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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Aliment Pharmacol Ther 2010; 32: 394–400

Summary

Background  Chronic infection of the stomach with Helicobacter pylori is widespread throughout the world and is the major cause of peptic ulcer disease and gastric cancer. Short-term benefit results from community programmes to eradicate the infection, but there is little information on cumulative long-term benefit.

Aim  To determine whether a community programme of screening for and eradication of H. pylori infection produces further benefit after an initial 2-year period, as judged by a reduction in GP consultations for dyspepsia.

Methods  A total of 1517 people aged 20–59 years, who were registered with seven general practices in Frenchay Health District, Bristol, had a positive 13C-urea breath test for H. pylori infection and were entered into a randomized double-blind trial of H. pylori eradication therapy. After 2 years, we found a 35% reduction in GP consultations for dyspepsia (previously reported). In this extension to the study, we analysed dyspepsia consultations between two and 7 years after treatment.

Results  Between two and 7 years after treatment, 81/764 (10.6%) of participants randomized to receive active treatment consulted for dyspepsia, compared with 106/753 (14.1%) of those who received placebo, a 25% reduction, odds ratio 0.84 (0.71, 1.00), P = 0.042.

Conclusions  Eradication of H. pylori infection in the community gives cumulative long-term benefit, with a continued reduction in the development of dyspepsia severe enough to require a consultation with a general practitioner up to at least 7 years. The cost savings resulting from this aspect of a community H. pylori eradication programme, in addition to the other theoretical benefits, make such programmes worthy of serious consideration, particularly in populations with a high prevalence of H. pylori infection.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Chronic infection of the stomach with Helicobacter pylori is widespread throughout the world, affecting more than half of the global population. It is a serious and costly public health problem,1 being the major cause of peptic ulcer disease and gastric cancer. H. pylori infection is usually acquired in early life and then persists long-term unless it is eradicated. Infected individuals may develop peptic ulcers at any age and they remain at risk of this throughout their lives. In contrast, gastric cancer develops generally in older age groups. Peptic ulcer disease is common, with a prevalence of 2–3% in developed countries like the United States and Australia.2, 3 Management is expensive, for example costing about six billion dollars each year in the USA.4 Gastric cancer is also common, being the second most frequent cause of cancer deaths worldwide, and accounting for approximately 800 000 deaths each year.5 This considerable morbidity might be prevented by a programme of screening for and eradication of H. pylori infection, because in adults re-infection following eradication is uncommon.

Eradication of H. pylori infection from a community should, in theory, be quite straightforward. The population would be screened for the infection and all infected subjects would then be given a course of H. pylori eradication therapy. The costs of carrying out such a programme would be offset by the potential future savings resulting from the reduced requirement to treat peptic ulcer disease and gastric cancer over subsequent years. The clinical and financial benefits of preventing gastric cancer would usually be delayed for many years after H. pylori eradication, making such a programme aimed at cancer prevention less immediately attractive financially.6 In contrast, dyspepsia due to peptic ulcer disease, although only one of several causes of dyspepsia, is much more common and can occur at any age. Cost savings due to prevention of H. pylori-related dyspepsia by a community H. pylori eradication programme should be apparent within a much shorter time. The rationale of such a programme differs from that of the ‘test and treat’ management of dyspepsia, since as many as possible of the population are included, irrespective of any symptoms. Some participants may benefit immediately, by being cured of previously untreated H. pylori-related dyspepsia, but the main effect of a community H. pylori eradication programme is to prevent the future development of any H. pylori-related peptic ulcers. If the benefits continue to accumulate over many years, the long-term savings in health costs could make a community H. pylori eradication programme an economically realistic possibility.7

