40

HELICOBACTER PYLORI

Treatment of Helicobacter pylori in functional dyspepsia

resistant to conventional management: a double blind
randomised trial with a six month follow up
H R Koelz, R Arnold, M Stolte, M Fischer, A L Blum, the FROSCH Study Group
.............................................................................................................................

Gut 2003;52:4046

See end of article for

authors affiliations

.......................
Correspondence to:
Professor H R Koelz,
Division of
Gastroenterology,
Department of Internal
Medicine, Triemli Hospital,
CH-8063 Zurich,
Switzerland;
[email protected]
Accepted for publication
20 August 2002

.......................

Background: Previous studies on the treatment of Helicobacter pylori infection in functional dyspepsia
have shown little, if any, effect on dyspeptic symptoms. However, whether such treatment might be of
benefit in patients resistant to acid inhibitors has not been formally tested.
Aim: The present study investigated the effect of H pylori treatment in patients with functional dyspepsia resistant to conventional treatment.
Patients: A total of 181 H pylori positive patients with chronic functional dyspepsia who had not
responded to a one week antacid run-in and two week double blind antisecretory or placebo treatment
were included.
Methods: Patients were randomised to two weeks of treatment with omeprazole 40 mg twice daily
combined with amoxicillin 1 g twice daily or omeprazole 20 mg once daily alone. The primary outcome variable (response) was defined as no need for further therapy or investigations for dyspeptic
symptoms 46 months after treatment.
Results: H pylori infection was healed in 10% of patients after omeprazole and in 52% after omeprazole plus amoxicillin. The respective response rates were 66% and 62% (NS). H pylori treatment and
cure of H pylori infection had no effect on complete resolution of all dyspeptic symptoms, individual
symptoms, or various aspects of quality of life.
Conclusion: In functional dyspepsia, H pylori treatment and cure of H pylori are no more effective for
symptoms over six months than short term acid inhibition. These results do not support treatment of H
pylori in functional dyspepsia.

pproximately half of patients with functional dyspepsia

are infected with Helicobacter pylori.1 The key question in
the treatment of H pylori infected patients with
functional dyspepsia is whether cure of H pylori infection
improves dyspeptic symptoms. In the last few years, several
large, randomised, double blind, controlled trials28 were
performed which produced conflicting results. If any, the
symptomatic benefit of H pylori eradication appeared to be
very modest, as has also been shown in a meta-analysis of
these data.9 However, in contrast with common practice,
patients included in these studies did not receive pretreatment
with standard drugs such as prokinetic or acid inhibitory
drugs. In addition, exclusion of patients who responded to
acid reducing drugs may facilitate the detection of a potential
effect of H pylori treatment. Thus we have conducted a study in
patients with functional dyspepsia who were resistant to
standard treatment.

PATIENTS AND METHODS

Study protocol
This investigation was a multicentre, double blind, randomised, clinical trial with parallel groups, carried out according to Good Clinical Practice and the revised Declaration of
Helsinki. The ethics committees of all German states approved
the protocol, and all patients participating gave written
informed consent. Patients were recruited between August
1994 and July 1996.
Selection of patients
H pylori positive patients, more than 18 years of age, with
chronic therapy resistant (see below) functional dyspepsia
were recruited from 46 private gastroenterological practices in

www.gutjnl.com

Germany. H pylori status was ascertained in all patients using

both the rapid urease test (HUT; AstraZeneca GmbH, Wedel,
Germany) and the 13C urea breath test (13C-UBT). In the event
of divergent results, the 13C-UBT test result was decisive. All
patients had participated in a previous trial10 on the effect of
acid inhibitory treatment in chronic functional dyspepsia (fig
1). Chronic functional dyspepsia was defined as severe epigastric symptoms, present for the last month, in the absence of
organic disease known to produce epigastric symptoms.
Organic disease was excluded by means of gastroscopy
(normal findings except for hiatal hernia, mucosal erythema,
less than 10 gastric erosions, and minor deformation of the
pylorus and duodenal bulb), laboratory tests, and sonography
(normal findings except for minor hepatic steatosis, small
uncomplicated liver cysts, and small haemangiomas). Initial
dyspeptic symptoms had to be severe enough to require management (defined as treatment other than liquid antacids
and/or endoscopy or other diagnostic tests). In this previous
study, patients with antacid resistant severe functional
dyspepsia had been randomised to two weeks of treatment
with omeprazole 20 mg once daily, omeprazole 10 mg once
daily, ranitidine 150 mg at bedtime, or placebo in a double
blind, double dummy manner. If at the end of two weeks they
still had symptoms requiring therapy, or symptoms reappeared within six months of completing the randomised
treatment, they were eligible for the present study (fig 1).
When the period between screening for the previous study

.............................................................
Abbreviations:
per protocol.

