COCHRANE FOR CLINICIANS: PUTTING EVIDENCE INTO PRACTICE

Symptomatic Treatment and H. pylori Eradication Therapy for Nonulcer Dyspepsia



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Am Fam Physician. 2001 Nov 1;64(9):1605-1610.

Clinical Scenario

A 50-year-old man presents with a history of one month of intermittent epigastric discomfort and belching. The physical examination is unremarkable. The patient has a normal hemoglobin level and tests positive for Helicobacter pylori antibody. An upper endoscopic examination is negative for ulcers, cancer and esophagitis.

Clinical Questions

What symptomatic treatments are effective for nonulcer dyspepsia? Should clinicians prescribe H. pylori eradication therapy for patients with this condition?

Evidence-Based Answers

Bismuth subcitrate, histamine H2-receptor antagonists or proton pump inhibitors could be recommended for short-term relief of symptoms. Eradication of H. pylori would slightly decrease this patient's chance of having persistent symptoms over the next three to 12 months.

Cochrane Abstract

REVIEW 1: PHARMACOLOGIC INTERVENTIONS FOR NONULCER DYSPEPSIA1

Background. The most common cause of upper gastrointestinal symptoms is nonulcer dyspepsia, yet the pathophysiology of this condition has been poorly characterized, and the optimal treatment is uncertain.

Objectives. The aim of this review is to determine the effectiveness of six classes of drugs (antacids, H2 antagonists, proton pump inhibitors, prokinetic agents, mucosal-protecting agents and antimuscarinic agents) in the improvement of either individual or global dyspepsia symptom scores and quality-of-life scores in patients with nonulcer dyspepsia.

Search Strategy. Trials were located by searching the Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and text words, by searching bibliographies of retrieved articles, and through contacts with experts in the field of dyspepsia and with pharmaceutical companies.

Selection Criteria. All randomized controlled trials comparing drugs in any of the six groups with each other or with placebo for treatment of nonulcer dyspepsia.

Data Collection and Analysis. Data were collected on dyspeptic symptom scores, either individual or global assessments, in addition to quality-of-life-scores and adverse effects

Primary Results. A total of 11,775 citations were obtained. One hundred forty-four trials were retrieved, and 94 trials fulfilled eligibility criteria. However, subsequent data extraction was not possible in 37 trials. Fifty trials were excluded as they did not meet eligibility criteria. The final 57 trials were included in the final meta-analysis. Prokinetic agents (12 trials with dichotomous outcomes generating 829 patients; relative risk reduction [RRR], 50 percent; 95 percent confidence interval [CI], 30 to 65 percent) and H2 antagonists (eight trials generating 1,125 patients; RRR, 30 percent; 95 percent CI, 4 to 48 percent) were significantly more effective than placebo. Proton pump inhibitors (four trials generating 1,248 patients; RRR, 12 percent; 95 percent CI, −1to 24 percent) and bismuth salts (six trials generating 311 patients; RRR, 40 percent; 95 percent CI, −3 to 65 percent) were superior to placebo, but this finding was of marginal statistical significance. Antacids (one trial generating 109 patients; RRR, −2 percent; 95 percent CI, −36 to 24 percent) and sucralfate (two trials generating 246 patients; RRR, 29 percent; 95 percent CI, −40 to 60 percent) were statistically not significantly superior to placebo. A funnel plot suggested that the prokinetic result could be due to publication bias. The funnel plot of antagonists did H2 not show evidence of publication bias, but the quality of the trials was generally poor.

Reviewers' Conclusions. There is some evidence that antisecretory therapy may be effective in nonulcer dyspepsia. The trials evaluating prokinetic therapy are difficult to interpret because the meta-analysis result could have been due to publication bias. Further research using prokinetic agents and antisecretory therapy is required before any firm conclusions can be reached. The effect of these drugs is likely to be small, and many patients will take them on a long-term basis, so the therapies need to be inexpensive and well tolerated.

