HELICOBACTER
PYLORI ERADICATION FOR PEPTIC ULCERATION:
AN
OBSERVATIONAL STUDY IN A SCOTTISH PRIMARY CARE SETTING.
Ewan
H Forrest
Departments of Gastroenterology and Surgery
Royal
Infirmary
Glasgow
Correspondance
to:
Dr
AJ Morris
Department of Gastroenterology
Royal
Infirmary
Castle
Street
Glasgow
G4 0SF
Scotland
UK
Summary
Background- Despite being established for the treatment of peptic ulcer (PU) disease, few studies have assessed the long-term effectiveness and economic benefits of Helicobacter pylori (Hp) eradication in primary care.
Aims- To investigate the effect of community based Hp eradication for patients with chronic peptic ulcer disease requiring maintenance acid suppression.
Endpoints-
Patient's dyspeptic symptoms
and the requirement for the prescription of maintenance acid suppression
therapy.
Setting- Seven general practices in the Glasgow area.
Methods-
Patients with previously diagnosed peptic ulcer disease receiving prescribed
acid suppression therapy were invited to a dyspepsia clinic. Hp
status was assessed by Helisal rapid blood test (HRBT). Positive patients
received Hp eradication therapy and
were reviewed six weeks later. At six months a review of practice records was
carried out, and two years after eradication a postal questionnaire was sent to
participating patients.
Results-
243 patients attended the initial clinic of which 81.9% were HRBT positive. 156
of 196 patients offered Hp eradication
re-attended at six weeks. The per protocol eradication rate was 91.7%. After six
months patients who had received eradication therapy were less likely to require
maintenance acid suppression therapy compared with those to whom eradication was
not given. Two years after treatment 76.5% of patients felt their symptoms were
improved, but 42.2% were still receiving maintenance therapy. The estimated cost
of treatment per month per patient had fallen from £20.23 to £9.39 after
eradication.
Conclusions-
Community based Hp
eradication for patients with chronic PU disease is effective, however it does
not completely alleviate dyspepsia. Predictors of symptomatic response or of no
longer requiring acid suppression therapy after two years were younger age of
onset of PU disease and absence of pre-documented gastro-oesophageal reflux
disease or hiatus hernia. Hp
eradication improves patient's symptoms, reduces the requirement for maintenance
acid suppression and is cost-effective after two years follow-up in this
targeted group.
INTRODUCTION
Since the recognition of Helicobacter Pylori (Hp) as the major cause of peptic ulcer (PU) disease in the 1980s, the treatment of this condition has altered radically. However whilst most medical practitioners now accept the role of Hp in the development of PU disease, the translation of this knowledge into clinical practice has been slower, particularly amongst primary care physicians. By the mid 1990s almost all specialist Gastroenterologists but only two thirds of primary care physicians were using Hp eradication routinely1,2. This is particularly important as it is in the community that the main burden of dyspepsia management rests. It is estimated that 40% of the population experience dyspepsia, of which one half take medication and one fifth attend their general practitioner3. Despite this the majority of studies investigating the effectiveness of Hp eradication have been hospital based, and have predominantly studied patients with newly diagnosed PU disease. Such patients constitute a very small proportion of dyspeptic patients in the community. Whilst only approximately 10-15% of primary care consultations for dyspepsia are for patients with previously diagnosed peptic ulcer4, these patients may account for nearly 50% of long-term prescriptions of acid suppressants5. Studies of Hp eradication in the community out-with controlled clinical trials appear to show less successful outcomes and more confused prescribing practices. One Scottish study revealed 56 different eradication regimens amongst 154 patients, and a recurrence of symptoms in over half the patients treated6. A postal study of medical practitioners in the United States revealed 103 different eradication regimens being prescribed, many of which were judged to be ineffective. In addition not all clinicians felt that Hp eradication was indicated for confirmed PU disease7. In a similar study based in Germany, an even greater proportion of clinicians felt eradication therapy was not indicated on the first presentation of duodenal ulcer8. It is perhaps unsurprising that some disillusionment has arisen concerning the effectiveness of Hp eradication, particularly as patients often continue to complain of dyspeptic symptoms after successful treatment perhaps due to the unmasking or development of gastro-oesophageal reflux disease (GORD)9.
