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

licensed (in a number of European countries) for on-demand strategy in the 6-month follow-up phase, patients with symp-
use in patients with GERD without oesophagitis who require toms suggestive of GERD (heartburn as the predominant
maintenance therapy (16). The esomeprazole clinical pro- symptom with or without acid regurgitation) for 3 days or
gramme has demonstrated patient satisfaction with on- more during the previous 7 days (Visit 1) received treatment
demand treatment (17,18). with esomeprazole 40 mg once-daily for 4 weeks.
Several health economic analyses have been performed in the In order to ensure having a homogenous patient popula-
treatment of GERD (19), but these have, with very few excep- tion regarding GERD symptoms before staring maintenance
tions, been made retrospectively based on clinical study results, treatment, only patients who were symptom-free (defined as
not on prospective data (20). There is clearly a need for further no more than one day with mild symptoms of GERD, heart-
evidence on the effectiveness of, as well as cost associated with, burn with or without acid regurgitation, during the previous
treatment alternatives in a clinical practice setting. 7 days) after the initial 4-week treatment entered the follow-
The types of cost that should be included in an economic up phase (Visit 2). These patients were randomized to 6-
evaluation depend mainly on the perspective of the analysis. It month maintenance treatment with one of the following
is generally recommended that a societal perspective is regimens for preventing the recurrence of GERD symptoms:
adopted and that both direct and indirect costs are included esomeprazole 20 mg once-daily continuously, esomeprazole
(21). Direct costs include medical costs to the health care 20 mg on-demand or ranitidine 150 mg twice-daily continu-
provider (e.g. drugs, health care visits, etc.) and costs to the ously. A follow-up visit was made 3 months after randomiza-
patient (e.g. travel expenses), whereas indirect costs typically tion (Visit 3) and a completion visit after 6 months (Visit 4).
include loss of productivity because of absenteeism from work At Visit 1, patients’ medical and surgical history was taken
(22). The aim of this study is to assess from a clinical practice and a physical examination was performed. Patients’ symptoms
perspective the effectiveness and costs, both direct and indir- and quality of life were assessed and patients were administered
ect, of continuous esomeprazole, ‘on-demand’ esomeprazole esomeprazole 40 mg once-daily for 4 weeks. At Visit 2,
and continuous ranitidine treatments. 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
PATIENTS AND METHODS repeated at the scheduled visits after 3 and 6 months and any
unscheduled visits during the follow-up phase.
Study Design
Throughout the follow-up phase, patients could contact
Male and female patients aged >18 years were recruited into the clinic if they identified a need for a change in therapy,
281 centres in Norway for this prospective, randomized, such as experiencing a relapse in symptoms. If this happened,
open, parallel-group study. A diagram of the study design during any stage of the follow-up phase, patients who were
has been showed in Figure 1. The study consisted of a 4-week receiving either of the esomeprazole treatments were switched
symptom control phase followed by a 6-month follow-up to a 4-week treatment course of esomeprazole 40 mg once-
phase. Before randomization to either maintenance treatment 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


Patients with Esomeprazole
Clinical
GERD 40 mg for 4 R Esomeprazole 20 mg on-demand treatment
course
symptoms weeks

Ranitidine 600 mg
for Failure
4 weeks

Relapse Symptom resolution


Ranitidine 300 mg maintenance treatment

Months
–1 0 3 6

Visit 1 Visit 2 Follow-up visit Completion visit

Figure 1 Overview of study design

ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 655–664
COST-EFFECTIVENESS OF ESOMEPRAZOLE 657

