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4-page summary in Adobe Acrobat format (suitable for printing) Health Technology Assessment 2000; Vol. 4: No. 39
Executive summary
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B Delaney1*
S Wilson1
P Moayyedi2
R Oakes1
J Deeks3
A
Harris4
M Innes1
J Raftery1
S Soo2
R Hobbs1
P Barton1
D Forman2
1 University of Birmingham, UK
2 University of Leeds, UK
3 ICRF/NHS Centre for Medical Statistics, Oxford, UK
4 Kent & Sussex NHS Trust, UK
* Corresponding author
Managing dyspepsia costs the NHS in excess of £500 million per year; 2% of the population consult their general practitioner (GP) with dyspepsia each year, and 450,000 endoscopies are performed at a cost of £90 million. Most patients undergoing endoscopy have no significant abnormality and are termed as having non-ulcer dyspepsia (NUD). The initial management of uninvestigated dyspepsia in primary care is considered in this review together with treatments for proven NUD. The study linked systematic reviews with simulation modelling to provide the best available evidence for managing patients with dyspepsia.
2. How effective is early endoscopy?
3. How effective is Helicobacter pylori screening before endoscopy in patients with dyspepsia?
4. How effective is H. pylori screening before eradication therapy in patients with dyspepsia?
5. Does subdividing dyspepsia on the basis of symptom patterns predict response to particular therapies?
6. What are the most cost-effective combinations of initial investigation strategy and prescribing for patients?
7. What are the most important strategies to compare in future trials?
2. How effective is H. pylori eradication?
3. What is the most cost-effective therapy?
4. What are the most important therapies to compare in the treatment of NUD?
The Cochrane Collaboration Controlled Trials Register and Database of Systematic Reviews, MEDLINE, EMBASE, CINAHL, SIGLE and ISCI were searched up until January 1999. Experts in the field of dyspepsia, major pharmaceutical companies and journal editors were also contacted. Authors of publications only available as abstracts were contacted for full trial results.
Dyspepsia was defined following the 1988 Rome Working Party definition as any symptom referable to the upper gastrointestinal tract lasting for more than 4 weeks. Two reviewers independently selected eligible trials, according to the following criteria.
Patients with NUD were defined as those with dyspepsia and insignificant findings at endoscopy or barium meal, who were not required to have had 24-hour oesophageal pH studies, upper abdominal ultrasound or computed tomography scans. Patients with hiatus hernia, less than five gastric erosions or mild duodenitis were included, as these lesions correlate poorly with dyspepsia symptoms.
Data from eligible trials were collected for analysis.
Data from ordinal outcomes, such as dyspepsia rating scales, were combined by transforming to a binary scale. Fixed effect models (Mantel–Haenszel) were used for pooling data to obtain a pooled relative risk (RR) unless significant heterogeneity was present, when the random effects model (DerSimonian and Laird) was adopted. For continuous outcomes, the inverse variance (Woolf’s method) model was used as the fixed effect method and the DerSimonian and Laird method for random effects. Egger’s test of asymmetry was used to detect publication bias. Numbers-needed-to-treat (NNTs) and their confidence intervals (CIs) were calculated. For continuous measures, Hedges’ adjusted g was used to calculate standardised mean differences, expressing the treatment effect in units of standard deviation.
RRs, mean differences and standardised mean differences were pooled. Additional analyses investigating heterogeneity and publication bias were undertaken.
All health economics modelling adopted an NHS perspective. Effects of treatment were obtained from the systematic reviews where possible; other necessary data, including test performance, prevalence and outcome data were obtained systematically from papers collected alongside the reviews, but not relating directly to the study questions. Cost data were obtained from the Drug Tariff and NHS 1998 Reference Costs. Markov cost-effectiveness models of therapy for proven NUD were constructed. The discrete event simulation model of the management of dyspepsia in primary care was programmed directly in Visual Basic©. Costs were discounted at 6% and benefits at 3%. Cost-effectiveness ratios and incremental cost-effectiveness ratios (ICERs) for comparisons of strategies were obtained and a wide sensitivity analysis of variation in both costs and effectiveness was performed.
In all, 12 papers reporting 14 comparisons were found, with a further four trials being available as abstracts. Meta-analysis of trials comparing PPIs with antacids and H2-receptor antagonists, and of early endoscopy compared with initial acid suppression was possible. PPIs were very significantly more effective than both H2-receptor antagonists and antacids. RR reductions with 95% CIs were: for PPIs versus antacids, 29% (36 to 21); for PPIs versus H2-receptor antagonists 37% (53 to 15). Results for other drug comparisons were either absent or inconclusive. Early endoscopy may be more effective than initial prescribing but the effect size was small and non-significant (RR reduction, 11% (1 to 22)). Although economic data are not yet available, cost-effectiveness is likely to be low. H. pylori test-and-endoscope was associated with no significant difference in effectiveness compared with selective endoscopy at the GP’s discretion, and no reduction in costs. H. pylori test-and-treat has been shown to be as effective as early endoscopy and to reduce costs in patients referred for investigation, but uncertainty remains as to its cost-effectiveness in primary care compared with empirical acid suppression.
