ORIGINAL PAPER doi: 10.1111/j.1368-5031.2005.00563.

Six-month management of patients following treatment for

gastroesophageal reflux disease symptoms – a Norwegian
randomized, prospective study comparing the costs and
effectiveness of esomeprazole and ranitidine treatment strategies
in a general medical practitioners setting
A . N . H AN S EN , 1 P . W AH L Q V I S T , 2 E . J Ø R G E N S E N , 3 R . B E R G H E I M , 4 H . F A G E R T U N , 5 H . L U N D , 6
B. MOUM7
Harbitzallèen Legesenter,1 Harbitzallèen 2A, Oslo, Norway, Health Economics,2 AstraZeneca R& D, Mölndal, Sweden, AstraZeneca
AS,3 GI/CNS AstraZeneca,4 Oslo, 3S-Scandinavian Statistical Services AS,5 Kjeller, Medical Department,6 AstraZeneca AS, Oslo,
Medical Department,7 Østfold Central Hospital, Fredrikstad, Norway

(n ¼ 610) and 248.8 Euros for continuous esomeprazole

SUMMARY
This study assesses the difference in direct medical costs
between on-demand treatment with esomeprazole 20 mg,
continuous treatment with esomeprazole 20 mg once-daily
and continuous treatment with ranitidine 150 mg twice-
daily to prevent symptomatic relapse in patients with gas-
troesophageal reflux disease over 26 weeks. Two hundred
eighty-one GP clinics in Norway enrolled 2156 patients to
an open, randomized, parallel group, Norwegian society
perspective study during 2000–2001. The total direct med-
ical costs of each strategy were 171.9 Euros for on-demand
esomeprazole (n ¼ 634), 221.6 Euros for ranitidine
(n ¼ 658). The total costs for on-demand and continuous
esomeprazole treatment and ranitidine treatment were
221.5, 286.5 and 295.8 Euros, respectively. The highest
proportion of costs was because of the study medication
cost in each strategy. The on-demand and continuous
treatment strategies with esomeprazole were found to be
cost-effective, compared with ranitidine.
Keywords: Continuous treatment strategy; cost-effectiveness;
esomeprazole; medical costs

2005 Blackwell Publishing Ltd

INTRODUCTION increased use of empirical treatment of GERD without any

prior costly endoscopy (non-endoscoped GERD).
Gastroesophageal reflux disease (GERD) is a common dis-
Proton pump inhibitors (PPI) are effective in relieving the
ease, with the predominant symptom, heartburn, affecting
symptoms of GERD, providing 24-h control of oesophageal
20–40% of adults (1,2). GERD symptoms (primarily heart-
acid reflux (7–11). The GENVAL guidelines identify PPI as
burn and acid regurgitation) do not accurately predict the
being the most effective initial and long-term therapy across all
presence or severity of mucosal damage (3,4). In addition,
GERD patients and recommend that PPI be the first-line
health-related quality of life is equally impaired in GERD
therapy for the management of GERD (12). After initial ther-
patients with or without oesophagitis (5,6).
apy to resolve GERD symptoms, there are three main options
Therapy for GERD aims to relieve symptoms of heartburn,
available to the treating physician for the long-term manage-
promote healing of the oesophageal mucosa, prevent compli-
ment of the disease. The physician can prescribe continuous
cations arising from gastroesophageal reflux and prevent
daily treatment with a PPI or an H2-receptor antagonist or on-
relapse of erosive oesophagitis. However, the presence of
demand treatment (as required to control symptoms).
mucosal damage can only be determined endoscopically and
Esomeprazole, the S-isomer of omeprazole, is the first PPI
there is a trend towards decreasing management costs by an
to be developed as an optical isomer and is highly effective
across the GERD spectrum. Esomeprazole has an improved
efficacy (healing and symptom resolution), compared to ome-
Correspondence to:
prazole (13,14) and lansoprazole (15) in patients with reflux
Aage Norman Hansen, Harbitzalléen Legesenter, N-0213 Oslo,
oesophagitis. The greater and faster control of intragastric
Norway
Tel.: þ 47 22 51 58 58 acidity facilitates on-demand use of esomeprazole, whereby
Fax: þ 47 22 51 58 51 the patient takes the medication to control symptoms as and
Email: age.normanhansen@harbitzalleen.onh.no when they occur. Indeed, esomeprazole is the only PPI

ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 655–664
656
licensed (in a number of European countries) for on-demand
use in patients with GERD without oesophagitis who require
maintenance therapy (16). The esomeprazole clinical pro-
gramme has demonstrated patient satisfaction with on-
demand treatment (17,18).
Several health economic analyses have been performed in the
treatment of GERD (19), but these have, with very few excep-
tions, been made retrospectively based on clinical study results,
not on prospective data (20). There is clearly a need for further
evidence on the effectiveness of, as well as cost associated with,
treatment alternatives in a clinical practice setting.
The types of cost that should be included in an economic
evaluation depend mainly on the perspective of the analysis. It
is generally recommended that a societal perspective is
adopted and that both direct and indirect costs are included
(21). Direct costs include medical costs to the health care
provider (e.g. drugs, health care visits, etc.) and costs to the
patient (e.g. travel expenses), whereas indirect costs typically
include loss of productivity because of absenteeism from work
(22). The aim of this study is to assess from a clinical practice
perspective the effectiveness and costs, both direct and indir-
ect, of continuous esomeprazole, ‘on-demand’ esomeprazole
and continuous ranitidine treatments.
PATIENTS AND METHODS
Study Design
Male and female patients aged >18 years were recruited into
281 centres in Norway for this prospective, randomized,
open, parallel-group study. A diagram of the study design
has been showed in Figure 1. The study consisted of a 4-week
symptom control phase followed by a 6-month follow-up
phase. Before randomization to either maintenance treatment
Patients with Esomeprazole
GERD 40 mg for 4
symptoms weeks
Months
–1 0 3
Visit 1 Visit 2
Figure 1 Overview of study design
COST-EFFECTIVENESS OF ESOMEPRAZOLE
strategy in the 6-month follow-up phase, patients with symp-
toms suggestive of GERD (heartburn as the predominant
symptom with or without acid regurgitation) for 3 days or
more during the previous 7 days (Visit 1) received treatment
with esomeprazole 40 mg once-daily for 4 weeks.
In order to ensure having a homogenous patient popula-
tion regarding GERD symptoms before staring maintenance
treatment, only patients who were symptom-free (defined as
no more than one day with mild symptoms of GERD, heart-
burn with or without acid regurgitation, during the previous
7 days) after the initial 4-week treatment entered the follow-
up phase (Visit 2). These patients were randomized to 6-
month maintenance treatment with one of the following
regimens for preventing the recurrence of GERD symptoms:
esomeprazole 20 mg once-daily continuously, esomeprazole
20 mg on-demand or ranitidine 150 mg twice-daily continu-
ously. A follow-up visit was made 3 months after randomiza-
tion (Visit 3) and a completion visit after 6 months (Visit 4).
At Visit 1, patients’ medical and surgical history was taken
and a physical examination was performed. Patients’ symptoms
and quality of life were assessed and patients were administered
esomeprazole 40 mg once-daily for 4 weeks. At Visit 2,
patients’ symptoms, satisfaction with the study treatment, qual-
ity of life and health economic variables were assessed. Adverse
events were also recorded at this visit. These assessments were
repeated at the scheduled visits after 3 and 6 months and any
unscheduled visits during the follow-up phase.
Throughout the follow-up phase, patients could contact
the clinic if they identified a need for a change in therapy,
such as experiencing a relapse in symptoms. If this happened,
during any stage of the follow-up phase, patients who were
receiving either of the esomeprazole treatments were switched
to a 4-week treatment course of esomeprazole 40 mg once-
daily, and patients receiving ranitidine were switched to a
Esomeprazole 20 mg maintenance treatment
Relapse Symptom resolution
Esomeprazole
40 mg for 4 weeks Failure
Relapse Symptom resolution
Clinical
R Esomeprazole 20 mg on-demand treatment
course
Ranitidine 600 mg
for Failure
4 weeks
Relapse Symptom resolution
Ranitidine 300 mg maintenance treatment
6
Follow-up visit Completion visit
ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 655–664
COST-EFFECTIVENESS OF ESOMEPRAZOLE
4-week treatment course of ranitidine 300 mg twice-daily. If,
following this additional 4-week treatment period, patients
were then symptom-free (defined as no more than one day
with mild symptoms of GERD during the previous 7 days),
they would resume the long-term treatment they were origin-
ally randomized to. If patients were not symptom-free, fol-
lowing this additional 4-week treatment period, they were
treated at the discretion of the physician.
The study was designed to be a ‘real life’ study in accordance
with health economic methodology, while still maintaining
control of events where possible (23). An open study design
is in accordance with treatment in clinical practice, where both
the treating physician and the patient are aware of the treat-
ment regimen. In the follow-up phase, unscheduled health care