As a result many patients investigated and diagnosed as having PU disease in the ‘pre-Hp’ era remain on maintenance acid suppression therapy. Not only do these patients represent a significant on-going financial cost to the health services, there are theoretical reasons why long-term acid suppression in combination with active Hp infection might predispose to atrophic gastritis, intestinal metaplasia and subsequent neoplasia10. Therefore Hp eradication in this population of patients may have benefits beyond that of symptomatic response.
We
sought to determine whether patients with established PU disease who were still
requiring acid suppression therapy could be effectively treated with Hp eradication in the community, and whether this would
significantly reduce their symptoms and the subsequent prescription of
maintenance treatment.
METHODS
Setting
and Patients.
Patients
in seven General Practices in Glasgow were studied. Practice prescribing records
were used to identify those patients who had received a prescription of acid
suppression therapy, either histamine-2 receptor antagonists (H2RA)
or proton pump inhibitors (PPI). Patients who were receiving regular repeat
prescriptions or prescribed more than two prescriptions per year during the
previous two years were included. Patients receiving non-steroidal
anti-inflammatory drugs were excluded, although patients taking low dose aspirin
were included. The indication for the prescription was then reviewed from
medical records, and those who had had a diagnosis of PU disease (duodenal ulcer
(DU), erosive duodenitis (ED), or gastric ulcer (GU) by either barium meal (BM)
or upper gastro-intestinal endoscopy (UGIE) were identified. Patients with
concomitant GORD or hiatus hernia noted at the time of upper gastro-intestinal
investigation were not excluded. These patients were invited to attend a
Dyspepsia Clinic run by Clinical Nurse Specialists based at the patient’s own
General Practice. Patients who had received Hp
eradication therapy within the last twelve months, and patients who were
pregnant were excluded.
Initial
Dyspepsia Clinic Visit.
At the initial visit, the purpose of the study was explained to the patient and written informed consent obtained from those willing to participate. Details were recorded of the patient’s dyspeptic symptoms over the previous week, other medical conditions, smoking habit and usual weekly alcohol ingestion. It was also recorded whether the original investigation for dyspepsia had documented the presence of GORD or hiatus hernia. Patients who reported ‘sinister’ symptoms of weight loss, melaena, dysphagia, or haematemesis were referred back to their own General Practitioner for further management and excluded from the study. Oesophageal symptoms were defined as heartburn, regurgitation, or odynophagia. A Helisal Rapid Blood Test (HRBT) was performed on each patient. Patients who were positive were offered Hp eradication therapy. The basic regimen was a one week course of Omeprazole 40mg/day, Metronidazole 400mg tds, and Amoxycillin 500mg tds. If a patient had a history of allergy or intolerance to one of the antibiotics, Clarithromycin 500mg bd was used as an alternative. Lansoprazole 30mg bd was used if there was a history of intolerance to Omeprazole.
In
addition to the HRBT, a small random selection of patients had a C13
urea breath test (UBT) performed to test the specificity and sensitivity of the
blood test. HRBT positive but UBT negative patients were not given eradication
therapy.
Second
Dyspepsia Clinic Visit.
After
six weeks, those patients who had received Hp
eradication were invited back to the Dyspepsia Clinic. Dyspeptic symptoms over
the previous two weeks, and the need to restart regular maintenance
prescriptions of acid suppressants were recorded. Patients were asked directly
if they felt their symptoms had improved. Each patient had a UBT performed.
Six
Month Review.
Prescription
records were reviewed, and the need for prescribed acid suppressants recorded.
Two
Year Review.
A
postal questionnaire was sent to all patients who had received Hp
eradication. This asked patients to detail their dyspeptic symptoms as before,
and to record their need for acid suppressants.
