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Managing dyspepsia: what do we know and what do we need to know?
THE AMERICAN JOURNAL OF GASTROENTEROLOGY Copyright © 1998 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 93, No. 6, 1998 ISSN 0002-9270/98/$19.00 PII S0002-9270(98)00158-0
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 the role of Helicobacter pylori in the pathogenesis of peptic ulcer disease has raised the larger question of how to integrate this new information into the management of patients with dyspepsia. The aim of this research was to critically evaluate current knowledge about dyspepsia and its management. Methods: Relevant articles on dyspepsia were identified from MEDLINE searches and from the bibliographies of identified articles. Studies that contained information on the prevalence of dyspepsia, endoscopic findings, and evaluations of alternative management strategies were reviewed. Results: By coupling H. pylori serological testing with clinical factors such as age and nonsteroidal antiinflammatory drug use, strategies have been developed that identify patients with organic disease. Although the use of these strategies can reduce the volume of endoscopies, their effects on dyspepsia symptoms are unknown. Computerized decision analysis models have been used to evaluate the cost-effectiveness of alternative strategies. The indirect evidence obtained from these models suggests that empiric therapy, guided by H. pylori testing, may be the preferred approach. However, the models have been hampered by the lack of information concerning dyspepsia symptoms, the primary health outcome of the majority of patients seen in primary practice settings. Conclusions: Currently, the knowledge needed to integrate H. pylori tests and antimicrobial therapies into the management of patients with dyspepsia in primary practice settings has not been developed. A pressing need exists for a randomized controlled trial to evaluate alternative management strategies. In conducting such a trial, valid, reliable instruments for measuring dyspepsia will be needed. (Am J Gastroenterol 1998;93:920 –924. © 1998 by Am. Coll. of Gastroenterology)
integrity and the destructive effects of gastric acid secretion (1). According to this concept treatment with antisecretory agents was the cornerstone of management. However, in 1984 Helicobacter pylori infection was reported in the stomachs of patients with peptic ulcers (2). Since then, a large body of evidence has accumulated that demonstrates an important role for this bacterial agent in the pathogenesis of peptic ulcer disease. Antimicrobial agents now have a central role in the management of peptic ulcer disease. In addition, serological tests to detect H. pylori infection are readily available. This conceptual revolution in the pathogenesis and treatment of peptic ulcer disease has raised the larger question of how to integrate these new tests and therapies into the management of patients with dyspepsia in primary practice settings. The purposes of this paper are to critically appraise what we know and to determine what further information we need to appropriately manage patients with dyspepsia in the H. pylori era. MATERIALS AND METHODS We identified articles by searching the MEDLINE database for the period from 1990 through 1997 using the Medical Subject Heading Terms “dyspepsia,” “Helicobacter pylori,” and “peptic ulcer.” We identified further articles from the references cited in the articles obtained from the search. In selecting articles to include in this review, we gave preference to primary rather than secondary sources, such as review articles and book chapters. Abstracts, letters, editorials, articles not published in English, and those pertaining to children were excluded. For articles focusing on endoscopic findings, reports that contained fewer than 150 patients 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 dyspepsia for use in clinical research. The consensus is that dyspepsia denotes episodic or persistent upper abdominal pain or discomfort that is thought by the physician to arise in the proximal or upper gastrointestinal tract (3– 6). The pain may be associated with other symptoms, and some
INTRODUCTION In the past the prevailing concept of the pathogenesis of peptic ulcer was that of an imbalance between mucosal Received July 28, 1997; accepted Mar. 6, 1998. 920
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TABLE 1 Period Prevalence of Dyspepsia Reference No.
Country
Year
N
Prevalence*
(7) (8) (9) (10) (11) (12) (13) (14) (15) (16)
UK UK UK UK UK Norway USA USA Denmark Sweden
1951 1968 1989 1989 1990 1990 1992 1993 1994 1995
5951 1487 2066 1085 7428 1802 835 5430 3606 1156
31% (5 yr) 20% (3 months) 38% (6 months) 16% (NR) 41% (6 months) 28% (ever) 26% (1 yr) 13% (3 months) 19% (1 yr) 32% (3 months)
Study Sample $ 14 yr Men; $ 15 yr $ 20 yr Men; 50–75 yr $ 20 yr 20–69 yr 30–64 yr $ 15 yr 30–60 yr 19–79 yr
* Figures in parentheses indicate time period over which prevalence was reported. Year 5 year published; N 5 number in study sample; NR 5 not reported. TABLE 2 Endoscopic Findings (%) in Individuals With Dyspepsia Reference
Country
Year
N
GU
DU
Esoph
Cancer
(18) (19) (20) (21) (22) (23) (12) (24) (25) (26) (27) (28) (29) (30)
UK UK Sweden Norway UK Sweden Norway UK Norway Norway USA Germany Italy UK
1979 1980 1985 1986 1988 1989 1990 1990 1990 1991 1993 1993 1993 1994
187 346 165 676 686 172 309 2585 930 273 820 220 2253 1540
5.9 6.4 4.2 NR 7.9 4.1 1.6 6.5 4.7
5.3 (25)* 12.1 (24) 10.3 NR 12.1 9.3 (13) 2.3 (8) 10.2 12.7 8.4‡ 3.5 10.0 5.0 (6) (26)
17.6 NR 0 NR 14.1 10.5 NR NR 14.1 12.1 14.3 16.8 5.3 NR
1.1 1.2 1.2 1.3 1.6 1.2 0 2.2 1.0 0 3.4 1.8 2.0 3.2
8.2 5.0 1.6 6.8
Sample R R PC R R PC P PC† R P R R R 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. Year 5 year published; N 5 number in study sample; GU 5 gastric ulcer; DU 5 duodenal ulcer; esoph 5 erosive esophagitis; cancer 5 gastric cancer; R 5 study sample obtained from patients referred for endoscopy; PC 5 study sample obtained by offering endoscopy to all patients with dyspepsia presenting in primary care settings; P 5 study sample obtained by offering endoscopy to all individuals who reported dyspepsia in population-based survey questionnaire.