contacts were guided by the patient’s need for a change of
therapy or the patient’s need for medical consultation. The
investigator was allowed to refer the patient for endoscopy or
other investigations when needed during the study. Efforts
were made to continue collecting data throughout the follow-
up phase, even after a patient- or investigator-driven decision
was taken that the patient should no longer continue with the
study treatment strategy. Thus, resource utilization associated
with treatment of relapses was included in cost calculations.
Furthermore, the definition of relapse (i.e. need for change of
therapy) was chosen with the aim to reflect clinical practice.
Health economic data on consumed quantities of cost
items were collected from the patients and were recorded in
the case report forms (CRF) during the study.
The primary aim of the study is to assess the direct medical
costs associated with on-demand treatment with esomeprazole
20 mg once-daily, continuous treatment with esomeprazole
20 mg once-daily and continuous treatment with ranitidine
150 mg twice-daily. The direct medical cost data collected
during the study were study medication used and other
GERD-related prescribed medication, GERD-related over-
the-counter (OTC) medication, unscheduled health care con-
tacts because of GERD, GERD-related tests and procedures
and GERD-related hospitalizations. Data collection, in addi-
tion, included GERD-related medication prescribed by, con-
tacts with, as well as tests and procedures performed by
physicians other than the study investigator.
Among the secondary goals of the study were measurements
of direct non-medical costs and indirect costs during the follow-
up phase. Other secondary goals were to assess the effectiveness
of treatment strategies during the follow-up phase by measure-
ment of patient satisfaction with treatment strategy, assessment
of time to first relapse (defined as time to need for change of
therapy), assessment of GERD symptoms and assessment of
health-related quality of life. Satisfaction with treatment was
assessed by patients filling in a questionnaire, which used a
seven-point Likert scale – completely satisfied; very satisfied;
quite satisfied; satisfied; dissatisfied; very dissatisfied; completely
dissatisfied. Severity (none; mild; moderate; severe) of symptoms
ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 655–664
657
(heartburn; acid regurgitation; dysphagia; epigastric pain) during
the last 7 days was assessed at each visit retrospectively by the
investigator in a standardized manner. Frequency of heartburn
symptoms was recorded at each visit as the number of days with
episodes during the last 7 days. Patients’ quality of life was
assessed with the Quality of Life in Reflux and Dyspepsia
(QOLRAD) questionnaire (24). This disease-specific question-
naire covers five dimensions: emotions, sleep, food/drink, phys-
ical/social function and vitality. Assessments on satisfaction,
symptoms and quality of life were performed during any sched-
uled or unscheduled visits during the study.
No single effectiveness variable was prospectively chosen to
relate differences in costs to a difference in effectiveness
between the treatment strategies. Instead, a cost-consequence
analysis approach was chosen (21). The aim with a cost-
consequence analysis is to list various costs and consequences
associated with the treatment strategies (including differences
between strategies). Making individual judgements of advan-
tages and disadvantages of the treatment strategies, the readers
of the information is, thus, relied upon to draw their own
conclusions on which strategy can be considered cost-
effective. The main reason for choosing a cost-consequence
approach was that a prospective cost-effectiveness evaluation
is associated with certain methodological difficulties regarding
statistical uncertainty when making sample size estimations
and when reporting results (25). Sample size calculations were
performed on the basis of being able to detect a differ-
ence between two treatment strategies of NOK 200
(1 Euro ¼ NOK 8.049)1 regarding direct medical costs for
the intention-to-treat (ITT) population.
Analysis of Costs
The analysis of costs associated with the individual treatment
strategies during the 6-month follow-up period was made
using a societal perspective, which includes GERD-related
costs irrespective of the actual payer. One of the major prob-
lems with the use of clinical trial data for cost assessment
arises when the clinical trial protocol requires more visits,
consultations and tests than would normally be found in
clinical practice. In order not to overestimate the costs gath-
ered, measures were taken to exclude protocol-driven treat-
ment and healthcare provider contact. For example, the
scheduled follow-up visits after 3 and 6 months were only
included in the cost analysis, if the investigator had showed
that the healthcare contact was likely to have occurred in
clinical practice. Total costs were divided into direct medical
costs, direct non-medical costs and indirect costs.
1
Average exchange rate for the year 2001.
658
Direct Medical Costs
Direct medical costs included were the costs of physician con-
