Aliment Pharmacol Ther 2005; 21: 1189–1202. doi: 10.1111/j.1365-2036.2005.02466.

Heartburn-dominant, uninvestigated dyspepsia: a comparison of

‘PPI-start’ and ‘H2-RA-start’ management strategies in primary
care – the CADET-HR Study
D. AR MSTRON G*, S. J. O. V ELDH UYZEN V AN ZANTEN , A . N. BARKU Nà, N. CH IBA* , §,
A. B. R. TH OMSON–, S. SMYTH**, P. SINCLA IR  , B. CHA KRABOR TY**, R. J. WHITE** &
THE CADET-HR STUD Y G ROUP 1
Divisions of Gastroenterology, *McMaster University, Hamilton, Ontario, Canada;  Dalhousie University, Halifax, Nova
Scotia, Canada; àMcGill University, Montréal, Québec, Canada; §Surrey GI Research, Guelph, Canada; –University of
Alberta, Edmonton, Canada; **AstraZeneca Canada, Mississauga, Ontario, Canada;   INSINConsulting, Guelph, Ontario,
Canada
Accepted for publication 20 March 2005

toms. Daily diaries documented heartburn relief (score

SUMMARY
Background: There are few data on empiric, stepped
therapy for heartburn relief or subsequent relapse in
primary care.
Aims: To compare heartburn relief produced by a proton
pump inhibitor-start or an H2-receptor antagonist-start
with step-up therapy, as needed, followed by a treat-
ment-free period to assess relapse.
Methods: Heartburn-dominant uninvestigated dyspepsia
patients from 46 primary care centres were randomized
to one of two active treatment strategies: omeprazole
20 mg daily (proton pump inhibitor-start) or ranitidine
150 mg bid (H2-receptor antagonist-start) for the first
4–8 weeks, stepping up to omeprazole 40 or 20 mg
daily, respectively, for 4–8 weeks for persistent symp-
£ 3/7 on £ 1 of 7 prior days) and relapse (score ‡4 on
‡2 of 7 prior days).
Results: For ‘proton pump inhibitor-start’ (n ¼ 196) vs.
‘H2-receptor antagonist-start’ (n ¼ 194), respectively,
heartburn relief occurred in 55.1% vs. 27.3%
(P < 0.001) at 4 weeks and in 88.3% vs. 87.1% at
16 weeks. After therapy, 308 patients were heartburn-
free (159 vs. 149); median times to relapse were 8 vs.
9 days and cumulative relapse rates were 78.6% vs.
75.8%, respectively.
Conclusions: An empiric ‘proton pump inhibitor-start’
strategy relieves heartburn more effectively than an
‘H2-receptor antagonist-start’ strategy up to 12 weeks
but has no effect on subsequent relapse, which is rapid
in most patients.

(GERD)1–3 are the primary inclusion criteria for studies

INTRODUCTION
Heartburn, retrosternal burning and regurgitation, the
cardinal symptoms of gastro-oesophageal reflux disease
Correspondence to: Dr D. Armstrong, Division of Gastroenterology, HSC-
4W8, McMaster University Medical Centre, 1200 Main Street West,
Hamilton, Ontario L8N 3Z5, Canada.
E-mail: armstro@mcmaster.ca
1
The CADET HR Study group of principal investigators are given in the
Appendix.
in patients with erosive oesophagitis or endoscopy
negative reflux disease (ENRD)4–12 However, patients
with erosive oesophagitis have generally been studied
separately from those with ENRD despite evidence that
they have symptoms which are comparable in severity,
frequency and duration.5 As a result, there are few data
on which to base management strategies for patients
with uninvestigated GERD13–16 despite the fact that
most patients with heartburn or regurgitation are

2005 Blackwell Publishing Ltd 1189

1190 D. ARMSTRONG et al.
managed in primary care practice as a subset of patients
with uninvestigated dyspeptic symptoms.17, 18
Patients with heartburn-dominant symptoms com-
prised 38% of a Canadian, uninvestigated dyspepsia
study population17 and erosive oesophagitis was iden-
tified in 55% of these patients at endoscopy; the
Canadian Dyspepsia Working Group recommended that
such patients be treated empirically for reflux disease,
provided that they have no alarm features.18 Initial acid
suppression therapy with a proton pump inhibitor (PPI)
for 4 weeks was recommended,18 based on evidence
that PPIs are superior to H2-receptor antagonists (H2-
RAs) for relief of symptoms in erosive oesophagitis and
ENRD and for healing of erosive oesophagitis.7, 19–21
However, there is continuing debate as to the merit of
both ‘H2-RA-start’ 22, 23 and ‘PPI-start’ strategies
despite accumulating evidence to suggest that PPI
therapy is cost effective in patients with erosive
oesophagitis or ENRD.24, 25
Patients enrolled in this study were classed as having
heartburn-dominant dyspepsia because, although the
main enrolment criterion – heartburn or retrosternal
burning – was similar to that of most GERD studies,
primary care patients with dominant heartburn may
have endoscopic lesions other than oesophageal ero-
sions.17 The current study was designed to compare the
efficacies of ‘H2-RA-start’ and ‘PPI-start’ strategies for
the management of heartburn-dominant uninvestigated
dyspepsia (HDUD) in primary care practice, to compare
the proportions of patients requiring ‘step-up’ therapy in
each strategy because of insufficient initial symptom
control and to document the recurrence of symptoms
after cessation of a successful therapeutic regimen.
METHODS
Patients
Patients, aged 18 years or older, were eligible if they
had at least 3 months of heartburn and moderate-to-
severe heartburn (score ‡4 on a 7-point Likert scale) on
at least three of the 7 days before randomization.
Heartburn was defined as ‘a burning feeling rising from
the stomach or lower part of the chest up towards the
neck’.1 Patients were excluded if they had alarm
features (unintentional weight loss, persistent vomiting,
dysphagia, haematemesis, melaena, fever, jaundice, or
anaemia),18 irritable bowel syndrome (IBS: ‡3 Manning
criteria),26 serious concomitant disease, and investiga-