relationship with food intake is often present, but this is not an essential feature. Table 1 summarizes the population-based estimates of the period prevalence of dyspepsia, which range from 13% to 41% (7–16). This variation is largely accounted for by differences in research methods, which include the spectrum of symptoms encompassed, the duration of symptoms required for inclusion in the study, and the time period over which the prevalence was estimated. Regardless of these methodological differences, it is clear that dyspepsia is a very common symptom in the general population. Approximately 25% of individuals with dyspepsia in the general population seek health care (9), the provision of which accounts for substantial resource use and costs. For example, in the U.S., it is estimated that in 1985 gastritis and dyspepsia accounted for $1.1 billion in direct costs (17).
Findings on diagnostic work-up Table 2 summarizes reports of the main endoscopic findings in patients with dyspepsia (12, 18 –30). Two major methodological differences among the studies should be noted. First, differences exist in the sampling frame, i.e., how the subjects were recruited. In the majority of studies, subjects were referred for endoscopy by their primary care physicians (referral-based) (18, 19, 21, 22, 25, 27–30). However, in three studies subjects were recruited by offering endoscopy to all patients with dyspepsia presenting for care to their primary care physicians (primary-care based) (20, 23, 24). In two studies all patients who reported dyspepsia on a mailed questionnaire were offered endoscopy (population-based) (12, 26). Second, the inclusion/exclusion criteria differed. In half the studies patients with complicating features, such as previous gastric surgery (25, 27, 29),
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were excluded. In one study patients , 40 yr of age were excluded (24). The distribution of endoscopic findings varied across the study populations, reflecting these methodological differences. The four major findings were gastric ulcer (1.6 – 8.2%), duodenal ulcer (2.3–12.7%), erosive esophagitis (0 – 17.6%), and gastric cancer (0 –3.4%). The higher rates of gastric cancer ($ 2%) were obtained in the referral-based studies (27, 29, 30) and the study that excluded patients , 40 yr of age (24). A variable proportion of patients had gastric or duodenal erosions of uncertain relationship to their symptoms. Some patients with normal upper endoscopy undoubtedly had gastroesophageal reflux disease, although this was not consistently reported. Regardless of these methodological differences, clearly, a substantial proportion 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 have a negative diagnostic work-up, efforts have been made to identify clinical factors that are associated with the presence of organic disease. The underlying hypothesis is that these factors could be used to identify those with organic disease so that the remaining patients could be managed without barium x-rays or endoscopy. In a study of 483 patients referred for upper gastrointestinal (UGI) barium series, 95% of those with an abnormal radiograph had at least one of the following: age . 50 yr, previous history of peptic ulcer, relief of pain by food, and pain that occurred within an hour of eating (31). However, despite their high sensitivity, the specificity of these factors was poor. Approximately 70% of individuals without organic disease had one or more positive factors. Subsequent studies focusing on patients referred for upper endoscopy found similar results. From these studies it is clear that organic disease is more common in patients aged . 40 yr (22, 25, 32). In particular, gastric cancer is very uncommon in patients aged , 45 yr (22). In addition to age, other clinical factors reported to be associated with peptic ulcer disease are night pain (20), relief of pain with food or antacids (20, 32), previous history of peptic ulcer disease (20, 32), family history of peptic ulcer disease (32), a long history (at least 4 yr) (32), male gender (25), and smoking (32). Although it is well established that the use of nonsteroidal antiinflammatory drugs (NSAIDS) is associated 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 have been developed to identify patients with organic disease (35–38). However, these scoring systems have not met with widespread acceptance because their generalizability has been questioned (39) and some are based on computer models that are not widely available (37, 38). Clinical features have been used to categorize patients into subgroups that might reflect differences in underlying
AJG – Vol. 93, No. 6, 1998 pathophysiology (3). These subgroups are ulcer-like, dysmotility-like, reflux-like, and nonspecific. However, the usefulness of this approach is doubtful because considerable overlap exists among the subgroups (13, 16), which do not discriminate well between patients with and without organic disease (27). Strategies for managing patients with dyspepsia Before the H. pylori era. Before the H. pylori era, the question was whether patients should undergo prompt diagnostic work-up (UGI series or endoscopy) to establish a firm diagnosis, or whether a course of empiric therapy should be given with endoscopy reserved for nonresponders. In 1985 the Health and Public Policy Committee of the American College of Physicians (ACP) recommended initial empiric therapy with antacids or H2-blockers for patients with uncomplicated dyspepsia, with endoscopy reserved for those with no or minimal response to therapy after 7 to 10 days, and those with persisting symptoms after a 6- to 8-wk period (40). This approach, which was based on a critical review of the published evidence (41), has been the standard of care in primary practice settings. Subsequently, a randomized clinical trial reported that prompt endoscopy was more cost-effective than empiric H2-blocker therapy (42). Regardless of the strengths and weaknesses of this trial, the question must now be revisited because H. pylori infection was not taken into account. During the H. pylori era. In 1994 an NIH Consensus Development Panel stated that H. pylori-infected patients with gastric or duodenal ulcers should be treated with antimicrobials (43). What the NIH Panel did not address was the question of how to incorporate the new information concerning H. pylori into the management of patients with dyspepsia. H. pylori infection is extraordinarily common in asymptomatic individuals; its prevalence increases with age and reaches approximately 50% by age 50 yr (44). Although the majority of infected individuals have asymptomatic chronic superficial gastritis, H. pylori infection is strongly associated with peptic ulcer disease, which in turn is present in up to 20% of patients with dyspepsia. These links between H. pylori infection, peptic ulcer disease, and dyspepsia provide the impetus for evaluating H. pylori-based patient management strategies. Algorithms based on H. pylori serological testing and clinical factors (age, NSAID use) have been used to identify patients with organic disease (45, 46). Although the use of these algorithms can reduce the volume of endoscopies, their effects on dyspepsia symptoms are unknown, and they do not provide guidance to primary care physicians in the use of noninvasive tests and antimicrobial therapies. Computerized decision analysis models have been used to compare the cost-effectiveness of alternative management strategies. Using this approach, the alternative strategies and the outcomes to be compared are depicted in a decision tree structure. The data used to estimate the model parameters