Hp
Testing
HRBT
kits were obtained from Cortecs Diagnostics Ltd, UK. C13 UBTs were
carried out as previously described11. Prior to UBT, patients were
fasted overnight and patients were advised to avoid taking antibiotics or acid
suppressants for two weeks. Samples were sent for analysis at the Department of
Biochemistry, Glasgow Royal Infirmary.
Socio-economic
Grouping (SEG).
This
was carried out using two grading systems. Firstly the occupation based
Registrar General’s grade12 was used and secondly the
geographically based Carstair’s Deprivation score (CDS)13.
Smoking and Alcohol Ingestion Grading
Smoking
habits and alcohol ingestion was graded using a standard scale.
Cost
Estimates.
The
cost of Hp eradication and acid
suppression therapy was calculated from the British National Formulary,
September 1998. The cost of maintenance therapy was calculated for those
patients who had received Hp
eradication and who had complete follow-up for 2 years. The cost is estimated
over one month.
Statistical
Analysis.
Statistical
analysis was performed using SigmaStat for Windows (v2.03), SPSS Inc. Data is
described as mean ±
standard error or median (range). Comparisons between groups were made with c2
tests or Mann-Whitney Rank Sum tests. Predictors of outcome were calculated
using Logistic Regression.
RESULTS
Patient
Characteristics and Follow-up.
Of
450 patients identified and invited to the initial Dyspepsia Clinic, 243
attended. The characteristics of these patients are shown in Table
1. Either hiatus hernia or gastro-oesophageal reflux disease (GORD) had been
diagnosed at the time of investigation in 46 (18.9%) of patients. Sixty-six (27.2%) patients also had significant co-morbid illness. The
median time since attempted eradication of the 16 patients who had been
previously treated was 1.75 years (range 1.5 – 5 years). Follow-up of patients
is shown in Figure 1.
HRBT
Testing.
No patient refused HRBT testing. At the initial Dyspepsia clinic 199 (81.9%) of the patients were HRBT positive. Although the ages of the positive and negative groups were not significantly different (57.7 ± 1.0 cf. 61.3 ± 1.9 years), the HRBT positive patients had PU disease diagnosed at a younger age than the HRBT negative patients (45.4 ± 1.3 CF 51.7 ± 2.0 years, p<0.05). 61.3% of HRBT negative patients had oesophageal symptoms at the time of initial assessment compared with only 49.2% of HRBT positive patients (p=0.05).
Forty-three
patients had a UBT in addition to their original HRBT. Of the 25 HRBT negative
patients tested with a UBT, 11 were UBT positive. Only 3 of the 18 HRBT positive
patients had a negative UBT, but one of these had had an attempt at Hp
eradication 2 years before the study began. This gives a sensitivity of only
58%, and a specificity of 88%.
Six
Week Assessment of Eradication.
Of
the 196 patients prescribed Hp
eradication therapy, 156 (79.6%) re-attended the Dyspepsia Clinic six weeks
after treatment. Only 6 patients did not complete their Hp
eradication because of side-effects. However in total 63 patients (40.4%)
experienced side-effects of their treatment. These are shown in Table
2. Only 13 patients were UBT positive at six weeks, however nine patients
had re-started a PPI at the time of assessment and so may have had false
negative results. The per protocol eradication rate was 91.7% and the intention
to treat eradication rate 71.8%.
Symptom
Response.
After
six weeks, 105 patients (67.3%) felt their symptoms had improved after
eradication therapy and there was a significant reduction in reports of nausea
and vomiting.
This general symptomatic improvement after eradication appeared to persist for two years after Hp eradication amongst the majority of patients (78 patients, 76.5%). However overall the patient’s reported symptoms changed little (Figure 2). Actual abdominal discomfort amongst the whole group did not change throughout the period of study. Patients who noted no general improvement after eradication experienced a worsening of specific symptoms, particularly abdominal pain, bloating, and nausea (Table 3). Patients who felt improvement were younger at the time of PU diagnosis (42.2 ± 2.1 cf. 51.0 ± 3.0 years, p<0.05), but there was no significant difference in site of the PU, or in socio-economic status, or smoking and drinking habits.
