Maintenance treatment with esomeprazole following initial relief of non-steroidal anti-inflammatory drug-associated upper gastrointestinal symptoms: the NASA2 and SPACE2 studies.

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 (COX-2) inhibitors, cause upper gastrointestinal (GI) symptoms that are relieved by treatment with esomeprazole. We assessed esomeprazole for maintaining long-term relief of such symptoms. Six hundred and ten patients with a chronic condition requiring anti-inflammatory therapy who achieved relief of NSAID-associated symptoms of pain, discomfort, or burning in the upper abdomen during two previous studies were enrolled and randomly assigned into two identical, multicentre, parallel-group, placebo-controlled studies of esomeprazole 20 mg or 40 mg treatment (NASA2 [Nexium Anti-inflammatory Symptom Amelioration] and SPACE2 [Symptom Prevention by Acid Control with Esomeprazole] studies; ClinicalTrials.gov identifiers NCT00241514 and NCT00241553, respectively) performed at various rheumatology, gastroenterology, and primary care clinics. Four hundred and twenty-six patients completed the 6-month treatment period. The primary measure was the proportion of patients with relapse of upper GI symptoms, recorded in daily diary cards, after 6 months. Relapse was defined as moderate-to-severe upper GI symptoms (a score of more than or equal to 3 on a 7-grade scale) for 3 days or more in any 7-day period. Esomeprazole was significantly more effective than placebo in maintaining relief of upper GI symptoms throughout 6 months of treatment. Life-table estimates (95% confidence intervals) of the proportion of patients with relapse at 6 months (pooled population) were placebo, 39.1% (32.2% to 46.0%); esomeprazole 20 mg, 29.3% (22.3% to 36.2%) (p = 0.006 versus placebo); and esomeprazole 40 mg, 26.1% (19.4% to 32.9%) (p = 0.001 versus placebo). Patients on either non-selective NSAIDs or selective COX-2 inhibitors appeared to benefit. The frequency of adverse events was similar in the three groups. Esomeprazole maintains relief of NSAID-associated upper GI symptoms in patients taking continuous NSAIDs, including selective COX-2 inhibitors.

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Vol 9 No 1Research article
Maintenance treatment with esomeprazole following initial relief
of non-steroidal anti-inflammatory drug-associated upper
gastrointestinal symptoms: the NASA2 and SPACE2 studies
Christopher J Hawkey1, Nicholas J Talley2, James M Scheiman3, Roger H Jones4,
Göran Långström5, Jorgen Næsdal5, Neville D Yeomans6 for the NASA/SPACE author group
1Institute of Clinical Research, Trials Unit, Wolfson Digestive Diseases Centre, University Hospital, Derby Road, Nottingham, NG7 2UH, UK
2Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
3Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center, 3912 Taubman Center, Ann Arbor, MI 48109-
0362, USA
4GKT Department of General Practice, King's College, 5 Lambeth Walk, London, SE11 6SP, UK
5AstraZeneca R&D, Karragatan 5, Pepparedsleden 1, Mölndal 431 83, Sweden
6Medical School, University of Western Sydney, Locked Bag 1797, Penrith South DC, NSW 1797, Australia
Corresponding author: Christopher J Hawkey, cj.hawkey@nottingham.ac.uk
Received: 21 Dec 2005 Revisions requested: 26 Jan 2006 Revisions received: 3 Nov 2006 Accepted: 9 Feb 2007 Published: 9 Feb 2007
Arthritis Research & Therapy 2007, 9:R17 (doi:10.1186/ar2124)
This article is online at: http://arthritis-research.com/content/9/1/R17
© 2007 Hawkey et al.; licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs), including
selective cyclo-oxygenase-2 (COX-2) inhibitors, cause upper
gastrointestinal (GI) symptoms that are relieved by treatment
with esomeprazole. We assessed esomeprazole for maintaining
long-term relief of such symptoms. Six hundred and ten patients
with a chronic condition requiring anti-inflammatory therapy who
achieved relief of NSAID-associated symptoms of pain,
discomfort, or burning in the upper abdomen during two
previous studies were enrolled and randomly assigned into two
identical, multicentre, parallel-group, placebo-controlled studies
of esomeprazole 20 mg or 40 mg treatment (NASA2 [Nexium
Anti-inflammatory Symptom Amelioration] and SPACE2
[Symptom Prevention by Acid Control with Esomeprazole]
studies; ClinicalTrials.gov identifiers NCT00241514 and
NCT00241553, respectively)
rheumatology, gastroenterology, and primary care clinics. Four
hundred and twenty-six patients completed the 6-month
treatment period. The primary measure was the proportion of
performed at various
patients with relapse of upper GI symptoms, recorded in daily
diary cards, after 6 months. Relapse was defined as moderate-
to-severe upper GI symptoms (a score of more than or equal to
3 on a 7-grade scale) for 3 days or more in any 7-day period.