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(e.g., rate of recurrent dyspepsia symptoms) are obtained from the published literature. To judge the relevance of a model to clinical practice, one can ask the following: 1) Is the structure clinically sensible? In other words, is the sequence of decisions depicted by the decision tree what one would do in practice? 2) Are the parameter estimates based on valid data? 3) Are the outcomes clinically relevant? The first model compared two invasive strategies (prompt endoscopy with or without biopsies to detect H. pylori) versus three noninvasive strategies (serological H. pylori testing and treatment of those infected; empiric antisecretory agents with or without antimicrobial therapy) and found that the noninvasive strategies were associated with lower costs per ulcer cured and costs per patient at 1 yr (47). The second model compared prompt endoscopy versus empiric therapy guided by serological H. pylori testing and found no difference in costs per patient at 1 yr (48). The structures of the two models are clinically sensible. However, lacking valid data for several parameters, the two groups of investigators used different estimates, leading to discrepant results. In addition, neither model addresses a key clinical outcome, relief of dyspepsia symptoms. The third model compared empiric antisecretory therapy versus serological H. pylori testing coupled with prompt endoscopy in the infected patients and found that empiric therapy was associated with lower costs per patient at 1 yr (49). Cost savings for the testing strategy did not begin to accrue for at least 8 yr. Here again, the model did not address dyspepsia symptoms. The fourth model compared prompt endoscopy versus empiric antisecretory and antimicrobial therapy in patients with dyspepsia known to be infected with H. pylori based on serological testing. Empiric therapy was associated with lower costs per patient at 1 yr (50). The structure of the model is clinically sensible, and complications of both endoscopy and antimicrobial therapy were taken into account. However, largely to cope with existing data gaps, the investigators assumed that the clinical outcomes for the two strategies were the same, and conducted a cost comparison. Taken together, the central finding of these four decision analysis models is that at 1 yr, compared with strategies based on prompt endoscopy, costs are the same or lower for the empiric antimicrobial strategies. From a payor’s perspective, this finding is of major importance. However, patients and their physicians need to be able to weigh these costs against relief of dyspepsia symptoms. Here the decision analysis models fall short, in large part because valid data for key parameters are lacking. Thus, the question of the most cost-effective approach for managing patients with dyspepsia in primary care practice remains unresolved.
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1985 ACP recommendation (40), empiric antisecretory therapy became the standard of practice in primary care settings. However, since then a conceptual revolution relating to H. pylori has occurred. The issue needs to be addressed in the context of the H. pylori era. In patients with dyspepsia seen in primary care settings the central question is: Are the additional upfront costs of noninvasive H. pylori testing and antimicrobial therapy offset by better outcomes and overall cost savings in the long term? We hypothesize that these better outcomes and savings would accrue because of reduced rates of recurrence and complications among those with peptic ulcers. Note that this hypothesis does not invoke a benefit for antimicrobial therapy among patients with nonulcer dyspepsia, for which there is currently no evidence. To address this question, we propose a randomized controlled trial in dyspepsia patients without complicating features (e.g., anemia, previous gastric surgery). The strategies to be compared are empiric antisecretory therapy versus an H. pylori-based strategy (noninvasive H. pylori testing coupled with antimicrobial therapy in those infected). We do not propose to examine a strategy of empiric antimicrobial therapy in all dyspepsia patients regardless of H. pylori status, because we are concerned about the side-effects of these agents. A major strength of the proposed trial is that it would allow the direct measurement of dyspepsia symptoms, the primary health outcome in these patients, for which scant data are available. Critically important tools that are needed for such a trial are valid, reliable instruments to measure dyspepsia symptoms. However, despite the need for such instruments, limited attention has been given to their development. This is surprising because dyspepsia symptoms are the reason these patients seek health care. In addition, the ability to measure dyspepsia symptoms is of fundamental importance to investigators for conducting clinical research in dyspepsia. Indeed, the failure to adequately measure dyspepsia symptoms constitutes a major flaw in previous trials (51). The conceptual revolution in the pathogenesis of peptic ulcer disease has raised the larger question of how to integrate noninvasive H. pylori tests and antimicrobial therapy into the management of patients with dyspepsia seen in primary practice settings. To address this question, we need direct evidence from a randomized controlled trial. However, before embarking on such a trial we need valid, reliable instruments for measuring dyspepsia-related health, lest we repeat our past mistakes (51). ACKNOWLEDGMENT
DISCUSSION Before the H. pylori era the central question in the initial management of patients with dyspepsia was whether to prescribe empiric antisecretory therapy or to perform prompt endoscopy to establish a firm diagnosis. After the
This research was supported by the Department of Veterans Affairs Health Services Research and Development (HSR&D) Houston Field Program. Dr. Rabeneck is the recipient of a Veterans Affairs HSR&D Career Development Award.