tacts and visits, tests and procedures and medication (this
included consumed quantities of study medication, other
GERD-related concomitant medication and purchased quanti-
ties of GERD-related OTC medication). There were no
GERD-related hospitalizations during the course of the study,
therefore, these costs have not been included within the analysis.
Direct Non-medical Costs
The only direct non-medical cost considered was the use of
transportation in relation to non-protocol-driven visits. Data
on the mode of transportation and the distance travelled were
collected at Visit 2. This information was then transformed
into a travelling cost per visit.
Indirect Costs
There were two indirect costs considered. The first was the
loss of production because of GERD-related absence from
work. Data on absence from work since the previous visit
were recorded in CRFs. The second was loss of leisure time
because of GERD-related healthcare visits. Data on lost
leisure time were collected at Visit 2. This information was
then transformed into a leisure time cost per visit. Production
losses and leisure time were valued as the number of hours
absent from work or unavailable for leisure multiplied by
the average wage rate for the relevant age group and sex.
The wage rates used were based on the Norwegian National
Accounts. Total wages and salaries are divided on the total
number of man-years in 1999. This number has been
adjusted to reflect differences in salaries between age groups
and sexes according to statistics from the PAI-register, assum-
ing that the distribution would be similar across the economy
as a whole. The lost working hours were valued at the wage
rate including taxes and social costs. Leisure time was valued
at the wage rate excluding taxes and social costs, assuming
that the net wage rate correctly reflected the value workers put
on an extra hour of leisure at the margin.
Price/Unit Costs
All prices and unit costs used in the calculations have been
presented in Tables 1 and 2. All costs refer to 2001 prices in
Norwegian kroner converted to Euro (1 Euro ¼ 8049).
Prices for medication equalled the retail prices using the
nationally accepted formula; prices of other items were esti-
mated using nationally available data. It would have been
preferable to apply an alternative cost approach to finding
unit prices; however, owing to a lack of information about the
correct alternative value, it was necessary to use tariffs and
ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 655–664
COST-EFFECTIVENESS OF ESOMEPRAZOLE
calculating costs based on various reports. Costs were calcu-
lated at 2001 levels by using the most relevant price indexes
available. Some assumptions are particularly worth noting.
Because this was a ‘real-life’ study, all resource consumption
was measured during the 6-month study period; this, in
addition, included unaccounted study medication.
Medication that was lost or given away was part of that
resource consumption and was relevant if it was reflective of
what happens in the daily clinical setting. According to the
protocol, only purchases of OTC medication that occurred
28 days or less before a physician’s visit were recorded. All
purchase dates that were outside this period have, therefore,
not been accounted for. In the cost calculations, a linear
backward extrapolation of purchased OTC medication up
to the preceding visit was made for each recorded period,
adjusted for time elapsed between two consecutive visits.
Only prescription drugs have a listed retail price; therefore,
OTC medication that is not sold with reimbursement does
not have a listed retail price, but it does have a listed
ex-wholesale price. In these instances, a formula that calculates
the retail price depending on various package sizes was used.
Statistical Analysis
Statistical analysis was performed using the ITT approach.
Patients who left the study at any time after randomization
were still included in the cost analysis. The main analysis and
the sensitivity analyses of costs were performed using an
ANOVA model with study treatment and centre as fixed factors.
Duncan’s test for pairwise comparison of means in multiple
groups was applied. Sex distribution in treatment groups was
tested using Fisher exact test.
Sensitivity Analysis
The sensitivity analyses performed included variation in the
unit costs/prices of both direct and indirect costs. In many
cases, the costs/prices were increased or decreased by an
arbitrary amount of 25%. Full details of the analyses can be
found in Table 3. Owing to the relatively short-term nature
of the clinical trial, no discounting was applied to either the
costs or the benefits of the treatments.
RESULTS
A total of 2156 patients (58.1% men and 41.9% women)
with a mean age of 50 years entered the 4-week symptom
control phase of the study. Following 4-week treatment with
esomeprazole 40 mg once-daily, 1902 patients were random-
ized to the 6-month follow-up phase of the study and 254
patients were discontinued from the study. The first patient
was enrolled on 14 September 2000 and the last patient
completed the study on 14 November 2001.
COST-EFFECTIVENESS OF ESOMEPRAZOLE 659

