GASTROENTEROLOGY 2004;127:1038 1043

CLINICALALIMENTARY TRACT
Celecoxib Versus Diclofenac Plus Omeprazole in High-Risk
Arthritis Patients: Results of a Randomized Double-Blind Trial
FRANCIS K. L. CHAN,* LAWRENCE C. T. HUNG,* BING Y. SUEN, VINCENT W. S. WONG,*
ARIC J. HUI,* JUSTIN C. Y. WU,* WAI K. LEUNG,* YUK T. LEE,* KA F. TO,
S. C. SYDNEY CHUNG, and JOSEPH J. Y. SUNG
Departments of *Medicine and Therapeutics, Surgery, and Anatomical and Cellular Pathology, Prince of Wales Hospital,
The Chinese University of Hong Kong, Hong Kong

See editorial on page 1256.

Background & Aims: The gastric safety of cyclooxgenase-2 inhibitors and prophylactic antisecretory therapy in high-risk arthritis patients is unclear. We studied the ulcer incidence and factors predicting ulcer
recurrence in a prospective, double-blinded trial.
Methods: We studied patients who presented with
nonsteroidal anti-inammatory drug-associated ulcer
bleeding. After ulcer healing, patients who were negative for Helicobacter pylori were randomly assigned
to celecoxib 200 mg twice a day plus omeprazole
placebo once daily or diclofenac 75 mg twice daily
plus omeprazole 20 mg once daily for 6 months.
Patients underwent endoscopy if they developed recurrent bleeding. Those without recurrent events underwent endoscopy at their last follow-up visit.
Results: Two hundred eighty-seven patients were enrolled; 24 had recurrent gastrointestinal complications. Among 259 patients without events, 222 underwent endoscopy (116 received celecoxib and 106
received diclofenac plus omeprazole). The probability
of recurrent ulcers in 6 months was 18.7% in the
celecoxib group and 25.6% in the diclofenac plus
omeprazole group (difference, 6.7%; 95% CI:
17.8% to 3.9%) (P 0.21). Combining bleeding and
endoscopic ulcers, 24.1% in the celecoxib group and
32.3% in the diclofenac plus omeprazole group had
recurrent ulcers in 6 months (difference, 8.2%; 95%
CI: 19.5% to 2.9%) (P 0.15). Treatment-induced
signicant dyspepsia (hazard ratio, 5.3; 95% CI: 2.6
10.8), age >75 (hazard ratio, 2.0; 95% CI: 1.13.5),
and comorbidity (hazard ratio, 2.1; 95% CI: 1.2
3.7) independently predicted ulcer recurrence.
Conclusions: Among patients with previous ulcer
bleeding, neither celecoxib nor diclofenac plus omeprazole adequately prevents ulcer recurrence. Treatment-induced signicant dyspepsia is an indication
for endoscopic evaluation.

astrointestinal (GI) toxicity of nonsteroidal antiinflammatory drugs (NSAIDs) is a global health

care problem. In the United States, NSAIDs account
for about 25% of all reported adverse drug reactions.
The annual cost of treating NSAID-associated GI
adverse events exceeds 4 billion dollars.1,2 Current
strategies of preventing NSAID-associated ulcer include prophylactic treatment with a proton pump
inhibitor (PPI) or substitution of NSAIDs with cyclooxygenase (COX)-2 inhibitors. There is good evidence
that these treatments effectively prevent gastroduodenal ulcers35 and, in some studies, reduce clinical GI
events.6,7 The updated American College of Rheumatology Guidelines for the management of osteoarthritis recommends prophylactic co-therapy or COX-2
inhibitors in patients at risk for ulcer disease.8
Patients with a history of ulcer bleeding who use
NSAIDs belong to the highest risk category.9 However,
whether co-therapy with a PPI or substitution for a
COX-2 inhibitor can protect high-risk patients from
ulcer complications is unclear. In a prospective, doubleblinded, randomized comparison of celecoxib vs. diclofenac plus omeprazole in patients with a recent episode of
ulcer bleeding, we previously reported that about 5% of
patients in each group still had recurrent ulcer bleeding
in 6 months.10 However, 2 issues remained unresolved.
First, the result of this study raises doubt about the
gastric protective effect of these 2 treatments in patients
with prior ulcer bleeding.11 Second, factors predicting
treatment failure in these high-risk patients are unknown.