13

C-UBT, 13C urea breath test; ITT, intention to treat; PP,

H pylori treatment in functional dyspepsia

Screening (

41

Hp positive or negative)

Antacid for 7 days

Response: stop

Antisecretory
treatment

Placebo

No response

v ranitidine v OM10 v OM20

randomised, double blind, for 2 weeks

Response

No response

Anti-

Hp

treatment

or

Follow up

recurrence

for up to 6 months

If

Hp positive:
v OM

AMO + OM

randomised, double blind for 2 weeks

Follow up for 6 months

Figure 1 Design of the previous (broken lines)10 and present (continuous line) studies. Hp, H pylori; OM10, omeprazole 10 mg once
daily; OM20, omeprazole 20 mg once daily; AMO+OM,
amoxicillin 1 g twice daily plus omeprazole 40 mg twice daily; OM,
omeprazole 20 mg once daily. Ranitidine was given as 150 mg at
bedtime.

and entry into the present study exceeded four weeks,

gastroscopy, HUT, and blood tests were repeated.
Patients were excluded for the following reasons:
heartburn/acid regurgitation without concomitant epigastric
symptoms; predominant symptoms suggesting irritable bowel
syndrome, in particular pain in the lower abdomen, flatulence,
diarrhoea, or constipation; previously documented erosive or
ulcerative oesophagitis; peptic ulcer; previous abdominal surgery (except for inguinal hernia, appendectomy, hysterectomy,
and Caesarean section); alarm symptoms during the previous three months (for example, dysphagia, involuntary weight
loss, gastrointestinal bleeding, unexplained fever, abdominal
mass, and jaundice); proton pump inhibitors and/or antibiotic
treatment within one month prior to the screening period;
regular treatment one week prior to the screening period with
drugs which might interfere with symptom assessment (for
example, non-steroidal anti-inflammatory drugs or bismuthates); and more than 80 ml of ethanol daily.
Treatment
Patients were treated for two weeks with omeprazole 40 mg
twice daily plus amoxicillin 1 g twice daily (OM+AMO) or
omeprazole 20 mg once daily plus placebo (OM) (all from
AstraZeneca Pharmaceutical Production AB, Sdertlje, Sweden). Drug intake was monitored by counting returned medication. No other treatment for dyspepsia was allowed during
the treatment period (for example, H2 receptor antagonists,
prokinetic drugs, or spasmolytics).
Follow up
All patients were followed for six months regardless of their
symptoms. They were given a supply of a weak antacid (bags of
10 ml suspension of aluminium hydroxide gel 3.13 g,
magnesium oxide 0.27 g, and aluminium hydroxide magnesium carbonate gel 0.63 g) and were permitted to take up to 30
ml daily for up to three consecutive days in case of occasional
dyspepsia. Follow up visits were scheduled at the end of the
treatment period, and one and six months later. Unscheduled
visits were encouraged at any time when more severe dyspeptic
symptoms recurred. These symptoms were treated at the