Table 1 Unit costs/prices for direct cost items

Resource Fee Patient co-payment Municipal subsidy Unit cost
Physician
GP consultation 13.67 13.67 9.83 23.49
Specialist consultation 23.11 22.98 13.94 37.05
Tests and procedures
Blood sample for laboratory test 3.11 3.11
Upper GI endoscopy* 168.22
Upper GI endoscopy with biopsy* 171.33
Radiological examination† 48.42
Upper abdominal ultrasound† 53.35
24-h pH monitoring‡ 255.91
Manometry‡ 255.91
Resting ECG (performed by GP)§ 13.67
Exercise ECG (performed by 83.64
specialist){
Pack size Pharmacy purchase price Pharmacy retail price
Study Medication
Nexium enterotablet 20 mg 12.42 117.65 157.42
Nexium enterotablet 40 mg 3.48 45.18 63.07
Zantac tablet 150 mg 11.18 38.35 54.17
Zantac tablet 300 mg 3.73 25.20 37.05
Prescription concomitant
medication/OTC medication**
Transportation costs Cost per km
Car†† 0.13
Bus†† 0.03
Taxi‡‡ 6.58 þ 0.76
All prices in EUR 2001.
EUR, Euro; GI, gastrointestinal; GP, general practitioner; km, kilometre.
*Upper GI endoscopies can take place at public outpatient departments and at private specialists. The cost presented in this table is the average of the two prices.
The additional cost of a biopsy is EUR 3.11.
†Radiological and ultrasound examinations can take place in both public and private facilities. The unit cost is the weighted average of the public and private costs
using the percentage of examinations that take place in each kind of facility (26,27).
‡Manometry and 24-h pH monitoring take place in public hospital outpatient units. The average cost for an outpatient consultation was calculated as EUR
231.32 in 1998 (28) and then inflated to 2001 prices (29–31).
§A resting ECG takes place at the GP and involves no additional cost to the patient. The GP is entitled to another EUR 6.22 from the Norwegian social
insurance fund.
{Exercise ECG only take place at a specialist. The unit cost is, therefore, the sum of the costs for the specialists’ consultation, the procedure itself and additional
fees for interpreting the ECG results.
**Costs were derived from Norwegian Medicinal Depot. The recording of some of the unit prices was commissioned to Farmastat. Medication was defined as
GERD-related if it belonged to the following classes of drugs (ATC); calcium compounds, H2-receptor antagonists, proton pump inhibitors, Belladonna and
derivatives in combination with analgesics, propulsives, other antiemetics, bulk producers, osmotically acting laxatives, antibiotics, anti-propulsives, intestinal
anti-inflammatory agents, aminosalicylic acid and similar agents, peripherally acting anti-obesity products, enzyme preparations.
††Refer to Ref. (31,32).
‡‡Costs derived from pricing formulas (33). The formula for fares outside local traffic areas were used, i.e. 6.58 þ 0.76
Km.

The demographic and baseline characteristics for the ran-
domized patients have been presented in Table 4. The three
treatment groups were comparable in terms of age and per-
centage of male and female patients, and degree of symptoms
at the randomization visit.
Costs
The health economic variables assessed during the study were
the differences between treatment strategies in direct medical
costs, direct non-medical costs and total direct and indirect
costs. The total costs associated with each of the three treat-
ment strategies have been presented in Table 5 and a com-
parison between strategies has been presented in Table 6. In
terms of direct medical costs and total costs, esomeprazole
20 mg once-daily on-demand was associated with signifi-
cantly lower costs than both esomeprazole 20 mg once-daily
continuous and ranitidine 150 mg twice-daily continuous
treatment. Ranitidine 150 mg twice-daily continuous treat-
ment resulted in lower direct medical costs than esomeprazole
20 mg continuous treatment because of the lower study med-
ication costs, but ranitidine was showed to have higher mean

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660 COST-EFFECTIVENESS OF ESOMEPRAZOLE

