Clinical trial: healing of NSAID-associated gastric ulcers in

patients continuing NSAID therapy a randomized study

comparing ranitidine with esomeprazole
J. L. GOLDSTEI N* , J. F. JOHANSON, C. J. HAWKEY, L. J. SUCHOWER & K. A. BROWN
*University of Illinois at Chicago, Chi-
cago, IL, USA; Rockford Gastroenter-
ology Associates, Rockford, IL, USA;
Nottingham University Medical
School, Nottingham, UK; AstraZeneca
LP, Wilmington, DE, USA
Correspondence to:
Dr J. L. Goldstein, Department of
Medicine, University of Illinois at
Chicago, 840 South Wood Street,
Room 1020, 10th Floor, Chicago, IL
60612, USA.
E-mail: jlgoldst@uic.edu
Publication data
Submitted 21 June 2007
First decision 12 July 2007
Resubmitted 25 July 2007
Accepted: 25 July 2007
SUMMARY
Background
The use of non-steroidal anti-inammatory drugs (NSAID) is associated
with an increased risk of gastric ulcer (GU) development.
Methods
This multicentre, randomized, double-blind, parallel-group trial com-
pared endoscopic healing rates at 4 and 8 weeks after treatment with
oral esomeprazole 40 or 20 mg once daily, or ranitidine 150 mg twice
daily, in patients with 1 baseline GU 5 mm but no GUs or duodenal
ulcers >25 mm in diameter who received continued cyclooxygenase-2
selective or non-selective NSAID therapies. The primary outcome was
the percentage of patients in each treatment group who had no GUs at
week 8.
Results
Four hundred and forty patients were randomized to treatment. At week
8, GU healing rates (95% CI) with esomeprazole 40 mg, esomeprazole
20 mg and ranitidine were 85.7 (79.891.7)%, 84.8 (78.890.8)% and
76.3 (69.283.3)%, respectively; between-group differences were not
statistically signicant. Week-4 GU healing rates were 70.7 (62.9
78.4)% and 72.5 (65.079.9)% with esomeprazole 40 and 20 mg, respec-
tively, and were signicantly higher (P < 0.01 for both doses) than
those with ranitidine [55.4 (47.163.7)%].
Conclusion
In patients who require continued NSAID therapy, GU healing rates at
8 weeks numerically favoured esomeprazole but were not signicantly
different from ranitidine.
Aliment Pharmacol Ther 26, 11011111
Alimentary Pharmacology & Therapeutics
2007 AstraZeneca Pharmaceuticals LP 1101
doi:10.1111/j.1365-2036.2007.03460.x
I NTRODUCTI ON
Non-steroidal anti-inammatory drugs (NSAIDs) are
commonly used to treat inammatory conditions and
to reduce pain. However, the use of NSAIDs is associ-
ated with an increased risk of developing clinically
relevant upper gastrointestinal (GI) tract injury that
includes symptomatic gastric (GUs) or duodenal ulcers
(DUs) and their potential ulcer complications (e.g.,
haemorrhage, perforation).
14
While cyclooxygenase
(COX) 2selective NSAIDs are associated with a lower
rate of endoscopic upper GI ulcers and ulcer complica-
tions, as compared with non-selective NSAIDs, the risk
of ulcer complications is not insignicant.
58
The mechanisms by which NSAIDs lead to the devel-
opment of gastric and duodenal mucosal injury are
multifactorial. While inhibition of the COX-1 isozyme
is widely accepted as a signicant predisposing mecha-
nism for mucosal injury, intragastric acidity is clearly
an important factor in the development of mucosal
ulceration.
911
The results of several studies have
shown that proton pump inhibitors (PPIs) are more
effective than ranitidine in controlling intragastric pH,
specically in NSAID users.
1216
Extending this con-
cept, we recently reported the results of a trial demon-
strating that esomeprazole is more effective than
ranitidine for the healing of GUs in patients who need
to continue NSAID therapy.
17
This nding is clinically
relevant as some patients with a documented NSAID-
associated GU or a recent ulcer complication
2
may still
require continued treatment with a COX-2selective or
non-selective NSAID for control of arthritis and or
pain relief.
To conrm and extend our ndings, the primary
aim of the current study was to assess the efcacy of
8 weeks of treatment with esomeprazole 40 mg and
20 mg once daily versus ranitidine 150 mg twice daily
for the healing of GUs in patients who continue to
receive daily selective or non-selective NSAID therapy.
METHODS
Trial design
This multicenter, randomized, double-blind, double-
dummy, parallel-group, 8-week study (AstraZeneca
code SH-NEN-0006 Study 286) was in design similar
to a previously published trial that also compared
esomeprazole 40 and 20 mg once daily with ranitidine
150 mg twice daily in patients who had GUs and con-
tinued to receive daily selective or non-selective
NSAID therapy.
17
Institutional Review Board approval was obtained
before enrolment of any patient into the study.
Patients provided signed informed consent before any
study-specic procedures were performed. The study
procedures were performed in accordance with the
Declaration of Helsinki, Good Clinical Practice (GCP),
and applicable regulatory requirements.
Patients
Patients aged 18 years were recruited from gastroen-
terology, rheumatology, internal medicine, and general
