Papers

Randomised trial of endoscopy with testing for Helicobacter pylori compared with non-invasive H pylori testing alone in the management of dyspepsia

K E L McColl, professor of gastroenterology ^a, L S Murray, statistician ^a, D Gillen, consultant gastroenterologist ^a, A Walker, health economist ^b, A Wirz, research sister ^a, J Fletcher, consultant gastroenterologist ^a, C Mowat, specialist registrar in gastroenterology ^a, E Henry, specialist registrar in gastroenterology ^a, A Kelman, physicist ^a, A Dickson, study manager ^a. 

^a Primary care p 1012 University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, ^b Robertson Institute, University of Glasgow, Glasgow G12 8QQ

Correspondence to: K McColl K.E.L.McColl{at}clinmed.gla.ac.uk

	Abstract

Top Abstract Introduction Methods Results Discussion References

Objective: To compare the efficacy of non-invasive testing for Helicobacter pylori with that of endoscopy (plus H pylori testing) in the management of patients referred for endoscopic investigation of upper gastrointestinal symptoms.
Design: Randomised controlled trial with follow up at 12 months.
Setting: Hospital gastroenterology unit.
Participants: 708 patients aged under 55 referred for endoscopic investigation of dyspepsia, randomised to non-invasive breath test for H pylori or endoscopy plus H pylori testing.
Main outcome measure: Glasgow dyspepsia severity score at one year. Use of medical resources, patient oriented outcomes, and safety were also assessed.
Results: In 586 patients followed up at 12 months the mean change in dyspepsia score was 4.8 in the non-invasive H pylori test group and 4.6 in the endoscopy group (95% confidence interval for difference -0.7 to 0.5, P=0.69). Only 8.2% of patients followed up who were randomised to breath test alone were referred for subsequent endoscopy. The use of non-endoscopic resources was similar in the two groups. Reassurance value, concern about missed pathology, overall patient satisfaction, and quality of life were similar in the two groups. The patients found the non-invasive breath test procedure less uncomfortable and distressing than endoscopy with or without sedation. No potentially serious pathology requiring treatment other than eradication of H pylori was missed.
Conclusion: In this patient group, non-invasive testing for H pylori is as effective and safe as endoscopy and less uncomfortable and distressing for the patient. Non-invasive H pylori testing should be the preferred mode of investigation.

What is already known on this topic Endoscopy is a commonly used investigation for upper gastrointestinal symptoms, but its effectiveness has been questioned Non-invasive testing for Helicobacter pylori has been shown to predict endoscopic diagnosis in patients with dyspepsia What this study adds In patients less than 55 years of age with uncomplicated dyspepsia, non-invasive testing for H pylori is as effective and as safe as endoscopy Non-invasive H pylori testing is as reassuring to the patient as endoscopy and is less uncomfortable and distressing

	Introduction

Top Abstract Introduction Methods Results Discussion References

More than 1% of the population of the United Kingdom undergo gastroscopy each year.¹ Despite this widespread use of the procedure, a recent qualitative systematic review concluded that "the preponderance of available data does not support the effectiveness of endoscopy in the management of dyspepsia."² One of the main reasons for performing endoscopy in patients with dyspepsia is to detect underlying ulcer disease. However, non-invasive testing for Helicobacter pylori has been shown to be a useful predictor of endoscopic diagnosis in patients with dyspepsia.^3-6

Considerable interest exists in using non-invasive H pylori testing in place of endoscopy to determine the management of patients presenting with upper gastrointestinal symptoms. Patients with a negative H pylori test could be reassured that they do not have underlying ulcer disease and could be treated symptomatically, as would occur after an endoscopic examination showing no abnormality or evidence of oesophagitis. Patients with a positive H pylori test could all be given treatment to eradicate H pylori, which would cure the subgroup with underlying ulcer disease.

We present the results of a randomised trial comparing non-invasive testing for H pylori with endoscopy in the management of patients referred for endoscopic investigation of upper gastrointestinal symptoms.

	Methods

Top Abstract Introduction Methods Results Discussion References

We recruited participants from patients referred by their general practitioners to the hospital for endoscopic investigation of upper gastrointestinal symptoms. Exclusion criteria were age 55 or over, use of non-steroidal anti-inflammatory drugs (excluding low dose aspirin), presence of sinister symptoms (dysphagia, recent weight loss of more than 3 kg, persistent vomiting, recent evidence of upper gastrointestinal bleeding), first degree relative with upper gastrointestinal malignancy, or history of gastric surgery.