discretion of the investigator, but H pylori treatment with antibiotics or bismuth was not allowed. Patients who required
management for their symptoms at scheduled or unscheduled
visits during the last three months of the study were classed as
treatment failures.
Primary and secondary outcome criteria
The main outcome criterion was dyspepsia during the last
three months of follow up; treatment success was defined as
lack of dyspeptic symptoms requiring management (defined
as treatment other than liquid antacids and/or diagnostic tests
including endoscopy). A clinically relevant difference in
response rates on the primary outcome criterion at the end of
the six months of follow up was defined as 20% (60% without,
80% with H pylori treatment). In order to confirm such a
difference, accepting a error of 0.20 and an error of 0.05
(Fishers exact test, two sided), the required number of
patients per group in an intention to treat analysis was 91.
Secondary outcome variables included: time until relapse
that is, lack of overall response during the six months of the follow up period; gastrointestinal symptoms according to the
investigators judgement as well as the patients opinion; and
quality of life parameters. At each visit, specific symptoms were
elicited: epigastric pain or burning, epigastric pressure or
fullness, heartburn, acid regurgitation, nausea and/or vomiting,
pain in the lower abdomen, flatulence, diarrhoea, and constipation. The severity of individual symptoms during the previous
week was graded according to a scale from 0 to 3 (0=no
complaints, 1=complaints not interfering with daily activities
and not requiring treatment, 2=complaints requiring treatment
but not interfering with daily activities, and 3=complaints
interfering with daily activities and requiring treatment). In
addition, patients answered the question How were your
symptoms in the area of the oesophagus and stomach? and
How was your general condition during the last seven days?
by making a mark on a 10 cm visual analogue scale (best possible condition 10 cm, worst condition 0 cm). Quality of life during the previous week was assessed using a validated questionnaire adapted to German lifestyle.11 12 This form contained 40
general items relating to physical strength, ability to enjoy and
relax, positive mood, absence of negative mood, social contacts,
and social well being. An additional questionnaire consisted of
nine questions that had been validated in Germany by Eypasch
and colleagues,13 and which related to impairment of quality of
life by dyspeptic symptoms. They assessed the influence of dyspeptic symptoms on eating, other daily activities, social
contacts, sleep, and fears of serious disease. Finally, the patients
time spent off work and/or in hospital was recorded.
Data management and statistics
Data were transferred to and analysed by an independent statistical institute (Institute for Numerical Statistics, Cologne,
Germany). Both an intention to treat (ITT) and per protocol
(PP) analysis were performed, and all outcome variables were
analysed by treatment group and by the 13C-UBT result (four
weeks after the end of treatment).
The following 13 characteristics were selected prospectively
for univariate and logistic regression analyses using the main
outcome criterion as the dependent variable: age, sex, foreign
nationality (country of birth outside of Germany), overweight
(body mass index >27.8 kg/m2 for males and >27.3 kg/m2 for
women), daily smoking, daily alcohol drinking, previous dyspepsia (dyspeptic symptoms before the present painful
episode), duration of dyspepsia (>2 years), presence of reflux
symptoms (acid regurgitation and/or regurgitation), severity
of dyspepsia (visual analogue scale), general condition (visual
analogue scale), cure of H pylori infection, and treatment
group. The same independent variables (except 13C-UBT
result) were used for a second logistic regression analysis
using cure of H pylori infection as the dependent variable.
All analyses were based on SAS (version 6.11) and SPSS
(version 7.5) for Windows.

www.gutjnl.com

42

Koelz, Arnold, Stolte, et al

Figure 2 Trial profile showing
progress through the various stages of
the study. 13C-UBT, 13C urea breath
test.

Randomised (n = 205)

Received omeprazole (n = 100)

Included with positive

13

C-UBT result (n = 92)

Received omeprazole plus amoxicillin (n = 105)

Included with positive

13

C-UBT result (n = 89)

Withdrawn before 2 weeks (n = 4)

Withdrawn before 2 weeks (n = 3)

- Intervention ineffective (n = 1)

- Intervention ineffective (n = 1)

- Lost or unwilling to continue (n = 2)

- Lost or unwilling to continue (n = 1)

- Adverse event (n = 1)

- Adverse event (n = 1)

Followed up for 2 weeks (n = 88)

Followed up for 2 weeks (n = 86)

Withdrawn between 2 weeks and 6 months

Withdrawn between 2 weeks and 6 months

(n = 9)

(n = 8)

- Intervention ineffective (n = 2)

- Intervention ineffective (n = 0)

- Lost or unwilling to continue (n = 6)

- Lost or unwilling to continue (n = 6)

- Adverse event (n = 0)

- Adverse event (n = 1)

Followed up for 6 months (n = 79)

Followed up for 6 months (n = 78)

Assignment
The randomisation list was computer generated in blocks of
two; the block size was kept secret until the code was broken
for analysis. The allocation sequence was concealed in
sequentially numbered sealed opaque envelopes. Complete
sets of envelopes were kept at Astra Hssle AB and at the
Institute for Numerical Statistics. The blocks were consecutively ordered by random number. Each centre received complete blocks together with the corresponding sealed envelopes
containing the treatment allocation; in no case was the code
broken prematurely. Patients fulfilling all entry criteria (with
the exception of the 13C-UBT result, which became available to
the investigators with a few days delay) were allocated a random number, and treatment was started. Patients with a
negative 13C-UBT result were excluded from analysis.
Blinding
The randomised study treatment was given in a double blind
double dummy manner using matching placebo preparations.
Patients in the OM+AMO group received omeprazole capsules
(40 mg twice daily) plus amoxicillin tablets (1 g twice daily)
and those in the OM group received omeprazole capsules (20
mg once daily) plus omeprazole placebo capsules, and amoxicillin placebo tablets (twice daily). Placebo and active medications as well as omeprazole 20 and 40 mg capsules were similar in appearance and taste. The treatment code was broken
after clean filing and allocation of individual patients to ITT
and PP analyses.