Abbreviations used in this paper: NSAIDs, nonsteroidal anti-inammatory drugs; PPI, proton pump inhibitor.
2004 by the American Gastroenterological Association
0016-5085/04/$30.00
doi:10.1053/j.gastro.2004.07.010

October 2004

To evaluate further the gastric safety of COX-2 inhibitors or prophylactic PPIs in high-risk patients, we prospectively assessed the overall incidence of ulcers and
factors predicting ulcer recurrence in a prospective, double-blinded study comparing celecoxib and diclofenac
plus omeprazole in patients with arthritis and prior ulcer
bleeding.10 Although the previous study assessed the
incidence of recurrent ulcer bleeding,10 we performed
follow-up endoscopy on patients who had no recurrent
GI complications at their last visit. Endoscopic evaluation of recurrent ulcers at the termination of the study
was one of the prespecified endpoints. We anticipated
that the incidence of ulcers would be low if celecoxib or
diclofenac plus omeprazole conferred adequate gastric
protection in high-risk patients.

Materials and Methods

Study Population and Setting
We screened consecutive patients with arthritis who
presented with ulcer bleeding while receiving NSAIDs to the
Endoscopy Center of Prince of Wales Hospital at The Chinese
University of Hong Kong. The inclusion criteria were ulcer
healing confirmed on follow-up endoscopy, a negative test for
Helicobacter pylori or successful eradication of Helicobacter pylori
based on histology, and anticipated regular use of NSAIDs for
the duration of the trial. The exclusion criteria were concomitant use of anticoagulants or corticosteroids, a history of
gastric or duodenal surgery other than a patch repair, the
presence of erosive esophagitis, gastric outlet obstruction, renal
failure (defined by a serum creatinine level of more than
2.26 mg per deciliter), terminal illness, or cancer.

Study Design
The protocol was approved by the Clinical Trial Ethics
Committee of The Chinese University of Hong Kong. All
participants provided written informed consent. After ulcer
healing, we randomly assigned patients who were negative for
H. pylori infection to celecoxib 200 mg twice daily plus
omeprazole placebo daily or diclofenac 75 mg twice daily plus
omeprazole 20 mg daily for 6 months in a double-blinded
fashion as previously described.10 Randomization was carried
out through the use of a computer-generated list of random
numbers. Concealed allocation was achieved by an independent staff, who assigned treatments according to consecutive
numbers in sealed envelopes.

Monitoring
After randomization, the patients were contacted by
telephone at month 1, and they returned to the Endoscopy
Center at month 2 and every 2 months thereafter until the end
of the study. At each visit, hemoglobin levels, serum biochemical values, drug compliance, efficacy, dyspeptic symptoms,
and other adverse events were assessed. Dyspepsia was defined

CELECOXIB VS. DICLOFENAC PLUS OMEPRAZOLE

1039

as upper abdominal pain or discomfort. We classified the

severity of dyspepsia as absent, minimal (easily tolerated), or
significant (interfering with normal activities). Drug compliance was assessed by pill counts. Patients were permitted to
take antacids; paracetamol; non-NSAID analgesics; and disease-modifying, antirheumatic drugs. Nonstudy NSAIDs (except for low-dose aspirin up to 325 mg daily), misoprostol,
histamine H2-receptor antagonists, sucralfate, and proton
pump inhibitors were prohibited during the study.

Outcomes
Patients who were suspected to have recurrent GI
bleeding according to prespecified criteria underwent endoscopy.10 Patients without recurrent GI complications within
the study period were invited to undergo follow-up endoscopic
evaluation at their last follow-up visit. A single endoscopist
performed all endoscopic examinations in a treatment-blinded
fashion to avoid between-observer variation. The end point was
recurrent gastric or duodenal ulcer. An ulcer was defined as a
circumscribed mucosal break that was at least 0.5 cm in
diameter and had a perceptible depth. The location of ulcers
was recorded according to prespecified regions of the stomach
(cardia, fundus, greater curvature, lesser curvature, angular
incisura, antrum, and pylorus) and the duodenum (first part,
junction of first and second parts, second part, and beyond
second part). Biopsy specimens were taken from the margin of
gastric ulcers to exclude malignancy and from the antrum and
the corpus to detect any recurrent H. pylori infection based on
histology. Treatment codes remained unbroken throughout
the study and an independent data review committee analyzed
the results.

