Primary care

Treating Helicobacter pylori infection in primary care patients with uninvestigated dyspepsia: the Canadian adult dyspepsia empiric treatmentHelicobacter pylori positive (CADET-Hp) randomised controlled trial

Naoki Chiba, associate clinical professor of medicine ^a, Sander J O Veldhuyzen van Zanten, professor of medicine ^b, Paul Sinclair, research scientist ^c, Ralph A Ferguson, research scientist ^c, Sergio Escobedo, statistician ^c, Eileen Grace, health economist ^c. 

^a Papers p 999 Division of Gastroenterology, McMaster University, Hamilton, ON, Canada L8N 3Z5, ^b Division of Gastroenterology, Dalhousie University, Halifax, NS, Canada B3H 2Y9, ^c AstraZeneca Canada Inc, 1004 Middlegate Road, Mississauga, ON, Canada L4Y 1M4

Correspondence to: N Chiba, Surrey GI Clinic/Research, 105-21 Surrey Street West, Guelph, ON, Canada N1H 3R3 chiban{at}on.aibn.com

	Abstract

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Objective: To determine whether a "test for Helicobacter pylori and treat" strategy improves symptoms in patients with uninvestigated dyspepsia in primary care.
Design: Randomised placebo controlled trial.
Setting: 36 family practices in Canada.
Participants: 294 patients positive for H pylori (¹³C- urea breath test) with symptoms of dyspepsia of at least moderate severity in the preceding month.
Intervention: Participants were randomised to twice daily treatment for 7 days with omeprazole 20 mg, metronidazole 500 mg, and clarithromycin 250 mg or omeprazole 20 mg, placebo metronidazole, and placebo clarithromycin. Patients were then managed by their family physicians according to their usual care.
Main outcome measures: Treatment success defined as no symptoms or minimal symptoms of dyspepsia at the end of one year. Societal healthcare costs collected prospectively for a secondary evaluation of actual mean costs.
Results: In the intention to treat population (n=294), eradication treatment was significantly more effective than placebo in achieving treatment success (50% v 36%; P=0.02; absolute risk reduction=14%; number needed to treat=7, 95% confidence interval 4 to 63). Eradication treatment cured H pylori infection in 80% of evaluable patients. Treatment success at one year was greater in patients negative for H pylori than in those positive for H pylori (54% v 39%; P=0.02). Eradication treatment reduced mean annual cost by $C53 (86 to 180) per patient.
Conclusions: A "test for H pylori with ¹³C-urea breath test and eradicate" strategy shows significant symptomatic benefit at 12 months in the management of primary care patients with uninvestigated dyspepsia.

What is already known on this topic Dyspepsia is a common problem in primary health care, although controversy exists about its definition Studies of H pylori eradication in patients with uninvestigated dyspepsia have shown reduced need for endoscopy and thus significant cost savings compared with a strategy of prompt endoscopy The "test for H pylori and treat" strategy has been recommended for uninvestigated dyspepsia, but there have been no randomised controlled trials showing improvement in symptoms What this study adds When given eradication treatment in primary care, H pylori positive patients with uninvestigated dyspepsia show improvement in overall dyspepsia symptoms at 12 months This supports the "test for H pylori and treat" strategy

	Introduction

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Dyspepsia is a common condition that affects up to 40% of the general population and has adverse effects on quality of life.¹ In Canada, 7% of visits to family practitioners are for dyspepsia.² Most patients presenting with upper gastrointestinal symptoms in primary care are uninvestigated, and the cause of the symptoms is usually unknown. Family practitioners are comfortable treating patients without an initial diagnosis, prescribing up to 2.5 courses of empirical drug treatment before referring the patient for investigations.² In most (up to 60%) of these patients, results of investigations are normal and the diagnosis is functional dyspepsia.³

A suggested strategy for managing uninvestigated dyspepsia is to screen patients aged under 50 without alarm symptoms with a non-invasive test for H pylori and to treat patients with positive results with drugs to eradicate H pylori.⁴ As this recommendation is not based on evidence from randomised controlled trials, we undertook a study to determine whether a non-invasive H pylori "test and treat" strategy in primary care for adult patients of any age with uninvestigated dyspepsia would result in improvement or cure of dyspepsia over one year.