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202
tions related to the upper gastrointestinal tract on one
occasion (i.e. one or more investigations arising from
presentation to a physician for dyspepsia symptoms)
during the prior 6 months or more than two occasions
during the previous 10 years.17, 27, 28
Exclusion criteria included a history of gastrointestinal
disease (including peptic ulcers, malignancy, oesopha-
geal dysmotility and a previous endoscopic or radiolo-
gical diagnosis of GERD and Barrett’s oesophagus),
gastrointestinal surgery (except appendectomy, colonic
resection and cholecystectomy). Hiatus hernia and non-
specific endoscopic or radiological findings were
not exclusion criteria. NSAIDs, ASA (>325 mg/day),
H2-RAs, PPIs, prokinetic agents, misoprostol or sucral-
fate were not permitted for 15 days prior to randomiza-
tion, or during the study whilst warfarin, theophylline,
phenytoin, bisphosphonates, methotrexate, ketocon-
azole, fluconazole, itraconazole, diazepam, aminopyrine
and antipyrine were not permitted at any time dur-
ing the study. Antacids were not permitted, other
than alginate/antacid tablets (Gaviscon; SmithKline
Beecham Consumer Healthcare, Oakville, Ontario,
Canada), provided during study visits as rescue medi-
cation. Women of childbearing potential were eligible if
they used effective contraception and had a negative
urine hCG pregnancy test at randomization.
Study design and medications
This was a prospective, randomized, controlled, double-
blind, double-dummy active treatment trial, conducted
at 46 primary care centres in Canada, with a 4–16-
week treatment phase, followed by a treatment-free,
follow-up phase up to a maximum of 6 months. At the
initial screening visit, medical history and demographic
features (including alcohol and tobacco use, age, gender
and race) were recorded and a physical examination
was performed; eligible patients received a supply of
antacid/alginate tablets and a daily diary in which to
record heartburn severity. On reassessment, 2 weeks
later, patients with a heartburn score ‡4 on a 7-point
Likert scale on at least three of the preceding
7 days were eligible for randomization to the ‘PPI-start’
or ‘H2-RA-start’ treatment strategies. Randomization,
using a computer-generated table of random numbers,
was concealed from patients, investigators and study
personnel. Patient compliance with treatment was
checked by counting the number of dispensed study
tablets returned at each clinic visit. Patients were
 MANAGEMENT OF HEARTBURN-DOMINANT UNINVESTIGATED DYSPEPSIA
considered compliant if <25% of the dispensed study
medication was returned, indicating that at least 75%
had been consumed.
Treatment phase. All patients received therapy, dispensed
as four tablets daily (three tablets in the morning and
one tablet in the evening) for the entire treatment phase
of up to 16 weeks. For the ‘PPI-start’ strategy, patients
received omeprazole 20 mg once daily (Losec
MUPSTM AstraZeneca R&D, Mölndal, Sweden) and for
the ‘H2-RA-start’ strategy, they received ranitidine
150 mg twice daily (Glaxo, Italy), each for 4 weeks.
Double-blind dosing was maintained with an appropri-
ate combination of active and placebo tablets (e.g.
initially, in the ‘PPI-start’ strategy, patients received one
active omeprazole tablet and one identical-looking
placebo omeprazole tablet in the morning in addition
to two placebo ranitidine tablets, one in the morning and
one in the evening). Patients with intolerable heartburn
at 4 weeks were stepped-up (‘PPI-start’: to omeprazole
40 mg once daily; ‘H2-RA-start’: to omeprazole 20 mg
once daily) and reassessed at 8 and 12 weeks; all
remaining patients, who did not report heartburn relief
at 4 weeks, continued their initial therapy for another
4 weeks. At 8 weeks, all patients who did not report
heartburn relief on their initial therapy were stepped up
(‘PPI-start’: to omeprazole 40 mg once daily; ‘H2-RA-
start’: to omeprazole 20 mg once daily) and reassessed at
12 and 16 weeks. Double-blind dosing was again
maintained (e.g. ‘PPI-start’ patients who stepped up to
omeprazole 40 mg once-daily were given two active
omeprazole tablets in addition to two placebo ranitidine
tablets, one in the morning and one in the evening).
Patients who did not report heartburn relief at 12 weeks
(after step up at 4 weeks) or at 16 weeks (after step up at
8 weeks), were withdrawn from the study and offered
further investigation (endoscopy) in the ‘PPI-start’
strategy or open-label treatment with omeprazole
40 mg once daily in the ‘H2-RA-start’ strategy. Algin-
ate/antacid tablets were supplied as rescue medication at
a dose of two to four tablets, as required, up to a
maximum of 16 tablets a day.
At all follow-up visits (4, 8, 12 and 16 weeks), patients
with heartburn relief were withdrawn and entered into
the treatment-free, follow-up phase.
Follow-up phase. Patients’ symptom status in the
6-month follow-up phase was evaluated in a tele-
phone interview after 4, 12 and 20 weeks and by

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202
1191
direct, face-to-face interview after 8, 16 and 24 weeks
by reference to the daily diary. The follow-up phase
was terminated if heartburn had recurred on more
than one of the previous 7 days with a severity score
>3 on a 7-point Likert scale. Alginate/antacid tablets
were supplied as rescue medication at a dose of two to
four tablets, as required, up to a maximum of 16
tablets a day.
Measurement of outcomes
Primary outcome: heartburn relief. The primary outcome
of the study – ‘treatment success’ – was the proportion
of patients with ‘heartburn relief’, defined as heart-
burn on no more than one of the previous 7 days, with
a maximal allowable score of 3 on the 7-point Likert
scale at 4 weeks (1 – no symptoms, 2 – minimal, 3 –
mild, 4 – moderate, 5 – moderately severe, 6 – severe,
7 – very severe problem) (Table 1), based on the Global
Overall Symptom (GOS) scale.29 ‘Sustained heartburn
resolution’, defined as a maximal allowable score of 1
on all of the previous 7 days (i.e. no heartburn in the
previous week) (Table 1), was a secondary outcome.
Relapse, during the treatment-free follow-up phase
was defined as the occurrence of heartburn on ‡2 days
of the previous 7 days with a severity score ‡4 on a
7-point Likert scale (Table 1).29
The assessment of heartburn symptoms and their
severity during the 7 days before each clinic and
telephone visit, was based on the patients’ record, in a
daily diary, of the severity of any heartburn symptoms,
during the previous day and night. The daily diary was
completed during the 16-week treatment phase and the
subsequent 6-month treatment-free follow-up phase,
using a 7-point Likert scale.29
Secondary outcomes. At each visit, patients used the
7-point Likert scale to rate the overall severity of any
heartburn, regurgitation (‘flow of sour acidic or bitter
fluid into the mouth’), epigastric pain (‘abdominal pain
centred in the upper abdomen’) and nausea during the
previous week. Patients reporting a score ‡4 (moderate)
were defined as ‘symptomatic’. For each symptom, relief
was defined as a score or 3 or less and resolution was
defined as a score of 1 (Table 1). Vomiting was recorded
as absent or present at each visit. At the screening and
final visits in the treatment phase, patients reported the
presence of IBS symptoms according to the Manning
criteria.26
1192 D. ARMSTRONG et al.

Table 1. Definitions of symptom severity

No more than mild heartburn (score £ 3/7)
used to characterize patients’ responses
on no more than one day during the 7 days
during the study
Heartburn relief prior to the visit (patient diary)

Sustained heartburn resolution No heartburn (score 1/7) on all 7 days

Overall relief of other reflux
symptoms (heartburn,
acid regurgitation,
epigastric pain, nausea)
Complete overall relief of other
reflux symptoms (heartburn,
acid regurgitation,
epigastric pain, nausea)
Relapse
in the week prior to the visit (patient diary).
No more than mild symptoms overall
(score £ 3/7) over the 7 days prior to the
visit (investigator query about ‘overall’
symptom response)
No symptoms overall (score 1/7) over the
7 days prior to the visit (investigator query
about ‘overall’ symptom response)
Moderate to severe heartburn (score ‡4/7)
on ‡2 days during a 7-day period in the
treatment-free follow-up period (patient diary)

The number of antacids consumed each day was
recorded in the daily symptom diary. Quality of life was
assessed using validated, self-administered question-
naires at each study visit, after a training session at
the screening visit. The Quality of Life in Reflux and
Dyspepsia (QoLRAD)30 questionnaire assessed dimen-
sions of emotional distress, sleep, vitality, food/drink
habits, and physical/social functioning and the Gastro-
intestinal Symptom Rating Scale (GSRS)31 assessed
dimensions of indigestion, diarrhoea, constipation,
abdominal pain and reflux. At the final treatment visit
of the study, the overall treatment evaluation (OTE)32
evaluated the magnitude of change in health status on a
15-point scale ()7 to )1 ¼ worse; 0 ¼ no change and
1 to 7 ¼ better) and the Satisfaction Survey (SS)
evaluated patient satisfaction with treatment using a
14-point scale ranging from completely satisfied (7) to
completely dissatisfied ()7).
Helicobacter pylori. Helicobacter pylori status was deter-
mined by 13C-urea breath test at the randomization
visit; both patient and investigator were blinded to the
results until the study was completed.
Sample size calculation
The calculated sample size was adjusted to ensure
adequate enrolment for a maintenance treatment study
that followed the present acute treatment study.32
Assuming complete heartburn resolution rates of 61
and 40% (a treatment difference of 21%) for omeprazole
and ranitidine,4 respectively, after 4 weeks of therapy, a
two-sided significance level of 0.05 and a minimum
power of 99.5% (Fisher’s exact test), at least 125
completed patients were needed for each treatment arm.
Allowing for a 15% withdrawal rate of evaluable
patients due to study discontinuation or persistence of
symptoms, 295 patients were needed for randomization
to both treatment arms. In all, 390 patients were
enrolled to ensure adequate numbers of patients for the
subsequent maintenance treatment study.33
Data analysis
The primary analysis of efficacy was an intention-
to-treat (ITT) analysis of treatment success (heartburn
relief) at 4 weeks, using daily diary card responses, for
all randomized patients. Based on a priori hypotheses,
the proportions of patients with treatment success at
4 weeks were stratified by H. pylori status (positive or
negative) and age (less than or greater than or equal to
50 years of age) and results were compared between
treatment strategies using the Cochran–Mantel–Haens-
zel test, controlling for geographical region. In addition,
a proportional hazards survival analysis was performed
to identify independent predictors of symptom relief in
the treatment phase and symptom relapse in the follow-
up phase.
The cumulative proportions of patients with heartburn
relief and sustained heartburn resolution over the
16-week treatment phase were compared between the
treatment strategies using the Cochran–Mantel–Haens-
zel test. QoLRAD and GSRS results were analysed using
a mixed model ancova method with change from
baseline as response and treatment and geographical
region as covariates. The SS and OTE results were