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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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REFERENCES 28. 1. Grossman MI, Guth PH, Isenberg JI, et al. A new look at peptic ulcer. Ann Intern Med 1976;84:57– 67. 2. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;i:1311–5. 3. Colin-Jones DG. Management of dyspepsia: Report of a working party. Lancet 1988;i:576 –9. 4. Barbara L, Camilleri M, Corinaldesi R, et al. Definition and investigation of dyspepsia: Consensus of an international ad hoc working party. Dig Dis Sci 1989;34:1272– 6. 5. Heading RC. Definitions of dyspepsia. Scand J Gastroenterol 1991; 26(suppl 182):1– 6. 6. Talley NJ, Colin-Jones D, Koch KL, et al. Functional dyspepsia: A classification with guidelines for diagnosis and management. Gastroenterol Int 1991;4:145– 60. 7. Doll R, Jones FA, Buckatzsch MM. Occupational factors in the aetiology of gastric and duodenal ulcers with an estimate of their incidence in the general population. London: HMSO, 1951; Medical Research Council Special Report Series No. 276, pp 1–96. 8. Weir RD, Backett EM. Studies of the epidemiology of peptic ulcer in a rural community: Prevalence and natural history of dyspepsia and peptic ulcer. Gut 1968;9:75– 83. 9. Jones R, Lydeard S. Prevalence of symptoms of dyspepsia in the community. Br Med J 1989;298:30 –2. 10. Harrison JD, Morris DL. Dyspepsia in coalminers and the general population: A comparative study. Br J Industrial Med 1989;46:428 –9. 11. Jones RH, Lydeard SE, Hobbs FDR, et al. Dyspepsia in England and Scotland. Gut 1990;31:401–5. 12. Bernersen B, Johnsen R, Straume B, et al. Towards a true prevalence of peptic ulcer: The Sorreisa gastrointestinal disorder study. Gut 1990; 31:989 –92. 13. Talley NJ, Zinsmeister AR, Schleck CD, et al. Dyspepsia and dyspepsia subgroups: A population-based study. Gastroenterology 1992;102: 1259 – 68. 14. Drossman DA, Li Z, Andruzzi E, et al. U.S. householder survey of functional gastrointestinal disorders: Prevalence, sociodemography, and health impact. Dig Dis Sci 1993;38:1569 – 80. 15. Kay L, Jorgensen T. Epidemiology of upper dyspepsia in a random population: Prevalence, incidence, natural history, and risk factors. Scand J Gastroenterol 1994;29:1– 6. 16. Agreus L, Svardsudd K, Nyren O, et al. Irritable bowel syndrome and dyspepsia in the general population: Overlap and lack of stability over time. Gastroenterology 1995;109:671– 80. 17. Brown DM, Everhart JE. Cost of digestive diseases in the United States. In: Everhart JE, ed. Digestive diseases in the United States: Epidemiology and impact. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, NIDDK. Washington, D.C.: NIH Publication no. 94-1447, U.S. Government Printing Office, 1994. 57– 82. 18. Beavis AK, La Brooy S, Misiewicz JJ. Evaluation of one-visit endoscopic clinic for patients with dyspepsia. Br Med J 1979;1:1387–9. 19. Gear MWL, Barnes RJ. Endoscopic studies of dyspepsia in a general practice. Br Med J 1980;280:1136 –7. 20. Edenholm M, Gustavsson R, Jansson O, et al. Endoscopic findings in patients with ulcer-like dyspepsia. Scand J Gastroenterol 1985; 20(suppl 109):163–7. 21. Fjosne U, Kleveland PM, Waldum H, et al. The clinical benefit of routine upper gastrointestinal endoscopy. Scand J Gastroenterol 1986; 21:433– 40. 22. Williams B, Luckas M, Ellingham JHM, et al. Do young patients with dyspepsia need investigation? Lancet 1988;ii:1349 –51. 23. Kagevi I, Lofstedt S, Persson LG. Endoscopic findings and diagnoses in unselected dyspeptic patients at a primary health care center. Scand J Gastroenterol 1989;24:145–50. 24. Hallissey MT, Allum WH, Jewkes AJ, et al. Early detection of gastric cancer. Br Med J 1990;301:513–5. 25. Johannessen T, Petersen H, Kleveland PM, et al. The predictive value of history in dyspepsia. Scand J Gastroenterol 1990;25:689 –97. 26. Johnsen R, Bernersen B, Straume B, et al. Prevalences of endoscopic
29. 30. 31. 32. 33. 34.