practice centres in Eastern Europe, Indonesia, and the
United States. Patients were required to have at least 1
GU veried by oesophagogastroduodenoscopy (OGD)
at baseline that was 5 mm in diameter but not
>25 mm at its greatest diameter. An ulcer was dened
as a mucosal lesion with the following features: a base
(a circular or elliptical white or gray-white punched-
out defect in the mucosa that could be smooth and
regular); a margin (discrete, sharply demarcated, regu-
lar, smooth, and usually raised in relation to the ulcer
base); and lack of an associated mass lesion or other
features suggesting malignancy. Concurrent erosions
(gastric or duodenal), DUs, and multiple GUs were
allowed provided that each ulcer was 25 mm at its
greatest diameter. Eligible patients were also required
to have a chronic condition that necessitated a stable
daily oral dose of NSAID therapy (selective or non-
selective) for at least 4 weeks before the baseline
endoscopy that was expected to remain stable for the
duration of the 8-week study. NSAID therapy could
include non-selective or COX-2selective NSAIDs,
multiple NSAIDs, or aspirin (including dosages of
80 mg day).
To be randomized, patients were supposed to
be negative for infection with Helicobacter pylori
(H. pylori), based on the results of either a serologi-
cal test (FlexSure; Beckman Coulter, Inc., Fullerton,
CA, USA) or a Campylobacter-like organism test
(CLOtest; Kimberly-Clark Health Care, Roswell, GA,
USA), which were used for screening purposes. Single
gastric antral and corpus biopsy specimens were also
taken at the time of the baseline OGD for histological
evaluation and conrmation of H. pylori status. The
H. pylori histology results were not available at the
time patients were randomized to treatment. A single
pathologist at a central laboratory performed the
1102 J . L. GOLDSTEI N et al.
2007 AstraZeneca Pharmaceuticals LP, Aliment Pharmacol Ther 26, 11011111
histological evaluations for H. pylori. These histology
results provided the denitive determination of
H. pylori status and comprise the H. pylori results
reported as baseline in this paper.
Exclusion criteria included any of the following:
history of GI surgery (except for simple ulcer closure),
ZollingerEllison syndrome, inammatory bowel dis-
ease, a non-NSAIDrelated pathology or inltrative
process in the stomach, or any condition that might
have required surgery during the study; malignancy;
or current or historical evidence (within 3 months) of
malabsorption, oesophageal stricture, oesophagitis,
endoscopic Barretts oesophagus >3 cm or documented
dysplastic changes of any grade in the oesophagus,
signs and symptoms of gastric outlet obstruction, pan-
creatitis, or any other severe concomitant disease.
Patients who needed continuous concomitant therapy
with antiepileptic medications, corticosteroids, antico-
agulants (except aspirin), drugs classied as anticho-
linergics used for GI indications, promotility drugs,
sucralfate or who had contraindications to the study
drugs were excluded. For patients receiving concomi-
tant therapy with glucocorticoids or disease-modifying
antirheumatic therapy (e.g., methotrexate) or with
immunosuppressive drugs (e.g., azathioprine, 6-mer-
captopurine, iniximab, cyclosporine), dosages must
have been stable for at least 4 weeks or 6 months,
respectively, before randomization and were expected
to remain stable for the studys duration, with white
blood cell counts greater than the lower limit of nor-
mal. The use of PPIs, prostaglandin analogs, or daily
histamine2-receptor antagonists within 2 weeks before
the baseline endoscopy or during the study (except
study medication) was not allowed. Antineoplastic
agents and antacids (other than the rescue medications
supplied for the study) were not allowed during the
study. Women could not be pregnant (as documented
by negative urine test at baseline) or lactating and
were required to maintain effective contraception
(as judged by the site investigator) during the study
period.
Protocol, assignment and masking
Eligible patients were randomized in a blinded fashion
to oral treatment with esomeprazole 40 mg once daily
plus a ranitidine dummy twice daily; esomeprazole
20 mg once daily plus a ranitidine dummy twice daily;
or ranitidine 150 mg twice daily plus an esomeprazole
dummy once daily. Treatments were to be swallowed
whole with a glass of water in the morning before
breakfast and in the evening. All study medications
and their placebo controls were packaged and labelled
identically to maintain blinding. The randomization
schedule was computer-generated by AstraZeneca LP
using a block size of 6, and blocks of allocation num-
bers were sent to each investigator site. All patients
were assigned allocation numbers in sequential order
at each site. Randomization information was supplied
to the investigator(s) or pharmacists at the study
centres in the form of individual, tamper-evident,
sealed envelopes. The blinding was not to be broken
except in medical emergencies or for patient safety