RESULTS

Participant flow and follow up

A full trial profile is given in fig 2. The ITT analysis included
181 patients (OM 92, OM+AMO 89). Patients in the two
groups were well matched with regard to demographic
characteristics and dyspeptic symptoms (table 1). Intake of
less than 75% of the study medication, a reason for exclusion
from the ITT analysis, was found in only two patients in the
OM+AMO group, indicating good compliance. The PP analysis included 144 patients who completed the study without
major deviations from the protocol: 74 in the omeprazole only
group and 70 in the combination group (table 2).

www.gutjnl.com

Analysis

Effect of treatment on cure of H pylori

Four weeks after the end of treatment, 13C-UBT values were

negative in nine of 92 (10%) patients after omeprazole and in
46 of 89 (52%) patients after omeprazole and amoxicillin
treatment (table 3, ITT analysis). Analysing only patients with
known 13C-UBT results, the respective H pylori cure rates were
9/78 (12%) and 33/81 (57%).

Symptomatic response during follow up

The results for the primary outcome variableno need for

further management of dyspepsia 46 months after the end of
treatmentare shown in fig 3. On an ITT basis, 61 of 92
patients (66%; 95% confidence interval (CI) 5676%) were
considered to be responders after OM treatment compared
with a similar number after OM+AMO treatment (55 of 89
(62%); 95% CI 5172%; p=0.54, Fishers exact test). In
addition, no difference was seen when the proportions of
patients who were free of any dyspeptic symptoms were compared (fig 3). These results were similar to those of the PP
analysis. As the cure rate of H pylori after OM+AMO treatment
was only 46/89 (52%, 95% CI 4162%), the response rates were
also calculated according to the 13C-UBT results after therapy
(table 3). The response rate did not differ significantly
between patients in whom H pylori infection was cured (41/55
(75%); 95% CI 6185%) and those with persistent infection
(71/104 (68%); 95% CI 5877%) (table 3). The seemingly high
failure rate of patients with unknown post-treatment H pylori
status is explained by early withdrawal from the study.
The life table curves shown in fig 4 comprise the
proportions of patients whose dyspepsia was judged not to
require further management at two weeks. The curves indicate
the proportion of patients without a first recurrence of
dyspepsia requiring management. There was no significant
difference between the two treatment groups (fig 4A) or
between patients with were or were not cured of H pylori
infection (fig 4B).

Impairment of general condition, suffering caused by

dyspepsia, and individual symptoms

The time course of impairment by dyspepsia and the three

most frequent dyspeptic symptoms (epigastric pain or
burning, epigastric pressure or fullness, and heartburn)

H pylori treatment in functional dyspepsia

Table 1
to treat

43

Comparison of treatment groups. Results are given according to intention

Presenting characteristic

OM (n=92)

Age (y) (mean (SD))

Sex (% male)
Body mass index (kg/m2) (mean (SD))
Current smoker (%)
Alcohol consumption, current (%)
Treatment in previous study (%)
Omeprazole 10 mg
Omeprazole 20 mg
Ranitidine 150 mg
Placebo
Entering this study from previous study (%)
Immediately after treatment period
During follow up
History of dyspepsia (%)
<1 y
15 y
>5 y
Previous unsuccessful treatment of H pylori (%)
Dyspeptic symptoms (VAS)
General condition (VAS)

OM+AMO (n=89)

46 (15)
42%
25 (4)
21
44

49 (16)
40%
25 (4)
21
51

27
17
34
22

20
20
24
36

86
14

87
14

10
52
38
2
50.5
48.0

15
49
36
7
51.0
46.0

OM, omeprazole; OM+AMO, omeprazole plus amoxicillin; VAS, median of visual analogue scale values,
determined by the patient.
There was no significant difference between groups for any of the characteristics.

Table 2 Major protocol deviations and number of patients in the intention to treat
(ITT) and per protocol (PP) analyses
OM
Patients in ITT analysis
Discontinuation due to adverse event
Lost/refused to continue
Non-compliance
Study medication*
Use of prohibited medication
Day of visit
Other
Total patients with major protocol deviation
Patients in PP analysis

OM+AMO

Total

92
1
7

89
2
7

181
3
14

0
5
2
3
18
74

2
4
3
1
19
70

2
9
5
4
37
144

*More than 25% of study medication was returned.

OM, omeprazole; OM+AMO, omeprazole plus amoxicillin.
There was no significant difference between the treatment groups.