Esomeprazole was significantly more effective than placebo in
maintaining relief of upper GI symptoms throughout 6 months of
treatment. Life-table estimates (95% confidence intervals) of the
proportion of patients with relapse at 6 months (pooled
population) were placebo, 39.1% (32.2% to 46.0%);
esomeprazole 20 mg, 29.3% (22.3% to 36.2%) (p = 0.006
versus placebo); and esomeprazole 40 mg, 26.1% (19.4% to
32.9%) (p = 0.001 versus placebo). Patients on either non-
selective NSAIDs or selective COX-2 inhibitors appeared to
benefit. The frequency of adverse events was similar in the three
groups. Esomeprazole maintains relief of NSAID-associated
upper GI symptoms in patients taking continuous NSAIDs,
including selective COX-2 inhibitors.
Introduction
Continuous users of non-steroidal anti-inflammatory drugs
(NSAIDs) often experience treatment-associated upper gas-
trointestinal (GI) side effects, including upper abdominal pain
and heartburn [1-3]. Although recently introduced drugs that
selectively inhibit the cyclo-oxygenase-2 (COX-2) enzyme
(selective COX-2 inhibitors) were expected to have better GI
tolerability, it is clear that these drugs are also associated with
AE = adverse event; COX-2 = cyclo-oxygenase-2; GERD = gastroesophageal reflux disease; GI = gastrointestinal; GSRS = Gastrointestinal Symp-
tom Rating Scale; HRQL = health-related quality of life; NASA = Nexium Anti-inflammatory Symptom Amelioration; NSAID = non-steroidal anti-inflam-
matory drug; PPI = proton pump inhibitor; QOLRAD = Quality of Life in Reflux and Dyspepsia; SPACE = Symptom Prevention by Acid Control with
Esomeprazole.

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a substantial level of drug-related symptomatic upper GI
adverse events (AEs) requiring treatment [4,5].
Upper GI symptoms, together with the underlying inflamma-
tory disease, lead to substantial reductions in health-related
quality of life (HRQL) in patients taking long-term NSAID ther-
apy [6,7] and often lead to dose reduction or discontinuation
of NSAID treatment [3,8]. Treatments that relieve upper GI
symptoms associated with NSAIDs may thus allow patients to
continue therapy with these drugs. However, it is important
that such additional treatments are themselves well tolerated
and effective for long periods of time given that many patients
with chronic inflammatory conditions require continuous
NSAID therapy for many years.
In animal studies, NSAID-associated gastric mucosal damage
has been shown to be highly pH-dependent [9]. Conse-
quently, a combination of NSAID treatment and acid suppres-
sive therapy may minimise the risk of NSAID toxicity and
associated upper GI symptoms, and human studies have
established a major role for proton pump inhibitors (PPIs) in
this regard [10,11]. In addition, there are growing indications
that PPIs are effective in relieving the upper GI symptoms
associated with the use of NSAIDs, including selective COX-
2 inhibitors [12].
We therefore conducted two pairs of placebo-controlled stud-
ies that evaluated the efficacy, tolerability, and safety of acid
suppression with esomeprazole in the treatment and preven-
tion of NSAID-associated upper GI symptoms. Each study
consisted of an acute and a maintenance study. The acute 4-
week symptom relief studies (Nexium Anti-inflammatory Symp-
tom Amelioration [NASA1] and Symptom Prevention by Acid
Control with Esomeprazole [SPACE1] studies) have shown
that esomeprazole (20 and 40 mg) relieves upper GI symp-
toms in patients using NSAIDs, including selective COX-2
inhibitors [12]. In this paper, we report a comparison of
esomeprazole 20 and 40 mg with placebo in the long-term (6
months) maintenance of relief of upper abdominal pain, dis-
comfort, or burning in patients continuing to use NSAIDs,
including selective COX-2 inhibitors.