reasons.
Patients in the United States were provided Gelusil
tablets [200 mg aluminium hydroxide, 200 mg magne-
sium hydroxide, 25 mg simethicone; Warner-Lambert
Consumer Healthcare (Parke-Davis), Morris Plains, NJ,
USA], and patients in non-US countries were provided
antacids with a maximal acid-binding effect of 16
mmol HCl per tablet as rescue medication for upper GI
symptoms. Patients were permitted a maximum of six
rescue medication tablets per day.
Study assessments
Efcacy
Each patient was to have an OGD at baseline and at
weeks 4 and 8 to assess ulcer status. The primary end
point was GU healing status at week 8. Healing was
dened as the OGD-veried absence of all GUs.
Patients were to be continued in the study and to con-
tinue using medications regardless of the OGD ndings
at week 4. GU healing status at week 4 and DU healing
status at weeks 4 and 8 (for patients with concurrent
DUs at baseline) were evaluated as secondary end
points.
Patients answered a question each day on a diary card
(non-US sites) or using a telephone-based interactive
voice response system (US sites) regarding whether they
had taken their NSAID medication as it was prescribed.
Study drug compliance and rescue antacid medication
usage were assessed by counting returned drug.
Safety
Spontaneously reported and elicited adverse events
(AEs) occurring as the previous visit were recorded at
all scheduled or unscheduled patient visits. Clinical
CLI NI CAL TRI AL: NSAI D-ASSOCI ATED GASTRI C ULCER HEALI NG 1103
2007 AstraZeneca Pharmaceuticals LP, Aliment Pharmacol Ther 26, 11011111
laboratory evaluations [clinical chemistry (creatinine,
uric acid, bilirubin, alkaline phosphatase, aspartate
aminotransferase, alanine aminotransferase, sodium,
potassium) and haematology (haemoglobin, leucocytes,
platelet count)] were completed at baseline and at
weeks 4 and 8 (or the time of premature withdrawal
from the study, when possible). Laboratory values out-
side of the dened normal ranges that were considered
by the investigator to be clinically signicant were
recorded as AEs. Other safety assessments included
physical examinations at the baseline and last visits,
and the measurement of vital signs at each visit.
Statistical analyses
The efcacy analyses included all patients who took
at least one dose of study drug, had at least 1 GU
at the baseline OGD, and were enrolled in a site that
followed GCP criteria [modied intention-to-treat
(mITT)]. Patients who had positive H. pylori status by
histology at baseline were not excluded from the anal-
yses. The safety population included all patients who
had taken at least one dose of study drug and had
any available post-baseline information. The analysis
populations were dened before the data were
unblinded.
Based on results from previous studies,
13, 15
it was
determined that a sample size of 390 patients (130
randomized patients per treatment group) would be
needed to provide 90% power to detect a 20% differ-
ence in GU healing rates (80% for the esomeprazole
groups and 60% for the ranitidine group) at a signi-
cance level of 0.025. All statistical tests performed
were 2-tailed.
For analysis of the primary efcacy end point
(observed GU healing status at week 8), the Hochberg
procedure
18
was used for multiplicity adjustment of
the two pairwise treatment group comparisons of
interest (esomeprazole 40 mg vs. ranitidine and
esomeprazole 20 mg vs. ranitidine). The Hochberg pro-
cedure requires that both treatment group comparisons
(i.e., both esomeprazole treatment groups vs. raniti-
dine) have P values 0.05 for both comparisons to be
declared statistically signicant. If the P value for one
comparison is >0.05, then the P value for the other
comparison must be 0.025 to be declared statistically
signicant. The results for the observed GU healing
status at week 4 were analysed using the same
approach. Secondary analyses are presented with nom-
inal P values only, and no adjustments were made; a
probability level of 0.05 was used to determine statis-
tical signicance.
Differences between treatment groups in the observed
GU healing rates at weeks 4 and 8 were analysed using
a v
2
test as the primary efcacy analysis. For patients
who did not have an OGD at week 4, the baseline GU
result was used for that time point. If a patient was
missing, a value for the week-8 visit, the value from
the week-4 visit was carried forward. Subgroup analy-
ses, including GU healing rates by age group, baseline
H. pylori status (by histology from biopsy samples
taken at the baseline OGD), and type of baseline NSAID
(non-selective or COX-2selective), were summarized
descriptively. DU healing rates for patients with
concurrent DUs at baseline were also summarized
descriptively.
As a secondary planned analysis for GU healing, the
estimated GU healing rate was analysed using a log-
rank test to assess differences between the treat-
ment groups time-to-event curves. The KaplanMeier
method was used to estimate the time-to-event curves