Table 3 Patients with no need for further treatment and/or diagnostic tests for
dyspepsia during the last three months of the six month follow up according to
assigned treatment and to Helicobacter pylori status after treatment
H pylori status after
treatment

OM

OM+AMO

Total

Cured
Not cured
Unknown
Total

8/9 (89%)
51/69 (74%)
2/14 (14%)**
61/92 (66%)

33/46 (72%)
20/35 (57%)
2/8 (25%)*
55/89 (62%)

41/55 (75%)
71/104 (68%)
4/22 (18%)**
116/181 (64%)

*p=0.03, **p<0.0001 compared with patients in the same column with known H pylori status.
OM, omeprazole; OM+AMO, omeprazole plus amoxicillin.
There was no significant difference between treatment groups (intention to treat analysis).

showed little change between entry into the double blind

antisecretory study and entry into the present study (fig 5).
However, regardless of treatment group, a dramatic improvement in all parameters (p<0.0001) was seen during the treatment phase of the present study, with no further change
occurring during the follow up period. The time course of
changes within the two treatment groups was almost
identical. The prevalence of nausea/vomiting and lower
abdominal pain, flatulence, diarrhoea, and constipation was
low and did not change during the study.

Quality of life

One dyspepsia specific and six general aspects of quality of life

were assessed. Irrespective of the therapy, every parameter
(physical strength, ability to relax and enjoy, positive mood,
absence of negative mood, social contact, social well being,
and absence of impairment by dyspepsia) improved significantly to normal levels12 13 during the 14 day treatment period,
and no further change was observed during the six month
follow up period (data not shown). In no instance was there a
significant difference between treatment groups.

www.gutjnl.com

44

Koelz, Arnold, Stolte, et al

100
80

40

VAS (mm)

60
66%

62%

OM

OM + AMO

A
OM

75

60 Epigastric pain
40
20

or burning
Heartburn
a

B
Hp +
Hp _

50
25
0

50

100

Follow up (day)

150

200

Figure 4 Life table analysis of patients in remission (no need for

further management for dyspepsia) according to the randomised
treatment (A) and to Helicobacter pylori status after treatment (B).
Intention to treat analysis. OM, omeprazole (n=89); OM+AMO,
omeprazole plus amoxicillin (n=92). There was no significant
difference between treatment groups or between H pylori positive
(n=104) and negative (n=55) patients. Note that the onset (day 0) of
the life table curves is below 100% because of the fraction of
patients who did not reach remission during the two week treatment
period.

There was no significant difference in days off work (OM: 77

patients none, seven patients ranging from 1 to 29 days, no
data for eight; OM+AMO: 78 patients no days, seven ranging
from 2 to 24, no data for four). Only one patient, from the
OM+AMO group, was hospitalised for 18 days.

Factors associated with outcome

No significant correlation was found in either the univariate or

logistic regression analysis between any of the 13 preselected
presenting characteristics. In particular, cure of H pylori infection did not correlate with outcome. A separate analysis, with
cure of H pylori infection as the dependent variable and using
the same presenting characteristics (except 13C UBT results),
showed, as predicted, a correlation with treatment group
(OM+AMO; p<0.0001) and a direct correlation with age
(p=0.026). Logistic regression analysis revealed that the two
factors were independent of each other. In the first step,
treatment group appeared with a p value of <0.001; the
second step identified age as an additional significant inde-

www.gutjnl.com

Follow up (month)

Figure 5 Time course of impairment by dyspepsia (A) and of the

three most frequent individual dyspeptic symptoms severe enough to
require treatment (B) from the beginning of the previous and during
the present study. Values in (A) are medians (because of skewed
distribution) of visual analogue scales (VAS) and those in (B) are
percentage of patients who needed treatment for the given individual
symptom. A significant (p<0.0001) improvement in all parameters
was noted during the treatment period in the present study but no
change occurred during follow up. There was no significant
difference between the treatment groups. Intention to treat analysis.
OM, omeprazole; OM+AMO, omeprazole plus amoxicillin. a,
beginning of previous study; b, start of treatment in the present study;
and c, end of treatment in the present study.

75

Epigastric
pressure
or fullness

80

25

% of patients

100

OM + AMO

50

40

25%

21%

Figure 3 Effect of omeprazole (OM) and omeprazole plus

amoxicillin (OM+AMO) on symptomatic response 46 months after
the treatment period (intention to treat analysis). The proportion of
patients who did not need further management of dyspepsia
(treatment and/or diagnostic tests) and the proportion of patients
who did not complain of any dyspeptic symptoms are shown. Bars
indicate 95% confidence intervals.

100

OM
OM + AMO

20

20

100

Impairment
by dyspepsia

60

% patients with therapy

requiring symptom

% of patients

No need for management

No dyspeptic symptoms

pendent variable that improved the correlation (p=0.04).

When the variable treatment group was removed from the
analysis, age remained as the only significant factor
(p=0.03), thus indicating that H pylori is more easily treated in
older patients.