Predictors
of improvement two years after Hp
eradication were younger age at time of PU diagnosis (p<0.05), absence of
pre-documented hiatus hernia or GORD (p<0.05), and not requiring maintenance
acid suppression six weeks after eradication (p<0.001).
Use
of Maintenance Acid Suppression.
Six weeks after Hp eradication 119 patients of the 156 re-attending (76.3%) no longer required maintenance acid suppression. At six months the records of 202 of the original 243 patients (83.1%) were available to be reviewed. Of these 175 had received Hp eradication therapy after positive Hp testing, and 27 had been negative on Hp testing at the original Dyspepsia Clinic. Of the 175 patients who had received Hp eradication therapy, 91 patients (52%) were no longer prescribed acid suppression. This was a significantly greater number of patients no longer requiring acid suppression than the patients with PU disease for whom Hp eradication had not been indicated at the original Dyspepsia Clinic (7 of 27 patients, 26%; p<0.02). Two years after Hp eradication 59 (57.8%) of the 102 patients followed up did not require regular treatment for dyspepsia (Figure 3). Of the 43 patients taking treatment 55.8% were using PPIs.
Those off treatment were younger at the time of assessment (54.2 ± 1.8 cf. 60.8 ± 1.9 years, p<0.02) and younger at the time of diagnosis (40.1 ± 2.3 cf. 50.0 ± 2.4 years, p<0.005). There were no differences in socio-economic status, or smoking and drinking habits.
Predictors
of no longer requiring maintenance acid suppression two years after Hp eradication were younger age at time of PU diagnosis (p<0.01),
absence of pre-documented hiatus hernia or GORD (p<0.005), symptomatic
improvement six weeks after eradication (p<0.005), and the absence of
co-morbid illness (p<0.05).
Cost-Effectiveness.
The
estimated cost per patient per month of maintenance acid suppression therapy
prior to Hp eradication was £20.23.
The cost of Hp eradication treatment
per patient was £17.73. Two years after Hp
eradication the estimated cost per patient per month of maintenance acid
suppression therapy had fallen to £9.39.
DISCUSSION
There are relatively few published community based studies of Hp eradication. The questions to be answered in primary care differ from those in hospital studies Not only is it important whether the eradication rate is high enough, or whether there is adequate healing of ulceration, but more relevantly whether patients symptoms improve, and whether patients continue to require maintenance therapy. Some community studies have focused upon empirical Hp eradication for sero-positive patients presenting with undiagnosed dyspepsia14,15,16,17. Whilst benefits of this approach are present, these are often small and any financial gain might be slow to become apparent. It would seem more likely that eradication therapy to the satisfaction of both clinician and patient would be achieved if specific patient groups can be targeted for treatment. In the case of patients who have a prior diagnosis of peptic ulcer disease and who are taking long-term acid suppression, the potential benefits of successful eradication are manifest. With healing of their underlying PU disease patients might become asymptomatic, no longer require daily medication, and so reduce GP’s drugs bill. Whilst hospital based studies have suggested clear cost savings after Hp eradication for PU disease18, only few studies have examined this group of patients in the community19,20,21. These studies have suggested that a policy of Hp eradication for patients with long-standing peptic ulcer diagnosis is of both symptomatic and economic benefit.
The current study is less clear with regard to these benefits. We found evidence of Hp infection using ‘near-patient’ HRBT serological testing in the majority of patients with a previous diagnosis of PU disease. The eradication therapy was successful using a standard regimen with an intention to treat eradication rate of 72.9%, and a per protocol eradication rate of 91.7%. This per protocol eradication rate is comparable with other studies that have used similar regimens,22,23. The eradication therapy was well tolerated and the initial patient response was also encouraging, as approximately two-thirds of patients reported a subjective improvement and less than a quarter of patients had sought resumption of their acid suppression therapy six weeks after receiving eradication therapy. However by six months and two years after Hp eradication nearly half the patients had restarted maintenance therapy. Failure of symptoms to resolve completely post-eradication has been noted in previous hospital based studies. Whilst resolution of dyspeptic symptoms is predictive of successful eradication, over 50% of PU patients may continue to complain of significant dyspepsia despite eradication of Hp24.