Materials and methods
Study design
Two 6-month randomised, double-blind, parallel-group, pla-
cebo-controlled studies (NASA2 [SH-NEN-0002] and
SPACE2 [SH-NEN-0004]) were conducted in 149 outpatient
centres, including rheumatology, gastroenterology, and pri-
mary care, in Europe, USA, Canada, South Africa, and Aus-
tralia. Signed informed consent was obtained from all patients
prior to entry into the study. The study was approved by an
independent ethics committee.
Patients
Patients (male and female, at least 18 years old) who achieved
relief of upper GI symptoms (pain, discomfort, or burning in the
upper abdomen) in the NASA1 and SPACE1 studies, whether
taking placebo, esomeprazole 20 mg, or esomeprazole 40 mg,
were eligible for immediate inclusion in the subsequent 6-
month maintenance studies. Relief during the acute studies
was defined as having a diary assessment of 'none' or 'minimal'
(scores of 0 or 1, respectively, on a 7-grade scale) on at least
5 of the final 7 days and no more than 'mild' (a score of 2) on
no more than 2 days. Patients satisfying these criteria were re-
randomised (in equal proportion in blocks of six according to
a computer-generated randomisation list) upon entry to the 6-
month studies to receive esomeprazole 20 mg, esomeprazole
40 mg, or placebo once daily for 6 months, in addition to their
NSAID therapy.
All patients included had a chronic condition requiring contin-
uous daily treatment with one or more oral NSAIDs (including
selective COX-2 inhibitors and high-dose aspirin [>325 mg/
day]) for at least 5 days in any given week for the duration of
the study. Patients using low-dose aspirin (<325 mg/day) in
conjunction with an NSAID or COX-2 inhibitor were allowed to
participate in the study but were categorised as receiving non-
selective NSAID therapy (reflecting the COX-1 inhibitory
effects of this therapy) regardless of whether aspirin was used
alone or in combination with a non-selective NSAID or a selec-
tive COX-2 inhibitor. For assessment of the effect of NSAID
type on study variables, patients were included in the selective
COX-2 inhibitor group only if they were taking a selective
COX-2 inhibitor alone.
Exclusion criteria included pain, discomfort, or burning in the
upper abdomen precipitated by exercise, relieved by defeca-
tion, or not associated with the use of NSAIDs; a history of
symptomatic gastroesophageal reflux disease (GERD) not
associated with the use of NSAIDs; a history of erosive
esophagitis, gastric, or duodenal ulcer or of esophageal, gas-
tric, or duodenal surgery; a need for concomitant therapy with
drugs likely to affect the outcome of the study (stable treat-
ment with disease-modifying anti-rheumatic drugs was permit-
ted, as was limited glucocorticoid use).
Assessments
The severity of NSAID-associated upper GI symptoms (pain,
discomfort, or burning in the upper abdomen) was rated by the
patient on daily diary cards on a 7-grade scale from 0 (none:
no symptoms) to 6 (very severe: cannot be ignored and mark-
edly limits daily activities and often requires rest). In addition,
at baseline and after 1, 3, and 6 months, the severity of four
other upper GI symptoms during the previous 7 days (heart-
burn, acid regurgitation, upper abdominal bloating, and nau-
sea) was assessed by the investigator and graded from 0
(none: no symptoms) to 3 (severe: incapacitating with inability
to perform normal activities).

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Upper GI symptom severity and HRQL were also assessed
using two validated patient-reported outcome instruments, the
Gastrointestinal Symptom Rating Scale (GSRS) [13] and the
Quality of Life in Reflux and Dyspepsia (QOLRAD) question-
naire [14,15]. Both instruments use 7-grade Likert scales and
group related aspects into five dimensions: reflux, abdominal
pain, indigestion, diarrhoea, and constipation (for the GSRS)
and emotional distress, sleep disturbance, food/drink prob-
lems, vitality, and physical/social functioning (for the QOLRAD
questionnaire). The QOLRAD questionnaire is a disease-spe-
cific instrument that was developed for patients with upper GI
symptoms, including heartburn and dyspepsia. The GSRS is
also a disease-specific instrument and was developed specif-
ically to assess GI symptom severity. Mean change from base-
line in the three QOLRAD dimensions of emotional distress,
sleep disturbance, and food/drink problems was assessed, as
was mean change from baseline in the three GSRS dimen-
sions of reflux, abdominal pain, and indigestion. Compliance
with NSAIDs and with the study drug was monitored by diary
cards and by the investigator (counting unused tablets),
respectively. AEs were monitored at 1, 3, and 6 months by the
investigator.