Adverse events and change of diagnosis

No relevant adverse effects attributable to treatment were

observed. At various time points after the first visit, the
following diagnoses of organic abdominal diseases were
made: duodenal ulcer (one 42 year old female with persistent
H pylori after OM, diagnosed on study day 194); erosive
oesophagitis (one 62 year old male after OM, day 104); gastric
leiomyosarcoma with liver metastases (one 58 year old male
after OM, five weeks after the end of follow up); pancreatic
carcinoma (one 51 year old male after OM+AMO, day 135);
and ovarian carcinoma (one 74 year old female after
OM+AMO, day 96).

DISCUSSION

Successful outcome, as predefined by the absence of severe

dyspeptic symptoms during the final three months of follow
up, was no more frequent after H pylori treatment than after
simple short term antisecretory treatment. The same was
found for all additional outcome criteria tested in multiple
exploratory analyses. If anything, there was a tendency in
favour of antisecretory treatment alone compared with the
combination with amoxicillin. Hence it is unlikely that a significant or clinically relevant difference in outcome in favour
of H pylori treatment would have been reached with a much
larger number of patients. The success of simple antisecretory

H pylori treatment in functional dyspepsia

treatment is even more surprising as our patients were not

blinded to the result of the 13C-UBT after treatment. Cure of H
pylori infection might have fulfilled patients expectations and
thus have favoured success in the group with treatment of H
pylori.
An important distinction between this and other studies28
of H pylori therapy in functional dyspepsia was restrictive
patient selection. All patients had normal or nearly normal
findings at gastroscopy, abdominal sonography, and in laboratory tests, supporting the assumption of functional dyspepsia.
In addition, they appeared to be resistant to acid inhibitory
therapy in the previous prospective study.10 Hence the remaining management alternatives for functional dyspepsia were
prokinetics, whose efficacy is currently being challenged,14 and
H pylori therapy, which, in the opinion of many physicians and
patients, offers the possibility of cure of dyspepsia. In these
patients we expected a greater chance of demonstrating an
effect of H pylori therapy than in a general population of
patients with functional dyspepsia.28
The 52% cure rate of H pylori infection achieved using dual
therapy with high dose omeprazole and amoxicillin was rather
low. We chose this regimen because initial data suggested very
high healing rates.15 The study was already ongoing when
subsequent studies showed disappointing results with this
combination,16 17 comparable with those in the present trial.
This weakens the ITT analysis according to treatment.
However, almost identical results were obtained when we
compared patients with healed and unhealed infection
instead of the two treatment groups.
A major criticism of previous studies on H pylori therapy in
functional dyspepsia was the short duration of follow up. We
considered the six month follow up period in the present
study to be sufficient for the following histopathological and
functional reasons. The major improvement in gastritis, in
particular regression of infiltrates with polymorphonuclear
leucocytes, occurs within a few days after the beginning of
effective antimicrobial therapy,18 and superficial epithelial
damage recovers within a few weeks,19 20 while it takes longer
for disappearance of chronic inflammatory cells.1922 Recent
evidence suggests that chronic inflammatory cells may not
disappear even after several years.23 Most importantly, there
are no data indicating that a favourable effect after one year is
not already present after six months.3 24 25 The favourable effect
seen in the study by McCarthy and colleagues24 after one year
appears to be weak as the study was not randomised. In a
more recent study from the same group,25 a positive effect of H
pylori therapy on a subgroup of patients with ulcer-like
dyspepsia was, if anything, stronger after six than after 12
months of follow up. Finally, follow up of our patients over six
months as well as of those in a similar study4 over one year do
not suggest even a trend for improvement of symptoms after
cure of H pylori infection. Therefore, there is no rational basis
for the hope that longer follow up would change the result.
The surprisingly prompt and long lasting improvement in
symptoms during the two week treatment period was
unexpected in view of the previous resistance to active therapy
demonstrated by this patient group. One explanation is that in
the previous study10 only 25% of patients received the stronger
acid inhibitory dose of omeprazole (20 mg) that was shown to
be effective, the majority having received omeprazole 10 mg,
ranitidine 150 mg, or placebo. In contrast, the present
treatment consisted of omeprazole at a daily dose of 20 or 80
mg. A more likely explanation implies that there was some
bias of both investigators and patients towards more severe
symptoms in order to be eligible for H pylori therapy. The dramatic improvement may have been due to the very high
expectations that this last resort would be effective. A similar
bias was suspected in the preceding study where H pylori positivity correlated with lack of symptomatic response.10
In conclusion, the results of this study indicate that
treatment of H pylori does not lead to improvement in

45

functional dyspepsia resistant to conventional management.

Together with other trials28 that fulfil important quality
criteria,26 27 more evidence is accumulating that H pylori treatment is of little, if any, value in the treatment of functional
dyspepsia.