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202

 MANAGEMENT OF HEARTBURN-DOMINANT UNINVESTIGATED DYSPEPSIA 1193

summarized in frequency tables by treatment strategy.
The cumulative proportions of patients with recurrent
symptoms during the treatment-free observation period
were compared using the Cochran–Mantel–Haenszel
test.
RESULTS
Patient characteristics and disposition
In total, 613 patients were screened (Figure 1), of
whom 390 fulfilled the inclusion criteria; 196 patients
were randomized to the ‘PPI-start’ strategy and 194 to
the ‘H2-RA-start’; strategy. There were no significant
differences in clinical characteristics between the two
groups (Table 2) and compliance with therapy (con-
sumption of at least 75% of dispensed study medication)
was excellent during the first 4 weeks (‘PPI-start’: 184/
196; 93.9% [95% CI: 90.5–97.2%], ‘H2-RA-start’:
177/194; 91.2% [87.3–95.2%]) and for the entire
treatment phase (‘PPI-start’: 185/196; 94.4% [91.2–
97.6%], ‘H2-RA-start’: 180/194; 92.8% [89.1–96.4%]).
Symptom frequency prior to therapy was comparable in
the two treatment arms (Table 1); 195 of 390 (50.2%)
patients reported heartburn and/or regurgitation and
180 of 390 (46.2%) reported heartburn and/or regur-
gitation in combination with epigastric pain and/or
nausea (Figure 2). After randomization, 11 (2.8%)
patients without symptoms were discontinued (5 –
‘PPI-start’; 6 – ‘H2-RA-start’) as they had not fulfilled
the entry criteria [did not have moderate to severe
heartburn symptoms for at least 3 days in the previous
week before randomization (6), IBS (2), previous history
of oesophagitis (2), prohibited medication (1)]; they
were, however, included in the ITT analyses.
Treatment phase
Symptom response at 4 weeks. From the daily diary,
heartburn relief was reported by 55.1% (108/196; 95%
CI: 48.1–62.1%; ‘PPI-start’) and 27.3% (53/194; 21.1–
33.6%; ‘H2-RA-start’) of patients (Figure 3) with a
difference in heartburn relief of 27.8% (18.4–37.2%;
P < 0.001); sustained heartburn resolution was
reported by 36.2% (71/196; 25.9–43.0%; ‘PPI-start’)
and 12.9% (25/194; 8.2–17.6%; ‘H2-RA-start’) of
patients (Figure 3) with a difference between groups of
23.3% (15.1–31.6%; P < 0.001). The median times to
heartburn relief were 3 (2–5) and 8 (5–15) days and to
sustained heartburn resolution were 5 (2–8) and 29
(15–35) days, respectively for ‘PPI-start’ and ‘H2-RA-
start’, respectively. At 4 weeks, the ‘number needed to
treat’ for the ‘PPI-start’ strategy to achieve an addi-
tional heartburn relief success was 4 (95% CI 3–5) and

Screened Discontinued (233)

N = 613 Criteria not fulfilled (183)
Lost to follow-up (19)
Moved residence (1)
No reason given (1)
Non-compliant (5)
Randomised Withdrew consent (14)
N = 390

PPI Start H2-RA start

Discontinued (15)
Adverse event (2)
Criteria not fulfilled (5)
Lost to follow-up (3)
Non-compliant (1)
Withdrawn in error (1)
Withdrew consent (3)
Discontinued (9)
Adverse event (2)
Intolerable symptoms (3)
Lost to follow-up (1)
Moved residence (1)
Non-compliant (1)
Withdrew consent (1)
Completed 16 weeks
Figure 1. Flow diagram showing numbers
of patients enrolled and randomized to each Discontinued (27)
Criteria not fulfilled (1)
treatment strategy, and reasons for discon- Lost to follow-up (6)
No relief (13)
tinuation at baseline, 4 and 16-week time Withdrew consent (7)
points during the 16-week treatment phase
Started treatment -free
and the 24 weeks of treatment-free obser-
vation period.
Discontinued (17)
N = 196 N = 194
Adverse event (3)
Criteria not fulfilled (4)
Disease deteriorated (1)
Lost to follow-up (2)
Moved residence (1)
Non-compliant (2)
Withdrawn in error (2)
Withdrew consent (2)
Completed 4 weeks Completed 4 weeks
N = 181 N = 177
Discontinued (19)
Criteria not fulfilled (2)
Intolerable symptoms (5)
Lost to follow-up (2)
Moved residence (1)
Withdrew consent (3)
Withdrawn in error (6)
Completed 16 weeks
N = 172 N = 158
Discontinued (22)
Lost to follow-up (4)
Moved residence (2)
No relief (9)
Non-compliant (1)
Pregnancy (1)
Withdrawn in error (1)
Withdrew consent (4)
Started treatment -free
observation period observation period
N = 145 N = 136

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1194 D. ARMSTRONG et al.

Table 2. Demographic characteristics of patients at baseline Heartburn 0.8% 0.8%

(intention-to-treat analysis) Regurgitation 0.5%
1.0% 0.8%
Epigastric pain
‘PPI-start’ ‘H2-RA-start’
Nausea
n ¼ 196 n ¼ 194 3.8%
8.5% 1.0%
Gender 12.3%
Female, n (%) 100 (51.0) 92 (47.4)
Age (years) 18.5%
Mean 44 (12) 44 (12)
19.2%
Minimum–maximum 20–83 18–76
<50 years, n (%) 138 (70.4) 133 (68.6)
Prior upper GI investigations (>6 months previously)
Endoscopy 13 (6.6%) 11 (5.7%)
30.0%
Radiology 52 (26.5%) 49 (25.3%) No symptoms 2.8%
Endoscopy + radiology 7 (3.6%) 15 (7.7%)
Helicobacter pylori infection 30.0% 31.6%
Current smoker, n (%) 52 (27%) 60 (31%) Figure 2. Venn diagram showing overall percentages of
Alcohol use, n (%) 127 (65%) 117 (60%) randomized patients (‘PPI-start’ and ‘H2-RA-start’, combined;
Reflux symptoms (score ‡4 at baseline) n ¼ 390) with each of the four major upper gastrointestinal
Heartburn 190 (97.4%) 180 (93.3%) symptoms; 11 patients had no recorded symptoms and were
Regurgitation 94 (48.2%) 107 (55.4%) withdrawn from the study.
Epigastric pain 79 (40.5%) 84 (43.3%)
Nausea 31 (15.9%) 29 (15.0%)
Heartburn duration
indicated heartburn relief in 75.8% (144/190;
<12 months 19 (9.7%) 14 (7.2%)
>1 year £ 5 years 73 (37.2%) 52 (26.8%)
69.7–81.9%) of the ‘PPI-start’ group compared with
>5 year £ 10 years 43 (21.9%) 43 (22.2%) 57.8% (104/180; 50.6–65.0%) of the ‘H2-RA-start’
>10 £ 20 years 34 (17.3%) 56 (28.9%) group (P ¼ 0.0002) but there were no differences
>20 years 27 (13.8%) 29 (14.9%) between treatment strategies with respect to regurgi-
Mean (s.d.) years 9.4 (9.9) 11.1 (9.6) tation, epigastric pain, nausea or vomiting (data not
Days (n) during previous week with heartburn score ‡3
shown).
3 12 (6.1%) 18 (9.3%)
4 15 (7.7%) 17 (8.8%)
5 31 (16.3%) 22 (11.3%) Symptom response from 4 to 16 weeks. ‘Step-up’ therapy
6 40 (20.3%) 35 (18.0%) was required by 143 patients (Figure 4), 51 of 196
7 97 (49.5%) 102 (52.6%) (26.0%; 19.9–32.2%) from the ‘PPI-start’ group and 92
PPI, proton pump inhibitor; H2-RA, H2-receptor antagonist; GI, gas- of 194 (47.4%; 40.4–54.5%) from the ‘H2-RA-start’
trointestinal. group by 8 weeks; step up at 4 weeks because of
intolerable heartburn occurred in 16 of 196 (8.2%;
to achieve an additional sustained heartburn resolution 4.3–12.0%) and 37 of 194 (19.1%; 13.5–24.6%)
success was 4 (95% CI 3–7) compared with the ‘H2-RA- patients, respectively.
start’ strategy. The ‘PPI-start’ strategy produced heartburn relief in a
On univariate analysis, neither H. pylori status nor age significantly greater proportion of patients up to
was associated with a difference in heartburn relief 8 weeks and sustained heartburn resolution in a
(Table 3); however, proportional hazards survival ana- significantly greater proportion up to 12 weeks than
lysis indicated that heartburn relief was less likely and did the ‘H2-RA-start’ strategy (Figure 2). There were
slower if patients had (i) received ranitidine (‘H2-RA- no significant differences between the treatment strat-
start’) strategy: hazard ratio ¼ 0.77 (95% CI 0.62– egies with respect to heartburn relief or sustained
0.96, P ¼ 0.02); (ii) more IBS symptoms, hazard heartburn resolution by the end of the 16-week
ratio ¼ 0.85 (0.74–0.98, P ¼ 0.03); and (iii) a higher treatment period. The mean (s.d.) and median percent-
heartburn symptom score at the start, hazard ratio ¼ ages of heartburn-free days during the entire 16-week
0.78 (0.69–0.89, P < 0.001). treatment periods were: ‘PPI-start’: 52.2% (38.6%) and
A global assessment of upper gastrointestinal symp- 58.2% and ‘H2-RA-start’: 41.0% (31.4%), and 38.0%
toms over the 7-day period before the week 4 visit (P ¼ 0.002).