Statistical analyses
The primary variable was the proportion of patients with
relapse of upper GI symptoms associated with the use of daily
NSAIDs, including selective COX-2 inhibitors, after 6 months
of treatment. Relapse was defined as moderate-to-severe
upper GI symptoms (more than or equal to 3 on the 7-grade
severity scale) on at least 3 days in any 7-day period. The pro-
portions of patients with relapse of upper GI symptoms were
analysed by life-table analysis (Kaplan-Meier estimates of time
to first event) with differences between active treatment and
placebo compared using the log-rank test. This analysis was
performed for all patients and for those in the non-selective
NSAID or selective COX-2 inhibitor subgroups. For analysis of
the primary variable, the study populations were analysed sep-
arately. The two study populations were pooled for the assess-
ment of the effect of NSAID type (non-selective versus
selective COX-2 inhibitor).
The number needed to treat was calculated as the number of
patients who need to be treated with esomeprazole 20 or 40
mg to avoid one case of upper GI symptom relapse, relative to
placebo, during 6 months of treatment. Secondary variables
included mean change in the three dimensions pre-specified
as relevant to upper GI symptoms on each of the GSRS and
QOLRAD questionnaires from baseline to last visit, analysed
by analysis of covariance. The proportion of patients main-
tained free of investigator-assessed symptoms of heartburn,
acid regurgitation, upper abdominal bloating, and nausea at 6
months was assessed post hoc with differences analysed by
the Fisher exact test. A post hoc regression analysis using a
Cox proportional hazards model was also performed to assess
the influence of the following factors on time to relapse of pain,
discomfort, or burning in the upper abdomen: age (less than
65 versus more than or equal to 65 years), gender (male ver-
sus female), Helicobacter pylori status (positive versus nega-
tive), selective COX-2 inhibitors (yes versus no), treatment
during NASA1/SPACE1 (esomeprazole 40 mg, esomeprazole
20 mg, placebo), and treatment during NASA2/SPACE2
(esomeprazole 40 mg, esomeprazole 20 mg, placebo).
To determine the reliability of diary card measurements, the
correlation coefficient for 7 days of diary card recordings was
estimated using the GSRS abdominal pain domain. Pearson
correlations between GSRS abdominal pain and mean of diary
cards for the last 7 days were also assessed in terms of base-
line values, last values, and change from baseline.
Each study was planned to include 300 patients in order to
provide 90% power to detect a difference in upper GI symp-
tom relapse rates of 19% for the esomeprazole groups and
42% for the placebo group at the significance level of 0.025
using the Fisher exact test. This was based on observed differ-
ences in relapse rates of respective variables between study
drug and placebo in the ASTRONAUT (Acid Suppression
Trial: Ranitidine versus Omeprazole for NSAID-Associated
Ulcer Treatment) [11] and OMNIUM (Omeprazole versus Mis-
oprostol for NSAID-Induced Ulcer Management) [10] studies.
Results
Of 334 and 276 patients randomly assigned, 328 and 276
patients constituted the intention-to-treat populations for
NASA2 and SPACE2, respectively. Enrolment for the NASA2
and SPACE2 studies started in February and April 2001,
respectively, and the last patient completed both studies in
February 2003. The flow of patients through the studies is
shown in Figure 1. At study entry, the treatment groups were
similar with respect to demographic and clinical characteris-
tics, although slightly more patients receiving placebo during
the maintenance phase had received esomeprazole 20 mg
than either esomeprazole 40 mg or placebo during the acute
phase (Table 1). The most common NSAIDs during mainte-
nance treatment were rofecoxib (21%), celecoxib (20%),
diclofenac (20%), ibuprofen (9%), piroxicam (4%), and
naproxen (3%). The proportion of patients compliant with
study drug (mean dosing: 75% to 125% relative to protocol)
was more than 90% in all three treatment arms. Patient com-
pliance with NSAID treatment (drugs used on at least 70% of
days according to diary data) was similarly high (more than
90% of patients) in the three treatment arms in both studies.