ACKNOWLEDGEMENT

We are grateful to Dr Madeline Frame for expert assistance with the

manuscript preparation. Supported by Swiss Science Research Foundation, grant No 31-43240.95, and by AstraZeneca GmbH, Wedel, Germany

APPENDIX

The FROSCH Study Group

Werner Abels (Nrnberg), Krikor Amdja (Wermelskirchen), Herbert

Bock (Frankfurt), Dibor Bojanovski (Hannover), Hilmar Bneke
(Lienen), Burkhardt Cyrus (Mnchen), Axel Dettmer (Mnchen),
Reinhard Diedrich (Marburg), Klaus Dietrich (Saarbrcken), Wolfgang Dbel (Berlin), Michael Dudek (Dsseldorf), Dieter Ebbinghaus
(Lnen), Wolfgang Fortelny (Waldsassen), Roland Graf (Leutkirch),
Wolfgang Gttel (Rastatt), Hans-Jrgen Hagel (Schwabach), Bernt
Hawickhorst (Wlfrath), Martin Hell (Salzgitter-Lebenstedt), Rdiger Hildebrandt (Clausthal-Zellerfeld), Walter Hofmeister (Weiden),
Wolfgang Huppertz (Essen), Harvey Jrgens (lde), Bernhard Klesser
(Ulm), Horst Klewer (Wetzlar), Michael Klters (Spaichingen),
Andreas Kocjan (Ldenscheid), Justine Kosmowski (Marburg),
Joachim Labenz (Essen), Gnter Leiber (Marburg), Helmut Lichti
(Gladenbach), Andrei Mares (Frankfurt), Peter Mayr (Stockach),
Bernd Metscher (Berlin), Heinrich Miks (Hamm), Hubert Mnnikes
(Marburg), Michael Mller (Delmenhorst), Claus Nolte (Mettmann),
Paul-Peter Pech (Mnster), Stefan Pfffl (Nrnberg), Thomas Rachel
(Rastatt), Axel Rambow (Marburg), Gerd Rosprich (Saarbrcken),
Thomas Schdlich (Ellefeld), Andreas Schober (Gttingen), Michael
Schumacher (Wolmirstedt), Rainer Stroband (Mnster), Huschang
Toluipur (Schiffweiler), Rdiger Vogt (Mannheim), Rainer Wack
(Berlin), Gnter Wilhelms (Goslar), Jrgen Zeus (Erlangen).
.....................

Authors affiliations

H R Koelz, Division of Gastroenterology, Department of Medicine,

Triemli Hospital, Zurich, Switzerland
R Arnold, Centre of Internal Medicine, Clinic of the Philipps University,
Marburg, Germany
M Stolte, Department of Pathology, University of Bayreuth, Bayreuth,
Germany
M Fischer, Institute for Numerical Statistics, Cologne, Germany
A L Blum, Division of Gastroenterology, Department of Medicine,
University Hospital, Lausanne, Switzerland

REFERENCES

1 Pantoflickova D, Blum AL, Koelz HR. Helicobacter pylori and

dyspepsia: A real causal link? Baillieres Clin Gastroenterol
1998;12:50332.
2 Blum AL, Talley NJ, OMorain C, et al. Lack of effect of treating
Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl
J Med 1998;339:187581.
3 McColl K, Murray L, El Omar E, et al. Symptomatic benefit from
eradicating Helicobacter pylori infection in patients with nonulcer
dyspepsia. N Engl J Med 1998;339:186974.
4 Talley NJ, Janssens J, Lauritsen K, et al. Eradication of Helicobacter
pylori in functional dyspepsia: randomized double blind placebo
controlled trial with 12 months follow up. BMJ 1999;318:8337.
5 Talley NJ, Vakil N, Ballard II ED, et al. Absence of benefit of eradicating
Helicobacter pylori in patient with nonulcer dyspepsia. N Engl J Med
1999; 341:110611.
6 Miwa H, Hirai S, Nagahara A, et al. Cure of Helicobacter pylori
infection does not improve symptoms in non-ulcer dyspepsia patientsa
double-blind placebo-controlled study. Aliment Pharmacol Ther
2000;14:31724.
7 Froehlich F, Gonvers JJ, Wietlisbach V, et al. Helicobacter pylori
eradication treatment does not benefit patients with nonulcer dyspepsia.
Am J Gastroenterol 2001; 96:232936.
8 Bruley Des Varannes S, Flejou JF, Colin R, et al. There are some
benefits for eradicating Helicobacter pylori in patients with non-ulcer
dyspepsia. Aliment Pharmacol Ther 2001;15:117785.
9 Moayyedi P, Soo S, Deeks J, et al. Systematic review and economic
evaluation of Helicobacter pylori eradication treatment for non-ulcer
dyspepsia. Dyspepsia Review Group. BMJ 2000;321:65964.