Statistical Analysis
Sample size estimation was based on the hypothesis of
noninferiority between 2 treatments as previously described.10
We used the KaplanMeier method to estimate the likelihood
of reaching the end point of gastroduodenal ulcers within
6 months, based on the modified intention-to-treat population, defined as patients who had taken at least 1 dose of study
drugs and had undergone follow-up endoscopy at their last
visit. The log-rank test was used for between-treatment comparisons. A Cox proportional-hazards model with backward
stepwise regression was used to identify possible covariates as
significant (P 0.05) predictors of recurrent ulcer, which
included age (below or 75 years), treatment assignment
(celecoxib or diclofenac plus omeprazole), the presence or
absence of comorbidity (including ischemic heart disease, heart
failure, stroke, cirrhosis, chronic obstructive airway disease,
renal diseases, and diabetes with renal and vascular complications), concomitant use of low-dose aspirin, smoking, location
of ulcers (stomach or duodenum), diameter of the ulcer
(smaller than or 2 cm), and severity of treatment-induced
dyspepsia (absent/minimal or significant), which may predict
ulcer recurrence (SPSS 10.0, SPSS Inc., Chicago, IL). All P
values and 95% CI are 2-sided.

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CHAN ET AL.

GASTROENTEROLOGY Vol. 127, No. 4

Table 1. Baseline Characteristics of the Patients

Characteristic
Male sex, no. (%)
Age, yr
Current smoking, no. (%)
Current drinking, no. (%)
Location of ulcers at index bleeding, no. (%)
Gastric ulcer
Duodenal ulcer
Gastric and duodenal ulcers
Patients with more than 1 episode of ulcer bleeding, no. (%)
Size of ulcer, cm
Size of ulcer 2 cm, no. (%)
Ulcers with active bleeding or nonbleeding visible vessels, no. (%)
Transfusion required, no. (%)
Types of arthritis, no. (%)
Osteoarthritis
Rheumatoid arthritis
Others
Comorbidity, no. (%)a
Serum creatinine 1.2 mg/dL, no. (%)
Minimal dyspepsia at baseline, no. (%)
Concomitant use of low-dose aspirin, no. (%)
Previous H. pylori infection, no. (%)

Celecoxib group
(n 116)

Diclofenac plus
omeprazole group
(n 106)

54 (46.6)
65.3 (14.6)
13 (11.2)
13 (11.2)

52 (49.1)
68 (12.8)
17 (16.0)
9 (8.4)

68 (58.6)
43 (37.1)
5 (4.3)
24 (20.7)
1.0 0.8
19 (16.4)
33 (28.4)
53 (45.7)

55 (51.9)
41 (38.7)
10 (9.4)
23 (21.7)
1.0 0.7
19 (17.9)
25 (23.6)
41 (38.7)

98 (84.4)
5 (4.3)
13 (11.2)
34 (39.3)
25 (21.6)
7 (4.9)
6 (5.2)
68 (41.4)

93 (87.8)
1 (0.9)
12 (11.3)
30 (28.3)
20 (18.9)
1 (0.7)
13 (12.3)
62 (58.5)

NOTE. Plus-minus values are means SD.

included ischemic heart disease, heart failure, stroke, cirrhosis, chronic obstructive airway disease, renal diseases, and diabetes
with renal and vascular complications.
aComorbidity