(i.e., curves of time-to-GU healing where GU healing
was dened for each patient as the study day of the rst
endoscopy that showed all GUs were healed for that
patient). Because the dates that an OGD was performed
did not necessarily reect the actual date of healing,
dates were grouped into biweekly intervals. For this
analysis, missing values at week 4 or 8 were not
imputed.
Safety data and compliance of study medication or
NSAIDs were summarized descriptively. A patient was
considered compliant with prescribed study NSAID
medication if at least 70% of the recorded daily
responses about NSAID medication were yes. Study
drug compliance was assessed by counting returned
drug, and patients were considered treatment compli-
ant if they used between 75% and 125% of the study
medication.
RESULTS
Patients and disposition
The study was conducted from February 2001 to April
2003. In all, 440 patients were randomized at 75 study
sites as follows: Bulgaria, 89 patients from nine sites;
Indonesia, 51 patients from two sites; Romania, 45
patients from seven sites; the Ukraine, eight patients
from three sites, and the US, 247 from 54 sites. Patient
disposition in the study is shown in Figure 1. Of the
1104 J . L. GOLDSTEI N et al.
2007 AstraZeneca Pharmaceuticals LP, Aliment Pharmacol Ther 26, 11011111
440 patients randomized, 30 were not included in the
primary efcacy analysis because of no study drug
use, the lack of a documented baseline GU, or a GCP
violation at a single site identied after the site was
audited. Of 410 patients included in the primary ef-
cacy analyses, 88 (21%) were in Bulgaria, 51 (12%)
were in Indonesia, 45 (11%) were in Romania, 8 (2%)
were in the Ukraine and 218 (53%) were in the United
States.
Baseline demographics and characteristics for
patients included in the efcacy analysis are summa-
rized in Table 1. The study population included more
women than men, and most patients were white. The
proportion of patients with positive H. pylori status, as
determined by histology, was similar among the three
groups and included 13.8% (30 of 218) of patients in
the United States and 40.1% (77 of 192) of patients in
the non-US countries. The most common chronic con-
dition for which patients were taking NSAIDs was
osteoarthritis (51% of the patients). Across the three
treatment groups, most patients (88%) used non-selec-
tive NSAIDs; the most commonly used non-selective
NSAIDs were aspirin, diclofenac, ibuprofen, and
naproxen. Of these patients, approximately 14%
(51 362) used only low-dose aspirin (80 to 325 mg per
day). Baseline OGD ndings showed that the mean
maximum GU size was approximately 8.2 mm, and
129 patients (31%) had GUs 10 mm (Table 2). Also,
four patients (<1%) had baseline GUs of maximum size
<5 mm. The GU healing results for these four patients
were included in the mITT analysis for completeness.
Excluding the healing results for these patients would
not have changed the results of the analysis. Only 34
patients included in the efcacy population had con-
current baseline DUs (Table 2).
Overall, for patients in the efcacy analysis, compli-
ance with study medication was 97% (396 of 410
patients) and was similar among the three treatment
groups. NSAID compliance was also generally similar
among the treatment groups with an overall compli-
ance rate of 88% (361 of 410) of the patients.
Efcacy
Table 3 reports the GU healing rates at 4 and 8 weeks.
Although the observed GU healing rates at week 8
d e z i m o d n a R 0 4 4
) 1 4 1 = n ( y l i a d e c n o g m 0 4 e l o z a r p e m o s E ) 0 5 1 = n ( y l i a d e c n o g m 0 2 e l o z a r p e m o s E ) 9 4 1 = n ( y l i a d e c i w t g m 0 5 1 e n i d i t i n a R
) 8 1 = n ( s l a w a r d h t i W
t n e v e e s r e v d A 7
n w a r d h t i w t n e s n o C 3
p u - w o l l o f o t t s o L 3
r e t i r c y t i l i b i g i l E 2 d e l l i f l u f t o n a i
e s n o p s e r c i t u e p a r e h t f o k c a L 2
r e h t O 1
t n e m t a e r t d e t e l p m o C 2 3 1
) 9 1 = n ( s l a w a r d h t i W
t n e v e e s r e v d A 6
n w a r d h t i w t n e s n o C 6
p u - w o l l o f o t t s o L 3
r e t i r c y t i l i b i g i l E 4 d e l l i f l u f t o n a i
t n e m t a e r t d e t e l p m o C 0 3 1
s n o i s u l c x e s i s y l a n a y c a c i f f E
g u r d y d u t s o N 1
e n i l e s a b t a U G o N 2
n o i t a l o i v P C G 5
s e s y l a n a y c a c i f f e n i d e d u l c n I 3 3 1 s e s y l a n a y c a c i f f e n i d e d u l c n I 8 3 1
s e s y l a n a y c a c i f f e n i d e d u l c n I 9 3 1
s n o i s u l c x e s i s y l a n a y c a c i f f E
g u r d y d u t s o N 2
e n i l e s a b t a U G o N 5
n o i t a l o i v P C G 5
* ) 6 5 = n ( s n o i t a i v e d l o c o t o r p r o j a M
e l b a t s t o n e g a s u D I A S N 2
t e m t o n a i r e t i r c U G e n i l e s a B 5
3 4 y g o l o t s i h y b e v i t i s o p
g u r d y d u t s h t i w e c n a i l p m o c n o N 6
n o i t a l o i v P C G 5
r e h t O 1
) 3 1 = n ( s l a w a r d h t i W
t n e v e e s r e v d A 4
n w a r d h t i w t n e s n o C 3
p u - w o l l o f o t t s o L 2