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202

 MANAGEMENT OF HEARTBURN-DOMINANT UNINVESTIGATED DYSPEPSIA 1195

Heartburn relief domains (Table 4) and in all QoLRAD domains

100 100
PPI start (n = 196) (Figure 5); however, by the end of the treatment
H2-RA start (n = 194) 75.5 81.1 76.8 phase (from 4 to 16 weeks), there was no difference
80 80
68.4 70.1 between treatment groups for either scale. At the end of
60
55.1
60 the treatment phase, OTE scores did not differ between
51.6
treatment groups (data not shown) but SS were
40 40 significantly higher in the ‘PPI-start’ group compared
27.3 with the ‘H2-RA-start’ group (P ¼ 0.0063; Table 5).
20 20

Outcomes after 16-week, blinded treatment phase. After

0 0
4 weeks 8 weeks 12 weeks 16 weeks completion of the treatment phase, 22 patients had not
P < 0.0001 P = 0.0009 P = 0.256 P = 0.321 achieved heartburn relief (‘PPI-start’: 13; ‘H2-RA-start:
Weeks after starting treatment 9). Seven of the nine patients in the ‘H2-RA-start’ arm
achieved heartburn relief after an 8-week open label
Sustained heartburn resolution
100 100 course of omeprazole 40 mg daily. Of the 13
PPI start (n = 196)
patients who underwent endoscopy because of persist-
H2-RA start (n = 194)
80 80 ent symptoms, six had mild, ‘LA’ grade ‘A’ (‘PPI-
start’: 1, ‘H2-RA-start’: 2) or ‘LA’ grade ‘B’ (‘PPI-start’:
60 60 1, ‘H2-RA-start’: 2) oesophagitis.34, 35
44.9 45.9
36.2 41.3 36.0
40 34.0 40
24.2 Follow-up phase
20 12.9 20
Symptom response. Of the 390 patients randomized, 308
0 0 patients with heartburn relief at the end of the
4 weeks 8 weeks 12 weeks 16 weeks
P < 0.0001 P = 0.0004 P = 0.029 P = 0.051
treatment phase (‘PPI-start’: 159, ‘H2-RA-start’: 149)
Weeks after starting treatment were eligible to enter the treatment-free, follow-up
phase; after withdrawal of ineligible patients [e.g.
Figure 3. Percentages (95% CI) of patients, by treatment strategy, withdrew consent (11), lost to follow-up (10), moved
at 4, 8, 12 and 16 weeks of treatment, reporting heartburn relief (2), other (4)], 281 patients were eligible to start
(heartburn score <3 on no more than 1 day during the previous
the treatment-free, follow-up phase (‘PPI-start’: 145,
week; upper graph) and sustained heartburn resolution (heart-
burn score ¼ 1 during the previous week; lower graph); P-values ‘H2-RA-start’: 136). There were no differences in relapse
indicate differences between treatment strategies at each time rates between patients assigned to the initial ‘PPI-start’
point (Cochran–Mantel–Haenszel test – intention-to-treat and ‘H2-RA-start’ treatment strategies (Figure 6). Based
analysis). on the daily patient diary data, heartburn relapse
occurred in 79% (114/145; 72–85%: ‘PPI-start’) and
Quality of life and assessment of treatment effect. At 76% (103/136; 69–83%: ‘H2-RA-start’) at 6 months.
4 weeks, patients in the ‘PPI-start’ group had signifi- Median times to relapse were 8 (7–9) and 9 (8–11)
cantly greater improvements in GSRS scores for indi- days, respectively. The median number of days to the
gestion, abdominal pain, reflux and overall GSRS first occurrence of moderate-to-severe heartburn (score

Table 3. Effect of Helicobacter pylori status and age on heartburn relief at 4 weeks

‘PPI-Start’ (% [95% CI] n) ‘H2-RA-Start’ (% [95% CI] n) Total (% [95% CI] n)

H. pylori positive 59.7% [46.9–72.4%] 57 32.2% [20.3–44.1%] 59 45.7% [36.6–54.8%] 116

H. pylori negative 53.4% [44.9–61.9%] 133 24.2% [16.8–31.6%] 128 39.1% [33.2–45.0%] 261
Age <50 years 52.2% [43.8–60.5%] 138 27.8% [20.2–35.4%] 133 40.2% [34.4–46.1%] 271
Age ‡50 years 62.1% [49.6–74.6%] 58 26.2% [15.2–37.3%] 61 43.7% [34.8–52.6%] 119

PPI, proton pump inhibitor; H2-RA, H2-receptor antagonist.

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202

1196 D. ARMSTRONG et al.

Week 4 Week 8 Week 12 Week 16 Total

‘H2-RA-start’
Unblind 7 7 3 17

Withdraw 17 5 2 3 1 28

Relief 53 27 20 36 13 149

Ranitidine 150 194 87

Omeprazole 20 37 55 8 63 17

Step-up 37 55 92

‘PPI-start’
Unblind 3 6 7 16

Withdraw 15 3 0 1 2 21

Relief 108 19 7 14 11 159 Figure 4. Flow diagram showing number

Omeprazole 20 196 57 of patients who achieved heartburn relief at
Omeprazole 40 16 35 6 41 20 each visit, were withdrawn for other rea-
sons or required step-up therapy for each
Step-up 16 35 51
treatment strategy.