We have carried out a large double-blind community-based trial of the effects of H. pylori infection and its eradication on the symptoms, treatment and costs of dyspepsia in the community, the Bristol Helicobacter Project.8 This has shown that screening for and eradication of H. pylori infection in a community is feasible and effective. Beneficial effects were seen within 2 years, with a 35% reduction in general practitioner (GP) consultations for dyspepsia in the group receiving active treatment.9 Cost-effectiveness calculations showed a slightly greater cost in the group given active treatment, the difference being approximately equivalent to the cost of the eradication therapy. However, if further benefit continued to accumulate over subsequent years, cost-effectiveness would most probably be substantially increased.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study extended the original Bristol Helicobacter Project.8, 9 All people aged 20–59 years who were registered with seven general practices in North East Bristol (total 26 203) were invited to participate in a community-based prospective randomized controlled trial of the effects of H. pylori eradication on dyspepsia, quality of life and health resource utilization. A total of 10 537 individuals (40.2%) gave informed consent to take part in the study and had a 13C-urea breath test for active H. pylori infection, using a standard orange juice and citric acid test meal, with a cut-off of δ3.5 per mL.10

In all, 1558 of 1634 participants whose 13C-urea breath test showed that they had H. pylori infection (95.2%) were randomized in equal numbers to receive clarithromycin, 500 mg twice daily and ranitidine bismuth citrate 400 mg twice daily for 2 weeks or matching placebo.8 The unit of randomization was the individual. Randomization was stratified by age into four bands of 10 years (20–29 to 50–59) and by gender. Staff independent of the study prepared the randomization schedule by computer with a block size of ten. Pharmacists who prepared the study medication had no contact with study participants and knew only their age stratum, gender and study number. Sealed opaque envelopes containing individual randomization codes were held by the study coordinator (JA Lane). These envelopes were only opened after 2 years, unless a participant was being withdrawn from the study (e.g. following a suspected adverse reaction to the treatment or at the request of their physician). We asked participating primary care physicians not to prescribe H. pylori eradication therapy during the first 2 years of follow-up.

Sample size calculations were based on the primary end point. H. pylori prevalence was projected to be 15%. It was assumed that the eradication of H. pylori infection would only reduce dyspepsia in those participants who suffered from undiagnosed peptic ulcer disease. On the basis of findings from a survey done in the same region as this study,11 and other evidence,12 we assumed that in a 6-month period 8.5% of 20–59 years olds would consult their general practitioner because of dyspepsia and that 20–25% of these would have peptic ulcers, with at least 80% of these ulcers being caused by H. pylori infection. A total sample size of 1500 participants would detect a reduction in the consultation rate from 8.5% to 4.25% in the eradication group, with 90% power at a significance level of 5%.

The main outcome measure was a consultation with the general practitioner between 2 and 7 years after randomization and treatment, which had been recorded in the participants’ primary care notes as being for upper abdominal pain or discomfort.13 Consultations for heartburn or reflux were also noted. During the trial, the randomization codes for each participant were held in opaque sealed envelopes, the participants being identified only by trial number. After 2 years and again after 7 years, the research nurse (who was blind to the treatment allocation) visited the relevant general practice surgery during the outcome assessment. The nurse retrieved the medical records of each participant and reviewed all entries made over the period of the study, recording the dates and details of any consultations for any of the above upper alimentary symptoms, together with any medications prescribed and any related hospital referrals. The primary outcome measure was any consultation for dyspepsia, defined as pain or discomfort centred in the upper abdomen, as described in the Rome criteria for functional dyspepsia.13 A secondary outcome was a consultation for heartburn or reflux. The reliability of the data extraction from the medical records by the nurse was validated by a consultant gastroenterologist in a random sample of 20 successive participants and found to be accurate and complete. Details of the numbers in each category are shown in the Consort flow chart (Figure 1).

image

Figure 1.  Trial profile.

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The study was approved by Frenchay Healthcare NHS Trust Research Ethics Committee for Bristol and District Health Authority. All prospective participants were sent an information sheet with full details of the project, and written informed consent was obtained by a research nurse when they attended for their first breath test.

Statistical analysis of the data was carried out using spss version 10.14 The significance of differences was assessed by Pearson’s chi-square test. Analyses of consultation rates between 2 and 7 years after treatment were performed using odds ratios on an intention-to-treat basis. In addition, the influence of age and gender were analysed by randomization groups, also using Pearson’s chi-square test and odds ratios.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study population

Of the 10 537 participants who had a 13C-urea breath test, 1634 (15.5%) were positive for H. pylori infection and were eligible for inclusion in the randomized controlled trial of H. pylori eradication therapy. A total of 1558 (95.2% of those testing positive) were randomized to receive either active treatment (n = 787) or placebo (n = 771). The characteristics of the two groups were similar, and are shown in Table 1.