Baseline assessment
At their single visit to the clinic, the patients had a structured interview by either a consultant gastroenterologist or a specialist registrar in gastroenterology. Details recorded included the character of the patient's predominant symptom and any history of use of non-steroidal anti-inflammatory drugs or other drugs. We assessed the severity of symptoms over the six months preceding the visit with the Glasgow dyspepsia severity score.⁷

We assessed quality of life with the short form health survey (SF-36).⁸ We asked patients about their degree of worry about their condition and about their degree of concern that they might have a sinister underlying disease. These were recorded on a 0-10 Likert-type scale.

Intervention
We then invited all eligible patients to participate in the study by being randomised to endoscopy plus breath test for H pylori or breath test alone. Immediately after allocation, patients underwent either endoscopy plus the breath test or the breath test alone. During the endoscopy, we took biopsies from both the antrum and body region for histology and urease slide test. We performed the ¹⁴C-urea breath test as previously described,⁹ except that we used a citric acid drink in place of a fatty drink in order not to obscure the endoscopic view. The patients randomised to endoscopy also underwent the breath test. The breath test was analysed on site, and the result was available within 30 minutes.

Patients who had undergone endoscopy were informed of the findings and of their H pylori status. Patients who had only the breath test were also informed of the result. If it was positive, we told them that they might have an underlying ulcer that would benefit from treatment of the infection and that studies in our population also indicated symptomatic benefit from treating the infection even in the absence of an ulcer.¹⁰ We reassured patients with a negative breath test result that they were very unlikely to have an ulcer and that their symptoms were likely to be due to gastro-oesophageal reflux disease or non-ulcer dyspepsia. All patients testing positive for H pylori were given a seven day course of H pylori eradication treatment consisting of omeprazole 20 mg twice daily, clarithromycin 250 mg three times daily, and amoxycillin 500 mg three times daily. All patients were told to see their general practitioner for further treatment if their symptoms persisted.

Before they left the clinic, we asked patients to score the degree of discomfort or distress caused by their diagnostic test on an 0-6 integer scale. In addition, we asked them if they would have the same test again happily, reluctantly, or never. We asked patients who had had an endoscopy whether they would have it again with or without sedation.

Follow up
One year after randomisation, the Glasgow dyspepsia severity score and the SF-36 quality of life assessment were repeated. Details were also obtained from the patient about visits to the general practitioner or hospital for dyspepsia or other conditions, further investigations, and use of prescribed and over the counter drugs for dyspepsia or other conditions since randomisation. In addition, patients were asked about their concern regarding their condition, their concern about possible missed underlying disease, and their overall satisfaction with their initial investigation and management. The patients also had a ¹⁴C-urea breath test to re-check their H pylori status.

	Results

Top Abstract Introduction Methods Results Discussion References

From October 1997 to October 1999, we saw 967 patients aged under 55 at the one stop dyspepsia clinic, which represented 81% of those who had been sent appointments. Of these 967 patients, 248 were not eligible for randomisation and 11 refused. In total, 352 patients were randomised to endoscopy with H pylori testing and 356 patients to non-invasive H pylori testing alone. The two groups were similar at baseline (table 1). Table 2 shows the endoscopic findings in the patients randomised to that investigation, subclassified according to predominant symptom and H pylori status.

One year after randomisation 292 (83%) of the 352 patients randomised to endoscopy and 294 (83%) of the 356 patients randomised to non-invasive H pylori testing could be reassessed. The H pylori eradication rates at one year in the two groups were 79% (119/150) and 84% (118/141).

Primary outcome
One year after randomisation, the mean change in the Glasgow dyspepsia severity score was similar in the endoscopy and non-invasive H pylori testing groups at 4.8 and 4.6 (95% confidence interval for difference 0.7 to 0.5, P=0.69). The mean scores at one year were similar at 5.4 and 5.6 in the two groups. The proportion of patients with complete resolution of dyspepsia (score <2) was similar in the two groups at 42/291 (14%) and 33/293 (11%) (2% to 9% for difference, P=0.25).

Subsequent use of medical resources
The two groups were similar at one year with respect to proportions attending their general practitioner and hospital and use of prescribed and over the counter drugs over the 12 month period since randomisation. They were also similar with respect to repeat referral for further non-endoscopic investigations (table 3).