r e t i r c y t i l i b i g i l E 1 d e l l i f l u f t o n a i
r e h t O 3
t n e m t a e r t d e t e l p m o C 8 2 1
* ) 6 4 = n ( s n o i t a i v e d l o c o t o r p r o j a M
t e m t o n a i r e t i r c U G e n i l e s a B 5
5 3 - i r o l y p H y g o l o t s i h y b e v i t i s o p
g u r d y d u t s h t i w e c n a i l p m o c n o N 5
n o i t a l o i v P C G 5
r e h t O 1
* ) 0 5 = n ( s n o i t a i v e d l o c o t o r p r o j a M
t e m t o n a i r e t i r c U G e n i l e s a B 5
6 3 y g o l o t s i h y b e v i t i s o p
g u r d y d u t s h t i w e c n a i l p m o c n o N 6
n o i t a l o i v P C G 5
e h t O 2 Other
s n o i s u l c x e s i s y l a n a y c a c i f f E
g u r d y d u t s o N 2
e n i l e s a b t a U G o N 3
n o i t a l o i v P C G 5
H pylori-
H pylori-
Figure 1. Patient disposition. GCP, good clinical practice; NSAID, non-steroidal anti-inammatory drug; GU, gastric ulcer.
* Some patients had more than one type of protocol deviation.
CLI NI CAL TRI AL: NSAI D-ASSOCI ATED GASTRI C ULCER HEALI NG 1105
2007 AstraZeneca Pharmaceuticals LP, Aliment Pharmacol Ther 26, 11011111
Table 1. Demographic and baseline characteristics of patients included in efcacy analyses (mITT population)
Variable
Esomeprazole 40 mg
once daily (n = 133)
Esomeprazole 20 mg
once daily (n = 138)
Ranitidine 150 mg
twice daily (n = 139)
Mean (s.d.) age, years 56.2 (13.1) 58.8 (12.8) 57.3 (13.9)
Range 2186 2685 2288
Women, n (%) 85 (64) 95 (69) 89 (64)
Race, n (%)
White 100 (75) 109 (79) 105 (76)
Black 6 (5) 5 (4) 8 (6)
Asian 19 (14) 17 (12) 17 (12)
Other 8 (6) 7 (5) 9 (6)
Mean (s.d.) BMI, kg m
2
28.1 (5.8) 28.4 (6.5) 28.2 (5.9)
H. pylori-positive
(by histology), n (%)
34 (26) 33 (24) 40 (29)
Chronic condition, n (%)
Rheumatoid arthritis 22 (17) 20 (14) 27 (19)
Osteoarthritis 68 (51) 77 (56) 64 (46)
Other 43 (32) 41 (30) 48 (35)
NSAID type,* n (%)
COX-2selective only 14 (11) 12 (9) 21 (15)
Celecoxib 10 (8) 7 (5) 14 (10)
Rofecoxib 4 (3) 5 (4) 7 (5)
Non-selective 119 (89) 126 (91) 117 (84)
Low-dose aspirin only 16 (12) 21 (15) 14 (10)
BMI, body mass index; COX-2, cyclooxygenase-2; NSAID, non-steroidal anti-inammatory drug.
* One patient in the ranitidine group was not taking NSAID therapy before or during the study; Patients taking a COX-2
selective with a non-selective NSAID or aspirin were included in the non-selective NSAID group; 80325 mg day.
Table 2. Summary of baseline endoscopy ndings of patients included in the efcacy analyses (mITT population)
Esomeprazole 40 mg
once daily (n = 133)
Esomeprazole 20 mg
once daily (n = 138)
Ranitidine 150 mg
twice daily (n = 139)
Total no. of GUs 240 209 221
No. of GUs per patient
Mean (s.d.) 1.8 (1.3)* 1.5 (0.9)* 1.6 (1.0)
Range 18 17 18
Maximum GU size, mm
Mean (s.d.) 8.2 (3.3) 8.0 (3.4) 8.5 (3.6)
Patients with maximum GU size
<5 mm, n (%) 2 (2) 1 (1) 1 (1)
10 mm, n (%) 38 (29) 42 (30) 49 (35)
Patients with DUs, n (%) 10 (8) 16 (12) 8 (6)
Total no. of DUs. 18 19 10
No. of DUs per patient, range 15 14 13
DU, duodenal ulcer; GU, gastric ulcer.
* One patient each in the esomeprazole 40-mg group and esomeprazole 20-mg group had GUs but did not record the number
of GUs present at baseline.
1106 J . L. GOLDSTEI N et al.
2007 AstraZeneca Pharmaceuticals LP, Aliment Pharmacol Ther 26, 11011111
were numerically higher with the esomeprazole treat-
ments than with ranitidine, these results were not sta-
tistically signicant. In contrast, at week 4, the
observed GU healing rates were signicantly higher
for patients treated with esomeprazole 40 and 20 mg
than for patients treated with ranitidine (Table 3). The
observed GU healing rates in the esomeprazole groups
compared with the ranitidine group are shown for sub-
groups evaluated according to age group (Figure 2),
baseline H. pylori status determined by histology
(Figure 3), and non-selective vs. selective baseline
NSAID used (Figure 4).
The observed GU healing rates were reanalysed
including the 15 patients (ve in each treatment group)
that were excluded from the mITT population because
of GCP violations. The results of this reanalysis pro-
vided healing rates that were almost identical to those
seen in Table 3. Therefore, removing these patients from
the mITT analysis did not affect the ndings of this
study.
Table 3. Number (%) of patients with no GUs (observed GU healing rates) at weeks 4 and 8 (mITT population)
Esomeprazole 40 mg
once daily (n = 133)
Esomeprazole 20 mg
once daily (n = 138)
Ranitidine 150 mg
twice daily (n = 139)
Week 4
No. of patients healed 94 100 77
GU healing rate, % (95% CI) 70.7 (62.978.4) 72.5 (65.079.9) 55.4 (47.163.7)
v
2
P value (vs. ranitidine) 0.009* 0.003*
Week 8
No. of patients healed 114 117 106
GU healing rate, % (95% CI) 85.7 (79.891.7) 84.8 (78.890.8) 76.3 (69.283.3)
v
2
P value (vs. ranitidine) 0.047 0.073
* Signicant vs. ranitidine 150 mg twice daily (Hochberg-adjusted, see Methods for details). GU, gastric ulcer.
0
20
40
60
80
100
E40 (n = 133)
R150 (n = 139)
E20 (n = 138)
< 65 years 65 years < 65 years 65 years
Week 4
%