Table 1.   Baseline characteristics of the two groups of subjects with Helicobacter pylori infection who entered the prospective double-blind study
 Active treatment (n = 787)Placebo treatment (n = 771)
  1. The slight differences in the figures for total number are due to incomplete or missing data entry by some of the subjects.

Age (years) at time of recruitment (%)
 20–39120/787 (15.2)110/771 (14.3)
 40–54452/787 (57.5)451/771 (58.5)
 55–59215/787 (27.3)210/771 (27.2)
Gender (%)
 Male385 (48.9)378 (49.0)
 Female402 (51.1)393 (51.0)
Lifestyle (%)
 Smoking – (never)405/767 (52.8)389/764 (50.9)
  (past)179/767 (23.3)190/764 (24.9)
  (current)183/767 (23.9)185/764 (24.2)
 NSAIDs (any in last 3 months)177/732 (24.2)191/720 (26.5)
 BMI 30 or greater221/787 (28.2)195/771 (25.3)

Completeness of Helicobacter pylori eradication and of follow-up

Six months after treatment, the second 13C-urea breath test showed that H. pylori infection was no longer present in 714/787 (90.7%) of those receiving active treatment. Follow-up 7 years after treatment was complete in 1517 of the 1558 participants (97.4%), the remaining 41 having either died11 or moved away (30).

Participants consulting for dyspepsia

In the period between 2 and 7 years after treatment, 81/764 (10.6%) of participants given active therapy consulted their general practitioner for symptoms of dyspepsia, compared with 106/753 (14.1%) of those who had placebo, odds ratio (OR) 0.84 (0.71, 1.00), P = 0.042. Of these, 47/764 (6.2%) of the participants given active therapy and 61/753 (8.1%) of those who received placebo consulted for dyspepsia for the first time more than 2 years after randomization, having not consulted previously OR 0.85 (0.69, 1.06), P = 0.084 (Table 2). Over the whole 7-year period, 102/782 participants given active treatment consulted for dyspepsia, compared with 139/757 given placebo, OR 0.69 (0.51, 0.88), P = 0.041.

Table 2.   Number of participants consulting for dyspepsia in the 7 years after randomization
Randomization group0–2 years2–7 years0–7 years
Participants consulting for dyspepsiaParticipants consulting for dyspepsia who had not consulted between 0 and 2 yearsParticipants consulting for dyspepsia who consulted in first 2 yearsAll participants consulting for dyspepsia after 2 yearsAll participants consulting for dyspepsia
Placebo78/757 (10.3%)61/753 (8.1%)45/753 (6.0%)106/753 (14.1%)139/757 (18.4%)
Active therapy55/782 (7.0%)47/764 (6.2%)34/764 (4.4%)81/764 (10.6%)102/782 (13.0%)

Influence of gender on consultations for dyspepsia

The benefit of receiving active H. pylori eradication therapy appeared to be greater in men than in women. In the period between 2 and 7 years after treatment, 41/366 (11.2%) of men given active therapy consulted for dyspepsia, compared with 64/348 (18.4%) of those who had placebo, [OR 0.73 (0.57, 0.94), P = 0.008]. In the same period, 40/398 (10.1%) of women given active therapy consulted for dyspepsia, compared with 42/405 (10.4%) of those who had placebo, OR 0.98 (0.78, 1.24), P = 0.908.

Influence of age on consultations for dyspepsia

The benefits of active treatment were more obvious in older participants; in those aged 45 years and above who were given active therapy, 57/543 (10.5%) consulted, compared with 82/545 (15.0%) of those given placebo, OR 0.80 (0.65, 0.99), P = 0.029. In contrast, of those aged 44 or less who were given active therapy 24/221 (10.9%) consulted, compared with 24/208 (11.5%) of those given placebo, OR 0.97 (0.72, 1.30), P = 0.879.

Participants consulting for heartburn or reflux

There was no difference in the rate of consultation for new heartburn and/or reflux (i.e. developing for the first time more than 2 years after randomization) [OR 0.99 (0.83, 1.15), P = 0.81 (Table 3)].