The diary card measurements demonstrated good reliability;
the estimated correlation coefficient for the mean of 7 days of
measurements (using GSRS abdominal pain score) was 0.62.
Furthermore, the correlation between GSRS abdominal pain
and the mean diary card measurements for the preceding 7
days ranged from 0.52 to 0.74 for the baseline values, last val-
ues, and change from baseline, indicating satisfactory validity.

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Efficacy
Significantly fewer patients on esomeprazole 20 or 40 mg,
compared with placebo, experienced relapse of upper GI
symptoms (upper abdominal pain, discomfort, or burning)
based on diary data (Figure 2a). Among patients who were
treated with esomeprazole (either 20 or 40 mg) during the
acute phase and who went on to receive placebo during the
maintenance phase, high rates of relapse were observed (Fig-
ure 2b). Patients with an apparent response to placebo treat-
ment during the acute phase had a lower relapse rate when
treated with placebo during the maintenance phase than those
who received active treatment during the maintenance phase.
Relapse rates were, in general, lower in those who received
esomeprazole during the maintenance phase, regardless of
initial therapy. Data for the individual trials are shown in Table
2. Number needed to treat analysis showed that, throughout 6
months of treatment, 11 and 8 patients need to be treated with
esomeprazole 20 mg or esomeprazole 40 mg, respectively, in
order to avoid 1 patient experiencing relapse of upper GI
symptoms. The exploratory regression analysis identified three
factors as having a significant effect on time to relapse of
upper GI symptoms. Treatment with esomeprazole 20 mg or
esomeprazole 40 mg was associated with a significant reduc-
tion in upper GI symptoms (p = 0.0035 and p = 0.0017,
respectively). Patients younger than 65 years old were signifi-
cantly more likely than those 65 years old or older to experi-
ence a relapse of upper GI symptoms (p = 0.0284). No other
variables included in the analysis were identified as having a
significant effect on time to relapse of symptoms.
Analysis by NSAID type
When patients taking non-selective NSAIDs or selective COX-
2 inhibitors were analysed separately, fewer patients on
esomeprazole experienced relapse of upper GI symptoms
compared with those on placebo (Figure 2c,d). Post hoc anal-
yses showed statistically significant differences for both doses
of esomeprazole versus placebo among those using non-
selective NSAIDs and for esomeprazole 40 mg among those
using selective COX-2 inhibitors.
Other individual investigator-assessed symptoms
As for upper abdominal pain, discomfort, or burning, the pro-
portion of patients with investigator-assessed heartburn, acid
regurgitation, nausea, and upper abdominal bloating at the 6-
month visit was significantly lower in patients treated with
esomeprazole (both 20 and 40 mg) than with placebo (Figure
3).
Figure 1
Flow diagram of patients through the studiesFlow diagram of patients through the studies. E20, esomeprazole 20 mg; E40, esomeprazole 40 mg; ITT, intention-to-treat; NSAID, non-steroidal
anti-inflammatory drug.

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Patient-reported outcomes
Baseline GSRS mean scores for the three relevant dimen-
sions were between 1.49 and 2.00 (1 = no symptoms, 7 =
most severe symptoms). At 6 months, esomeprazole 20 mg
and 40 mg were significantly more effective than placebo at
maintaining previous symptom improvements for the GSRS
dimensions of reflux (esomeprazole 20 mg: p = 0.002, esome-
prazole 40 mg: p = 0.0002) and abdominal pain
(esomeprazole 20 mg: p = 0.006, esomeprazole 40 mg: p =
0.002). A significant difference was also observed between
esomeprazole 20 mg and placebo for the indigestion dimen-
sion (esomeprazole 20 mg: p = 0.03, esomeprazole 40 mg: p
= 0.11) (Figure 4a).