It is interesting to note that maintenance treatment with PPIs became more common during the study period. This might be due to patients perceiving an improvement in their dyspeptic, possibly GORD-related, symptoms during Hp eradication, and subsequently wishing to continue with the PPI component of their treatment with its more potent acid suppressing ability.
The predictors of response in this study are perhaps not surprising. Those patients with evidence of hiatus hernia or GORD at the time of their initial investigation were more likely to require maintenance therapy, suggesting that reflux disease was the cause, or had become the cause of their dyspepsia. There has been debate concerning the role of Hp eradication in the natural history of GORD25. Our study showed no significant overall change in the prevalence of oesophageal symptoms two years after eradication therapy.
Symptom response and no longer requiring acid suppression after eradication were associated with younger age at the time of diagnosis of PU disease. Previous studies have recognised age-related variations in the natural history of PU disease. Presentation with PU disease at an early age tends to be associated with a family history of PU disease, had greater maximal gastric acid output and post-prandial gastrin levels26,27,28,29. Younger patients may be less likely to respond to cimetidine30, whereas early onset of symptoms was predictive of PU healing by antacids31.
Despite
the acknowledged associations of socio-economic status upon the prevalence of Hp
infection, neither CDS nor Registrar General’s SEG affected subsequent use of
maintenance therapy or patient’s subjective improvement. Outcome after
eradication therapy also appeared independent of alcohol and smoking habits.
Socio-economic status, alcohol use, and smoking have been cited as poor
predictors of PU response to cimetidine therapy30. This does not
appear to be the case for Hp
eradication and so these factors which might be perceived by some clinicians to
limit response should not exclude patients from receiving eradication therapy.
The recurrence of symptoms and requirement of maintenance therapy was much greater than that described in previous primary care studies19, 21, 22 which described a return to maintenance therapy in 4%, 8%, and 22% at one year, 6 months and one year respectively. Important differences exist between the patient population described by these other studies and the current study. Phull et al19 studied younger patients with a shorter time since diagnosis. The majority of patients studied by both Phull et al19 and Lai et al20 had been diagnosed at endoscopy. In addition all these previous studies were smaller in scale and did not have as long a follow-up as the current study. These differences may in part account for some of the apparent discrepancy. However we do concur with these studies that such a programme of Hp eradication is cost-effective and worthwhile.
Our study also gave an insight into methods of assessing Hp status in the community. HRBT has been advocated for the identification of those patients who might benefit from Hp eradication therapy in primary care32,33. However when HRBT was compared to UBT there was a concerning number of false negative results. Such failure to identify infection might prevent patients from receiving potentially beneficial treatment. Other groups have found similar difficulties with HRBT, and it would appear that it is an inadequate test of Hp infection34,35. In contrast the UBT used in this study proved to be an effective means by which Hp status can be detected in the community. The usefulness of breath testing in primary care has been described already36. Our findings suggest that this method of Hp detection is both useful and practical in identifying infected patients and assessing their response to treatment in a community setting.
In
conclusion our study has shown that Hp
eradication is effective for patients with established gastro-duodenal
ulceration in the community. Despite this many patients remain symptomatic and
still require maintenance acid suppression, although certain patient groups seem
more likely to respond to treatment. Hp
eradication should therefore not be regarded as a panacea for the treatment of
all dyspeptic symptoms even amongst such a targeted group of patients. However Hp
eradication is undoubtedly appropriate and cost-effective for patients with
established PU disease.
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Acknowledgements.
The
authors acknowledge the assistance and co-operation of the following: Dr Miller,
Bridgeton Health Centre; Dr Ritchie, Drymen Road, Bearsden; Dr Cassidy, Barrhead
Health Centre, Dr Sweeney, Fearness Road Health Centre; Dr Tarrant, Bargarron
Health Centre; Dr Doak, Arran Surgery, Kinning Park Health Centre; Dr McCartney,
Maryhill Health Centre.
Conflict
of Interests.
Funding was provided by Astra Pharmaceuticals Ltd for nursing and technical support.