Table 4. Mean Gastrointestinal Symptom

‘PPI-start’ mean ‘H2-RA-start’ Mean P-value for difference
Rating Scale (GSRS) scores (s.d.) for each of
score (s.d.) n score (s.d.) n between strategies
the five domains in patients at baseline,
Reflux 4 weeks and completion of treatment
Baseline 4.3 (1.2) 196 4.1 (1.2) 192 (4–16 weeks) and at relapse (intention-
4 weeks 2.1 (1.3) 188 2.8 (1.4) 186 <0.001 vs. baseline to-treat population); P-values indicate
4–16 weeks 1.7 (1.1) 188 1.8 (1.1) 186 NS vs. baseline whether the two strategies produced signi-
Relapse 3.8 (1.5) 150 3.6 (1.5) 143 NS vs. 4–16 wks ficantly different changes in symptom
Indigestion scores from baseline to 4 weeks and to
Baseline 3.1 (1.2) 196 3.3 (1.4) 193 4–16 weeks and from 4 to 16 weeks to
4 weeks 2.4 (1.2) 188 2.8 (1.7) 187 0.02 vs. baseline the time of relapse
4–16 weeks 2.1 (1.2) 188 2.2 (1.6) 187 NS vs. baseline
Relapse 2.4 (1.1) 150 2.5 (1.4) 142 NS vs. 4–16 weeks
Abdominal pain
Baseline 2.9 (1.2) 196 2.7 (1.1) 193
4 weeks 2.1 (1.2) 188 2.3 (1.2) 187 0.014 vs. baseline
4–16 weeks 1.9 (1.1) 188 1.8 (1.0) 187 NS vs. baseline
Relapse 2.4 (1.1) 150 2.3 (1.3) 143 NS vs. 4–16 weeks
Constipation
Baseline 2.0 (1.3) 195 2.2 (1.4) 193
4 weeks 1.8 (1.1) 187 2.0 (1.5) 187 NS vs. baseline
4–16 weeks 1.7 (1.0) 188 1.8 (1.3) 187 NS vs. baseline
Relapse 1.7 (1.0) 150 1.7 (1.3) 142 NS vs. 4–16 weeks
Diarrhoea
Baseline 1.9 (1.0) 195 1.9 (1.2) 193
4 weeks 1.7 (1.0) 188 1.8 (1.3) 187 NS vs. baseline
4–16 weeks 1.6 (0.9) 188 1.7 (1.1) 187 NS vs. baseline
Relapse 1.5 (0.8) 150 1.6 (1.0) 143 NS vs. 4–16 weeks
Total GSRS score
Baseline 2.8 (0.8) 196 2.8 (0.9) 193
4 weeks 2.0 (0.9) 188 2.4 (1.1) 187 <0.001 vs. baseline
4–16 weeks 1.8 (0.8) 188 1.9 (1.0) 187 NS vs. baseline
Relapse 2.4 (0.8) 150 2.3 (1.0) 143 NS vs. 4–16 weeks

NS, not significant (P > 0.05).

PPI, proton pump inhibitor; H2-RA, H2-receptor antagonist.

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202

 MANAGEMENT OF HEARTBURN-DOMINANT UNINVESTIGATED DYSPEPSIA 1197

Improvement after 4 weeks Heartburn relapse

PPI start 100
2.5
** H2-RA start (%)
78.6%
** ** ** 80
2.0
75.8%
P = 0.72
1.5 * 60

1.0 40

0.5 Median time to relapse

20 PPI start 8 days
0.0 H2-RA start 9 days
Emotional Sleep Food/drink Physical/ Vitality 0
distress disturbance problems social 0 28 56 84 112 140 168
functioning
Days after stopping treatment
QOLRAD domain
First day with heartburn score > 4/7
Deterioration at relapse 100
Physical/ (%) 86.8%
0.5
Emotional Sleep Food/drink social 80 86.6%
distress disturbance problems functioning Vitality P = 0.57
0.0
60
–0.5

40
–1.0
Median time to symptom score > 4/7
–1.5 20 6 days
PPI start
H2-RA start 6 days
–2.0 0
0 28 61 85 112 142 168
–2.5 Days after stopping treatment

Figure 5. Changes in mean Quality of Life in Reflux and
Dyspepsia scores for each domain assessed at 4 weeks, in
comparison with baseline (upper graph: *P < 0.01, **P < 0.001)
and at the time of heartburn relapse, in comparison with the end
of the initial treatment period (lower graph: all P > 0.05).
Figure 6. Incremental percentages of patients, by treatment
strategy, reporting heartburn relapse (upper graph) and a first
episode of moderate to severe heartburn (lower graph) during the
6-month treatment-free observation period; P-values indicate
differences between treatment groups (Cochran–Mantel–Haenszel
test – intention-to-treat analysis).

Table 5. Frequency distribution of Satisfaction Survey responses

at the end of the treatment phase (4–16 weeks: intention-to-treat heartburn relief and relapse, was also compar-
population) able between strategies (‘PPI-start’: 22% [18–26%],
‘H2-RA-start’: 23% [18–27%]; P ¼ 0.33).
‘PPI-start’, ‘H2-RA-start’,
Proportional hazards survival analysis indicated that
n (%) (n ¼ 196) n (%) (n ¼ 194)
symptom relapse was more likely and faster if patients
Completely satisfied 93 (47.4) 62 (32.0) had (i) a long history of symptoms, hazard ratio ¼ 1.03
Very satisfied 52 (26.5) 61 (31.4)
per year (1.02 to 1.04, P < 0.001); (ii) more severe
Quite satisfied 13 (6.6) 27 (13.9)
Satisfied 17 (8.7) 16 (8.2) regurgitation symptoms, hazard ratio ¼ 1.15 (1.05–
Dissatisfied 7 (3.6) 7 (3.6) 1.25, P ¼ 0.002); and (iii) no H. pylori infection, hazard
Completely dissatisfied 0 (0.0) 1 (0.5) ratio ¼ 1.46 (1.10–1.93, P ¼ 0.009).
PPI, proton pump inhibitor; H2-RA, H2-receptor antagonist.
Quality of life and assessment of treatment effect. At the
time of relapse in the follow-up phase, GSRS scores had
‡4) was 6 (95% CI 5–7) days and was comparable for deteriorated significantly for all domains (P < 0.03)
the two treatment strategies; the mean proportion of except diarrhoea and QoLRAD scores had deteriorated
days spent heartburn free, from the time between significantly for all domains (P < 0.0001) compared

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202

1198 D. ARMSTRONG et al.
with the end of the treatment phase, but there were no
differences for either GSRS or QoLRAD with respect to
the initial treatment strategy and no differences
between the initial treatment strategies with respect to
the magnitude of the decline in GSRS and QOLRAD
scores (Table 3).
Antacid consumption
Daily intake [mean (s.d.)] of antacid rescue medication
[‘PPI-start’: 4.9 (3.8) tablets vs. ‘H2-RA-start’: 4.2 (3.0);
P ¼ 0.192; Wilcoxon rank sum test] prior to random-
ization was similar for the two treatment strategies.
During the active treatment phase, daily antacid intake
decreased and was lower in the ‘PPI-start’ group [1.0
(1.8) tablets than in the ‘H2-RA-start’ group] [1.2
(1.6); P ¼ 0.003]. Antacid intake increased again in
the treatment-free, follow-up phase but there was
no difference between the two treatment groups
[‘PPI-start’: 2.7 (2.8) tablets vs. ‘H2-RA-start’: 2.5
(2.4); P ¼ 0.989].
Adverse events
Both treatment strategies were safe and well tolerated.
The frequency and total number of serious adverse
events (SAEs) and adverse events reported were similar
in both treatment arms. Altogether, seven non-fatal
SAEs were reported; there were four SAEs reported in
the ‘PPI-start’ (myocardial infarction, incarcerated
ventral hernia, deep venous thrombosis and miscar-
riage) and three SAEs in ‘H2-RA-start’ groups (chole-
lithiasis with post-operative pain, myocardial ischaemia
and lower abdominal pain); no SAE was judged by the
investigators to be causally related to study therapy.
The most frequently reported adverse events overall
were headache (7.5%), respiratory infection (8.2%),
diarrhoea (7.0%), and abdominal pain (6.6%) and these
were reported equally in both strategies.
DISCUSSION
Heartburn is common36–39 and, with regurgitation, it is
a cardinal symptom of GERD; it is also common in
association with other symptoms of dyspepsia.13–18
Despite management guidelines for GERD3, 22, 23 and
dyspepsia,18, 40 and studies of empiric therapy in
dyspepsia patients, many of whom may have heart-
burn,13–16 there are few data on the initial, symptom-