Table 2 Annual average wage costs (34,35) was maintained to a higher degree by means of esomeprazole
continuous treatment than by means of on-demand treatment,
Age group Women Men
and both esomeprazole strategies were superior to ranitidine in
<20 30,096 29,976 maintaining quality of life (36).
20–24 32,872 32,381
25–29 36,021 37,172
30–39 38,044 41,028 Sensitivity Analysis
40–49 38,247 43,568
50–59 37,638 44,525 The results of the sensitivity analyses have been presented in
>59 36,875 44,392 Table 7. Even applying some extreme cost scenarios (such as
All prices in EUR 2001.
esomeprazole at the highest retail price possible while raniti-
dine was costed at the lowest package price possible), the
results were relatively insensitive and on-demand esomepra-
costs on every other resource component, including those
zole was associated with lower mean total costs than the
indirect costs attributed to GERD-related illness. The differ-
continuous esomeprazole and ranitidine strategies in each
ence in total direct and indirect costs between esomeprazole
case. This would suggest that the main results of the study
continuous and ranitidine continuous treatments did not
were robust, even allowing for some potential uncertainties
reach a statistical significance.
regarding the cost estimates. Because the difference in costs
was relatively small between continuous esomeprazole and
ranitidine, results in this comparison were found to be sensi-
Effectiveness tive to the value of unit costs used.
The clinical and quality of life results have been presented, in
detail, elsewhere. However, brief details have been described in
DISCUSSION
this study. After 6-month treatment, more patients were ‘com-
pletely’/‘very satisfied’ with esomeprazole 20 mg once-daily The main aim of this study is to investigate the direct and indirect
either continuous (82.2%) or on-demand (75.4%) compared costs associated with alternative long-term empirical manage-
with ranitidine 150 mg twice-daily continuous (33.5%). At the ment strategies for patients following treatment of GERD symp-
final visit in the 6-month follow-up period, 72.2% of patients toms. Such a study of the costs associated with GERD is
in the esomeprazole continuous group had no heartburn, com- relatively unusual in a Norwegian setting; the only previous
pared with 45.1% in the esomeprazole on-demand group and studies to have prospectively assessed treatment costs have been
32.5% in the ranitidine group. The percentage of patients who those examining PPI treatment, compared with antireflux sur-
experienced at least one relapse during the study was lower for gery (37,38) or the costs associated with antireflux surgery (39).
the esomeprazole 20 mg continuous strategy (7.0%) than for The results of this study demonstrate that on-demand
both the esomeprazole on-demand (10.9%) and ranitidine esomeprazole 20 mg once-daily is associated with lower
continuous (34.4%) strategies. Furthermore, quality of life costs than continuous esomeprazole 20 mg once-daily or

Table 3 Scenarios used in the sensitivity analysis

Scenario title Change to parameter
High-cost endoscopy Cost of endoscopy increased by 25%
Low-cost endoscopy Cost of endoscopy reduced by 25%
High cost of leisure time Average wage rate increased by 25%
Low cost of leisure time Average wage rate reduced by 25%
No over-the-counter (OTC) extrapolation Only those OTC purchases recorded in the 28 days before a
visit are included in the costing
High cost of lost productivity Average wage rate increased by 25%
Low cost of lost productivity Average wage rate reduced by 25%
High cost of study medication Highest tablet prices used for esomeprazole and ranitidine based
on packages available in the Norwegian market
Low cost of study medication Lowest tablet prices used for esomeprazole and ranitidine based on
packages available in the Norwegian market
Expensive esomeprazole, cheapest ranitidine Highest tablet prices used for esomeprazole and lowest tablet price used for
ranitidine based on packages available in the Norwegian market
High cost of transportation Cost of all transport increased by 25%
Low cost of transportation Cost of all transport reduced by 25%

ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 655–664
COST-EFFECTIVENESS OF ESOMEPRAZOLE 661

Table 4 Demographic data and baseline characteristics

Esomeprazole 20 mg Esomeprazole 20 mg Ranitidine 150 mg
once-daily continuous once-daily on-demand twice-daily continuous
Number of patients 658 634 610
Percentage of sex (male/female) 57/43 55/45 57/43
Age, years (range) 50.6 (20–87) 51.4 (18–85) 51.2 (20–88)
Paid employment (%) 60.3 58.8 58.4
Mean number of days with heartburn (SD)* 5.7 (1.5) 5.6 (1.6) 5.6 (1.6)
SD, Standard deviation; sex: p ¼ 0.74; age: p ¼ 0.55.
*Before 4-week treatment with esomeprazole 40 mg.

ranitidine 150 mg twice-daily in uninvestigated GERD
patients following a 4-week symptom control phase. Because
on-demand esomeprazole 20 mg once-daily is also associated
with better effectiveness than continuous ranitidine 150 mg
twice-daily, the on-demand treatment strategy is clearly cost-
effective in this comparison. However, as the clinical results
demonstrate, in GERD patients continuous esomeprazole
20 mg once-daily is significantly more effective than either
on-demand esomeprazole 20 mg once-daily or continuous
ranitidine 150 mg twice-daily, as it keeps more patients in
remission, maintains health-related quality of life and main-
tains more patients symptom-free and satisfied on their treat-
ment. Therefore, decision makers need to balance the
increased effectiveness of treatment with continuous esome-
prazole against the higher cost associated with that treatment
strategy. When differences between the continuous esomepra-
zole and ranitidine strategies are compared with each other, it
seems likely that the small, observed difference in costs should
be offset by the effectiveness of esomeprazole. Thus, esome-
prazole is the most cost-effective treatment option in this
comparison. Adopting a societal perspective shows that
esomeprazole continuous treatment is a dominant strategy,
compared with ranitidine, because an enhanced effectiveness
is provided at similar total direct and indirect costs.
It is more difficult to draw a conclusion about which of the
esomeprazole on-demand or continuous strategies is cost-
effective relative to each other. In order to answer this question,
a prospective measurement should ideally have been made of
differences in patient health state utilities over time. However, a
previous study (40) investigated the association between
GERD symptoms and utility values in a Swedish GERD
population (n ¼ 504), which showed utility values (rating
scale estimates) of 0.85, 0.78, 0.70 and 0.62 for patients with
no, mild, moderate and severe heartburn, respectively. Using
these utility values, a simple quality-adjusted life-year (QALY)
analysis was performed on results from the current study,
assuming that health states are determined by heartburn sever-
ity at each given point in time during the 6-month follow-up.
Conservative assumptions were made regarding interpolation
between symptom assessments performed in the current study