4-week treatment course of ranitidine 300 mg twice-daily. If, (heartburn; acid regurgitation; dysphagia; epigastric pain) during
following this additional 4-week treatment period, patients the last 7 days was assessed at each visit retrospectively by the
were then symptom-free (defined as no more than one day investigator in a standardized manner. Frequency of heartburn
with mild symptoms of GERD during the previous 7 days), symptoms was recorded at each visit as the number of days with
they would resume the long-term treatment they were origin- episodes during the last 7 days. Patients’ quality of life was
ally randomized to. If patients were not symptom-free, fol- assessed with the Quality of Life in Reflux and Dyspepsia
lowing this additional 4-week treatment period, they were (QOLRAD) questionnaire (24). This disease-specific question-
treated at the discretion of the physician. naire covers five dimensions: emotions, sleep, food/drink, phys-
The study was designed to be a ‘real life’ study in accordance ical/social function and vitality. Assessments on satisfaction,
with health economic methodology, while still maintaining symptoms and quality of life were performed during any sched-
control of events where possible (23). An open study design uled or unscheduled visits during the study.
is in accordance with treatment in clinical practice, where both No single effectiveness variable was prospectively chosen to
the treating physician and the patient are aware of the treat- relate differences in costs to a difference in effectiveness
ment regimen. In the follow-up phase, unscheduled health care between the treatment strategies. Instead, a cost-consequence
contacts were guided by the patient’s need for a change of analysis approach was chosen (21). The aim with a cost-
therapy or the patient’s need for medical consultation. The consequence analysis is to list various costs and consequences
investigator was allowed to refer the patient for endoscopy or associated with the treatment strategies (including differences
other investigations when needed during the study. Efforts between strategies). Making individual judgements of advan-
were made to continue collecting data throughout the follow- tages and disadvantages of the treatment strategies, the readers
up phase, even after a patient- or investigator-driven decision of the information is, thus, relied upon to draw their own
was taken that the patient should no longer continue with the conclusions on which strategy can be considered cost-
study treatment strategy. Thus, resource utilization associated effective. The main reason for choosing a cost-consequence
with treatment of relapses was included in cost calculations. approach was that a prospective cost-effectiveness evaluation
Furthermore, the definition of relapse (i.e. need for change of is associated with certain methodological difficulties regarding
therapy) was chosen with the aim to reflect clinical practice. statistical uncertainty when making sample size estimations
Health economic data on consumed quantities of cost and when reporting results (25). Sample size calculations were
items were collected from the patients and were recorded in performed on the basis of being able to detect a differ-
the case report forms (CRF) during the study. ence between two treatment strategies of NOK 200
The primary aim of the study is to assess the direct medical (1 Euro ¼ NOK 8.049)1 regarding direct medical costs for
costs associated with on-demand treatment with esomeprazole the intention-to-treat (ITT) population.
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 Analysis of Costs
during the study were study medication used and other
GERD-related prescribed medication, GERD-related over- The analysis of costs associated with the individual treatment
the-counter (OTC) medication, unscheduled health care con- strategies during the 6-month follow-up period was made
tacts because of GERD, GERD-related tests and procedures using a societal perspective, which includes GERD-related
and GERD-related hospitalizations. Data collection, in addi- costs irrespective of the actual payer. One of the major prob-
tion, included GERD-related medication prescribed by, con- lems with the use of clinical trial data for cost assessment
tacts with, as well as tests and procedures performed by arises when the clinical trial protocol requires more visits,
physicians other than the study investigator. consultations and tests than would normally be found in
Among the secondary goals of the study were measurements clinical practice. In order not to overestimate the costs gath-
of direct non-medical costs and indirect costs during the follow- ered, measures were taken to exclude protocol-driven treat-
up phase. Other secondary goals were to assess the effectiveness ment and healthcare provider contact. For example, the
of treatment strategies during the follow-up phase by measure- scheduled follow-up visits after 3 and 6 months were only
ment of patient satisfaction with treatment strategy, assessment included in the cost analysis, if the investigator had showed
of time to first relapse (defined as time to need for change of that the healthcare contact was likely to have occurred in
therapy), assessment of GERD symptoms and assessment of clinical practice. Total costs were divided into direct medical
health-related quality of life. Satisfaction with treatment was costs, direct non-medical costs and indirect costs.
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
1
dissatisfied. Severity (none; mild; moderate; severe) of symptoms Average exchange rate for the year 2001.