REVIEW 2: ERADICATION OF H. PYLORI FOR NONULCER DYSPEPSIA2

Background. H. pylori is the main cause of peptic ulcer disease. The role of H. pylori in nonulcer dyspepsia is less clear.

Objectives. The objective of this review was to determine the effect of H. pylori eradication on dyspepsia symptoms and quality-of-life scores in patients with nonulcer dyspepsia.

Search Strategy. Trials were identified by searching the Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL and SIGLE using appropriate subject headings and keywords, searching bibliographies of retrieved articles, and through contacts with experts in the field of dyspepsia and with pharmaceutical companies.

Selection Criteria. All parallel group randomized controlled trials comparing drugs to eradicate H. pylori with placebo or other drugs known not to eradicate H. pylori in patients with nonulcer dyspepsia.

Data Collection and Analysis. Data were collected on individual and global dyspeptic symptom scores, quality-of-life measures and adverse effects. Dyspepsia outcomes were dichotomized into minimal/resolved versus same/worse symptoms.

Primary Results. Twelve randomized, controlled trials were included in the systematic review. Ten trials compared antisecretory dual or triple therapy with placebo antibiotics +/− antisecretory therapy, and evaluated dyspepsia at three to 12 months. Nine of these trials gave results as dichotomous outcomes evaluating 2,541 patients and there was no significant heterogeneity between the studies. There was 9 percent relative risk reduction in the H. pylori eradication group (95 percent CI, 4 to 14 percent) compared with placebo. The number needed to treat to cure one case of dyspepsia was 15 (95 percent CI, 10 to 31). Two further trials compared Bismuth-based H. pylori eradication with an alternative pharmacological agent. These trials were smaller and had a shorter follow-up but suggested H. pylori eradication was more effective than either H2 antagonists or sucralfate in treating nonulcer dyspepsia.

Reviewers' Conclusions. H. pylori eradication therapy has a small but statistically significant effect for H. pylori positive nonulcer dyspepsia. An economic model suggests the modest benefit may still be cost effective but more research is needed.


These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org)

Cochrane Critique

Did the authors address a focused clinical question? Yes.

Were the criteria used to select articles for inclusion appropriate? Yes.

Is it likely that important relevant articles were missed? No.

Was the validity of the individual studies appraised? Yes.

Were the assessments of studies reproducible? In both reviews, two investigators independently appraised the trials, but the reviews do not report how often the investigators agreed.

Were the results similar from study to study? In review 1, the answer is no. In every class of drugs for which more than one placebo-controlled trial was conducted, there was significant heterogeneity in the results between the trials. In review 2, the five proton pump inhibitor-based therapy were analyzed separately from the two bismuth-based therapy trials. The results of the proton pump inhibitor trials were similar (four of the five trials did not show any benefit, and there was no statistical heterogeneity). The results of the bismuth trials were similar to each other.

Can the results be applied to patient care? The answer from review 1 is yes and no. Cisapride is no longer available for routine use because of concern about cardiac arrhythmias. Pirenzepine is not available in the United States. The other effective drugs are available and usually well tolerated. The answer from review 2 is yes. All of the therapies used in review 2 are available in the United States.

Reading the Numbers

Funnel Plots

Trials that have positive results are more likely to be published, to be published in English and to be cited by other trials. Therefore, when meta-analyses are limited to published trials (in particular, English-language only), the summary results may overestimate the effectiveness of a therapy. Funnel plots can detect this bias and are therefore useful in assessing the validity of meta-analyses.3

In a funnel plot, the x axis represents the effect sizes (such as odds ratios or relative risks) of the trials included in the meta-analysis, and the y axis some measure of their sizes (such as sample sizes, standard errors or precision). Meta-analyses without publication bias should have funnel plots shaped like an inverted funnel; if there is publication bias, the plot may be asymmetric. If the funnel plots in a meta-analysis are asymmetric, we should be cautious about the conclusions, because they probably overestimate the effectiveness of the treatment in question. In the Cochrane reviews summarized in this article, the funnel plot for prokinetic agents for nonulcer dyspepsia therapy was asymeradication were metric, and plots for H2 antagonists and H. pylori symmetric. A reliable funnel plot for proton pump inhibitors could not be generated because there were too few trials included.