O
f

p
a
t
i
e
n
t
s

w
i
t
h

h
e
a
l
e
d

G
U
67/94
64/85
53/90
27/39
36/53
24/49
83/94 75/85
75/90
31/39 42/53
31/49
Week 8
Figure 2. Gastric ulcer (GU) healing rates by age. E40,
esomeprazole 40 mg once daily; E20, esomeprazole
20 mg once daily; R150, ranitidine 150 mg twice daily
(mITT population).
0
20
40
60
80
100
Negative
73/98
75/105
56/99
21/34
25/33
21/40
84/98
86/105
73/99
30/34
31/33
33/40
E40 (n = 133)
R150 (n = 139)
E20 (n = 138)
Week 4 Week 8
%

O
f

p
a
t
i
e
n
t
s

w
i
t
h

h
e
a
l
e
d

G
U
Positive Negative Positive
Figure 3. Gastric ulcer (GU) healing rates by baseline
Helicobacter pylori status determined by histology. E40,
esomeprazole 40 mg once daily; E20, esomeprazole
20 mg once daily; R150, ranitidine 150 mg twice daily.
Baseline H. pylori status was missing for one patient in
the esomeprazole 40-mg group (mITT population).
CLI NI CAL TRI AL: NSAI D-ASSOCI ATED GASTRI C ULCER HEALI NG 1107
2007 AstraZeneca Pharmaceuticals LP, Aliment Pharmacol Ther 26, 11011111
As a secondary analysis of GU healing, the esti-
mated GU healing rates through the nal visit (based
on KaplanMeier estimation) were 92.1% (95% CI,
87.4%96.8%), 94.6% (95% CI, 90.7%98.5%) and
89.2% (95% CI, 83.7%94.7%) in the esomeprazole
40-mg, esomeprazole 20-mg and ranitidine groups,
respectively. Estimated GU healing rates through week
4 (based on Kaplan-Meier estimation) were 71.6%
(95% CI, 63.9%79.4%), 75.2% (95%CI, 67.8%82.5%),
and 58.4% (95% CI, 49.9%66.8%) for the esomepra-
zole 40-mg, esomeprazole 20-mg, and ranitidine
groups, respectively. Comparisons of the time-to-event
curves showed that the time to rst healing of GUs
was signicantly different for esomeprazole 40 mg
and esomeprazole 20 mg compared with ranitidine,
(P = 0.047 and P = 0.002, respectively).
For the 34 patients in the efcacy analysis who had
concurrent DUs at baseline, the DU healing rates at
week 8 were 90% (nine of 10 patients) with esomep-
razole 40 mg, 68.8% (11 of 16 patients) with esomep-
razole 20 mg, and 87.5% (seven of eight patients) with
ranitidine.
Safety
The safety population included 432 patients: 140
patients in the esomeprazole 40-mg group, 145 patients
in the esomeprazole 20-mg group, and 147 patients in
the ranitidine 150-mg group. The overall percentage of
patients with AEs in this study was 56% (79 140) with
esomeprazole 40 mg, 58% (84 145) with esomeprazole
20 mg and 58% (85 147) with ranitidine 150 mg. The
number of patients with AEs considered by the site
investigator to be related to study drug was also similar
among the three treatment groups: 12 (9%) for esomep-
razole 40 mg, 13 (9%) for esomeprazole 20 mg and 10
(7%) for ranitidine 150 mg. The most commonly
reported AEs for esomeprazole 40 mg, esomeprazole
20 mg and ranitidine 150 mg were gastrointestinal and
included gastritis [22 (16%), 25 (17%) and 25 (17%)
patients, respectively], atulence [18 (13%), 27 (19%)
and 20 (14%), patients respectively], new onset or wors-
ening of existing dyspepsia [14 (10%), 19 (13%) and 18
(12%) patients, respectively], and new onset or worsen-
ing of existing nausea [17 (12%), 11 (8%) and 17 (12%)
patients, respectively].
Fourteen of the 440 randomized patients had 16
serious AEs (four patients in the esomeprazole 40-mg
group, six in the esomeprazole 20-mg group and four
in the ranitidine group), but none was the same and
none was considered related to treatment. There was
one death that occurred due to an unknown cause on
the third day of treatment with esomeprazole 20 mg;
the investigator did not consider the death to be
related to study medication. Of 440 patients, 17 (3.9%)
discontinued the study due to AEs; the number in each
treatment group was similar. There were no clinically
relevant trends in the results of laboratory tests, physi-
cal examinations or vital signs.
DI SCUSSI ON
In this study, healing rates for NSAID-associated GUs
were not signicantly different for patients treated with
esomeprazole or ranitidine who continued to receive
daily NSAID therapy. Although esomeprazole did not
differentiate signicantly from ranitidine for the pri-
mary end point after 8 weeks of treatment, it did show
numerically higher GU healing rates at 8 weeks and
signicantly higher GU healing rates than ranitidine
after 4 weeks of treatment. These qualitative ndings
did not change regardless of patient age, baseline
H. pylori status by histology, or the type of baseline
0
20
40
60
80
100
COX-2-selective
NSAID
Nonselective
NSAID
COX-2-selective
NSAID
Nonselective
NSAID
E40 (n = 133)
R150 (n = 139)
E20 (n = 138)
101/119
13/14
11/12
13/21
81/119
89/126
64/117
13/14
10/12
16/21
107/126
90/117
Week 4 Week 8
%