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

Direct Medical Costs calculating costs based on various reports. Costs were calcu-
lated at 2001 levels by using the most relevant price indexes
Direct medical costs included were the costs of physician con-
available. Some assumptions are particularly worth noting.
tacts and visits, tests and procedures and medication (this
Because this was a ‘real-life’ study, all resource consumption
included consumed quantities of study medication, other
was measured during the 6-month study period; this, in
GERD-related concomitant medication and purchased quanti-
addition, included unaccounted study medication.
ties of GERD-related OTC medication). There were no
Medication that was lost or given away was part of that
GERD-related hospitalizations during the course of the study,
resource consumption and was relevant if it was reflective of
therefore, these costs have not been included within the analysis.
what happens in the daily clinical setting. According to the
protocol, only purchases of OTC medication that occurred
Direct Non-medical Costs 28 days or less before a physician’s visit were recorded. All
purchase dates that were outside this period have, therefore,
The only direct non-medical cost considered was the use of not been accounted for. In the cost calculations, a linear
transportation in relation to non-protocol-driven visits. Data backward extrapolation of purchased OTC medication up
on the mode of transportation and the distance travelled were to the preceding visit was made for each recorded period,
collected at Visit 2. This information was then transformed adjusted for time elapsed between two consecutive visits.
into a travelling cost per visit. Only prescription drugs have a listed retail price; therefore,
OTC medication that is not sold with reimbursement does
Indirect Costs not have a listed retail price, but it does have a listed
ex-wholesale price. In these instances, a formula that calculates
There were two indirect costs considered. The first was the the retail price depending on various package sizes was used.
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 Statistical Analysis
because of GERD-related healthcare visits. Data on lost Statistical analysis was performed using the ITT approach.
leisure time were collected at Visit 2. This information was Patients who left the study at any time after randomization
then transformed into a leisure time cost per visit. Production were still included in the cost analysis. The main analysis and
losses and leisure time were valued as the number of hours the sensitivity analyses of costs were performed using an
absent from work or unavailable for leisure multiplied by ANOVA model with study treatment and centre as fixed factors.
the average wage rate for the relevant age group and sex. Duncan’s test for pairwise comparison of means in multiple
The wage rates used were based on the Norwegian National groups was applied. Sex distribution in treatment groups was
Accounts. Total wages and salaries are divided on the total tested using Fisher exact test.
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- Sensitivity Analysis
ing that the distribution would be similar across the economy The sensitivity analyses performed included variation in the
as a whole. The lost working hours were valued at the wage unit costs/prices of both direct and indirect costs. In many
rate including taxes and social costs. Leisure time was valued cases, the costs/prices were increased or decreased by an
at the wage rate excluding taxes and social costs, assuming arbitrary amount of 25%. Full details of the analyses can be
that the net wage rate correctly reflected the value workers put found in Table 3. Owing to the relatively short-term nature
on an extra hour of leisure at the margin. of the clinical trial, no discounting was applied to either the
costs or the benefits of the treatments.
Price/Unit Costs
RESULTS
All prices and unit costs used in the calculations have been
presented in Tables 1 and 2. All costs refer to 2001 prices in A total of 2156 patients (58.1% men and 41.9% women)
Norwegian kroner converted to Euro (1 Euro ¼ 8049). with a mean age of 50 years entered the 4-week symptom
Prices for medication equalled the retail prices using the control phase of the study. Following 4-week treatment with
nationally accepted formula; prices of other items were esti- esomeprazole 40 mg once-daily, 1902 patients were random-
mated using nationally available data. It would have been ized to the 6-month follow-up phase of the study and 254
preferable to apply an alternative cost approach to finding patients were discontinued from the study. The first patient
unit prices; however, owing to a lack of information about the was enrolled on 14 September 2000 and the last patient
correct alternative value, it was necessary to use tariffs and completed the study on 14 November 2001.

ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 655–664
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- costs. The total costs associated with each of the three treat-
domized patients have been presented in Table 4. The three ment strategies have been presented in Table 5 and a com-
treatment groups were comparable in terms of age and per- parison between strategies has been presented in Table 6. In
centage of male and female patients, and degree of symptoms terms of direct medical costs and total costs, esomeprazole
at the randomization visit. 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
Costs
treatment. Ranitidine 150 mg twice-daily continuous treat-
The health economic variables assessed during the study were ment resulted in lower direct medical costs than esomeprazole
the differences between treatment strategies in direct medical 20 mg continuous treatment because of the lower study med-
costs, direct non-medical costs and total direct and indirect ication costs, but ranitidine was showed to have higher mean

ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 655–664
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 comparison. Adopting a societal perspective shows that
patients following a 4-week symptom control phase. Because esomeprazole continuous treatment is a dominant strategy,
on-demand esomeprazole 20 mg once-daily is also associated compared with ranitidine, because an enhanced effectiveness
with better effectiveness than continuous ranitidine 150 mg is provided at similar total direct and indirect costs.
twice-daily, the on-demand treatment strategy is clearly cost- It is more difficult to draw a conclusion about which of the
effective in this comparison. However, as the clinical results esomeprazole on-demand or continuous strategies is cost-
demonstrate, in GERD patients continuous esomeprazole effective relative to each other. In order to answer this question,
20 mg once-daily is significantly more effective than either a prospective measurement should ideally have been made of
on-demand esomeprazole 20 mg once-daily or continuous differences in patient health state utilities over time. However, a
ranitidine 150 mg twice-daily, as it keeps more patients in previous study (40) investigated the association between
remission, maintains health-related quality of life and main- GERD symptoms and utility values in a Swedish GERD
tains more patients symptom-free and satisfied on their treat- population (n ¼ 504), which showed utility values (rating
ment. Therefore, decision makers need to balance the scale estimates) of 0.85, 0.78, 0.70 and 0.62 for patients with
increased effectiveness of treatment with continuous esome- no, mild, moderate and severe heartburn, respectively. Using
prazole against the higher cost associated with that treatment these utility values, a simple quality-adjusted life-year (QALY)
strategy. When differences between the continuous esomepra- analysis was performed on results from the current study,
zole and ranitidine strategies are compared with each other, it assuming that health states are determined by heartburn sever-
seems likely that the small, observed difference in costs should ity at each given point in time during the 6-month follow-up.
be offset by the effectiveness of esomeprazole. Thus, esome- Conservative assumptions were made regarding interpolation
prazole is the most cost-effective treatment option in this 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 esomeprazole continuous and on-demand treatments are
between the two studies. These calculations resulted in QALY compared.
estimates over 6 months of 0.413, 0.406 and 0.396 associated It is also important to consider that, from a patient’s
with the esomeprazole continuous, esomeprazole on-demand perspective, the effectiveness of treatment is likely to be of
and ranitidine strategies, respectively. Using mean values, this paramount importance. Effective treatment generally leads to
would imply an additional direct medical cost by using esome- greater satisfaction with treatment, improved quality of life
prazole continuous of about NOK 13 000 (Euro 1600) per and a more rapid return to work (5,43,44). Furthermore,
QALY gained, compared with ranitidine, and about NOK symptoms of GERD have been showed to have a significant
90,000 (Euro 11,000) per QALY gained, compared with impact on productivity while at work, as well as while per-
esomeprazole on-demand. Results from these calculations are, forming regular daily activities other than work (45,46).
of course, uncertain and should be interpreted with great care. However, instruments for prospectively assessing patient-
Nonetheless, it should be noted that an additional cost of reported reduced productivity were not included in the cur-
NOK 90,000 per QALY gained is considered low when related rent study, because these were not considered appropriate as a
to values that have been reported to be acceptable in the health basis for cost calculations in a long-term study because of
economic literature (41,42). Furthermore, the calculations on their short recall period.
additional costs per QALY gained do illustrate how a tradeoff The current study, which has examined the resource con-
between differences in costs and effectiveness needs to be made sumption of uninvestigated GERD patients, has the advan-
when interpreting results from the current study. The calcula- tage of applying the techniques of a prospective methodology.
tions also support a conclusion that continuous treatment with Resource use data were collected at points when they occurred
esomeprazole is likely to be cost-effective, compared with in the management of comparable groups of patients. The
continuous treatment with ranitidine, and that it is more principal advantage of such methodology is that it increases
uncertain which is the cost-effective alternative when 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 663