Baseline QOLRAD mean scores for the three pre-specified
relevant dimensions were between 6.30 and 6.59 (7 = no
impairment of HRQL, 1 = most severe impairment) following
improvements in the acute treatment studies [12]. At 6
Table 1
Baseline demographic and clinical characteristics of the pooled study populations
Pooled population
Characteristic Placebo (n = 209) Esomeprazole 20 mg (n = 201)Esomeprazole 40 mg (n = 194)
Male/female gender, percentage27.3:72.7 21.4:78.624.2: 75.8
Age in years, mean (standard deviation)57.1 (13.4) 54.4 (11.9)55.7 (13.6)
Type of chronic condition, percentage
Rheumatoid arthritis 24.418.420.6
Osteoarthritis43.145.342.8
Other chronic condition32.536.336.6
Time since first diagnosis of chronic
condition in years, median
979
Helicobacter pylori status (histology),
percentagea
Negative95.793.095.9
Positive 3.36.5 3.1
Unknown 1.0 0.51.0
NSAID type, percentage
Non-selective 64.165.767.0
Selective COX-2 inhibitor35.9 34.3 33.0
Study drug in acute study, percentage
Placebo24.429.3 32.5
Esomeprazole 20 mg43.1 32.836.1
Esomeprazole 40 mg32.5 37.831.4
aH. pylori status derived from the acute studies (NASA1 [Nexium Anti-inflammatory Symptom Amelioration] and SPACE1 [Symptom Prevention by
Acid Control with Esomeprazole]). COX-2, cyclo-oxygenase-2; NSAID, non-steroidal anti-inflammatory drug.
Table 2
Estimated proportion of patients with relapse of upper gastrointestinal symptoms
NASA2 study
p value versus placeboSPACE2 study
p value versus placebo
Placebo38.2%-39.8%-
Esomeprazole 20 mg28.3%0.0430.7%0.07
Esomeprazole 40 mg24.3%0.00428.4%0.05
Kaplan-Meier life-table estimates of proportion of patients with relapse of pain, discomfort, or burning in the upper abdomen throughout 6 months
of treatment with esomeprazole 20 mg, esomeprazole 40 mg, or placebo and log-rank comparisons for the individual studies. NASA, Nexium Anti-
inflammatory Symptom Amelioration; SPACE, Symptom Prevention by Acid Control with Esomeprazole.

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months, esomeprazole 20 and 40 mg were significantly more
effective than placebo for maintaining improvements in HRQL
as judged by mean changes in the QOLRAD questionnaire
dimensions of sleep disturbance (esomeprazole 20 mg: p =
0.02, esomeprazole 40 mg: p = 0.005) and food/drink prob-
lems (esomeprazole 20 mg: p = 0.003, esomeprazole 40 mg:
p = 0.004). Esomeprazole 40 mg was also significantly more
effective than placebo for the emotional distress dimension
(esomeprazole 20 mg: p = 0.05, esomeprazole 40 mg: p =
0.004) (Figure 4b).
Safety and tolerability
Esomeprazole 20 and 40 mg were well tolerated in combina-
tion with continuous daily NSAID use, and no safety concerns
Figure 2
Estimated proportion of patients with relapse of upper gastrointestinal symptomsEstimated proportion of patients with relapse of upper gastrointestinal symptoms. Kaplan-Meier life-table analyses of the proportion of patients with
relapse of pain, discomfort, or burning in the upper abdomen throughout 6 months of treatment with esomeprazole 20 mg (E20), esomeprazole 40
mg (E40), or placebo (a) for all patients, (b) according to treatment in the acute and maintenance studies, (c) for non-selective non-steroidal anti-
inflammatory drug (NSAID) users, and (d) for selective cyclo-oxygenase-2 (COX-2) NSAID users (pooled intention-to-treat population). Diary card
data were not available for 10 patients (placebo, n = 2; esomeprazole 20 mg, n = 6; esomeprazole 40 mg, n = 2). §p = 0.006, ¥p = 0.001, ‡p =
0.03, *p = 0.02, ¶p = 0.08, †p = 0.01, all versus placebo. CI, confidence interval.

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were raised. In the pooled population, AEs and discontinua-
tions due to AEs occurred in 47.4% and 8.5% of placebo
recipients, 55.9% and 7.4% of patients treated with esome-
prazole 20 mg, and 54.6% and 6.1% of patients taking
esomeprazole 40 mg, respectively. Serious AEs occurred in
5.2% of placebo recipients, 5.0% of patients taking esome-
prazole 20 mg, and 7.1% of patients taking esomeprazole 40
mg. Neither of the two deaths (both due to pancreatic carci-
noma, one in the placebo arm and one in the esomeprazole 40
mg arm) in the study was assessed as related to the study
drug.