The model indicated that strategies involving initial prescribing, or H. pylori eradication (test-and-treat) were more cost-effective than strategies involving endoscopy. Prescribing H2-receptor antagonists was more effective than antacid (ICER, £15.88 per additional month symptom-free over 5 years). PPIs were more effective than antacids (ICER, £21.76 per month) and H2-receptor antagonists (ICER, £41.64 per month). The results were sensitive to the costs and effectiveness of the medications. A mean saving of 3 weeks’ dyspeptic symptoms over 5 years was obtained by H. pylori test-and-treat rather than prescribing, with an ICER of £62.77 per month saved. The result was sensitive to the cost of ongoing dyspepsia treatment and the prevalence of H. pylori.
The one eligible trial suggested that antacids were no more effective than placebo in NUD. Meta-analysis was possible for prokinetics, H2-receptor antagonists, PPIs, bismuth, pirenzepine, sucralfate, and H. pylori eradication against placebo. Prokinetics and H2-receptor antagonists were more effective than placebo (prokinetics: RR reduction, 50% (95% CI, 30 to 70); H2-receptor antagonists, 29% (47 to 4)) but trials were often of poor quality with significant heterogeneity between studies. A funnel plot revealed that the results of the prokinetic meta-analysis could be due to publication bias or related quality issues. PPIs and bismuth tended to be more effective than placebo but this did not reach statistical significance. There was no evidence that sucralfate was superior to placebo. Pirenzepine showed a significant benefit (RR reduction, 4 (95% CI, 3 to 10) but this was based on only two trials and the drug is no longer available in the UK. H. pylori eradication was associated with a 9% RR reduction (95% CI, 14 to 4); an NNT of 15 (10 to 1) was calculated based on a control event rate of 72%.
Economic modelling based on these data, assuming a threshold ICER of £100 per month, and a wide sensitivity analysis indicated that PPIs and cisapride were unlikely to be cost-effective treatments for NUD. If cheaper prokinetics (domperidone or metoclopramide) were sufficiently effective to give an NNT of at most 55, or H2-receptor antagonists to give an NNT of 14, these treatments may represent cost-effective choices. H. pylori eradication was cost-effective with an ICER against antacid alone of £56 per month.
There is still much uncertainty around the management of dyspepsia, both uninvestigated dyspepsia and proven NUD. This review indicates that the treatment for NUD, for which the evidence is most reliable, is H. pylori eradication. The effect is small but cost-effective as the treatment is potentially curative rather than just suppressive. Whether the effect is due to treating latent peptic ulcer disease or some other mechanism, the implication is that patients diagnosed on the basis of a negative endoscopy will benefit from H. pylori eradication.
In primary care, the conclusions are much less robust. PPIs are the most effective treatment for undiagnosed dyspepsia and reasonably cost-effective. This is because the case-mix includes patients with peptic ulcer disease and gastro-oesophageal reflux disease, for which PPIs are effective treatments. The relative efficacy of H2-receptor antagonists is uncertain, because of a lack of trials comparing antacids and H2-receptor antagonists and a lack of trials in patients without reflux as a dominant symptom. Although management based on early endoscopy may lead to a small reduction in dyspeptic symptoms, the cost-effectiveness of endoscopy is uncertain. Modelling suggests that, for most patients, endoscopy-based management is not cost-effective as there is little gain in symptom relief and considerable additional cost. Of the empirical strategies, H. pylori test-and-treat is likely to be more cost-effective than endoscopy but well-designed, primary care based trials are needed to compare cost-effectiveness and effects on quality of life with empirical acid suppression.
In the treatment of NUD:
For the initial management of dyspepsia:
These reviews (in their Cochrane format) should be kept up-to-date, as research in this field is extremphasizely fast moving. Given the number of new trials and the potential for important subgroup analysis based on age or symptoms, there is potential for an individual patient data meta-analysis. The Cochrane Upper Gastrointestinal and Pancreatic Disease Review Group is actively planning such a review.
Delaney B, Moayyedi P, Deeks J, Innes M, Soo S, Barton P, et al. The management of dyspepsia: a systematic review. Health Technol Assess 2000;4(39).
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