	Methods

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This was a double blind placebo controlled parallel group multicentre randomised trial, performed in 36 family practitioner centres across Canada between September 1997 and April 1999.

Selection of patients
Patients were eligible if they were aged 18 years or over with uninvestigated symptoms of dyspepsia for at least the previous three months. We defined dyspepsia as a symptom complex of epigastric pain or discomfort thought to originate in the upper gastrointestinal tract and including any of the following additional symptoms: heartburn, acid regurgitation, excessive burping or belching, increased abdominal bloating, nausea, feeling of abnormal or slow digestion, or early satiety. ^{5 6} Patients with only heartburn, regurgitation, or both were considered to have a diagnosis of gastro-oesophageal reflux disease and were excluded. We also excluded patients investigated by upper gastrointestinal endoscopy, barium study, or both less than six months before randomisation or on more than two separate occasions within the preceding 10 years and patients given eradication therapy for H pylori less than six months before randomisation. Patients had to have a positive ¹³C-urea breath test result before randomisation.⁷

Randomisation and interventions
A computer randomisation was generated and given to each centre in sealed, numbered envelopes. Active and placebo medications were identical in appearance.

We allocated patients randomly to either omeprazole 20 mg, metronidazole 500 mg, and clarithromycin 250 mg ("eradication arm") or omeprazole 20 mg, placebo metronidazole, and placebo clarithromycin ("placebo arm") twice daily for seven days. The follow up period was 12 months, with assessments at monthly intervals. We did not include these scheduled visits in the economic analysis. We repeated the ¹³C-urea breath test at three months and 12 months after the end of treatment to determine H pylori status. Investigators remained blinded to results of breath tests throughout the study. During follow up, patients were managed by their family practitioners according to their usual clinical practice.

Outcome measures
Global overall symptoms of dyspepsiaWe assessed the global overall severity of dyspepsia symptoms over the preceding four weeks by using the following seven point Likert-type scale (GOS scale): (1) no problem; (2) minimal problemcan be easily ignored without effort; (3) mild problemcan be ignored with effort; (4) moderate problemcannot be ignored but does not influence daily activities; (5) moderately severe problemcannot be ignored and occasionally limits daily activities; (6) severe problemcannot be ignored and often limits concentration on daily activities; (7) very severe problemcannot be ignored, markedly limits daily activities, and often requires rest. ^{8 9} All enrolled patients had epigastric pain or discomfort and a symptom score of at least moderate severity (4/7) over the previous month. For the primary outcome measure, we defined treatment success as a score of either 1 (none) or 2 (minimal) on the symptom scale at the final visit.¹⁰ As secondary outcome measures, we determined the proportion of patients becoming completely asymptomatic and treatment success according to H pylori status.

Other questionnairesWe assessed quality of life by using a seven point Likert-type scale (QOLRAD) in which higher scores indicate better quality of life.¹¹ Results are reported as average change in each of five dimensions. We also used the gastrointestinal symptom rating scale (GSRS), a seven point Likert-type scale in five dimensions, to assess gastrointestinal symptoms (see bmj.com).

Dyspepsia related health utilisation costsOur objective was to compare the mean annual cost of H pylori eradication treatment with that of placebo. We measured dyspepsia related use of health resources prospectively at monthly intervals by telephone and clinic interviews with a health resource utilisation questionnaire. Direct costs included visits to the physician and other healthcare professionals, drugs, and investigations (for example, laboratory tests, radiography, endoscopy). Indirect costs of decreased productivity as a consequence of days lost through dyspepsia took into consideration whether the patient was employed, unemployed, or a senior citizen (aged over 65) and were calculated from Canadian labour force and unpaid work estimates. ^{12 13} We aggregated indirect and direct costs (Province of Ontario, Canada, Ministry of Health perspective) to determine the societal perspective. We did not discount costs.

Eradication of H pyloriWe calculated the proportion of patients in whom H pylori was eradicated on the basis of the result of the urea breath test at 12 months or, in the case of a missing 12 month value, the result at three months.