Reading the Numbers

View Table

Reading the Numbers

Funnel Plots

Trials that have positive results are more likely to be published, to be published in English and to be cited by other trials. Therefore, when meta-analyses are limited to published trials (in particular, English-language only), the summary results may overestimate the effectiveness of a therapy. Funnel plots can detect this bias and are therefore useful in assessing the validity of meta-analyses.3

In a funnel plot, the x axis represents the effect sizes (such as odds ratios or relative risks) of the trials included in the meta-analysis, and the y axis some measure of their sizes (such as sample sizes, standard errors or precision). Meta-analyses without publication bias should have funnel plots shaped like an inverted funnel; if there is publication bias, the plot may be asymmetric. If the funnel plots in a meta-analysis are asymmetric, we should be cautious about the conclusions, because they probably overestimate the effectiveness of the treatment in question. In the Cochrane reviews summarized in this article, the funnel plot for prokinetic agents for nonulcer dyspepsia therapy was asymeradication were metric, and plots for H2 antagonists and H. pylori symmetric. A reliable funnel plot for proton pump inhibitors could not be generated because there were too few trials included.

Do the conclusions make biological and clinical sense? The answer from review 1 is yes. Since hypersensitivity to gastric acid, atypical gastroesophageal reflux and gastric dysmotility have been implicated as causes of nonulcer dyspepsia, it makes sense that treatments directed at these problems would be beneficial in some patients. The finding that proton pump inhibitors, which are the most potent antisecretory agents, were not as effective compared to placebo as H2 antagonists may be because the trials of H2 antagonists were of poorer quality. Thus, their effectiveness may be overestimated.

In review 2 the answer is yes. H. pylori infection is a risk factor for nonulcer dyspepsia4 and, therefore, eradication therapy might be beneficial. In addition, since peptic ulcer disease is a relapsing and remitting condition, it is possible that even though some patients with nonulcer dyspepsia do not have demonstrable ulcers at the time of endoscopy, they may have a peptic ulcer diathesis and would therefore benefit from eradication therapy.

Are the benefits worth the harms and costs? In review 1, cisapride therapy is probably not worth the harms and costs. Where the other available and effective treatments are concerned, the numbers needed to treat to obtain one improved patient outcome are as follows: H2 antagonists, 6 (95 percent CI, 4 to 9); proton pump inhibitors, 11 (95 percent CI, 5 to infinity); bismuth, 4 (95 percent CI, 4 to infinity). H2 antagonists appear to be the best choice.

Review 2 shows that the number of patients who need to be treated with proton pump inhibitor-based eradication therapies so that one patient would be cured for three to 12 months is 19 (95 percent CI, 11 to 132). Side effects were not reported in the trials, but other studies have described them as mild and self-limiting. The cost effectiveness of eradication therapy for nonulcer dyspepsia is not clear.

Practice Pointers

Evidence regarding the effectiveness of symptomatic treatments for nonulcer dyspepsia is not conclusive because of the poor quality of many of the trials. Nonetheless, the best available evidence suggests that there are a few effective treatments. Bismuth subcitrate, H2 antagonists and proton pump inhibitors may decrease symptoms in the short term (two to 12 weeks), but their long-term effectiveness is unknown. Based on the available evidence and cost, prescription-strength H2 antagonists may be the best choice of therapy. The numberneeded to treat with H2 antagonists to make one patient feel better is fairly small, and these agents have few adverse effects and are less expensive than proton pump inhibitors. The effectiveness of over-the-counter–strength H2 antagonists is unknown because no trials examining their effectiveness were identified. Sixteen of the 17 placebo-controlled trials of prokinetic agents used cisapride, which is no longer available for routine use, so the effectiveness of other prokinetic agents (e.g., metoclopramide) is unclear. Long-term use of bismuth may be neurotoxic, so it should not be considered first-line therapy. The results of this review are consistent with those of previously published systematic reviews.5,6