cost study, some uncertainty is inherent in the cost estimates. Results from a multi-center clinical trial. Ital J Gastroenterol
It is also true that in some cases the costs used may reflect Hepatol 1998; 30: 19–27.
charges rather than costs, although the sensitivity analysis did 6 Tew S, Jamieson GG, Pilowsky I, Myers J. The illness behavior
not alter the dominant position of on-demand therapy with of patients with gastroesophageal reflux disease with and without
endoscopic esophagitis. Dis Esophagus 1997; 10: 9–15.
respect to ranitidine. The other potential weakness of the
7 Castell DO, Richter JE, Robinson M et al. Efficacy and safety of
study was patients being asked to recall their use of resources
lansoprazole in the treatment of erosive reflux esophagitis. Am J
and the number of days absent from work over a relatively
Gastroenterol 1996; 91: 1749–57.
long period of time, which might potentially have given rise 8 Corinaldesi R, Valentini M, Belaı̈che J et al. Pantoprazole and
to recall errors. Any recall errors are likely to have the effect omeprazole in the treatment of reflux esophagitis: a European
that indirect costs are higher than those reported in this study. multicentre study. Aliment Pharmacol Ther 1995; 9: 667–71.
Another potential limitation of the study is that the initial 9 Hallerbäck B, Unge P, Carling L et al. Omeprazole or ranitidine
4-week treatment period with esomeprazole 40 mg may have in long-term treatment of reflux esophagitis. Gastroenterology
had a bearing on the efficacy of the subsequent treatment 1994; 107: 1305–11.
following randomization to the various treatment arms. This 10 Hatlebakk JC, Berstad A. Lansoprazole 15 and 30 mg daily in
raises the question whether various efficacy and cost-effectiveness maintaining healing and symptom relief in patients with reflux
results would have been observed had patients received esophagitis. Aliment Pharmacol Ther 1997; 11: 365–72.
11 Mössner J, Holscher AH, Herz R, Schneider A. A double-blind study
ranitidine, for example, during the initial 4-week treatment
of pantoprazole and omeprazole in the treatment of reflux esophagi-
period. Although further study would be needed in order to
tis: a multicentre trial. Aliment Pharmacol Ther 1995; 9: 321–6.
ascertain the magnitude of any such effect, consideration of the
12 Dent J, Brun J, Fendrick AM et al. An evidence-based appraisal
study design is clearly important when interpreting the clinical of reflux disease management – the Genval Workshop Report.
relevance of the results reported in this study. Gut 1999; 44 (Suppl. 2): S1–S16.
The costs of GERD to Norwegian society are high. This study 13 Richter JE, Kahrilas PJ, Johanson J et al. Efficacy and safety of
provides valuable information concerning the costs and cost- esomeprazole compared with omeprazole in GERD patients with
effectiveness of various treatment strategies available for uninves- erosive esophagitis: a randomized controlled trial. Am J
tigated GERD. Both esomeprazole strategies were more effective Gastroenterol 2001; 96: 656–65.