O
f

p
a
t
i
e
n
t
s

w
i
t
h

h
e
a
l
e
d

G
U
Figure 4. Gastric ulcer (GU) healing rates by baseline
non-steroidal anti-inammatory drug (NSAID) type. The
non-selective NSAID group includes patients who were
taking a cyclooxygenase (COX) 2selective NSAID if they
were also taking a non-selective NSAID (including low-
dose aspirin). E40, esomeprazole 40 mg once daily; E20,
esomeprazole 20 mg once daily; R150, ranitidine 150 mg
twice daily. One patient in the ranitidine 150-mg group
was not taking an NSAID before or during the study
(mITT population).
1108 J . L. GOLDSTEI N et al.
2007 AstraZeneca Pharmaceuticals LP, Aliment Pharmacol Ther 26, 11011111
NSAID that patients were taking. Comparisons of the
time-to-event curves showed that the time to rst heal-
ing of GUs signicantly favoured esomeprazole when
compared with ranitidine. These results numerically
parallel the previously reported ndings by Goldstein
et al. (2005) in a study of similar design.
17
In that
study, esomeprazole 40 or 20 mg once daily was shown
to have signicantly higher GU healing rates than rani-
tidine 150 mg twice daily for the primary end point at
8 weeks [91.5% (118 of 129), 88.4% (122 of 138) and
74.2% (98 of 132), respectively].
H. pylori status was assessed at screening using a
serologic test or rapid urease test, because a positive
H. pylori status could potentially confound the study
results by introducing an independent risk factor for
ulcers and or ulcer healing. All but one of the ran-
domized patients in this study was negative for infec-
tion with H. pylori at baseline based on these
screening tests. Subsequently, it was found that
approximately 26% of the randomized patients were
positive for infection with H. pylori at baseline, based
on histological examination of biopsy samples. Posi-
tive samples were particularly prevalent in patients
enrolled at non-US sites [78 of 193 (40%) non-US
patients were H. pylori-positive, whereas 36 of 247
(15%) US patients were H. pylori-positive]. Inclusion
of these H. pylori-positive patients may provide a
study population that more closely reects ulcers
occurring in NSAID users. H. pylori infection has been
variously reported to increase, reduce, or have no
effect on the risk of ulceration in established users of
NSAIDs,
5, 19, 20
with a null effect the conclusion of
most cohort studies.
5, 8, 21
Ulcer healing by acid
suppression has been reported to be unaffected by
H. pylori status or to be increased in H. pylori infected
NSAID users,
1315
possibly due to the lower acid out-
put that has been observed in healthy subjects infected
with H. pylori who were receiving a PPI
22
or the
higher concentrations of prostaglandin E2, seen in
H. pylori-positive patients taking NSAIDs.
23
In our
study, a clear-cut increase in ulcer healing was not
seen, possibly because the total number of H. pylori-
positive patients in this study was relatively low.
Whether ulcer healing is maintained with long-term
esomeprazole therapy in patients who continue NSAID
therapy still needs to be conrmed. In one study,
esomeprazole 40 and 20 mg once daily signicantly
lowered the risk for GU during a 6-month period in
patients at risk of developing GUs or DUs associated
with continuous use of non-selective and COX-2
selective NSAIDs.
24
Antisecretory therapy with other
PPIs has also been shown to signicantly lower the
risk for GU recurrence during periods of 312 months
in patients who continue to take NSAIDs, with or
without low-dose aspirin therapy, including patients at
a high risk for recurrence of GU.
13, 15, 2528
CONCLUSI ONS
In conclusion, in this trial, NSAID-associated GU heal-
ing was not statistically different when comparing the
use of 20 and 40 mg of esomeprazole daily with the
use of ranitidine 150 mg twice daily after 8 weeks.
However, the numerical trends favouring esomeprazole
parallel the ndings of a similarly designed trial.
17
ACKNOWLEDGEMENTS
The authors thank Pete Probst (AstraZeneca LP) for
overall study coordination; Robert Genta (Baylor
College of Medicine, Houston, TX) for histological
examination of all biopsy specimens; Clara Hwang
(AstraZeneca LP) for statistical consultation; Caroline
Spencer (Hibiscus Coast, New Zealand) for medical
writing services (funded by AstraZeneca LP); John
Tumas and Mary Wiggin (both from AstraZeneca LP)
for editorial assistance; and the patients, the study-site
staff members, and the following primary investiga-