www.gutjnl.com

46

Koelz, Arnold, Stolte, et al

10 Blum AL, Arnold R, Stolte M, et al. Short course acid suppressive

treatment for patients with functional dyspepsia: results depend on
Helicobacter pylori status. The Frosch Study Group. Gut
2000;47:47380.
11 Siegrist J, Junge A, Fnfstck G. Lebensqualitt unter antihypertensiver
Therapie: Vergleich von Captopril und Metoprolol. Med Welt
1991;42:1338.
12 Siegrist J, Middeke M, Osterkorn K. Lebensqualitt hypertensiver rzte
unter Hochdrucktherapie. Fortschr Med 1991;109:34852.
13 Eypasch E, Wood-Dauphine S, Williams JI, et al. Der gastrointestinale
Lebensqualittsindex (GLQI). Ein klinimetrischer Index zur
Befindlichkeitsmessung in der gastroenterologischen Chirurgie. Chirurg
1993;64:26474.
14 Delaney B, Moayyedi P, Deeks J, et al. The management of dyspepsia:
a systematic review. Health Technol Assess 2000;4 (iii-v):1189.
15 Bayerdrffer E, Mannes GA, Sommer A, et al. High dose omeprazole
treatment combined with amoxicillin eradicates Helicobacter pylori. Eur J
Gastroenterol Hepatol 1992;4:697702.
16 Labenz J, Gyenes E, Ruhl GH, et al. Omeprazole plus amoxicillin:
efficacy of various treatment regimens to eradicate Helicobacter pylori.
Am J Gastroenterol 1993;88:4915.
17 Koelz HR, Beglinger C, Inauen W, et al. Double-blind comparison of
three different amoxicillin plus omeprazole regimens for eradication of
Helicobacter pylori in patients with duodenal ulcer (abstract).
Gastroenterology 1995;108:A133.
18 Plein K, Madisch A, Stolte M, et al. Short-term changes in Helicobacter
pylori gastritis and bulbitis during and after 2 weeks of treatment with
omeprazole and amoxicillin in duodenal ulcer patients. Z Gastroenterol
2001;39:50310.

19 Solcia E, Fiocca R, Villani L, et al. Effects of permanent eradication or

transient clearance of Helicobacter pylori on histology of gastric mucosa
using omeprazole with or without antibiotics. Scand J Gastroenterol
1996;31:10510.
20 van der Hulst RW, van der Ende A, Dekker FW, et al. Effect of
Helicobacter pylori eradication on gastritis in relation to cagA: a
prospective 1-year follow-up study. Gastroenterology 1997;113:2530.
21 Labenz J, Stolte M, Peitz U, et al. Omeprazole/amoxicillin versus triple
therapy for Helicobacter pylori in duodenal ulcer disease: two-year
follow-up of a prospective randomized study. Z Gastroenterol
1995;33:5903.
22 Dixon MF. Histological responses to Helicobacter pylori infection:
gastritis, atrophy and preneoplasia. Baillieres Clin Gastroenterol
1995;9:46786.
23 Kikuchi T, Kato K, Ohara S, et al. The relationship between persistent
secretion of RANTES and residual infiltration of eosinophils and memory
T lymphocytes after Helicobacter pylori eradication. J Pathol
2000;192;24350.
24 McCarthy C, Patchett S, Collins RM, et al. Long-term prospective study of
Helicobacter pylori in nonulcer dyspepsia. Dig Dis Sci 1995;40:11419.
25 Gilvarry J, Buckley MJM, Beattie S, et al. Eradication of Helicobacter
pylori affects symptoms in non-ulcer dyspepsia. Scand J Gastroenterol
1997;32:53540.
26 Veldhuyzen van Zanten SJ, Cleary C, Talley NJ, et al. Drug treatment
of functional dyspepsia: a systematic analysis of trial methodology with
recommendations for design of future trials. Am J Gastroenterol
1996;91:66073.
27 Mgraud F, OMorain C, Malfertheiner P, et al. Guidelines for clinical
trials in Helicobacter pylori infection. Working party of the European
Helicobacter pylori Study Group. Gut 1997;41(suppl 2):S123.

Want full text but don't have

a subscription?

Pay per view

For just $8 you can purchase the full text of individual articles using our secure online ordering service.
You will have access to the full text of the relevant article for 48 hours during which time you may
download and print the pdf file for personal use.
www.gutjnl.com

www.gutjnl.com