Elsevier

The Lancet

Volume 373, Issue 9659, 17–23 January 2009, Pages 215-225
The Lancet

Articles
Effect and cost-effectiveness of step-up versus step-down treatment with antacids, H2-receptor antagonists, and proton pump inhibitors in patients with new onset dyspepsia (DIAMOND study): a primary-care-based randomised controlled trial

https://doi.org/10.1016/S0140-6736(09)60070-2Get rights and content

Summary

Background

Substantial physician workload and high costs are associated with the treatment of dyspepsia in primary health care. Despite the availability of consensus statements and guidelines, the most cost-effective empirical strategy for initial management of the condition remains to be determined. We compared step-up and step-down treatment strategies for initial management of patients with new onset dyspepsia in primary care.

Methods

Patients aged 18 years and older who consulted with their family doctor for new onset dyspepsia in the Netherlands were eligible for enrolment in this double-blind, randomised controlled trial. Between October, 2003, and January, 2006, 664 patients were randomly assigned to receive stepwise treatment with antacid, H2-receptor antagonist, and proton pump inhibitor (step-up; n=341), or these drugs in the reverse order (step-down; n=323), by use of a computer-generated sequence with blocks of six. Each step lasted 4 weeks and treatment only continued with the next step if symptoms persisted or relapsed within 4 weeks. Primary outcomes were symptom relief and cost-effectiveness of initial management at 6 months. Analysis was by intention to treat (ITT); the ITT population consisted of all patients with data for the primary outcome at 6 months. This trial is registered with ClinicalTrials.gov, number NCT00247715.

Findings

332 patients in the step-up, and 313 in the step-down group reached an endpoint with sufficient data for evaluation; the main reason for dropout was loss to follow-up. Treatment success after 6 months was achieved in 238 (72%) patients in the step-up group and 219 (70%) patients in the step-down group (odds ratio 0·92, 95% CI 0·7–1·3). The average medical costs were lower for patients in the step-up group than for those in the step-down group (€228 vs €245; p=0·0008), which was mainly because of costs of medication. One or more adverse drug events were reported by 94 (28%) patients in the step-up and 93 (29%) patients in the step-down group. All were minor events, including (other) dyspeptic symptoms, diarrhoea, constipation, and bad/dry taste.

Interpretation

Although treatment success with either step-up or step-down treatment is similar, the step-up strategy is more cost effective at 6 months for initial treatment of patients with new onset dyspeptic symptoms in primary care.

Funding

The Netherlands Organisation for Health Research and Development.

Introduction

The initial management of dyspepsia remains a challenge. The high prevalence of the condition substantially increases the workload for physicians and has detrimental effects on patient quality of life, as well as important socioeconomic consequences.1, 2 Unfortunately, solid evidence on which to base the best initial management strategy is still lacking.3, 4 Most studies to date have reported on single drug comparisons and mainly involved patients with persisting dyspeptic symptoms referred to secondary care. Several meta-analyses and reviews have been done to address important questions concerning treatment strategies for patients with dyspeptic symptoms.5, 6, 7, 8, 9 A Cochrane review showed that only a few studies—mostly of inadequate methodology—dealt with initial management of dyspepsia.5 The investigators concluded that large gaps in knowledge on the most cost-effective management strategy for uninvestigated dyspepsia exist. Consequently, guidelines for management of dyspepsia are inconsistent.

The American Gastroenterological Association (AGA) and Canadian guidelines recommend empirical proton pump inhibitor treatment for patients with predominant gastro-oesophageal reflux disease (GORD), and Helicobacter pylori test-and-treat followed by empirical proton pump inhibitor treatment for all others.10, 11 According to the AGA guidelines, empirical proton pump inhibitor treatment is also an initial option in a population with low H pylori prevalence. UK guidelines state that there is currently insufficient evidence to guide which of these two options should be offered first.12 Scottish guidelines adopt the ROME II definition for dyspepsia, necessitating initial endoscopy for diagnosis.13 They advise treating functional dyspepsia with antacids or H2-receptor antagonists, followed by H pylori test-and-treat when symptoms persist. By contrast, Dutch guidelines recommend empirical treatment with antacids or H2-receptor antagonists for all patients with new onset dyspepsia, and reserve proton pump inhibitor treatment for patients with persistent predominantly GORD symptoms, and H pylori test-and-treat for all other patients with persistient symptoms (step-up strategy).14 Direct endoscopic diagnosis is only indicated for patients presenting with alarm symptoms. Initial treatment with proton pump inhibitors is used widely because of its presumed superior cost-effectiveness.5 To improve our insight into the best treatment for initial management of dyspepsia in primary care, we undertook a double-blind, randomised controlled trial comparing step-up versus step-down therapy.

Section snippets

Patients

From October, 2003, to January, 2006 a representative sample of 312 Dutch family doctors (general practitioners)15 agreed to include patients in the DIAMOND study (Dutch study on Initial Management Of Newly diagnosed Dyspepsia). The methodological aspects of the trial are outlined here, and details have been described elsewhere.15

Patients aged 18 years and older who consulted their general practitioner for new onset dyspepsia were eligible. Dyspepsia was defined as pain or discomfort centred in

Results

150 (48%) of the participating general practitioners recruited 664 patients.15 The trial profile is shown in figure 2. 332 (97%) of 341 patients in the step-up, and 313 (97%) of 323 patients in the step-down group reached an endpoint with sufficient data for assessment. 19 patients (step-up n=9, step-down n=10) did not reach an endpoint (figure 2). Baseline characteristics are shown in table 1. During the study period, 139 (41%), 84 (25%), and 118 (35%) of 341 patients assigned to the step-up

Discussion

Ideally, dyspepsia treatment should quickly and conveniently alleviate patients' symptoms while also reducing the use of health-care resources to a minimum. We have shown that a step-up strategy starting with antacids is more cost effective than a step-down strategy starting with proton pump inhibitors in the initial management of dyspepsia in primary care. Compared with the step-down approach, the step-up regimen resulted in slightly lower medical and overall costs with equal clinical

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