than ranitidine treatment and were associated with lower costs in 14 Kahrilas PJ, Falk GW, Johnson DA et al. Esomeprazole
all areas of resource use and indirect costs other than in drug improves healing and symptom resolution as compared with
acquisition costs for continuous esomeprazole treatment. omeprazole in reflux esophagitis patients: a randomized con-
trolled trial. Aliment Pharmacol Ther 2000; 14: 1249–58.
15 Castell DO, Kahrilas PJ, Richter JE et al. Esomeprazole (40 mg)
ACKNOWLEDGEMENT compared with lansoprazole (30 mg) in the treatment of erosive
esophagitis. Am J Gastroenterol 2002; 97: 575–83.
The authors thank all the investigators and study personnel at 16 Nexium Prescribing Information. AstraZeneca.
281 Norwegian GP Clinics, who participated in and gave 17 Talley NJ, Lauritsen K, Tunturi-Hihnala H et al. Esomeprazole
their contribution to the study. 20 mg maintains symptom control in endoscopy-negative gastro-
esophageal reflux disease: a controlled trial of ‘on-demand’ ther-
apy for 6 months. Aliment Pharmacol Ther 2001; 15: 347–54.
18 Talley NJ, Venables TL, Green JRB et al. Esomeprazole 40 mg
REFERENCES
and 20 mg is efficacious in the long-term management of
1 National Institute for Clinical Excellence 2000. Guidance on the patients with endoscopy-negative gastro-esophageal reflux disease
use of Proton Pump Inhibitors (Ppis) in the treatment of dys- – a placebo-controlled trial of ‘on-demand’ therapy for 6
pepsia. Available from www.Nice.Org.Uk. Date of Last months. Eur J Gastroenterol Hepatol 2002; 14: 857–63.
Accession 26/08/2003. 19 Vakil N, Rydén-Bergsten T, Bergenheim K. Systematic review:
2 Spechler SJ. Epidemiology and natural history of gastro- patient-centred endpoints in economic evaluations of gastroesopha-
esophageal reflux disease. Digestion 1992; 51 (Suppl. 1): 24–9. geal reflux disease. Aliment Pharmacol Ther 2002; 16: 1469–80.
3 Venables TL, Newland RD, Patel AC et al. Omeprazole 10 20 Sadowski D, Champion M, Goeree R et al. Health economics of
milligrams once daily, omeprazole 20 milligrams once daily, or gastroesophageal reflux disease. Can J Gastroenterol 1997; 11 (B):
ranitidine 150 milligrams twice daily evaluated as initial therapy 108B–12B.
for the relief of symptoms of gastro-esophageal reflux disease in 21 Torrance GW, Siegel JE, Luce BR. Framing and designing the
general practice. Scand J Gastroenterol 1997; 32: 965–73. cost-effectiveness analysis. In: Gold MR, Siegel JE, Russell LB,
4 Jones R. Gastro-esophageal reflux disease in general practice. Weinstein MC, eds. Cost-Effectiveness in Health and Medicine.
Scand J Gastroenterol 1995; 30 (Suppl. 211): 35–8. New York: Oxford University Press, 1996: 54–81.
5 Wiklund I, Bardhan KD, Müller-Lissner S et al. Quality of life 22 Luce BR, Elixhauser A. Standards for Socioeconomic Evaluation of
during acute and intermittent treatment of gastroesophageal Health Care Products and Services. Berlin: Springer-Verlag, 1990:
reflux disease with omeprazole compared with ranitidine. 56–67.