Discussion
In the two 4-week studies that directly preceded the two stud-
ies reported here, esomeprazole 20 and 40 mg were shown to
provide initial relief of NSAID-associated upper GI symptoms
(upper abdominal pain, discomfort, or burning) [12]. The
results presented here demonstrate that treatment with
esomeprazole 20 and 40 mg maintained relief of these symp-
toms during a further 6 months of once-daily treatment.
Esomeprazole-treated patients were also more likely to experi-
ence prolonged relief of other individual investigator-assessed
upper GI symptoms than those taking placebo. Moreover,
compared with those receiving placebo, esomeprazole-
treated patients reported better GI symptom relief and HRQL
as assessed using the GSRS and QOLRAD instruments.
The study had a number of limitations. First, patients were re-
randomised from the acute studies even if their initial response
had been to placebo, and this may have impacted on the study
findings. For example, it appeared that patients taking placebo
during the acute studies had a low relapse rate even when tak-
ing placebo during the maintenance phase; this is consistent
with a true placebo response. In theory, the higher relapse
rates in patients initially treated with esomeprazole who then
received placebo during the maintenance phase could be
attributed to acid rebound. However, it is difficult to distinguish
between acid rebound and recurrence of initial symptoms, the
latter of which seems more likely. Most of the benefits of acid
suppression were established by day 45 (because most cases
of symptom relapse in placebo recipients had already
occurred by this time point). It is unknown whether those tak-
ing esomeprazole during the maintenance phase would
require continued therapy beyond the 6-month time point in
order to achieve sustained benefits. However, taking the two
phases of this study as a whole, it seems likely that a substan-
tial proportion of patients would experience relapse of symp-
toms if treatment were stopped at this point. In practice,
prescribers may well assess the need for continued mainte-
nance treatment by a trial of drug cessation.
In the two studies described here and the two 4-week studies
that preceded them, NSAID-associated upper GI symptoms
were strictly defined so as to differentiate them from symptoms
more characteristic of GERD, primarily heartburn. For this rea-
son, patients with a history of GERD were excluded from the
studies. Moreover, the symptoms assessed as the primary var-
iable in the study, namely 'upper abdominal pain, discomfort,
or burning,' have been shown to be significantly increased by
NSAID use [2].
Although selective COX-2 inhibitors appear to cause fewer
upper GI events than NSAIDs, it is clear that drug-related
upper GI symptoms remain a problem with this group of drugs
Figure 3
Proportion of patients with investigator-assessed symptoms in the week preceding the 6-month visit (pooled intention-to-treat population) Proportion of patients with investigator-assessed symptoms in the week preceding the 6-month visit (pooled intention-to-treat population). Numbers
(n) relate to patients without the individual symptom upon entering the 6-month maintenance phase. †p = 0.02, ¥p = 0.002, ‡p = 0.003, §p = 0.0001,
****p < 0.0001, all versus placebo.

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[5,16]. When the studies were started, the use of selective
COX-2 inhibitors was already substantial, and because upper
GI symptoms requiring co-therapy are problematic for patients
taking these drugs as well as those taking non-selective
NSAIDs, our study design allowed trial entry on either type of
drug. Similar reductions in upper GI symptom relapse rates to
those seen in the whole study population were also observed
for the subgroups, although esomeprazole 20 mg did not
achieve statistical significance over placebo within the smaller
selective COX-2 inhibitor group. These data, in conjunction
with studies demonstrating that at-risk patients have a signifi-
cant ulcer risk reduction with esomeprazole therapy [17], offer
clinicians important treatment options for users of non-selec-
tive NSAIDs or selective COX-2 inhibitors. Our study also sup-
ports the previously established finding that dyspepsia is less
prevalent in older patients than in younger patients [18,19].
However, whether this is due to a true reduction, reduced per-
ception, or a disinclination to report symptoms is unknown.