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202
based treatment of primary care dyspepsia patients with
dominant heartburn, the effect of different empiric
treatment strategies on heartburn relief over periods of
up to 16 weeks or on relapse of heartburn after
treatment cessation.41–44
In the present study, initial therapy with a standard-
dose PPI (omeprazole 20 mg once daily) produced
heartburn relief in twice as many, and sustained
heartburn resolution in three times as many patients
as a standard-dose H2-RA (ranitidine 150 mg b.d.) at
4 weeks and this was associated with a greater
improvement in health-related quality of life and a
reduced requirement for ‘step-up’ therapy after
4–8 weeks. The ‘PPI start’ strategy was dominant until
12 weeks for sustained heartburn resolution and,
although heartburn relief was eventually achieved in
about 80% of patients with either strategy, the rapidity
of symptom resolution was significantly higher with the
‘PPI-start’ strategy and, by 8 weeks, it had produced
comparable results for sustained heartburn resolution to
those produced by the ‘H2-RA-start’ strategy at
16 weeks. Of patients in the H2RA-start group, 92 of
194 (47.4%; 37 at 4 weeks and 55 at 8 weeks) stepped
up to PPI therapy. Heartburn control was subsequently
achieved in 69 of these 92 patients (75.0%). After
treatment discontinuation for patients who had
achieved heartburn relief, relapse rates were compar-
able for the ‘PPI-start’ and ‘H2RA-start’ treatment
groups.
A small proportion of patients remained symptom-free,
off therapy, at the end of the 6-month follow-up phase
but the majority had recurrent symptoms within a few
weeks, sufficient to warrant resumption of treatment.
Thus, initial therapy with a PPI rather than an H2-RA
does not appear to predispose to more rapid relapse after
cessation of acute therapy.
Enrolment in this study, as in previous GERD
studies,4–10 was predicated on the symptom of ‘retros-
ternal burning, rising towards the neck’.1 In an
endoscopic study in Canadian primary care practice,17
about 55% of patients with dominant heartburn had
erosive oesophagitis, similar to the findings of other
endoscopic studies.5, 7, 45 These data support the
recommendation18 that patients with heartburn-dom-
inant dyspepsia should be offered empiric acid suppres-
sive therapy, before non-invasive testing for H. pylori
infection.27, 28 This does not preclude endoscopy46 but,
although heartburn may be associated with peptic
ulcer disease,17 Barrett’s oesophagus or malignancy,47
 MANAGEMENT OF HEARTBURN-DOMINANT UNINVESTIGATED DYSPEPSIA
clinically-significant lesions are infrequent in the
absence of alarm features17, 18 and severe oesophagitis
(LA Grades ‘C’ and ‘D’) occurs in <5–10% of patients
with heartburn-dominant symptoms. In patients who
had persistent symptoms after the 16-week treatment
phase, the only significant endoscopic findings were LA
Grade A or B oesophagitis. There is evidence that, for
patients receiving PPIs, heartburn relief is associated
with healing of erosive oesophagitis.48 Thus, a treat-
ment strategy that ‘starts high’, with the most effective
acid suppression therapy,8–10 is likely to be safe and
effective for the vast majority of patients with heart-
burn-dominant upper gastrointestinal tract symptoms.
Symptoms will persist in some patients who will,
therefore, need to be re-evaluated to determine whether
alarm features are present or whether there is another
underlying condition that requires further investiga-
tion18 but the empiric approach to therapy evaluated in
this study does, at least, obviate the need for investiga-
tion in a high proportion of patients.
Proton pump inhibitors produce healing and symptom
resolution in a higher proportion of erosive oesophagitis
patients than do H2-RAs or prokinetics3, 19, 49 and more
potent gastric acid suppression is associated with a
further improvement in outcomes.8–10 Standard dose
PPIs also produce symptom resolution in a higher
proportion of ENRD patients than do low-dose PPIs,6
H2-RAs4, 50 and prokinetics.7, 21 In the present study,
overall heartburn relief rates, with standard-dose PPI or
H2-RA therapy, were similar to those observed after
4 weeks in a previous Canadian study11 of GERD
patients with and without erosive oesophagitis, after
endoscopy. Endoscopy was not performed at enrolment
in the present study; although it would have allowed
risk stratification with respect to oesophagitis severity 8,
34, 35
and H. pylori infection,11, 51 it would also have
introduced the potential for bias52, 53 in a study
intended to assess heartburn response to empiric
therapy in a primary care environment.
The primary outcome measure – ‘heartburn relief’
(Table 1) – was selected because it was considered to be
a reasonable clinical outcome; the more stringent,
secondary outcome – ‘sustained heartburn resolution’
– was associated with markedly lower response rates.
The 7-point Likert scale used to rate symptom severity
was identical in wording to the GOS scale29 used in the
related CADET-Hp27 (H. pylori positive uninvestigated
dyspepsia) and CADET-HN28 (H. pylori negative unin-
vestigated dyspepsia) studies, although the evaluation

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202
1199
period (7 days) was different.28 Heartburn resolution
was identified less frequently by patients in their daily
diary assessments than when heartburn (as well as
regurgitation, epigastric pain, nausea and vomiting)
were assessed overall for the previous week. This
suggests that the daily diaries were completed regularly;
if there had been significant ‘hoarding’, one would have
expected less discrepancy between the daily diary data
and the retrospective assessment of symptoms. Both
measures of symptom response were based on the
patients’ recall, consistent with the increasing emphasis
on patient reported outcomes.54–56 As in previous
studies,30, 57 symptom relief was associated with an
improvement in patients’ quality of life. In the present
study, the disease-specific, quality of life tool (QOLRAD)
demonstrated a significant difference between strategies
after 4 weeks but not at the end of therapy; similarly,
the OTE was comparable for the two strategies by the
end of therapy as were the proportions of patients in
each group with symptom resolution. On the contrary,
the SS results suggested a persistent difference in
outcomes for the two groups, perhaps because of the
more rapid and complete symptom response in the ‘PPI-
start’ group.
The traditional ‘step-up’ approach,22, 23 progressing
from ‘life-style modifications’ to over-the-counter med-
ications and prescription H2-RAs and PPIs has been
challenged3, 18 by data demonstrating the superiority of
PPI therapy in randomized trials19, 20 and in a
comparison of ‘step up’ and ‘step down’ strategies.58
The present study did not compare ‘step up’ and ‘step
down’ GERD strategies directly as the latter addresses
both initial therapy and a switch to maintenance
therapy. Instead, the study evaluated two initial treat-
ment strategies, with respect to treatment response and
safety, for patients with heartburn-dominant symptoms;
the strategies were intended to be relevant to primary
care, clinical practice42 and consistent with published
guidelines.18 although this paper has not addressed the
economic consequences of these strategies. The subse-
quent treatment-free, follow-up phase, was designed to
determine how many patients would develop recurrent
symptoms during a 6-month period, requiring further
medical therapy.33
Risk factors for delayed symptom resolution included
the presence of IBS symptoms at baseline, consistent
with previous observations.59 The relationship between
H. pylori status and GERD remains controversial.60, 61
In this study, neither univariate nor multivariate
1200 D. ARMSTRONG et al.
analysis indicated a significant effect of H. pylori on
symptom relief although H. pylori negative subjects
were at greater risk of recurrent symptoms after
cessation of therapy. An interaction between H. pylori
and acid suppression therapy appears to be less marked
in HDUD than in GERD patients.11, 51 Despite some
evidence that H. pylori infection is less prevalent in
GERD patients,17, 60 a possible association between
H. pylori infection and delayed GERD symptom relapse is
probably not clinically significant.
In summary, empiric, ‘PPI-start’ therapy produces
relief of symptoms and improvement in health-related
quality of life in a higher proportion of primary care
patients with uninvestigated heartburn-dominant dys-
pepsia after 4 weeks than does an ‘H2-RA-start’ strat-
egy. A ‘step up’ of therapy in non-responders, at
4–8 weeks, produces a further increase in symptom
response in both groups and, although both groups
achieve good response rates by 16 weeks, sustained
symptom relief at 8 weeks with the ‘PPI-start’ regimen
is similar to that achieved at 16 weeks with the ‘H2-RA-
start’ regimen. This study confirms the appropriateness
of a PPI-based, empiric treatment strategy for primary
care practice patients with heartburn-dominant symp-
toms to provide effective acid suppression and rapid
symptom relief. The study also confirms that GERD is a
chronic condition; symptoms recur rapidly after cessa-
tion of therapy, suggesting that some form of mainten-
ance therapy is required for the majority of patients
with heartburn-dominant, uninvestigated dyspepsia.
The role of ‘on demand’ therapy in patients with
uninvestigated heartburn-dominant dyspepsia33 will be
reported separately.
ACKNOWLEDGEMENTS
This study was financially supported by AstraZeneca
Canada Inc.
APPENDIX
The CADET HR Study group of principal investigators
are: S. Arndt, Regina; M. D. Atin, Toronto; M. Audet,
Ste-Foy; J. Bachand, Sherbrooke; G. Baran, Kingston;
K. Bayly, Saskatoon; S. Behiels, Edmonton; B. Belle-
mare, Granby; W. Booth, Antigonish; R. Bouchard,
Sherbrooke; M. Bradette, Quebec; L. Breger, Pointe-
Claire; S. Brien, Peterborough; F. Bursey, St John’s;
A. Cockeram, Saint John; A. Cohen, Montreal; H. Conter,