Statistical evaluation
The intention to treat analysis included all randomised patients. Patients who discontinued at any time were considered treatment failures. We undertook a more clinically applicable analysis"all evaluable patients"in those patients who had data on symptoms at the 6-12 month assessments. We carried data forward from six months and beyond to replace missing 12 month data. We used the Cochran-Mantel-Haenszel test to compare proportions of success by treatment group.

The main objective of the economic analysis was to measure and describe the costs per patient over the year of the study. As costs were not normally distributed, we used corrected  percentile bootstrap methods to measure mean costs per patient. ^{14 15}

	Results

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A total of 294 patients were randomised, and the two groups were well matched (see bmj.com). The proportion of patients who were considered a treatment success was significantly greater for the eradication arm than for the placebo arm, with comparable results in the intention to treat and all evaluable patients analyses (table 1). The number needed to treat to achieve one treatment success in the eradication arm was 7 (95% confidence interval 4 to 63). A significant benefit for the eradication arm was also seen when we used the most stringent endpoint of defining only completely asymptomatic patients as responders (table 1). Subgroups of dyspepsia overlapped considerably and did not predict treatment success (see bmj.com).

Results according to H pylori status
H pylori was eradicated in 75% (109/145) of the patients in the eradication arm and in 14% (21/149) of those in the placebo arm in the intention to treat population. During follow up, a second course of H pylori eradication treatment resulted in eradication in only 2 of 11 treated patients in the eradication arm compared with 15 of 23 treated patients in the placebo arm. Patients who had H pylori eradicated had a treatment success rate of 54% (69/127; 95% confidence interval 45% to 63%) compared with 39% (54/137; 31% to 48%) in those who remained H pylori positive.

Quality of life assessments
Table 2 shows the impact of eradication treatment on disease specific measures of quality of life. The difference in the change in scores from pretreatment to study end showed significantly greater improvement in three of the five domains for the eradication arm.

Health resource utilisation
The mean total annual costs from the perspectives of society and the Ontario Ministry of Health were lower for the eradication arm than the placebo arm, although the differences were not significant (table 3). Few patients had endoscopy or upper gastrointestinal barium examination in the follow up year (table 4). The increased costs for patients randomised to placebo were primarily incurred through increased visits to the physician and drugs for dyspepsia (table 4). The proportion of patients needing additional prescriptions was 50% (73/145) in the eradication arm and 58% (87/149) in the placebo arm (see bmj.com).

Adverse events
Sixty one (42%) patients in the eradication arm and 62 (42%) patients in the placebo arm reported at least one adverse event (see bmj.com). One patient in the eradication arm stopped treatment owing to a skin rash. In the placebo arm, two patients stopped their pills because of adverse events: one had crampy abdominal pain and loose bowel movements, and the other had epigastric pain. Minor elevations of liver enzymes occurred more often in the eradication group than in the placebo group. Two deaths from cancer occurred during the study, both in the eradication arm. Neither death was considered to be related to the study (see bmj.com).

	Discussion

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H pylori is known to cause duodenal ulcers and gastric ulcers and is linked to gastric cancer¹⁶ and MALToma (mucosal associated lymphoid tumour),¹⁷ but its association with dyspepsia remains unclear. Most studies of H pylori and dyspepsia have been done in patients with functional (that is, investigated) dyspepsia. Meta-analyses of these trials have shown either no benefit from eradication of H pylori¹⁸ or at best a small benefit with a number needed to treat of 15.¹⁹

Patients do not present to the family physician with an identified cause for their dyspepsia, as they are uninvestigated at first presentation. They may have functional dyspepsia or diseases such as peptic ulcer or gastro-oesophageal reflux disease. Unfortunately, symptoms do not reliably predict endoscopic findings or allow reliable diagnosis.³ The Rome definition of dyspepsia considers the symptoms of heartburn and acid regurgitation to be synonymous with gastro-oesophageal reflux disease and not part of the symptom complex of dyspepsia,²⁰ but it is well known that most patients have multiple, overlapping symptoms, ^{1 21} as we confirmed in this study. Even among patients with proved peptic ulcers, 28% can have heartburn or acid reflux as the predominant presenting symptom.²² Therefore, a definition of dyspepsia that excludes reflux symptoms does not fit the conceptual framework of family physicians, and we believe that these symptoms form part of the symptom complex of dyspepsia. ^{2 6}

Our study showed consistent results in favour of eradication of H pylori for most outcome measures, including global improvement and complete resolution of dyspepsia and improvement in epigastric pain or discomfort and belching and some aspects of quality of life. The number needed to treat to achieve one treatment success was 7. The 14% clinical gain may be attributable to the patients with ulcer disease, but this is speculative as we did not perform endoscopy. Patients in whom H pylori was eradicated had better symptom relief than those in whom infection persisted, consistent with the hypothesis that H pylori is responsible for dyspepsia in some patients.