H. pylori eradication therapy may decrease dyspepsia symptoms over the longer term (three to 12 months) in a minority of patients who have nonulcer dyspepsia. However, considering the costs, compliance difficulties, and adverse effects of eradication therapy, it may not be appropraite to routinely prescribe H. pylori eradication therapy for all patients with nonulcer dyspepsia. It seems more reasonable to inform patients of the possible benefit and risk of eradication therapy, and allow them to share in the decision-making process. To highlight the controversy surrounding this topic, another recent meta-analysis using slightly different criteria for study selection concluded that eradication therapy is not significantly beneficial for patients with H. pylori- positive nonulcer dyspepsia.7

It is important to realize that these two reviews were limited to patients who already had endoscopy or barium studies to exclude ulcers and other disease. The results of these reviews do not necessarily apply to patients who first present with dyspepsia, many of whom will have an identifiable cause for their symptoms instead of nonulcer dyspepsia. For the initial management of patients with dyspepsia, current guidelines and recent trials suggest the following: patients older than 45 years or with alarm symptoms for malignancy should undergo prompt endoscopy (and should be managed according to the endoscopic results); younger patients without alarm symptoms should have a noninvasive H. pylori test. Patients with positive results should be prescribed eradication therapy, and those with negative results can be managed according to standards for nonulcer dyspepsia.811

The Author

John Smucny, M.D., is an assistant professor in the Department of Family Medicine at the State University of New York Upstate Medical University, Syracuse. Dr. Smucny graduated from Case Western Reserve University, Cleveland, Ohio and completed a residency in family practice at Womack Army Community Hospital, Fort Bragg, N.C. He also completed a fellowship in medical research at the Walter Reed Army Institute of Research, Washington, D.C.

The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation to help clinicians put evidence into practice. John Smucny, M.D., presents a clinical scenario and clinical questions based on the Cochrane Abstracts, along with evidence-based answers and a full critique of the abstracts.

Address correspondence to John Smucny, M.D., Department of Family Medicine, SUNY–Upstate Medical University, 475 Irving Ave., Suite 200, Syracuse, NY 13210. Reprints are not available from the author.

REFERENCES

1. Soo S, Moayyedi P, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev. 2000;(2):CD001960.

2. Moayyedi P, Soo S, Deeks J, Delaney B, Harris A, Innes M, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia (Cochrane Review). Cochrane Database Syst Rev. 2001;(1):CD002096.

3. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

4. Jaakkimainen RL, Boyle E, Tudiver F. Is Helicobacter pylori associated with non-ulcer dyspepsia and will eradication improve symptoms? A meta-analysis. BMJ. 1999;319:1040–4.

5. Finney JS, Kinnersley N, Hughes M, O'Bryan-Tear CG, Lothian J. Meta-analysis of antisecretory and gastrokinetic compounds in functional dyspepsia. J Clin Gastroenterol. 1998;26:312–20.

6. Veldhuyzen van Zanten SJ, Cleary C, Talley NJ, Peterson TC, Nyren O, Bradley L, et al. Drug treatment of functional dyspepsia: a systematic analysis of trial methodology with recommendations for design of future trials. Am J Gastroenterol. 1996;91:660–73.

7. Laine L, Schoenfeld P, Fennerty MB. Therapy for Helicobacter pylori in patients with nonulcer dyspepsia: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2001;134:361–9.

8. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology. 1998;114:579–81.

9. Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB. Helicobacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet. 2000;356:455–60.

10. Heaney A, Collins JS, Watson RG, McFarland RJ, Bamford KB, Tham TC. A prospective randomised trial of a “test and treat” policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut. 1999;45:186–90.

11. Asante MA, Mendall M, Patel P, Ballam L, Northfield TC. A randomized trial of endoscopy vs no endoscopy in the management of seronegative Helicobacter pylori dyspepsia. Eur J Gastroenterol Hepatol. 1998;10:983–9.


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