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202
Halifax; VS. J. Coyle, Winnipeg; B. N. Craig, Saint John;
D. Crowley, Strathroy; G. D’Ignazio, Hawkesbury;
O. Doiron, Saint John; J. Dollin, Ottawa; J. Drexler,
Winnipeg; B. Elfassy, St-Laurent; C. Ellis, Calgary;
D. Fay, Granby; W. Fouad, Winnipeg; G. Fullerton,
Woodstock; R. Hamilton, Wolfville; J. Hii, Vancouver;
R. Hilsden, Calgary; B. Hogenbirk, Pointe-Claire; W. P.
House, Vancouver; E. Howlett, Saskatoon; D. Johnson,
Winnipeg; H. A. Johnston, Orleans; A. Kelly, Edmonton;
J. Kennedy, Antigonish; E. N. L. Larkai, Saskatoon;
Y. Lee, North York; J. Li, Moncton; J. Loutfi, Pierrefonds;
J. MacKenzie, Ottawa; W. P. McKeough, London;
J. McMorran, Vancouver; J. T. Momoh, Winnipeg;
A. Munroe, Saint John; W. Olsheski, Toronto; P. O’Shea,
St John’s; G. Pannozzo, Waterloo; W. Paterson, Kings-
ton; L. Pontikes, Regina; I. Prokopiw, London; G.
Rideout, Goulds; L. Rochon, Ottawa; F. Schweiger,
Saint John; V. Senikas, Montreal; D. Shu, Coquitlam; R.
J. Smith, Mount Pearl; G. Tellier, St-Jerome; A. Thom-
son, Edmonton; F. Turcotte, Sherbrooke; S. J. O.
Veldhuyzen van Zanten, Halifax; G. R. Webb, Grand
Bay-Westfield; R. Whatley, Peterborough; D. P. Will-
oughby, Woodstock; B. Zidel, Mississauga.
REFERENCES
1 Carlsson R, Dent J, Bolling-Sternevald E, et al. The usefulness of
a structured questionnaire in the assessment of symptomatic
gastroesophageal reflux disease. Scand J Gastroenterol 1998;
33: 1023–9.
2 Armstrong D. Diagnostic significance, provocants and time-
course of heartburn and regurgitation. Eur J Gastroenterol
Hepatol 2001; 13(Suppl. 3): S21–3.
3 Dent J, Brun J, Fendrick AM, et al. An evidence-based
appraisal of reflux disease management: the Genval
Workshop Report. Gut 1999; 44(Suppl. 2): S1–6.
4 Venables TL, Newland RD, Patel AC, et al. Omeprazole
10 milligrams once daily, omeprazole 20 mg once daily, or
ranitidine 150 mg twice daily, evaluated as initial therapy for
the relief of symptoms of gastro-esophageal reflux disease in
general practice. Scand J Gastroenterol 1997; 32: 965–73.
5 Carlsson R, Galmiche J-P, Dent J, Lundell L, Frison L. Gastro-
esophageal reflux disease in primary care: an international
study of different treatment strategies with omeprazole. Eur
J Gastroenterol Hepatol 1997; 10: 119–24.
6 Lind T, Havelund T, Carlsson R, et al. Heartburn without
oesophagitis: efficacy of omeprazole therapy and features
determining therapeutic response. Scand J Gastroenterol
1997; 32: 974–9.
7 Galmiche JP, Barthelemy P, Hamelin B. Treating the
symptoms of gastro-oesophageal reflux disease: a double-
blind comparison of omeprazole and cisapride. Aliment
Pharmacol Ther 1997; 11: 765–73.
 MANAGEMENT OF HEARTBURN-DOMINANT UNINVESTIGATED DYSPEPSIA
8 Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole
(40 mg) compared with lansoprazole (30 mg) in the
treatment of erosive esophagitis. Am J Gastroenterol 2002;
97: 575–83.
9 Richter JE, Kahrilas PJ, Johanson J, et al. Efficacy and safety of
esomeprazole compared with omeprazole in GERD patients
with erosive esophagitis: a randomized controlled trial. Am J
Gastroenterol 2001; 96: 656–65.
10 Kahrilas PJ, Falk GW, Johnson DA, et al. Esomeprazole
improves healing and symptom resolution as compared with
omeprazole in reflux oesophagitis patients: a randomized
controlled trial. The Esomeprazole Study Investigators.
Aliment Pharmacol Ther 2000; 14: 1249–58.
11 Armstrong D, Paré P, Pericak D, Pyzyk M, Canadian Pantop-
razole GERD Study Group. Symptom relief in gastroesophageal
reflux disease: a randomized, controlled comparison of
pantoprazole and nizatidine in a mixed patient population
with erosive esophagitis or endoscopy-negative reflux disease.
Am J Gastroenterol 2001; 96: 2849–57.
12 Bate CM, Green JR, Axon AT, et al. Omeprazole is more
effective than cimetidine for the relief of all grades of gastro-
oesophageal reflux disease-associated heartburn, irrespective
of the presence or absence of endoscopic oesophagitis. Aliment
Pharmacol Ther 1997; 11: 755–63.
13 Goves J, Oldring JK, Kerri D, et al. First line treatment with
omeprazole provides an effective and superior alternative
strategy in the management of dyspepsia compared to
antacid/alginate liquid: a multicentre study in general
practice. Aliment Pharmacol Ther 1998; 12: 147–57.
14 Mason I, Millar LJ, Sheikh R, et al. The management of acid-
related dyspepsia in general practice: a comparison of an
omeprazole versus antacid-alginate/ranitidine management
strategy. Aliment Pharmacol Ther 1998; 12: 263–71.
15 Meineche-Schmidt V, Krag E. Antisecretory therapy in 1017
patients with ulcer-like or reflux-like dyspepsia in general
practice. Eur J Gen Pract 1997; 3: 125–30.
16 Jones RH, Baxter G. Lansoprazole 30 mg daily versus
ranitidine 150 mg bd in the treatment of acid-related
dyspepsia in general practice. Aliment Pharmacol Ther
1997; 11: 541–6.
17 Thomson ABR, Barkun AN, Armstrong D, et al. The
prevalence of clinically significant endoscopic findings in
primary care patients with uninvestigated dyspepsia: the
Canadian Adult Dyspepsia Empiric Treatment – Prompt
Endoscopy (CADET–PE) study. Aliment Pharmacol Ther
2003; 17: 1481–91.
18 Veldhuyzen van Zanten SJO, Flook N, Chiba N, et al. An
evidence-based approach to the management of
uninvestigated dyspepsia in the era of Helicobacter pylori.
CMAJ 2000; 162(Suppl. 12): S1–23.
19 Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing
and symptom relief in grade II to IV gastroesophageal reflux
disease: a meta-analysis. Gastroenterology 1997; 112: 1798–
810.
20 Caro JJ, Salas M, Ward A. Healing and relapse rates in
gastroesophageal reflux disease treated with the newer
proton-pump inhibitors lansoprazole, rabeprazole, and