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40. 41. 42. 43. 44.
45. 46. 47. 48. 49. 50. 51.
and histological findings in subjects with and without dyspepsia. Br Med J 1991;302:749 –52. Talley NJ, Weaver AL, Tesmer DL, et al. Lack of discriminant value of dyspepsia subgroups in patients referred for upper endoscopy. Gastroenterology 1993;105:1378 – 86. Klauser AG, Voderholzer WA, Knesewitsch PA, et al. What is behind dyspepsia? Dig Dis Sci 1993;38:147–54. Mansi C, Savarino V, Mela GS, et al. Are clinical patterns of dyspepsia a valid guideline for appropriate use of endoscopy? A report on 2253 dyspeptic patients. Am J Gastroenterol 1993;88:1011–5. Crean GP, Holden RJ, Knill-Jones RP, et al. A database on dyspepsia. Gut 1994;35:191–202. Marton KI, Sox HC, Jr, Wasson J, et al. The clinical value of the upper gastrointestinal tract roentgenogram series. Arch Intern Med 1980;140: 191–5. Petersen H, Johannessen T, Kleveland PM, et al. Do we need to listen to the patient? The predictive value of symptoms. Scand J Gastroenterol 1988;23(suppl 155):30 – 4. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: A meta-analysis. Ann Intern Med 1991;115:787–96. Kurata JH. An assessment of nonsteroidal anti-inflammatory drugs as a risk factor in ulcer disease, pp 311–315. In: Soll AH, moderator. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med 1991;114:307–19. Mann J, Holdstock G, Harman M, et al. Scoring system to improve cost effectiveness of open access endoscopy. Br Med J 1983;287:937– 40. Holdstock G, Harman M, Machin D, et al. Prospective testing of a scoring system designed to improve case selection for upper gastrointestinal investigation. Gastroenterology 1986;90:1164 –9. Davenport PM, Morgan AG, Darnborough A, et al. Can preliminary screening of dyspeptic patients allow more effective use of investigational techniques? Br Med J 1985;290:217–20. Crean GP, Card WI, Beattie AD, et al. Ulcer-like dyspepsia. Scand J Gastroenterol 1982;17(suppl 79):9 –15. Bytzer P, Schaffalitzky de Muckadell OB. Prediction of major pathologic conditions in dyspeptic patients referred for endoscopy: A prospective validation study of a scoring system. Scand J Gastroenterol 1992;27:987–92. Health and Public Policy Committee, American College of Physicians. Endoscopy in the evaluation of dyspepsia. Ann Intern Med 1985;102: 266 –9. Kahn KL, Greenfield S. The efficacy of endoscopy in the evaluation of dyspepsia: A review of the literature and development of a sound strategy. J Clin Gastroenterol 1986;8:346 –58. Bytzer P, Hansen JM, Schaffalitzky de Muckadell OB. Empirical H2-blocker therapy or prompt endoscopy in management of dyspepsia. Lancet 1994;343:811– 6. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. Helicobacter pylori in peptic ulcer disease. JAMA 1994;272:65–9. Graham DY, Malaty HM, Evans DG, et al. Epidemiology of Helicobacter pylori in an asymptomatic population in the United States: Effect of age, race, and socioeconomic status. Gastroenterology 1991; 100:1495–501. Sobala GM, Crabtree JE, Pentith JA, et al. Screening dyspepsia by serology to Helicobacter pylori. Lancet 1991;338:94 – 6. Patel P, Khulusi S, Mendall MA, et al. Prospective screening of dyspeptic patients by Helicobacter pylori serology. Lancet 1995;346: 1315– 8. Fendrick AM, Chernew ME, Hirth RA, et al. Alternative management strategies for patients with suspected peptic ulcer disease. Ann Intern Med 1995;123:260 – 8. Silverstein MD, Petterson T, Talley NJ. Initial endoscopy or empirical therapy with or without testing for Helicobacter pylori for dyspepsia: A decision analysis. Gastroenterology 1996;110:72– 83. Briggs AH, Sculpher MJ, Logan RPH, et al. Cost effectiveness of screening for and eradication of Helicobacter pylori in management of dyspeptic patients under 45 years of age. Br Med J 1996;312:1321–5. Ofman JJ, Etchason J, Fullerton S, et al. Management strategies for Helicobacter pylori-seropositive patients with dyspepsia: Clinical and economic consequences. Ann Intern Med 1997;126:280 –91. Talley NJ. A critique of therapeutic trials in Helicobacter pyloripositive functional dyspepsia. Gastroenterology 1994;106:1174 – 83.