Table 5 Summary of mean costs (EUR) associated with esomeprazole 20 mg once-daily continuous, esomeprazole 20 mg once-daily
on-demand and ranitidine 150 mg twice-daily continuous treatment (SD in brackets)
Esomeprazole 20 mg Esomeprazole 20 mg Ranitidine 150 mg
once-daily continuous once-daily on-demand twice-daily continuous p-value*
Number of patients 658 634 610
Physician contacts 15.3 (25.3) 15.0 (25.7) 24.4 (32.9)
Tests and procedures 7.5 (39.0) 7.3 (41.0) 15.5 (55.3)
Study medication 223.7 (56.5) 146.3 (8.8) 151.6 (73.3)
Concomitant medication 1.9 (20.4) 2.7 (26.5) 28.9 (81.5)
Over-the-counter medication 0.4 (3.6) 0.6 (7.0) 1.1 (5.7)
Total direct medical costs 248.8 (80.0) 171.9 (109.6) 221.6 (127.0) <0.0001
Transportation costs 1.5 (7.3) 1.2 (4.2) 2.0 (5.5)
Total direct costs 250.2 (81.6) 173.2 (110.4) 223.6 (128.0) <0.0001
Leisure time lost 6.7 (8.2) 6.3 (7.5) 9.1 (13.2)
Production lost 39.0 (235.3) 42.0 (276.7) 53.9 (622.8)
Indirect costs 45.6 48.3 63.0 0.69 (0.008)†
Total direct and indirect costs 295.8 (246.4) 221.5 (311.5) 286.6 (673.4) 0.0067
(0.0001)†
Costs are calculated for the 6-month treatment period.
*Overall F-test on drug effect (three-arm comparison).
†In groups that had a high variance, which resulted in the data not being normally distributed a logarithmic transformation was performed to stabilize variance.

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662 COST-EFFECTIVENESS OF ESOMEPRAZOLE

Table 6 Comparison of differences in mean costs (EUR) between each treatment strategy (95% CI in brackets)
Esomeprazole on-demand vs. Esomeprazole on-demand vs. Esomeprazole continuous vs.
Variable esomeprazole continuous ranitidine continuous ranitidine continuous
Total direct medical costs 76.8* (94 to 63) 49.6* (63 to 36) 27.2* (13 to 41)
Total direct costs 77.0* (91 to 63) 50.4* (64 to 36) 26.6* (13 to 41)
Indirect costs 2.7 (53 to 58) 14.7 (71 to 48) 17.4 (74 to 39)
Total direct and indirect costs 74.3* (134 to 14) 65.1* (126 to 4) 17.4 (51 to 33)
*p < 0.05; pairwise comparison results by using Duncan’s test, 5% significance level.