tors: Bulgaria: Dimitar Dimitrakov, MD (Plovdiv);
Iskren Kotzev, MD (Varna); Grigor Mechkov, MD
(Soa); Mario Markov, MD (Soa); Atanas Mihov, MD
(Dimitrovgrad); Dimiter Takov, MD (Soa); Tanyu
Tanev, MD (Plovdiv); Veska Tzanova, MD (Soa);
Borislav Vladimirov, MD (Soa); Indonesia: Chudah-
man Manan, MD (Jakarta); Pengarapen Tarigan, MD
(Medan); Romania: Catalin Codreanu, MD, PhD
(Bucharest); Alexandru Fraticiu, MD (Sibiu); Lia
Georgescu, MD (Targo Mures Mures); Adrian Goldis,
MD (Timisoara); Mircea Manuc, MD (Bucharest);
Valeriu Sbarcea, MD (Craiova Dolj); Carol Stanciu,
MD (Iasi); Ukraine: Kateryna Amosova, MD (Kiev);
Anatolii Svintsitskyi, MD (Kyiv); Valeriy Vdovy-
chenko, MD, PhD (Lviv); United States: Michael Ben-
nett, MD (San Diego, CA); Magued Beshay, MD
(Mission Hills, CA); J. Scott Buckley, MD (Indianapolis,
IN); John Carrougher, MD (Tacoma, WA); Richard
Chasen, MD (Laurel, MD); Tyler Cymet, DO (Baltimore,
MD); Paul Denault, MD (Golden, CO); Steven Duckor,
MD (Orange, CA); Amin Elashker, DO (Kingston, NY);
Roy Fleischmann, MD (Dallas, TX); Syam Gaddam, MD
CLI NI CAL TRI AL: NSAI D-ASSOCI ATED GASTRI C ULCER HEALI NG 1109
2007 AstraZeneca Pharmaceuticals LP, Aliment Pharmacol Ther 26, 11011111
(Garden Grove, CA); Raul Gaona, MD (San Antonio,
TX); Alan Kivitz, MD (Duncansville, PA); James Kopp,
MD (Anderson, SC); Ronald Kotla, MD (Jackson, MS);
Richard Krause, MD (Chattanooga, TN); Steven Krum-
holz, MD (West Palm Beach, FL); Michael LeVine, MD
(Marietta, GA); David Limauro, MD (Pittsburgh, PA);
Paul Maton, MD (Oklahoma City, OK); Radman Mo-
staghim, MD, PhD (Lanham, MD); James Novick, MD
(Towson, MD); Mandeep Oberoi, MD (Elizabeth, NJ);
Larry Popeil, MD (Ocala, FL); U. Prakash Rau, MD
(Braintree, MA); Dean Rider, MD (San Francisco, CA);
Mario Rosenberg, MD (Los Angeles, CA); Gary Ros-
man, MD (Egg Harbor Township, NJ); Sanford Roth,
MD (Phoenix, AZ); Michael Schwartz, MD (Jupiter,
FL); Harry Sperber, MD (Saint Petersburg, FL); John
Stoker, MD (Flint, MI); Mordo Suchov, MD, (Los Ange-
les, CA); Michael Weitz, MD (South Miami, FL); Wil-
liam Williams, III, MD (Pensacola, FL); Marc
Zuckerman, MD (El Paso, TX); Matthew Cohen, MD
(Hamden, CT); Dale Merrell, MD (Jacksonville, FL);
John Poulos, MD (Fayetteville, NC); Michael Safdi, MD
(Cincinnati, OH); Mark Ringold, MD (Christiansburg,
VA); Jose Hurtado, MD (Tucson, AZ); Manuel Rodri-
guez, MD (Bradenton, FL); Jay Beckwith, MD (Fort
Worth, TX); Christopher Forsmark, MD (Gainesville,
FL); Peter Meier, MD (Minneapolis, MN); Donald Bran-
don, MD (San Diego, CA); Peter Winkle, MD, FACP
(Cypress, CA); Bradley Freilich, MD (Kansas City, MO);
Eric Jay Goldberg, MD (West Palm Beach, FL); Umed-
chandra Shah, MD, FACG, FACP (Hollywood, MD);
and Louis Salas, MD (Baltimore, MD). Declaration of
personal interests: Jay L. Goldstein has served as a
speaker, a consultant and or an advisory board mem-
ber for AstraZeneca, Pzer, TAP, Novartis, Pozen,
Takeda, and Sucampo. John F. Johanson has served
as: a speaker for Novartis, Sucampo, and Takeda
Pharmaceuticals North America; as a consultant for
Boehringer Ingelheim, GlaxoSmithKline, Microbia,
Prometheus, Salix, Schering Plough, Sucampo, Takeda
Pharmaceuticals North America, and Theravance; and
has stock options with Sucampo. Lisa J. Suchower and
Kurt A. Brown are employees of AstraZeneca LP. Ini-
tial data analyses were undertaken by Lisa J. Suchower
who is an employee of AstraZeneca LP. Drs. Goldstein,
Johanson, and Hawkey participated actively in data
analysis, writing of the paper, and read and approved
the nal version. Declaration of funding interests: Jay
L. Goldstein has received research funding from Astra-
Zeneca, Pzer, TAP, Novartis, Pozen, Takeda, Su-
campo, Given, and GlaxoSmithKline. Christopher J.
Hawkey has received research funding and or com-
pensation for services from AstraZeneca, Bayer, Take-
da, and Merck Serono. This study was funded in full
by AstraZeneca LP, Wilmington, DE (AstraZeneca code
SH-NEN-0006 Study 286). The preparation of this
paper was funded in part by AstraZeneca LP.
Previous Presentations Publications: Goldstein Jay
L, Johanson John, Hawkey Chris, Suchower Lisa,
Levine Doug. The Comparative Healing of Gastric
Ulcers with Esomeprazole Versus Ranitidine in Patients
Taking Either Continuous COX-2 Selective NSAIDs or
Nonselective NSAIDs. Gastroenterology 2004; 126 (4;
Suppl 2): Abstract W 1310. Page A-610.
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