Vol. 93, No. 6, 1998 ISSN 0002-9270/98/$19.00 PII S0002-9270(98)00158-0
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 the role of Helicobacter pylori in the pathogenesis of peptic ulcer disease has raised the larger question of how to integrate this new information into the management of patients with dyspepsia. The aim of this research was to critically evaluate current knowledge about dyspepsia and its management. Methods: Relevant articles on dyspepsia were identified from MEDLINE searches and from the bibliographies of identified articles. Studies that contained information on the prevalence of dyspepsia, endoscopic findings, and evaluations of alternative management strategies were reviewed. Results: By coupling H. pylori serological testing with clinical factors such as age and nonsteroidal antiinflammatory drug use, strategies have been developed that identify patients with organic disease. Although the use of these strategies can reduce the volume of endoscopies, their effects on dyspepsia symptoms are unknown. Computerized decision analysis models have been used to evaluate the cost-effectiveness of alternative strategies. The indirect evidence obtained from these models suggests that empiric therapy, guided by H. pylori testing, may be the preferred approach. However, the models have been hampered by the lack of information concerning dyspepsia symptoms, the primary health outcome of the majority of patients seen in primary practice settings. Conclusions: Currently, the knowledge needed to integrate H. pylori tests and antimicrobial therapies into the management of patients with dyspepsia in primary practice settings has not been developed. A pressing need exists for a randomized controlled trial to evaluate alternative management strategies. In conducting such a trial, valid, reliable instruments for measuring dyspepsia will be needed. (Am J Gastroenterol 1998;93:920 –924. © 1998 by Am. Coll. of Gastroenterology)
integrity and the destructive effects of gastric acid secretion (1). According to this concept treatment with antisecretory agents was the cornerstone of management. However, in 1984 Helicobacter pylori infection was reported in the stomachs of patients with peptic ulcers (2). Since then, a large body of evidence has accumulated that demonstrates an important role for this bacterial agent in the pathogenesis of peptic ulcer disease. Antimicrobial agents now have a central role in the management of peptic ulcer disease. In addition, serological tests to detect H. pylori infection are readily available. This conceptual revolution in the pathogenesis and treatment of peptic ulcer disease has raised the larger question of how to integrate these new tests and therapies into the management of patients with dyspepsia in primary practice settings. The purposes of this paper are to critically appraise what we know and to determine what further information we need to appropriately manage patients with dyspepsia in the H. pylori era. MATERIALS AND METHODS We identified articles by searching the MEDLINE database for the period from 1990 through 1997 using the Medical Subject Heading Terms “dyspepsia,” “Helicobacter pylori,” and “peptic ulcer.” We identified further articles from the references cited in the articles obtained from the search. In selecting articles to include in this review, we gave preference to primary rather than secondary sources, such as review articles and book chapters. Abstracts, letters, editorials, articles not published in English, and those pertaining to children were excluded. For articles focusing on endoscopic findings, reports that contained fewer than 150 patients 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 dyspepsia for use in clinical research. The consensus is that dyspepsia denotes episodic or persistent upper abdominal pain or discomfort that is thought by the physician to arise in the proximal or upper gastrointestinal tract (3– 6). The pain may be associated with other symptoms, and some
INTRODUCTION In the past the prevailing concept of the pathogenesis of peptic ulcer was that of an imbalance between mucosal Received July 28, 1997; accepted Mar. 6, 1998. 920
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921
TABLE 1 Period Prevalence of Dyspepsia Reference No.
Country
Year
N
Prevalence*
(7) (8) (9) (10) (11) (12) (13) (14) (15) (16)
UK UK UK UK UK Norway USA USA Denmark Sweden
1951 1968 1989 1989 1990 1990 1992 1993 1994 1995
5951 1487 2066 1085 7428 1802 835 5430 3606 1156
31% (5 yr) 20% (3 months) 38% (6 months) 16% (NR) 41% (6 months) 28% (ever) 26% (1 yr) 13% (3 months) 19% (1 yr) 32% (3 months)
Study Sample $ 14 yr Men; $ 15 yr $ 20 yr Men; 50–75 yr $ 20 yr 20–69 yr 30–64 yr $ 15 yr 30–60 yr 19–79 yr
* Figures in parentheses indicate time period over which prevalence was reported. Year 5 year published; N 5 number in study sample; NR 5 not reported. TABLE 2 Endoscopic Findings (%) in Individuals With Dyspepsia Reference
Country
Year
N
GU
DU
Esoph
Cancer
(18) (19) (20) (21) (22) (23) (12) (24) (25) (26) (27) (28) (29) (30)
UK UK Sweden Norway UK Sweden Norway UK Norway Norway USA Germany Italy UK
1979 1980 1985 1986 1988 1989 1990 1990 1990 1991 1993 1993 1993 1994
187 346 165 676 686 172 309 2585 930 273 820 220 2253 1540
5.9 6.4 4.2 NR 7.9 4.1 1.6 6.5 4.7
5.3 (25)* 12.1 (24) 10.3 NR 12.1 9.3 (13) 2.3 (8) 10.2 12.7 8.4‡ 3.5 10.0 5.0 (6) (26)
17.6 NR 0 NR 14.1 10.5 NR NR 14.1 12.1 14.3 16.8 5.3 NR
1.1 1.2 1.2 1.3 1.6 1.2 0 2.2 1.0 0 3.4 1.8 2.0 3.2
8.2 5.0 1.6 6.8
Sample R R PC R R PC P PC† R P R R R 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. Year 5 year published; N 5 number in study sample; GU 5 gastric ulcer; DU 5 duodenal ulcer; esoph 5 erosive esophagitis; cancer 5 gastric cancer; R 5 study sample obtained from patients referred for endoscopy; PC 5 study sample obtained by offering endoscopy to all patients with dyspepsia presenting in primary care settings; P 5 study sample obtained by offering endoscopy to all individuals who reported dyspepsia in population-based survey questionnaire.
relationship with food intake is often present, but this is not an essential feature. Table 1 summarizes the population-based estimates of the period prevalence of dyspepsia, which range from 13% to 41% (7–16). This variation is largely accounted for by differences in research methods, which include the spectrum of symptoms encompassed, the duration of symptoms required for inclusion in the study, and the time period over which the prevalence was estimated. Regardless of these methodological differences, it is clear that dyspepsia is a very common symptom in the general population. Approximately 25% of individuals with dyspepsia in the general population seek health care (9), the provision of which accounts for substantial resource use and costs. For example, in the U.S., it is estimated that in 1985 gastritis and dyspepsia accounted for $1.1 billion in direct costs (17).
