscopy to establish a firm diagnosis. After the

1985 ACP recommendation (40), empiric antisecretory ther-apy became the standard of practice in primary care settings.However, since then a conceptual revolution relating toH.pylori has occurred. The issue needs to be addressed in thecontext of theH. pylori era.

In patients with dyspepsia seen in primary care settingsthe central question is: Are the additional upfront costs ofnoninvasiveH. pylori testing and antimicrobial therapy off-set by better outcomes and overall cost savings in the longterm? We hypothesize that these better outcomes and sav-ings would accrue because of reduced rates of recurrenceand complications among those with peptic ulcers. Note thatthis hypothesis does not invoke a benefit for antimicrobialtherapy among patients with nonulcer dyspepsia, for whichthere is currently no evidence.

To address this question, we propose a randomized con-trolled trial in dyspepsia patients without complicating fea-tures (e.g., anemia, previous gastric surgery). The strategiesto be compared are empiric antisecretory therapyversusanH. pylori-based strategy (noninvasiveH. pylori testing cou-pled with antimicrobial therapy in those infected). We donot propose to examine a strategy of empiric antimicrobialtherapy in all dyspepsia patients regardless ofH. pyloristatus, because we are concerned about the side-effects ofthese agents.

A major strength of the proposed trial is that it wouldallow the direct measurement of dyspepsia symptoms, theprimary health outcome in these patients, for which scantdata are available. Critically important tools that are neededfor such a trial are valid, reliable instruments to measuredyspepsia symptoms. However, despite the need for suchinstruments, limited attention has been given to their devel-opment. This is surprising because dyspepsia symptoms arethe reason these patients seek health care. In addition, theability to measure dyspepsia symptoms is of fundamentalimportance to investigators for conducting clinical researchin dyspepsia. Indeed, the failure to adequately measuredyspepsia symptoms constitutes a major flaw in previoustrials (51).

The conceptual revolution in the pathogenesis of pepticulcer disease has raised the larger question of how to inte-grate noninvasiveH. pylori tests and antimicrobial therapyinto the management of patients with dyspepsia seen inprimary practice settings. To address this question, we needdirect evidence from a randomized controlled trial. How-ever, before embarking on such a trial we need valid, reli-able instruments for measuring dyspepsia-related health, lestwe repeat our past mistakes (51).

ACKNOWLEDGMENT

This research was supported by the Department of Vet-erans Affairs Health Services Research and Development(HSR&D) Houston Field Program. Dr. Rabeneck is therecipient of a Veterans Affairs HSR&D Career Develop-ment Award.

AJG – June 1998 DYSPEPSIA MANAGEMENT 923

Reprint requests and correspondence: Linda Rabeneck, M.D., M.P.H.,VA Medical Center (111D), 2002 Holcombe Blvd, Houston, TX 77030.

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