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202
1201
pantoprazole compared with omeprazole, ranitidine, and
placebo: evidence from randomized clinical trials. Clin Ther
2001; 23: 998–1017.
21 Hatlebakk JG, Hyggen A, Madsen PH, et al. Heartburn
treatment in primary care: randomised, double blind study
for 8 weeks. Br Med J 1999; 319: 550–3.
22 De Vault KR, Castell DO. Updated guidelines for the diagnosis
and treatment of gastro-esophageal reflux disease. The
Practice Parameters Committee of the American College of
Gastroenterology. Am J Gastroenterol 1999; 94: 1434–42.
23 Beck IT, Champion MC, Lemire S, Thomson ABR, and con-
tributing participants. The second Canadian consensus
conference on the management of patients with
gastroesophageal reflux disease. Can J Gastroenterol 1997;
11(Suppl. B): 7B–20B.
24 Ofman JJ, Dorn GH, Fennerty MB, et al. The clinical and
economic impact of competing management strategies for
gastro-esophageal reflux disease. Aliment Pharmacol Ther
2002; 16: 261–73.
25 Gerson LB, Robbins AS, Garber A, et al. A cost-effectiveness
analysis of prescribing strategies in the management of
gastroesophageal reflux disease. Am J Gastroenterol 2000;
95: 395–407.
26 Manning AP, Thompson WG, Heaton KW, et al. Towards
positive diagnosis of the irritable bowel. Br Med J 1978; 2:
653–4.
27 Chiba N, Veldhuyzen van Zanten SJO, Sinclair P, et al.
Treating Helicobacter pylori infection in primary care patients
with uninvestigated dyspepsia: the Canadian Adult Dyspepsia
Empiric Treatment – Helicobacter Pylori positive (CADET-Hp)
randomised controlled trial. Br Med J 2002; 324: 1012–6.
28 Veldhuyzen van Zanten SJO, Chiba N, Armstrong D, et al. A
double-blind randomised controlled trial comparing
omeprazole, ranitidine, cisapride and placebo in 512
Helicobacter pylori (Hp) negative primary care patients with
uninvestigated dyspepsia (UD) – the CADET HN study. Can J
Gastroenterol 2002; 16(Suppl. A): A5.
29 Veldhuyzen van Zanten SJO, Chiba N, Armstrong D, et al. The
responsiveness of the Global Overall Symptom (GOS) score – a
7-point Likert scale for the measurement of dyspepsia
symptoms in clinical trials. Can J Gastroenterol 2003;
17(Suppl. A): 113A.
30 Wiklund IK, Junghard O, Grace E, et al. Quality of life in reflux
and dyspepsia patients. Psychometric documentation of a new
disease-specific questionnaire (QOLRAD). Eur J Surg 1998;
583: 41–9.
31 Svedlund J, Sjödin I, Dötevall G. GSRS – clinical rating scale
for gastrointestinal symptoms in patients with irritable bowel
syndrome and peptic ulcer disease. Dig Dis Sci 1988; 33: 129–
34.
32 Juniper EF, Guyatt GH, Willan A, et al. Determining a minimal
important change in a disease-specific quality of life
questionnaire. J Clin Epidemiol 1994; 47: 81–7.
33 Armstrong D, Barkun AN, Chiba N, et al. On demand therapy
for heartburn-dominant uninvestigated dyspepsia in primary
care practice: the CADET-HR study. Can J Gastroenterol 2003;
17(Suppl. A): 105A.
1202 D. ARMSTRONG et al.
34 Armstrong D, Bennett JR, Blum AL, et al. The endoscopic
assessment of esophagitis: a progress report on observer
agreement. Gastroenterology 1996; 111: 85–92.
35 Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of
oesophagitis: clinical and functional correlates and further
validation of the Los Angeles classification. Gut 1999; 45:
172–80.
36 Locke GR III, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ III.
Prevalence and clinical spectrum of gastroesophageal reflux: a
population-based study in Olmsted County, Minnesota.
Gastroenterology 1997; 112: 1448–56.
37 Nebel OT, Fornes MF, Castell DO. Symptomatic gastro-
esophageal reflux: incidence and precipitating factors. Am J
Dig Dis 1976; 21: 953–6.
38 Tougas G, Chen Y, Hwang P, et al. Prevalence and impact of
upper gastrointestinal symptoms in the Canadian population:
findings from the DIGEST study. Am J Gastroenterol 1999; 94:
2845–54.
39 Talley NJ, Weaver AL, Zinsmeister AR, Melton LJ III. Onset
and disappearance of gastrointestinal symptoms and
functional gastrointestinal disorders. Am J Epidemiol 1992;
136: 165–77.
40 American Gastroenterological Association (AGA) Clinical
Practice and Practice Economics Committee. AGA technical
review: evaluation of dyspepsia. Gastroenterology 1998; 114:
582–95.
41 Carlsson R, Galmiche JP, Dent J, Lundell L, Frison L.
Prognostic factors influencing relapse of oesophagitis during
maintenance therapy with antisecretory drugs: a meta-
analysis of long-term omeprazole trials. Aliment Pharmacol
Therap 1997; 11: 473–82.
42 Bardhan KD, Müller-Lissner S, Bigard MA, et al. Symptomatic
gastro-oesophageal reflux disease: double blind controlled
study of intermittent treatment with omeprazole or ranitidine.
The European Study Group. Br Med J 1999; 318: 502–7.
43 Hetzel DJ, Dent J, Reed WD, et al. Healing and relapse of severe
peptic esophagitis after treatment with omeprazole.
Gastroenterology 1988; 95: 903–12.
44 Sandmark S, Carlsson R, Fausa O, Lundell L. Omeprazole
or ranitidine in the treatment of reflux esophagitis. Results of a
double-blind, randomized, Scandinavian multicenter study.
Scand J Gastroenterol 1988; 23: 625–32.
45 Robinson M, Earnest D, Maton PN, et al. Frequent heartburn
symptoms should not be ignored in subjects who self-treat
with antacids. Gastroenterology 1996; 110: A241.
46 Armstrong D. Motion – all patients with GERD should be
offered once in a lifetime endoscopy: arguments for the
motion. Can J Gastroenterol 2002; 16: 549–51.
47 Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic
gastroesophageal reflux as a risk factor for esophageal
adenocarcinoma. N Engl J Med 1999; 340: 825–31.
48 Armstrong D. Symptom status as a surrogate for absence of
endoscopic oesophagitis. Eur J Gastroenterol Hepatol 2001;
13(Suppl. 3): S76–8.

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1189–1202
49 van Pinxteren B, Numans ME, Lau J, de Wit NJ, Hungin APS,
Bonis PAL. Short-term treatment of gastroesophageal reflux
disease. A systematic review and meta-analysis of the effect of
acid-suppressant drugs in empirical treatment and in
endoscopy-negative patients. J Gen Intern Med 2003; 18:
755–63.
50 Richter JE, Campbell DR, Kahrilas PJ, Huang B, Fludas C.
Lansoprazole compared with ranitidine for the treatment of
nonerosive gastroesophageal reflux disease. Arch Int Med
2000; 160: 1803–9.
51 Holtmann G, Cain C, Malfertheiner P. Gastric Helicobacter
pylori infection accelerates healing of reflux esophagitis during
treatment with the proton pump inhibitor pantoprazole.
Gastroenterology 1999; 117: 11–6.
52 Wiklund I, Glise H, Jerndal P, Carlsson J, Talley NJ. Does
endoscopy have a positive impact on quality of life in
dyspepsia? Gastrointest Endosc 1998; 47: 449–54.
53 Bytzer P, Hansen JM, Schaffalitzky Muckadell de OB. Empirical
H2-blocker therapy or prompt endoscopy in management of
dyspepsia. Lancet 1994; 343: 811–6.
54 Acquadro C, Berzon R, Dubois D, et al. Incorporating the
patient’s perspective into drug development and
communication: an ad hoc task force report of the Patient-
Reported Outcomes (PRO) Harmonization Group meeting at
the Food and Drug Administration. Value in Health 2003; 6:
522–31.
55 Madisch A, Kulich KR, Malfertheiner P, et al. Impact of reflux
disease on general and disease-related quality of life – evidence
from a recent comparative methodological study in Germany.
Z Gastroenterol 2003; 41: 1137–43.
56 Jones R, Horbach S, Sander P, Ryden-Bergsten T. Heartburn
in patients with gastro-oesophageal reflux disease in Germany
and Sweden: a study on patients’ burden of disease.
Pharmacoeconomics 2003; 21: 1091–102.
57 Havelund T, Lind T, Wiklund I, et al. Quality of life in patients
with heartburn but without esophagitis: effects of treatment
with omeprazole. Am J Gastroenterol 1999; 94: 1782–9.
58 Howden CW, Henning JM, Huang B, Lukasik N, Freston JW.
Management of heartburn in a large, randomized,
community-based study: comparison of four therapeutic
strategies. Am J Gastroenterol 2001; 96: 1704–10.
59 Carlsson R, Bolling-Sternevald E, Jerndal P, et al. Factors
predicting response to omeprazole treatment in patients with
functional dyspepsia. Gastroenterology 1996; 110: A76.
60 Raghunath A, Hungin APS, Wooff D, Childs S. Prevalence of
Helicobacter pylori in patients with gastro-oesophageal reflux
disease: systematic review. Br Med J 2003; 326: 737–43.
61 Harvey RF, Lane JA, Murray LJ, Harvey IM, Donovan JL, Nair
P. Randomised controlled trial of effects of Helicobacter pylori
infection and its eradication on heartburn and gastro-
oesophageal reflux: Bristol Helicobacter project. Br Med J
2004; 328: 1417–9.