and regarding bridging results on frequency of symptoms
between the two studies. These calculations resulted in QALY
estimates over 6 months of 0.413, 0.406 and 0.396 associated
with the esomeprazole continuous, esomeprazole on-demand
and ranitidine strategies, respectively. Using mean values, this
would imply an additional direct medical cost by using esome-
prazole continuous of about NOK 13 000 (Euro 1600) per
QALY gained, compared with ranitidine, and about NOK
90,000 (Euro 11,000) per QALY gained, compared with
esomeprazole on-demand. Results from these calculations are,
of course, uncertain and should be interpreted with great care.
Nonetheless, it should be noted that an additional cost of
NOK 90,000 per QALY gained is considered low when related
to values that have been reported to be acceptable in the health
economic literature (41,42). Furthermore, the calculations on
additional costs per QALY gained do illustrate how a tradeoff
between differences in costs and effectiveness needs to be made
when interpreting results from the current study. The calcula-
tions also support a conclusion that continuous treatment with
esomeprazole is likely to be cost-effective, compared with
continuous treatment with ranitidine, and that it is more
uncertain which is the cost-effective alternative when
esomeprazole continuous and on-demand treatments are
compared.
It is also important to consider that, from a patient’s
perspective, the effectiveness of treatment is likely to be of
paramount importance. Effective treatment generally leads to
greater satisfaction with treatment, improved quality of life
and a more rapid return to work (5,43,44). Furthermore,
symptoms of GERD have been showed to have a significant
impact on productivity while at work, as well as while per-
forming regular daily activities other than work (45,46).
However, instruments for prospectively assessing patient-
reported reduced productivity were not included in the cur-
rent study, because these were not considered appropriate as a
basis for cost calculations in a long-term study because of
their short recall period.
The current study, which has examined the resource con-
sumption of uninvestigated GERD patients, has the advan-
tage of applying the techniques of a prospective methodology.
Resource use data were collected at points when they occurred
in the management of comparable groups of patients. The
principal advantage of such methodology is that it increases
the precision of the estimates obtained. However, as with any

Table 7 Sensitivity analysis on mean total costs. (95% CI in brackets)

Esomeprazole 20 mg Esomeprazole 20 mg Ranitidine 150 mg
Scenario once-daily continuous once-daily on-demand twice-daily continuous p-value*
Endoscopy high cost 297.0 (278–316) 222.5 (198–247) 289.3 (235–343) 0.0052
Endoscopy low cost 294.7 (276–313) 220.5 (196–245) 283.9 (231–337) 0.0059
Leisure time high cost 297.5 (279–316) 223.1 (199–247) 288.8 (235–342) 0.0053
Leisure time low cost 294.2 (275–313) 220.0 (196–244) 284.4 (231–338) 0.0058
Over-the-counter high cost 294.2 (277–315) 221.8 (197–246) 286.9 (233–341) 0.0056
Over-the-counter low cost 293.9 (277–315) 221.4 (197–246) 286.4 (233–340) 0.0056
Over-the-counter 28 days before 295.6 (277–314) 221.0 (197–245) 286.0 (232–339) 0.0054
Productivity loss increased 305.6 (283–329) 232.1 (203–262) 300.2 (234–366) 0.0271
Productivity loss decreased 286.1 (271–301) 211.1 (192–230) 273.1 (232–315) 0.0003
Study medication at highest price 361.8 (343–381) 264.1 (239–289) 399.7 (346–453) 0.0001
Study medication at lowest price 294.8 (276–314) 220.5 (196–245) 284.5 (231–338) 0.006
Esomeprazole at highest price, ranitidine 373.7 (354–394) 275.6 (250–302) 284.5 (231–338) 0.0003
west price
Transportation high cost 296.2 (277–315) 221.9 (198–246) 287.1 (234–341) 0.0055
Transportation low cost 295.4 (277–314) 221.3 (197–245) 286.1 (233–340) 0.0056
All costs are in 2001 EUR
*Overall F-test on drug effect (three-arm comparison).

ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 655–664
COST-EFFECTIVENESS OF ESOMEPRAZOLE
cost study, some uncertainty is inherent in the cost estimates.
It is also true that in some cases the costs used may reflect
charges rather than costs, although the sensitivity analysis did
not alter the dominant position of on-demand therapy with
respect to ranitidine. The other potential weakness of the
study was patients being asked to recall their use of resources
and the number of days absent from work over a relatively
long period of time, which might potentially have given rise
to recall errors. Any recall errors are likely to have the effect
that indirect costs are higher than those reported in this study.
Another potential limitation of the study is that the initial
4-week treatment period with esomeprazole 40 mg may have
had a bearing on the efficacy of the subsequent treatment
following randomization to the various treatment arms. This
raises the question whether various efficacy and cost-effectiveness
results would have been observed had patients received
ranitidine, for example, during the initial 4-week treatment
period. Although further study would be needed in order to
ascertain the magnitude of any such effect, consideration of the
study design is clearly important when interpreting the clinical
relevance of the results reported in this study.
The costs of GERD to Norwegian society are high. This study
provides valuable information concerning the costs and cost-
effectiveness of various treatment strategies available for uninves-
tigated GERD. Both esomeprazole strategies were more effective
than ranitidine treatment and were associated with lower costs in
all areas of resource use and indirect costs other than in drug
acquisition costs for continuous esomeprazole treatment.
ACKNOWLEDGEMENT
The authors thank all the investigators and study personnel at
281 Norwegian GP Clinics, who participated in and gave
their contribution to the study.
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Paper received April 2004, accepted February 2005