BMJ  2003;326:1118 (24 May), doi:10.1136/bmj.326.7399.1118

Paper

Empirical prescribing for dyspepsia: randomised controlled trial of test and treat versus omeprazole treatment

¹ Department of Gastroenterology, Cardarelli Hospital, Via Solimena 101, 80129 Naples, Italy

Abstract

Objective To compare the efficacy of a "Helicobacter pylori test and treat" strategy with that of an empirical trial of omeprazole in the non-endoscopic management by empirical prescribing of young patients with dyspepsia.

Design Randomised controlled trial.

Setting Hospital gastroenterology unit.

Participants 219 patients under 45 years old presenting with dyspepsia without alarm symptoms.

Intervention Patients received treatment with omeprazole 20 mg (group A) or with a urea breath test followed by an eradication treatment in case of H pylori infection or omeprazole alone in non-infected patients (group B). Lack of improvement or recurrence of symptoms prompted endoscopy.

Main outcome measures Improvement in symptoms assessed by a dyspepsia severity score every two months; use of medical resources (endoscopic workload and medical consultation); clinical outcome.

Results 96/109 (88%) patients in group A and 61/110 (55%) in group B (P < 0.0001) had endoscopy: in 19 patients in group A and 32 in group B (20/67 infected and 12/43 non-infected) because of no improvement; in 77 further patients in group A and 29 in group B (7 infected and 22 non-infected) because of recurrence of symptoms during follow up. Endoscopy showed peptic ulcers only in group A; oesophagitis occurred significantly more often in group B than in group A. About 80% of examinations were normal in both groups, but nine duodenal scars occurred in group A.

Conclusions Eradication treatment allows resolution of symptoms in a large number of patients with dyspepsia and reduces the endoscopic workload. After a trial of omeprazole, symptoms recur in nearly every patient. Such treatment is also likely to mask an appreciable number of peptic ulcers and cases of oesophagitis.

Introduction

Dyspepsia is a common condition in the general population of industrialised countries. The increasing cost of treatments for dyspepsia has led to a search for safe and cost-effective management strategies. Agreement exists that patients older than 45 with dyspeptic symptoms and patients with alarm symptoms should undergo endoscopy. To reduce endoscopic workload empirical treatment with proton pump inhibitors has been proposed for young patients.^1–4 In industrialised countries people under the age of 45 who are not taking non-steroidal anti-inflammatory drugs are unlikely to be affected by serious gastroduodenal disease if they have a negative H pylori test. On the basis of these observations, the European H pylori Study Group advised that young dyspeptic patients without alarm symptoms and found to be infected by means of non-invasive tests should receive empirical eradication treatment without endoscopy.³

To date, no published prospective fully randomised trials have compared the efficacy of the "test and treat" strategy with that of empirical treatment with a proton pump inhibitor in a clinical setting as an initial management strategy for dyspeptic patients. We aimed to conduct such a trial.

Methods

We studied outpatients with symptoms of dyspepsia referred by their general practitioners to our department over a two year period. We included young adults (18-45 years of age) presenting with uninvestigated upper abdominal symptoms. Exclusion criteria were age less than 18 years, alarm symptoms, symptoms of gastro-oesophageal reflux disease, regular use of non-steroidal anti-inflammatory drugs, previous surgery to the upper gastrointestinal tract, pregnancy, and treatment with antibiotics, proton pump inhibitors, or H₂ antagonists in the previous four weeks.

We assessed symptoms at baseline,⁵ and randomly assigned patients to either empirical treatment with omeprazole 20 mg/day for four weeks (group A) or a¹³C-urea breath test for H pylori (group B). Patients whose H pylori test showed no infection received four weeks' treatment with omeprazole 20 mg/day. Infected patients received one week of triple eradication treatment (omeprazole 20 mg, clarithromycin 500 mg, and tinidazole 500 mg, all twice daily). We tested for H pylori again at the four week review and gave a further course of treatment if the test was positive. Patients who had improved symptoms at the four week visit entered the follow up phase. If symptoms had not improved we offered endoscopy, which we performed at least two weeks after the visit in order to reduce the rate of false negative H pylori test results.

An investigator who was blinded to group assignment followed up participants every two months for one year or when symptoms recurred. We defined a relapse as the recurrence of symptoms as judged by the patient on a four point Likert-type scale (no symptoms, improvement in symptoms, no change, worse symptoms). This was the primary endpoint of the trial. We offered endoscopy to patients who relapsed.

Statistical analysis
We assessed the rate of patients undergoing endoscopy as well as the time to first relapse. We analysed the data by using life table methods and compared the remission curves of the two groups by using the log rank test. We used the Mann-Whitney U test to compare symptom scores between the groups and the ² test to compare categorical variables. All analyses were intention to treat.

Results

Between November 1998 and November 2000 we randomised 109 patients to treatment with a proton pump inhibitor (group A) and 110 to a urea breath test (group B). Sixty seven (61%) patients in group B tested positive for H pylori and received eradication treatment. The other 43 had a negative result and received omeprazole. Baseline characteristics of the two groups were similar (table 1). The H pylori infection was eradicated in 63 patients in group B after the first treatment (eradication rate 94%) and in four patients after second line treatment. All patients identified for follow up were successfully reassessed.