Results
A total of 287 patients were enrolled. Twentyfour patients developed recurrent GI bleeding; 7 in the
celecoxib group and 9 in the diclofenac plus omeprazole
group were adjudicated to have recurrent ulcer bleeding
according to prespecified criteria.10 Among patients with
recurrent ulcer bleeding, 3 used concomitant low-dose
aspirin (1 in the celecoxib group and 2 in the diclofenac
plus omeprazole group), and 1 who received diclofenac
plus omeprazole had relapse of H. pylori infection. Eighteen patients used herbal products of unknown composition during the study period; 1 had recurrent ulcer
bleeding. One patient in the celecoxib group died of
lung cancer, and 1 patient in the diclofenac plus omeprazole group died of small-bowel perforation. One patient in each group was lost to follow-up.10
Two hundred fifty-nine patients did not have recurrent GI complications. Two hundred twenty-two patients (86%) gave consent to follow-up endoscopy at
their last visit. There was no significant difference in the
baseline characteristics between those who did and those
who did not allow repeat endoscopy (age: 66.6 vs. 70.7
years, P 0.09; male sex: 47.7% vs. 37.8%, P 0.26;
dyspepsia: 3.6% vs. 0%, P 0.61; osteoarthritis: 86.0%
vs. 94.6%, P 0.60; comorbidity: 28.8% vs. 21.6%,
P 0.37, respectively). One hundred sixteen patients in

the celecoxib group and 106 in the diclofenac plus

omeprazole group had repeated enodscopy. The 2 groups
were comparable in terms of their baseline demographics. There was numeric imbalance in the number of
patients receiving concomitant low-dose aspirin (5.2% in
the celecoxib group vs. 12.3% in the diclofenac plus
omeprazole group, P 0.06) and the presence of minimal dyspepsia at baseline (4.9% in the celecoxib group
vs. 0.7% in the diclofenac plus omeprazole group, P
0.07), but the differences did not reach statistical significance (Table 1). The median follow-up was 6 months
(range, 0.5 6). Twelve patients had recurrent H. pylori
infection at the end of the study period: 6 (5.2%) in the
celecoxib group and 6 (5.7%) in the diclofenac plus
omeprazole group. Rates of early withdrawal were similar in the 2 groups: 5.1% in the celecoxib group (3.4%
because of adverse events and 1.7% because of a lack of
efficacy) and 6.6% in the omeprazole group because of
adverse events. Ninety-four percent of patients in the 2
treatment groups took at least 70% of the study drugs.
Twenty patients receiving celecoxib and 26 receiving
diclofenac plus omeprazole had recurrent ulcers on follow-up endoscopy (P 0.18). The median diameter of
recurrent ulcers was 0.5 cm (range, 0.53.0 cm) in both
groups. Among the 46 patients with recurrent ulcers, 2
(4.3%) had relapse of H. pylori infection (1 received

October 2004

CELECOXIB VS. DICLOFENAC PLUS OMEPRAZOLE

Figure 1. KaplanMeier estimates of the cumulative probabilities of

recurrent ulcer in the celecoxib group and the omeprazole plus diclofenac group. There was no significant difference between the 2 treatment groups.

celecoxib and 1 received diclofenac plus omeprazole), and

7 (15.2%) used concomitant aspirin (3 in the celecoxib
group and 4 in the diclofenac plus omeprazole group).
None of the patients who used herbal products had
recurrent endoscopic ulcers. The probability of recurrent
ulcers in 6 months was 18.7% (95% CI: 11.3%26.1%)
in patients receiving celecoxib and 25.6% (95% CI:
17.1%34.1%) in patients receiving diclofenac plus omeprazole (difference, 6.7%; 95% CI for the difference:
17.8%3.9%, log-rank test, P 0.21) (Figure 1). Using
a combined end point of bleeding ulcers and endoscopic
ulcers in the intention-to-treat population of 246 patients, the probability of recurrent ulcers in 6 months
was 24.1% (95% CI: 16.3%31.8%) in the celecoxib
group and 32.3% (95% CI: 23.7% 40.9%) in patients
receiving diclofenac plus omeprazole (difference, 8.2%;
95% CI for the difference: 19.5%2.9%, log-rank test,
P 0.15).
Of the 203 patients who did not use concomitant
low-dose aspirin, 17 in the celecoxib group and 22 in the
diclofenac plus omeprazole group had recurrent ulcers on
follow-up endoscopy. The probability of recurrent ulcers