Table 3.   Number of participants consulting for heartburn and/or reflux
 0–2 years2–7 years0–7 years
  1. The slight differences in the total figures are due to incomplete data entry by some of the subjects.

Placebo20/753 (2.7%)71/753 (9.4%)86/753 (11.4%)
Active therapy32/764 (4.2%)61/764 (8.0%)84/764 (11.0%)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The Bristol Helicobacter Project was set up to assess the feasibility and costs of a programme aimed at the complete eradication of H. pylori infection from a community. This would have obvious health benefits, abolishing dyspepsia due to H. pylori-related peptic ulcer disease (as well as the serious complications of bleeding and perforation) and reducing the risk of gastric cancer. After 2 years, we found that detection and eradication of H. pylori infection was straightforward and effective. Consultations with the general practitioner for dyspepsia were reduced by 35% within 2 years.9 The costs per individual were dominated by the cost of the H. pylori eradication therapy we used. This was a nonstandard regime designed specifically for this trial, with the aim of achieving as high an eradication rate as possible, by using a 2-week course of acid suppressant, antibiotic and bismuth. The H. pylori eradication rate achieved (90.7%) was the best ever recorded in any community-based study, but the treatment cost at that time [£83.40 ($146, €121)] was more than three times greater than the cost of currently available regimes. We concluded then that the cost-effectiveness of a community H. pylori eradication programme in a population such as ours, with a relatively low prevalence of H. pylori infection, was inferior to that of a targeted H. pylori test and treat strategy focusing on un-investigated dyspeptic patients. There is still debate as to whether a test and treat strategy is more or less appropriate than initial management of dyspeptic patients with acid suppressant medication (in a UK population, the cost-effectiveness is similar),15–17 but the result of such comparisons depends, to a great extent, on the population concerned, in particular the local prevalence of H. pylori infection. In most developed countries, the prevalence of H. pylori infection has been falling in recent years, particularly in younger age groups, with a closely related decrease in the incidence of peptic ulcer disease.18 This relatively rapid decrease has not been due to the use of H. pylori eradication, but probably mostly to improvements in public health reducing the transmission of H. pylori infection. This process seems to be very variable, so that even within a single country like the UK, the prevalence of H. pylori infection varies greatly. Thus, in 50-year-old men, the prevalence of H. pylori infection is 15% in Bristol,8 30% in Leeds19 and 60% in Glasgow.20 The cost-effectiveness of a community H. pylori eradication programme would clearly be very different in these three areas and it could be argued that such a programme would, in any case, not be worth considering in a particular area if the spontaneous rate of decline in H. pylori infection in that area was rapid. Before considering any community H. pylori eradication programme, the local prevalence of the infection would therefore need to be ascertained. Thus, in Leeds, where the prevalence of H. pylori infection is approximately twice that in Bristol, a 40% follow-up of a community screening and H. pylori eradication programme in 40–49-year olds suggested that the savings in healthcare costs were greater than the costs of carrying out the programme.7 In areas where H. pylori infection is becoming less common, the proportion of non-H. pylori-related peptic ulcers is increasing. Most of these are related to treatment with NSAIDs, but a few seem not to have any known cause.

Our choice of a consultation with a general practitioner for dyspepsia as our main outcome measure was based on the hypothesis that H. pylori eradication would reduce dyspepsia by preventing the later development of peptic (mainly duodenal) ulcers. The most common symptom of such ulcers is pain in the upper abdomen, ‘dyspepsia’.13 Minor dyspepsia is extremely common in the community,21 which would create considerable background ‘noise’ against which any changes due to H. pylori eradication might appear to be relatively small. Dyspepsia due to peptic ulcer disease is usually marked, so would be more likely to result in the sufferer seeking a medical consultation. This hypothesis is supported by the findings of an unblinded but otherwise similar study to ours,22 in which a screening and H. pylori eradication programme in Denmark showed after 5 years no significant effect on dyspepsia prevalence, but a significantly reduced consultation rate for dyspepsia.23 A consultation would also represent objective ‘hard’ evidence, which would always be recorded in the medical notes and would thus be available for assessment over many later years, ensuring a maximal follow-up rate. Factors influencing the frequency and reasons for consultation for dyspeptic symptoms have been reviewed recently.24 Independent of any H. pylori infection, dyspepsia consultations are influenced by age and gender, so adequate randomization is essential, as achieved in this study.