Limited data are available on long-term symptom control in
patients with dyspepsia. Our results compare favourably with
those of one randomised controlled trial in H. pylori-negative
patients with dyspepsia [20]. Patients received omeprazole 20
mg once daily, ranitidine 150 mg once daily, cisapride 20 mg
twice daily, or placebo for 4 weeks followed by 5 months of on-
demand treatment with the same therapy. The proportions of
patients with symptom relapse (that is, score of more than or
equal to 3 on an amended 7-point Likert scale) at 6 months
were 56% for omeprazole, 59% for ranitidine, 60% for cis-
apride, and 65% for placebo [20]. In our study, relapse rates
of 26.1% to 39.1% were observed. However, due to differ-
ences in study design between this study and our study, it is
difficult to draw conclusions from these data.
Conclusion
The future use of selective COX-2 inhibitors is uncertain fol-
lowing the withdrawal of rofecoxib due to the risk of cardiovas-
cular events. The results of these studies, however, show a
benefit with esomeprazole therapy (20 and 40 mg) among
patients taking either non-selective NSAIDs or selective COX-
2 inhibitors. These findings are of particular relevance for
patients requiring long-term, continuous anti-inflammatory
therapy, who may otherwise need to discontinue treatment
because of upper GI side effects.
Competing interests
CJH has received research funding and/or honoraria from
AstraZeneca (Mölndal, Sweden), GlaxoSmithKline (Uxbridge,
Middlesex, UK), Merck (Whitehouse Station, NJ, USA),
NitroMed, Inc. (Lexington, MA, USA), Novartis International
AG (Basel, Switzerland), Pfizer, Inc. (New York, NY, USA),
Takeda Pharmaceutical Company Limited (Osaka, Japan),
Serono International SA (Geneva, Switzerland), Wyeth (Madi-
son, NJ, USA), and Grünenthal GmbH (Aachen, Germany).
NJT has participated in consultant advisory boards sponsored
by AstraZeneca and has received consultant's research sup-
port from TAP Pharmaceutical Products, Inc. (Lake Forest, IL,
USA). JMS has received grant/research support from
AstraZeneca, is a consultant to AstraZeneca, Merck, Novartis
International AG, TAP Pharmaceutical Products, Inc., Pfizer,
Inc., The GI Company, Inc. (Framingham, MA, USA), POZEN
Inc. (Chapel Hill, NC, USA), Bayer Corp. (Emeryville, CA,
Figure 4
Score changes in patient-reported outcome scalesScore changes in patient-reported outcome scales. Mean (and standard error) score change in (a) Gastrointestinal Symptom Rating Scale (GSRS)
and (b) Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire (pooled intention-to-treat population).

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Available online http://arthritis-research.com/content/9/1/R17
Page 9 of 9
(page number not for citation purposes)
USA), and GlaxoSmithKline, and has participated in Speaker's
Bureaus for AstraZeneca, TAP Pharmaceutical Products, Inc.,
and Santarus, Inc. (San Diego, CA, USA). RHJ has received
consultancy and speaker fees from AstraZeneca, Altana AG
(Bad Homburg, Germany), and Reckitt Benckiser plc (Slough,
Berkshire, UK). GL and JN are full-time employees of Astra-
Zeneca. NDY has received speaker fees from a maker of PPIs,
AstraZeneca, which financed the development of this
manuscript.
Authors' contributions
All authors were involved in study design and manuscript prep-
aration. CJH, NJT, JMS, RHJ, and NDY were responsible for
data acquisition and interpretation. JN was involved in data
interpretation. Data analysis was provided by GL. All authors
read and approved the final manuscript.
Acknowledgements
This research was supported by a grant from AstraZeneca. We thank
Claire Byrne and Steve Winter, from Wolters Kluwer Health (Chester,
Cheshire, UK), who provided medical writing support funded by Astra-
Zeneca. The other members of the NASA/SPACE author group are Her-
man Mielants (Belgium), Walter F Kean (Canada), Pavla Vavřincová
(Czech Republic), Wolfgang W Bolten, Michael Buchner and Johannes
Habbig (Germany), Gabriele Bianchi Porro (Italy), Jean-François Berg-
mann and Francis Philippe (France), Pàl Demeter (Hungary), Olav
Bjørneboe (Norway), Dariusz Kleczkowski and Janusz Rudzinski
(Poland), Jozef Rovenský (Slovak Republic), Anne Halland (South
Africa), Angel Lanas (Spain), Kjell-Arne Ung (Sweden), and Atul Patel
(UK).
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