1041

in 6 months was 16.9% (95% CI: 9.6%24.2%) in

patients receiving celecoxib and 24.6% (95% CI:
15.7%33.6%) in patients receiving diclofenac plus
omeprazole (difference, 7.7%; 95% CI for the difference: 19.3%3.3%, log-rank test, P 0.17). Combining bleeding ulcers and endoscopic ulcers, the probability of recurrent ulcers in 6 months was 21.2% (95%
CI: 13.5%28.9%) in the celecoxib group and 30.8%
(95% CI: 21.8%39.9%) in patients receiving diclofenac
plus omeprazole (difference, 9.6%; 95% CI for the
difference: 21.1%1.9%, log-rank test, P 0.10).
Eight patients (3.6%) had minimal dyspepsia before they
started treatment; 3 (37.5%) of them compared with 43
(20.1%) of 214 patients without dyspepsia at baseline had
recurrent ulcers (P 0.37). One hundred ninety-eight
patients (89%) experienced no or minimal dyspepsia during
the study period (100 in the celecoxib group and 98 in the
diclofenac plus omeprazole group). Among them, 35 (18%)
had silent ulcers recurring in 6 months (13 in the celecoxib
group and 22 in the diclofenac plus omeprazole group).
Twenty-four patients (11%) developed significant dyspepsia
on therapy within the study period (16 in the celecoxib
group and 8 in the diclofenac plus omeprazole group); 11 of
them (46%) had symptomatic ulcers recurring in 6 months
(7 in the celecoxib group and 4 in the diclofenac plus
omeprazole group) (Fisher exact test, P 0.003 vs. 18% of
patients with no or minimal dyspepsia had silent ulcers;
odds ratio 3.9, 95% CI: 1.6 9.2).
In the Cox proportional hazards model using backward
stepwise regression, treatment-induced significant dyspepsia, age 75 years, and comorbidity were independent risk
factors predicting ulcer recurrence (Table 2).

Discussion
We studied the overall incidence of ulcers to
evaluate the gastric safety of long-term treatment with
celecoxib or diclofenac plus omeprazole in very high-risk
patients, i.e., those with a recent episode of ulcer bleeding. Among patients without recurrent gastrointestinal

Table 2. Analysis of Possible Risk Factors Predicting Ulcer Recurrence Using the Cox Model
Multivariate analysis
Covariates

Univariate analysis
P value

Hazard ratio (95% CI)

P value

Treatment-induced significant dyspepsia

Age 75 yr
Comorbidity
Treatment assignment
Concomitant low-dose aspirin
Smoking
Location of ulcers (gastric ulcer)
Diameter of ulcer 2 cm

0.003
0.016
0.018
0.181
0.080
0.119
0.011
0.070

5.3 (2.6 to 10.8)

2.0 (1.1 to 3.5)
2.1 (1.2 to 3.7)
1.8 (0.97 to 3.23)
1.5 (0.6 to 3.9)
0.5 (0.2 to 1.8)
1.7 (0.8 to 3.6)
1.5 (0.8 to 3.0)

0.001
0.022
0.014
0.059
0.435
0.300
0.131
0.247

1042

CHAN ET AL.

complications within the study period, the incidence of

recurrent gastroduodenal ulcers was unexpectedly high:
19% of patients receiving celecoxib and 26% of patients
receiving diclofenac plus omeprazole had recurrent ulcers
in 6 months. Combining bleeding ulcers and endoscopic
ulcers, the 6-month incidence of recurrent ulcers was
24% in the celecoxib group and 32% in the diclofenac
plus omeprazole group. Neither relapse of H. pylori infection nor concomitant use of herbal products could
account for the high rate of ulcer recurrence. Our findings therefore indicate that neither treatment adequately
protects high-risk patients from ulcer recurrence. Treatment-induced significant dyspepsia, age 75 years, and
coexisting medical conditions independently predict
treatment failure.
Endoscopic ulcer has been widely used as a surrogate
for clinical events in the evaluation of different strategies
for the prevention of NSAID-induced ulcers. In general,
there is reasonable correlation between endoscopic and
clinical outcome studies. However, results derived from
average-risk subjects may not be generalized to high-risk
patients. Previous endoscopic studies have repeatedly
shown that prophylactic treatment with a PPI or substitution for a COX-2 inhibitor alone effectively prevents
gastroduodenal ulcers. In a randomized, placebo-controlled trial of omeprazole for the prevention of NSAIDinduced ulcer, 4.7% (18.8 per 100 patient-years) of
patients receiving omeprazole compared with 16.7%
(66.8 per 100 patient-years) of patients receiving placebo
developed ulcers in 3 months.12 Other studies reported
that COX-2 inhibitors caused minimal gastroduodenal
damage that was comparable with placebo.13,14 In one
study, the 12-week incidence of ulcer (5 mm in diameter) was 5.5% (22 per 100 patient-years) in the rofecoxib group and 8.2% (32.8 per 100 patient-years) in the
placebo group.13 In another study, the 12-week incidence of ulcer was 4% (16 per 100 patient-years) both in
celecoxib group and the placebo group.14 A note of
caution is that the vast majority of patients in previous
endoscopic studies did not have prior ulcer complications. Unlike previous studies, our finding indicates that
the rate of ulcers in high-risk patients (48 to 62 per 100
patient-years) who received celecoxib or diclofenac plus
omeprazole is about 3 times more frequent than that of
low-risk subjects (16 to 22 per 100 patient-years). Thus,
prophylactic treatment with a PPI or substitution for a
COX-2 inhibitor alone effectively prevents gastroduodenal ulcers in average-risk but not high-risk patients.
Another interesting observation in this study is that
treatment-induced significant dyspepsia (i.e., symptoms
interfering with normal activities) predicts recurrent gastroduodenal ulcers in high-risk patients. Recurrent ulcer