Our finding of an apparently greater benefit from H. pylori eradication in men than in women is unexplained. However, very similar findings were reported from the Leeds community H. pylori eradication study,19 where dyspepsia at 2 years was reduced in the eradication group from 36% to 27% in men, but only from 31% to 30% in women. One possible explanation is that peptic ulcer disease is more frequent among men than among women infected with H. pylori. Thus, in the mid-20th century, when most of the UK population had H. pylori infection, approximately 80% of peptic ulcers in the UK were seen in men.25 The biological explanation for these gender differences remains unknown.

Consultation rates for heartburn and gastro-oesophageal reflux over the period from 2 to 7 years after randomization were not affected by H. pylori eradication, confirming the findings after 2 years of follow-up.26

The strengths of this study are that large numbers of participants across a wide age range were recruited with few exclusions, thus increasing generalizability. The high rates of H. pylori eradication and follow-up enhance the internal validity of the study, whilst the breath test (the non-invasive ‘gold standard’ detection method) minimized misclassification biases and probably facilitated recruitment compared with serology, as no blood test was necessary. The clinically important primary outcome of dyspepsia consultations in primary care allowed objective reporting from the medical notes without further patient contact, giving a very high rate of follow-up, even after 7 years. All participants were followed up for 7 years, even if they had consulted their general practitioners after a shorter interval. Potential unblinding after 2 years did not seem to have been a significant problem, as very few requests for unblinding were received from the GPs. Prescribing information was obtained for all participants. Only 41 (2.6%) had been given H. pylori eradication therapy by their GPs, 35 of these had received placebo and were H. pylori positive and six had received H. pylori eradication therapy and were H. pylori negative.

In a community testing and eradication programme for H. pylori infection, Ford and his colleagues showed that participants who were negative for the infection and were informed of this fact were less likely to seek general practice consultations than those who were not informed.27 This response to knowledge of H. pylori status suggests that there would be further cost savings in any community programme, as there would be fewer consultations by uninfected subjects as well as by those in whom the infection had been eradicated. A further potential benefit might result from a reduction in the incidence of functional (non-ulcer) dyspepsia, some of which might be due to H. pylori infection.28

This present study indicates that H. pylori eradication has a prolonged beneficial legacy, by reducing the development of dyspepsia in individuals infected by H. pylori, so that treated individuals will benefit over many subsequent years, producing significant further cost savings. The costs of the community H. pylori eradication programme we started in the Bristol Helicobacter Project more than 10 years ago would now be substantially lower, as both 13C-urea breath tests and H. pylori eradication therapy have become much cheaper. The cost-effectiveness of such programmes could, in the future, be further increased by concentrating on populations with a high prevalence of H. pylori infection, and perhaps particularly on men. Further benefits would result from a reduction in healthcare use by individuals who know that they do not have H. pylori infection, and in the longer term from the anticipated reduction in gastric cancer. All of these factors together suggest that a combination of improvements in public health with targeted and affordable community H. pylori eradication programmes would speed up the eventual eradication of H. pylori infection from mankind.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Declaration of personal interests: None. We thank the participants in the Bristol Helicobacter Project and the general practitioners and Health Centre staff; the nursing team of Lynne Bradshaw, Julie Watson, Tina Critchley, Jo Lee, Carol Everson-Coombe, Penny Nettlefield and Joanne Smith; Judy Millward, Helen Davies, Amy Hawkins and Sarah Pike for secretarial support and Erwin Brown, Paul Thomas, Nick Pope and Phil Hedges of the Microbiology Department and Peter Spurr, Martin Bullock and Fiona Greenwood of the Pharmacy Department, Frenchay Hospital, for help with the 10 537 breath tests. Declaration of funding interests: This study was funded jointly by the NHS South and West Regional Research and Development Directorate and GlaxoSmithKline UK.

References

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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