Although extensive overlap of symptoms makes it impossible to completely exclude patients with gastro-oesophageal reflux disease, we excluded patients with reflux disease previously diagnosed by endoscopy or 24 hour oesophageal pH study and patients with symptoms of only heartburn or acid regurgitation without epigastric pain or discomfort. Studies in patients with reflux disease who test positive for H pylori show that eradication of H pylori either does not affect the subsequent clinical course of gastro-oesophageal reflux disease²³ or may worsen it. Inclusion of such patients in our study would have biased the results towards no effect. In this study, we saw a trend towards improvement and not worsening of dyspepsia in patients with predominant reflux symptoms (see bmj.com). These results are in keeping with a study in patients with peptic ulcers and concomitant reflux oesophagitis, in which symptoms improved after eradication of H pylori.²² Our data thus suggest that a proportion of patients with uninvestigated dyspepsia with predominant reflux symptoms and epigastric pain or discomfort benefit from treatment to eradicate H pylori, and our results are robust and generalisable to primary care.

Economic analysis
The cost analysis shows benefits in favour of eradication of H pylori, although the differences were not statistically significant. The study was not powered to detect economic differences. The cost data do, however, provide another justification to advocate the "test for H pylori and treat" strategy. As the time horizon for this study was only one year, economic benefits would be expected to increase over time for patients cured of their dyspepsia. Nevertheless, it is important to keep in mind that at least half of patients will need further prescriptions for dyspepsia after anti-H pylori treatment. We have done further economic modelling and analyses, which support the view that treatment to eradicate H pylori is cost effective.²⁴

Conclusion
This primary care study has shown that the "test with ¹³C-urea breath test and treat to eradicate H pylori" strategy in patients with uninvestigated dyspepsia provides long term relief from symptoms and may reduce healthcare costs.

	Acknowledgments

We thank Joanna Lee, AstraZeneca Canada, for statistical work. We also acknowledge the assistance of the other members of the CADET Summary Group: Alan Thomson, Alan Barkun, and David Armstrong. The CADET-Hp Study Group of principal investigators are G Achyuthan, Regina; D Barr, London; K Bayly, Saskatoon; W Booth, Antigonish; M Cameron, Regina; S Cameron, Halifax; H S Conter, Halifax; S J Coyle, Winnipeg; B N Craig, Saint John; R K Dunkerley, London; J Hii, Vancouver; W P House, Vancouver; E Howlett, Saskatoon; F F Jardine, Manuels; D Johnson, Winnipeg; K Kausky, Whistler; H Langley, Kingston; K R Loader, Brandon; P V Mayer, Kingston; D M McCarty, Edmonton; S Moulavi, Montreal; M Murty, Orleans; W O'Mahony, Corunna; P O'Shea, St John's; G Pannozzo, Waterloo; J Price, Portage La Prairie; P Sackman, Calgary; C L Sanderson-Guy, Nepean; K Saunders, Winnipeg; D Shu, Coquitlam; RJ Smith, Mount Pearl; T Tobin, Guelph; G R Webb, Grand Bay; P Whitsitt, Oshawa; W Winzer, Orleans; and P Wozniak, Cambridge.

Contributors: see bmj.com

	Footnotes

Funding: The study was financially supported by AstraZeneca Canada Inc.

Competing interests: NC and SJOVvanZ have acted as consultants and have received research support and honorariums for giving talks on this subject by the sponsor, AstraZeneca Canada, who manufacture omeprazole. PS and RAF are former employees of AstraZeneca Canada, and SE and EG are current employees of AstraZeneca Canada (sponsors of the study).

The full version of this article appears on bmj.com

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(Accepted 25 January 2002)