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

23 Coyle D, Davies L, Drummond M. Trials and tribulations. Moum B Esomeprazole is superior to ranitidine 150 mg bid in
Emerging issues in designing economic evaluations alongside maintaining quality of life (QoL) in patients with symptomatic
clinical trials. Int J Technol Assess Health Care 1998; 14: 135–44. GERD.
24 Wiklund I, Junghard O, Grace E et al. Quality of life in reflux 37 Myrvold HE, Lundell L, Mietinen P et al. The five year cost of
and dyspepsia patients. Psychometric documentation of a new medical treatment (omeprazole) versus antireflux surgery in
disease-specific questionnaire (QOLRAD). Eur J Surg Suppl patients with reflux esophagitis. Gastroenterology 2000; 118
1998; 583: 41–9. (Suppl. 2): 118.
25 Glick H, Briggs A, Polsky D. Quantifying stochastic uncertainty 38 Myrvold HE, Lundell L, Mietinen P et al. The cost of long term
and presenting results of cost-effectiveness analyses. Expert Rev therapy for gastro-esophageal reflux disease: a randomized trial
Pharmacoeconomics. Outcomes Res 2001; 1: 25–36. comparing omeprazole and open antireflux surgery. Gut 2001;
26 ECON 1998. ‘Evaluering Av Finansieringsordningen for 49: 488–94.
Laboratorier Og Røntgeninstitutter’ (Evaluation of the 39 Lundell L, Dalenback J, Janatuinen E et al. Comprehensive
Financing Scheme for Laboratories and Radiological Institutes). 1-year cost analysis of open antireflux surgery in Nordic coun-
ECON-, rapport no. 58/98. tries. Nordic GORD Study Group. Gastro-esophageal reflux
27 ECON 1999. ‘Kostnader Ved Produksjon Av Radiologiske disease. Br J Surg 1998; 85: 1002–5.
Tjenester’ (Radiological Production Costs). ECON-, rapport 40 Kartman B. Health state utilities and willingness to pay in
no. 68/99. GERD patients with heartburn. Value Health 2002; 5: 505.
28 Pedersen M, Solstad K. 2000 ‘Benchmarking av kostnader ved 41 Laupacis A, Feeney D, Detsky A, Tugwell PX. How attractive
sentralsykehus’ (Benchmarking of costs at county hospitals) does a new technology have to be to warrant adoption and
Sintef Unimed STF78 A00520. utilization? Tentative guidelines for using clinical and economic
29 Sintef Unimed 1999. ‘Samdata Sykehus – Tabeller 1998’ evaluations. CMAJ 1992; 146: 473–81.
(Samdata Hospital – tables 1998) NIS-rapport 4/99. 42 Towse A, Pritchard C. National Institute for Clinical Excellence
30 Sintef Unimed 2000. ‘Samdata Sykehus – Tabeller 1999’ (NICE): is economic appraisal working? Pharmacoeconomics
(Samdata Hospital – tables 1999) NIS-rapport 2/00. 2002; 20 (Suppl. 3): 95–105.
31 Statistics Norway 2000. Price indexes for gasoline and diesel. 43 Rush DR, Stelmach WJ, Young TL et al. Clinical effectiveness
Retrieved from Statistics Norway’s Intranet and sent to AZ. and quality of life with ranitidine vs placebo in gastrooesophageal
32 Ragnøy A. 1997 ‘Kjøretøyers driftskostnader – Fra kjørekostnadsh - reflux disease patients: a clinical experience network (CEN)
åndboken til EFFEKT 1997, 5.0’ (Vehicles operating costs). TØI- study. J Fam Pract 1995; 41: 126–36.
notat 1082/1997. 44 Revicki DA, Wood M, Maton PN, Sorensen S. The impact of
33 The Norwegian Competition Authority 1999. ‘Forskrift om gastroesophageal reflux disease on health-related quality of life.
maksimalpriser for kjøring med drosjebil’. (Maximum pricing Am J Med 1998; 104: 252–8.
scheme for taxi-fares) At. http://www.konkurransetilsynet, no. 45 Henke CJ, Levin TR, Henning JM, Potter LP. Work loss costs
May 2001. due to peptic ulcer disease and gastroesophageal reflux disease in
34 Kommunenes Sentralforbund ‘Lønns-og personalstatistikk – a health maintenance organization. Am J Gastroenterol 2000; 95:
Hovedoversikt Oktober 99’ (Wage- and employee statistics – 788–92.
Main overview October 99) Kommunenes sentralforbund 2000 46 Wahlqvist P, Carlsson J, Stålhammar NO, Wiklund I. Validity
(Referred to as PAI-registeret). of a work productivity and activity impairment questionnaire for
35 Statistics Norway 2001. ‘’Økonomisk analyser 1/ 2001 patients with symptoms of gastro-esophageal reflux disease
(Economic Survey 1/2001). (WPAI-GERD) – results from a cross-sectional study. Value
36 Abstract reference will be available from a presentation at Health 2002; 5: 106–13.
the Nordic Gastro meeting in June (http://www.congrex.com/
ngc2003/frames.htm ): Wiklund I, Hansen ÅN, Bergheim R, Paper received April 2004, accepted February 2005

ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 655–664