Of the 292 patients randomised to initial endoscopy and followed up, five (1.7%) were referred for a further endoscopy, compared with 24 (8.2%) of the 294 patients randomised to initial non-invasive H pylori testing (95% confidence interval for difference 3% to 10%, P<0.001).

Patient oriented outcome
One year after randomisation, mean overall concern of patients about their disease and concern about missed pathology were similar in the two groups (table 3). The relative reassurance after non-invasive H pylori testing compared with endoscopy was unaffected by the magnitude of concern about serious disease at the time of randomisation (see bmj.com). Overall satisfaction with initial investigation and management and SF-36 quality of life scores at one year after randomisation were similar in the two groups (see bmj.com).

We also assessed the patients' experience of the two investigational procedures on an integer scale of 0 to 6, with 0 indicating no recollection, 1 no discomfort, and 6 severe distress. After the breath test, 96% of patients gave the test a score of 1, whereas only 13% of patients randomised to endoscopy had a score of 0 or 1 (95% confidence interval for difference 78% to 87%, P=0.000) (see bmj.com). Of the patients randomised to endoscopy, 20% elected to have intravenous sedation with midazolam. Of those sedated, 32% could not remember the procedure, and the median score in the remainder was 2. The median score after the endoscopy without sedation was 4. After non-invasive H pylori testing, 341/342 (99.7%) said they would happily have it again compared with 38/66 (58%) after endoscopy with sedation and 79/256 (31%) after endoscopy without sedation. After endoscopy without sedation, 66/253 (26%) said they would take sedation if they had to have the procedure again (see bmj.com).

Safety
The only potentially serious abnormality detected was a low grade gastric mucosal associated lymphoid tumour (MALT) identified in a routine biopsy from one of the H pylori positive patients (table 2). Further investigation indicated that this was confined to the gastric mucosa and needed no treatment other than the H pylori eradication treatment that had been given under the routine study protocol. The endoscopic diagnosis in the 24 patients randomised to non-invasive H pylori testing and then referred later for endoscopy showed no abnormality in 17 patients, oesophagitis grade I in three, oesophagitis grade II in two, and duodenal ulcer in one; the remaining patient could not tolerate the examination.

	Discussion

Top Abstract Introduction Methods Results Discussion References

Safety
A concern about widespread implementation of non-invasive H pylori testing in place of endoscopy is that upper gastrointestinal malignancy may be missed in some patients. For that reason, we excluded patients with sinister symptoms and those aged 55 or over. A previous retrospective study in our catchment area¹¹ and one from another region in the United Kingdom¹² indicated that underlying malignancy in such patients presenting for endoscopy was extremely rare and when present was rarely curable. In this study, of the 352 patients who were randomised to initial endoscopy only one had a potentially serious condition.

It is often assumed that non-endoscopic investigation strategies will be inappropriate for patients who are particularly worried about an underlying serious disease at initial presentation. However, our study indicated that the most worried patients had equivalent reassurance from endoscopy and non-invasive breath test.

Generalisability
Are the results of our study generalisable to other regions and populations? The prevalence of infection with H pylori in our patients with dyspepsia was approximately 50%, which is similar to the mean value of 55% reported in a large meta-analysis of the prevalence of H pylori in patients with non-ulcer dyspepsia.¹³ However, the prevalence of the infection varies considerably, depending largely on the socioeconomic status and age of the group being studied.¹⁴ In populations with a very low prevalence of the infection and of H pylori related ulcer disease, both investigation strategies may be superfluous.

There is only one previous study randomising patients with upper gastrointestinal symptoms to non-invasive H pylori testing or endoscopy.¹⁵ That study concluded that the test and eradicate H pylori strategy was as efficient and safe as prompt endoscopy. However, slightly fewer patients were very satisfied one year after non-invasive H pylori testing (56%) than after endoscopy (62%). In contrast, we found that satisfaction was similar after the two strategies, and this may be related to our specialist team providing the patients with a fuller description of the relative merits of the two modes of investigation.

One previous study compared the cost of management by non-invasive H pylori testing or by endoscopy by randomising general practices to the two investigation strategies.¹⁶ Over the 12 months after randomisation, the total cost of consultations, referrals, investigations, and treatment was on average £404.31 in the endoscopy group compared with only £205.67 in the non-invasive H pylori testing group.

Two smaller studies have compared H pylori testing with endoscopy in subgroups of patients with dyspepsia referred for endoscopy. ^{4 6} No differences were found between the two investigation strategies with respect to resolution of dyspepsia, use of drugs, or visits to the general practitioner. Use of endoscopy was reduced by 83% over the two year follow up.