View this table: [in this window] [in a new window]   Table 1 Baseline characteristics of the study groups

 

Clinical efficacy and endoscopic assessment—Ninety (83%, 95% confidence interval 74% to 89%) patients in group A and 78 (71%, 61% to 79%) in group B described improvement in symptoms at the four week visit (P = 0.05) and entered the follow up. Overall, 96 patients (88%, 0.8 to 0.93) in group A and 61 (55%, 46% to 65%) patients in group B had an endoscopy during the study (P < 0.0001). Table 2 shows the diagnoses found by endoscopy in the patients in the two groups. No peptic ulcer occurred in group B; the prevalences of hiatus hernia and oesophagitis were significantly higher in the patients in group B who had an endoscopy. Interestingly, among the patients who did not show active lesions at endoscopy, nine (9%) in group A and none in group B showed a scar in the duodenal bulbus (P < 0.05).

View this table: [in this window] [in a new window]   Table 2 Diagnoses by upper gastrointestinal endoscopy in each of the two study groups. Values are numbers (percentages) unless stated otherwise

 

Symptom assessment—The dyspepsia score was significantly better in the proton pump inhibitor group then in the test and treat group at the first follow up visit but became significantly worse at six and 12 months (fig 1).

View larger version (21K): [in this window] [in a new window]   Fig 1 Mean dyspepsia scores over the various time points of the study in patients undergoing empirical treatment with omeprazole (group A) and a "test and treat" strategy (group B). Group B includes both patients who received eradication treatment for Helicobacter pylori infection and those who tested negative for the infection and received four weeks' treatment with omeprazole. (Data are expressed as mean and standard deviation; NS = not significant)

 

Relapses between 0 and 12 months—The proportion of days (number of days per patient) without symptoms was significantly higher in the test and treat group than in the proton pump inhibitor group (mean 231.5 (95% confidence interval 205.7 to 257.2) v 139.3 (117.9 to 160.7); P < 0.001), even including in the first group the H pylori negative patients who received omeprazole (fig 2).

View larger version (28K): [in this window] [in a new window]   Fig 2 Symptom remission curves from 0 to 12 months of follow up. At the first visit for assessment, four weeks after the beginning of the treatment (time 0), 90/109 (83%) patients in the omeprazole group (group A) and 78/110 (70.9%) in the "test and treat" group (group B) were in remission. The curves for patients undergoing Helicobacter eradication treatment (Group B HP+, 47/67 in remission) and those who tested negative for H pylori infection (Group B HP-, 31/43 in remission) and received omeprazole treatment are also shown

 

Adherence to treatment and adverse events—No patient was withdrawn as a result of poor adherence to drugs or because of adverse events. Thirty six (33%) patients in the omeprazole group and 40 (36%) in the test and treat group reported at least one adverse event. Nausea, taste perversion, diarrhoea, and headache were the most common events reported.

Discussion

The test and treat strategy is as efficient and safe as endoscopy in the management of patients with dyspepsia.^{6 7} Conversely, the cost effective use of endoscopy is hotly debated.^{2 8–12} Our study was not designed to estimate the cost effectiveness of the management strategies. In a public health perspective good clinical judgment, the patient's wishes, and the availability of resources will influence the choice of strategy. However, if we choose to offer an empirical treatment the test and treat strategy should be the preferred option.

A main concern regarding the empirical treatment of dyspepsia is the possibility of missing gastric cancer. No gastric cancer was diagnosed or missed in our study. Although a delay in diagnosis of a few weeks does not affect the likelihood of cure of gastric cancer, a shorter empirical treatment is likely to represent a better option. After discontinuation of treatment in our study, symptoms recurred earlier in the patients who received eradication treatment than in those treated with proton pump inhibitor.

The test and treat strategy was superior to empirical treatment with omeprazole in our study population, but this advantage might be less evident in populations with a lower prevalence of H pyloriinfection. A recent study shows that treatment with a proton pump inhibitor becomes less costly than the test and treat strategy when the prevalence of H pyloriis lower than 20%.¹³ The prevalence of H pyloriinfection in our study was about 60%, but we excluded patients with reflux symptoms, who have a lower prevalence of infection.¹⁴ Including patients with reflux symptoms, the prevalence of infection in our dyspepsia population would be 55%,¹⁵ similar to the value of 55.2% reported in a large meta-analysis.¹⁶

Although our study took place in a hospital clinic, we consider the results to be applicable to primary care patients. As a reference centre for dyspepsia, we invited primary care doctors to refer their uninvestigated patients to us, so our patients are likely to be similar to those seen in the primary care setting. We believe, however, that our findings would need to be assessed in the primary care setting before implementation is considered.

What is already known on this topic Dyspeptic patients aged under 45 without alarm symptoms are unlikely to have a malignancy An empirical prescribing approach has been recommended as a way to reduce endoscopic workload The "test for Helicobacter pylori and treat" strategy and acid suppressing drugs have both been recommended for uninvestigated dyspepsia, but no randomised controlled trials have compared the two approaches What this study adds Treatment to eradicate H pylori allows the resolution of symptoms in a large number of dyspeptic patients and reduces the endoscopic workload Treatment with omeprazole is likely to mask an appreciable number of peptic ulcers and cases of oesophagitis The H pylori test and treat strategy should be the preferred approach to dyspepsia, if we choose to perform an empirical treatment.

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This is an abridged version; the full version is on bmj.com

Contributors: See bmj.com

Funding: No pharmaceutical company or other commercial entity provided funding or other resources for the study.

Competing interests: None declared.

Ethical approval: The local ethics committee approved the trial.

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(Accepted April 4, 2003)

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Rapid Responses:

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Comparing H pylori eradication and simple anti-ulcer treatment lacks equipoise.

Christopher J Martin
bmj.com, 27 May 2003 [Full text]

Study of H.pylori test and treat v. PPI cannot be applied to the Primary Care setting.

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