GASTROENTEROLOGY Vol. 127, No. 4

occurred in 46% of patients with significant dyspepsia on

therapy as compared with only 18% of patients with no
or mild dyspepsia on therapy. Unlike high-risk patients,
dyspepsia correlates poorly with the occurrence of gastroduodenal ulcers in average-risk subjects receiving
NSAIDs, such that the optimal management of NSAIDassociated dyspepsia remains unclear.15 Our findings suggested that endoscopic evaluation is warranted in patients with a history of ulcer complications who
experience significant dyspepsia while receiving COX-2
inhibitors or co-therapy with a PPI. Early detection of
recurrent ulcers might prevent progression to ulcer complications in some of these high-risk patients.
Our study had limitations. First, concurrent use of
low-dose aspirin is known to increase the risk of ulcers
in patients receiving conventional or COX-2 selective
NSAIDs.16,17 In this study, concomitant low-dose aspirin
was found in about 15% of all patients with recurrent
ulcers. However, the number of patients using low-dose
aspirin was very small so that any definite effect of
low-dose aspirin on the risk of ulcer would not be
apparent. Likewise, the number of smokers was too small
to assess its true effect on ulcer recurrence. Alternatively,
the patients in this study were already at very high risk
of ulcer recurrence so that the deleterious effect of smoking might not be apparent. Second, the absolute difference between the 2 treatments was 8.2 percentage points
in terms of recurrent bleeding and endoscopic ulcers.
Although the difference did not reach statistical significance, the lower bound of the 95% confidence interval
for the difference in ulcer rates was 19.5%. This finding suggested that there might be a nonsignificant trend
in favor of celecoxib that would require a much larger
study to demonstrate.
In summary, among patients with prior ulcer bleeding
who require long-term regular NSAIDs, treatment with
celecoxib or diclofenac plus omeprazole causes a high
incidence of recurrent gastroduodenal ulcers. The development of significant dyspepsia on therapy is an indication for further endoscopic evaluation. Current guidelines on the management of arthritis patients at high risk
of ulcer complications need to be critically reconsidered.

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Received March 12, 2004. Accepted June 24, 2004.

Address requests for reprints to: Francis K. L. Chan, M.D., Department of Medicine and Therapeutics, Prince of Wales Hospital, 30-32
Ngan Shing Street, Shatin, Hong Kong SAR. e-mail: fklchan@
cuhk.edu.hk; fax: (852) 2637 3852.
Supported by a research grant from the Health Services Research
Committee of Hong Kong (HSRC S111009).
Dr. Francis Chan received a consulting fee from Pzer in 2002.
The authors thank Albert Cheung of the Center of Clinical Trials and
Epidemiological Research at The Chinese University of Hong Kong for
statistical advice, Jessica Ching and M.Y. Yung for data review, and the
nursing staff of the Endoscopy Center at the Prince of Wales Hospital
for their generous support.