Conclusion
Our current study and the previous studies, therefore, all indicate that non-invasive testing for H pylori is as effective as endoscopy in managing patients with uncomplicated upper gastrointestinal symptoms. The non-endoscopic strategy has two potential benefits. The first is that patients find the procedure of non-invasive H pylori testing less uncomfortable and distressing than endoscopic examination. The second is that non-invasive H pylori testing is substantially cheaper than endoscopy. For these reasons, non-invasive H pylori testing seems to be the preferred investigation for patients with uncomplicated dyspepsia.

Finally, it should be emphasised that our study provides information on the relative merits of only two investigational strategies. It is likely that other approaches, such as empirical treatment without investigation or the use of other investigations, will be more appropriate for certain patients.

	Acknowledgments

   Contributors: see bmj.com

	Footnotes

Funding: The study was commissioned and funded by the NHS Executive research and development technology assessment programme. The views expressed in this paper are those of the authors and not necessarily those of the Department of Health.

Competing interests: None declared.

The full version of this article appears on bmj.com

	References

Top Abstract Introduction Methods Results Discussion References

1.	Ryder SD, O'Reilly S, Miller RJ, Ross J, Jacyna MR, Levi AJ. Long term acid suppressing treatment in general practice. BMJ 1994; 308: 827-830[Abstract/Full Text].
2.	Ofman JJ, Rabeneck L. The effectiveness of endoscopy in the management of dyspepsia: a qualitative systematic review. Am J Med 1999; 106: 335-346[Medline].
3.	McColl KEL, El-Nujumi A, Murray L, El-Omar E, Gillen D, Dickson A, et al. The Helicobacter pylori breath test: a surrogate marker for peptic ulcer disease in dyspeptic patients. Gut 1997; 40: 302-306[Abstract].
4.	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: 983-989[Medline].
5.	Patel P, Khulusi S, Mendall MA, Lloyd R, Jazrawi R, Maxwell JD, et al. Prospective screening of dyspeptic patients by Helicobacter pylori serology. Lancet 1995; 346: 1315-1318[Medline].
6.	Heaney A, Collins JSA, Watson RGP, McFarland RJ, Bamford KB, Tham TCK. 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: 186-190[Abstract/Full Text].
7.	El-Omar EM, Banerjee S, Wirz A, McColl KEL. The Glasgow dyspepsia severity scorea tool for the global measurement of dyspepsia. Eur J Gastroenterol Hepatol 1996; 8: 967-971[Medline].
8.	Garratt AM, Ruta DA, Abdalla MI, Buckingham JK, Russell IT. The SF36 health survey questionnaire: an outcome measure suitable for routine use within the NHS? BMJ 1993; 306: 1440-1444[Medline].
9.	Mowat C, Murray L, Hilditch TE, Kelman A, Oien K, McColl KEL. Comparison of Helisal rapid blood test and 14C-urea breath test in determining Helicobacter pylori status and predicting ulcer disease in dyspeptic patients. Am J Gastroenterol 1998; 93: 20-25[Medline].
10.	McColl KEL, Murray L, El-Omar E, Dickson A, El-Nujumi A, Wirz A, et al. Symptomatic benefit from eradicating Helicobacter pylori infection in patients with non-ulcer dyspepsia. N Engl J Med 1998; 339: 1869-1874[Abstract/Full Text].
11.	Gillen D, McColl KEL. Does concern about missing malignancy justify endoscopy in uncomplicated dyspepsia in patients aged less than 55? Am J Gastroenterol 1999; 94: 75-79[Medline].
12.	Christie J, Shepherd NA, Codling BW, Valori RM. Gastric cancer below the age of 55: implications for screening patients with uncomplicated dyspepsia. Gut 1997; 41: 513-517[Abstract/Full Text].
13.	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: 1040-1044[Abstract/Full Text].
14.	Woodward M, Morrison C, McColl K. An investigation into factors associated with Helicobacter pylori infection. J Clin Epidemiol 2000; 53: 175-181[Medline].
15.	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: 455-460[Medline].
16.	Jones R, Tait C, Sladen G, Weston-Baker J. A trial of a test-and-treat strategy for Helicobacter pylori positive dyspeptic patients in general practice. Int J Clin Pract 1999; 53: 413-416[Medline].

(Accepted 2 February 2002)