Findings on diagnostic work-up Table 2 summarizes reports of the main endoscopic findings in patients with dyspepsia (12, 18 –30). Two major methodological differences among the studies should be noted. First, differences exist in the sampling frame, i.e., how the subjects were recruited. In the majority of studies, subjects were referred for endoscopy by their primary care physicians (referral-based) (18, 19, 21, 22, 25, 27–30). However, in three studies subjects were recruited by offering endoscopy to all patients with dyspepsia presenting for care to their primary care physicians (primary-care based) (20, 23, 24). In two studies all patients who reported dyspepsia on a mailed questionnaire were offered endoscopy (population-based) (12, 26). Second, the inclusion/exclusion criteria differed. In half the studies patients with complicating features, such as previous gastric surgery (25, 27, 29),
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were excluded. In one study patients , 40 yr of age were excluded (24). The distribution of endoscopic findings varied across the study populations, reflecting these methodological differences. The four major findings were gastric ulcer (1.6 – 8.2%), duodenal ulcer (2.3–12.7%), erosive esophagitis (0 – 17.6%), and gastric cancer (0 –3.4%). The higher rates of gastric cancer ($ 2%) were obtained in the referral-based studies (27, 29, 30) and the study that excluded patients , 40 yr of age (24). A variable proportion of patients had gastric or duodenal erosions of uncertain relationship to their symptoms. Some patients with normal upper endoscopy undoubtedly had gastroesophageal reflux disease, although this was not consistently reported. Regardless of these methodological differences, clearly, a substantial proportion 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 have a negative diagnostic work-up, efforts have been made to identify clinical factors that are associated with the presence of organic disease. The underlying hypothesis is that these factors could be used to identify those with organic disease so that the remaining patients could be managed without barium x-rays or endoscopy. In a study of 483 patients referred for upper gastrointestinal (UGI) barium series, 95% of those with an abnormal radiograph had at least one of the following: age . 50 yr, previous history of peptic ulcer, relief of pain by food, and pain that occurred within an hour of eating (31). However, despite their high sensitivity, the specificity of these factors was poor. Approximately 70% of individuals without organic disease had one or more positive factors. Subsequent studies focusing on patients referred for upper endoscopy found similar results. From these studies it is clear that organic disease is more common in patients aged . 40 yr (22, 25, 32). In particular, gastric cancer is very uncommon in patients aged , 45 yr (22). In addition to age, other clinical factors reported to be associated with peptic ulcer disease are night pain (20), relief of pain with food or antacids (20, 32), previous history of peptic ulcer disease (20, 32), family history of peptic ulcer disease (32), a long history (at least 4 yr) (32), male gender (25), and smoking (32). Although it is well established that the use of nonsteroidal antiinflammatory drugs (NSAIDS) is associated 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 have been developed to identify patients with organic disease (35–38). However, these scoring systems have not met with widespread acceptance because their generalizability has been questioned (39) and some are based on computer models that are not widely available (37, 38). Clinical features have been used to categorize patients into subgroups that might reflect differences in underlying
AJG – Vol. 93, No. 6, 1998 pathophysiology (3). These subgroups are ulcer-like, dysmotility-like, reflux-like, and nonspecific. However, the usefulness of this approach is doubtful because considerable overlap exists among the subgroups (13, 16), which do not discriminate well between patients with and without organic disease (27). Strategies for managing patients with dyspepsia Before the H. pylori era. Before the H. pylori era, the question was whether patients should undergo prompt diagnostic work-up (UGI series or endoscopy) to establish a firm diagnosis, or whether a course of empiric therapy should be given with endoscopy reserved for nonresponders. In 1985 the Health and Public Policy Committee of the American College of Physicians (ACP) recommended initial empiric therapy with antacids or H2-blockers for patients with uncomplicated dyspepsia, with endoscopy reserved for those with no or minimal response to therapy after 7 to 10 days, and those with persisting symptoms after a 6- to 8-wk period (40). This approach, which was based on a critical review of the published evidence (41), has been the standard of care in primary practice settings. Subsequently, a randomized clinical trial reported that prompt endoscopy was more cost-effective than empiric H2-blocker therapy (42). Regardless of the strengths and weaknesses of this trial, the question must now be revisited because H. pylori infection was not taken into account. During the H. pylori era. In 1994 an NIH Consensus Development Panel stated that H. pylori-infected patients with gastric or duodenal ulcers should be treated with antimicrobials (43). What the NIH Panel did not address was the question of how to incorporate the new information concerning H. pylori into the management of patients with dyspepsia. H. pylori infection is extraordinarily common in asymptomatic individuals; its prevalence increases with age and reaches approximately 50% by age 50 yr (44). Although the majority of infected individuals have asymptomatic chronic superficial gastritis, H. pylori infection is strongly associated with peptic ulcer disease, which in turn is present in up to 20% of patients with dyspepsia. These links between H. pylori infection, peptic ulcer disease, and dyspepsia provide the impetus for evaluating H. pylori-based patient management strategies. Algorithms based on H. pylori serological testing and clinical factors (age, NSAID use) have been used to identify patients with organic disease (45, 46). Although the use of these algorithms can reduce the volume of endoscopies, their effects on dyspepsia symptoms are unknown, and they do not provide guidance to primary care physicians in the use of noninvasive tests and antimicrobial therapies. Computerized decision analysis models have been used to compare the cost-effectiveness of alternative management strategies. Using this approach, the alternative strategies and the outcomes to be compared are depicted in a decision tree structure. The data used to estimate the model parameters
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(e.g., rate of recurrent dyspepsia symptoms) are obtained from the published literature. To judge the relevance of a model to clinical practice, one can ask the following: 1) Is the structure clinically sensible? In other words, is the sequence of decisions depicted by the decision tree what one would do in practice? 2) Are the parameter estimates based on valid data? 3) Are the outcomes clinically relevant? The first model compared two invasive strategies (prompt endoscopy with or without biopsies to detect H. pylori) versus three noninvasive strategies (serological H. pylori testing and treatment of those infected; empiric antisecretory agents with or without antimicrobial therapy) and found that the noninvasive strategies were associated with lower costs per ulcer cured and costs per patient at 1 yr (47). The second model compared prompt endoscopy versus empiric therapy guided by serological H. pylori testing and found no difference in costs per patient at 1 yr (48). The structures of the two models are clinically sensible. However, lacking valid data for several parameters, the two groups of investigators used different estimates, leading to discrepant results. In addition, neither model addresses a key clinical outcome, relief of dyspepsia symptoms. The third model compared empiric antisecretory therapy versus serological H. pylori testing coupled with prompt endoscopy in the infected patients and found that empiric therapy was associated with lower costs per patient at 1 yr (49). Cost savings for the testing strategy did not begin to accrue for at least 8 yr. Here again, the model did not address dyspepsia symptoms. The fourth model compared prompt endoscopy versus empiric antisecretory and antimicrobial therapy in patients with dyspepsia known to be infected with H. pylori based on serological testing. Empiric therapy was associated with lower costs per patient at 1 yr (50). The structure of the model is clinically sensible, and complications of both endoscopy and antimicrobial therapy were taken into account. However, largely to cope with existing data gaps, the investigators assumed that the clinical outcomes for the two strategies were the same, and conducted a cost comparison. Taken together, the central finding of these four decision analysis models is that at 1 yr, compared with strategies based on prompt endoscopy, costs are the same or lower for the empiric antimicrobial strategies. From a payor’s perspective, this finding is of major importance. However, patients and their physicians need to be able to weigh these costs against relief of dyspepsia symptoms. Here the decision analysis models fall short, in large part because valid data for key parameters are lacking. Thus, the question of the most cost-effective approach for managing patients with dyspepsia in primary care practice remains unresolved.
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1985 ACP recommendation (40), empiric antisecretory therapy became the standard of practice in primary care settings. However, since then a conceptual revolution relating to H. pylori has occurred. The issue needs to be addressed in the context of the H. pylori era. In patients with dyspepsia seen in primary care settings the central question is: Are the additional upfront costs of noninvasive H. pylori testing and antimicrobial therapy offset by better outcomes and overall cost savings in the long term? We hypothesize that these better outcomes and savings would accrue because of reduced rates of recurrence and complications among those with peptic ulcers. Note that this hypothesis does not invoke a benefit for antimicrobial therapy among patients with nonulcer dyspepsia, for which there is currently no evidence. To address this question, we propose a randomized controlled trial in dyspepsia patients without complicating features (e.g., anemia, previous gastric surgery). The strategies to be compared are empiric antisecretory therapy versus an H. pylori-based strategy (noninvasive H. pylori testing coupled with antimicrobial therapy in those infected). We do not propose to examine a strategy of empiric antimicrobial therapy in all dyspepsia patients regardless of H. pylori status, because we are concerned about the side-effects of these agents. A major strength of the proposed trial is that it would allow the direct measurement of dyspepsia symptoms, the primary health outcome in these patients, for which scant data are available. Critically important tools that are needed for such a trial are valid, reliable instruments to measure dyspepsia symptoms. However, despite the need for such instruments, limited attention has been given to their development. This is surprising because dyspepsia symptoms are the reason these patients seek health care. In addition, the ability to measure dyspepsia symptoms is of fundamental importance to investigators for conducting clinical research in dyspepsia. Indeed, the failure to adequately measure dyspepsia symptoms constitutes a major flaw in previous trials (51). The conceptual revolution in the pathogenesis of peptic ulcer disease has raised the larger question of how to integrate noninvasive H. pylori tests and antimicrobial therapy into the management of patients with dyspepsia seen in primary practice settings. To address this question, we need direct evidence from a randomized controlled trial. However, before embarking on such a trial we need valid, reliable instruments for measuring dyspepsia-related health, lest we repeat our past mistakes (51). ACKNOWLEDGMENT
DISCUSSION Before the H. pylori era the central question in the initial management of patients with dyspepsia was whether to prescribe empiric antisecretory therapy or to perform prompt endoscopy to establish a firm diagnosis. After the
This research was supported by the Department of Veterans Affairs Health Services Research and Development (HSR&D) Houston Field Program. Dr. Rabeneck is the recipient of a Veterans Affairs HSR&D Career Development Award.
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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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