Original Paper
Digestion 2015;91:37–41
DOI: 10.1159/000368810
Time Trends of the Impact of Helicobacter pylori
Infection and Nonsteroidal Anti-Inflammatory
Drugs on Peptic Ulcer Bleeding in Japanese
Patients
Tomohiro Nagasue a Shotaro Nakamura b Shuji Kochi a Koichi Kurahara a
Hiroki Yaita a Keisuke Kawasaki a Tadahiko Fuchigami a
a
Division of Gastroenterology, Matsuyama Red Cross Hospital, Matsuyama, and b Department of R/D for Surgical
Support System, Center for Advanced Medical Innovation, Kyushu University, Fukuoka, Japan
Key Words
Peptic ulcer bleeding · Helicobacter pylori · Nonsteroidal
anti-inflammatory drugs · Antithrombotic agents
Abstract
Background/Aims: Helicobacter pylori infection and the use
of nonsteroidal anti-inflammatory drugs (NSAIDs) are the
main causes of peptic ulcers. The purpose of the present
study was to elucidate the time trends of the impact of H.
pylori infection and use of NSAIDs and/or antithrombotic
agents on peptic ulcer bleeding (PUB) in Japanese patients.
Methods: We retrospectively reviewed 719 patients who
had received endoscopic hemostasis for PUB between 2002
and 2013. Subjects were divided into either the first-half
group (2002–2007, n = 363) or the second-half group (2008–
2013, n = 356). The clinical characteristics of the patients,
including the prevalence of H. pylori infection and use of
NSAIDs and antithrombotic agents, were compared be-
tween the two groups. Results: Compared to the first-half
group, patients in the second-half group were characterized
by older age (proportion of the patients above 60 years old,
63.9 vs. 76.7%, p = 0.0002), less frequent H. pylori infection
(71.6 vs. 57.9%, p < 0.001) and more frequent NSAID intake
(39.9 vs. 48.6%, p = 0.02). No significant difference was ob-
served regarding the use of antithrombotic agents between
© 2015 S. Karger AG, Basel
0012–2823/15/0911–0037$39.50/0
E-Mail karger@karger.com
www.karger.com/dig
Published online: January 20, 2015
the two groups (18.6 vs. 23.3%, p = 0.13). The prevalence of
H. pylori infection and proportion of patients above 60 years
old were significantly different between the two groups in a
multivariate analysis. Conclusion: The main cause of PUB has
clearly shifted from H. pylori infection to the use of NSAIDs
over the last decade. © 2015 S. Karger AG, Basel
Introduction
Peptic ulcer is one of the most common causes of gas-
trointestinal bleeding, which is occasionally associated
with hospitalization and mortality. It has been demon-
strated that Helicobacter pylori infection and the use of
nonsteroidal anti-inflammatory drugs (NSAIDs) are the
main causes of peptic ulcers [1, 2]. In a study from Spain
in 2004, H. pylori infection was recognized in 87% of pa-
tients with gastric ulcers and 96% of patients with duode-
nal ulcers [3]. In recent years, however, the prevalence of
H. pylori infection has been decreasing due to the im-
provement in hygienic conditions and widespread adop-
tion of eradication therapy [1, 4]. Accordingly, the inci-
dence of peptic ulcer has also decreased both in Western
countries [5, 6] and in Japan [4]. By contrast, the use of
NSAIDs and antithrombotic agents has recently been ris-
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Univ. of California San Diego
Tomohiro Nagasue, MD
Division of Gastroenterology
Matsuyama Red Cross Hospital
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1 Bunkyo-cho, Matsuyama-shi, Ehime 790-8524 (Japan)
E-Mail sue.0306 @ matsuyama.jrc.or.jp
ing because of the increase in the elderly population [1].
The use of NSAIDs is associated with an increased risk of
major upper gastrointestinal complications, including
bleeding and perforation [7].
Peptic ulcer bleeding (PUB) is one of the most impor-
tant disease presentations in the emergency department
[8]. H. pylori infection and NSAID use are also consid-
ered to be the two major causes of PUB [1, 9]. However,
there are limited data regarding the chronological chang-
es of the prevalence of H. pylori infection and concomi-
tant use of NSAIDs and antithrombotic agents in patients
with PUB [1, 10, 11]. In the present study, we retrospec-
tively analyze the time trends of H. pylori infection and
concomitant use of NSAIDs and antithrombotic agents
in Japanese patients with PUB.
Patients and Methods
Patients
From January 2002 to December 2013, 719 consecutive Japa-
nese patients received endoscopic hemostasis for PUB at Mat-
suyama Red Cross Hospital, Ehime Prefecture, Japan. Endoscopic
hemostasis was performed with one of the following techniques:
argon-plasma coagulation, high-frequency coagulation with he-
mostatic forceps, local injection of ethanol or hypertonic saline-
epinephrine, or hemostatic clipping. The choice of these methods
depended on the endoscopist. The demographic data of each pa-
tient were retrospectively obtained by chart reviews. The data on
admission included gender, age, the number of patients with gas-
tric ulcer or duodenal ulcer, hemoglobin levels and H. pylori infec-
tion rate, and the relative numbers of NSAIDs, antithrombotic
agents, histamine 2 receptor antagonists (H2RA) and proton
pump inhibitors (PPI) used.
H. pylori infection was investigated by the 13C urea breath test,
serum H. pylori IgG antibody and/or the culture of H. pylori from
gastric mucosal biopsy samples. We defined H. pylori status as pos-
itive when at least one of these tests showed positive results, and as
negative when the breath test and/or serology showed negative re-
sults. NSAID users were defined as patients who took low-dose-
aspirin (LDA) and/or nonaspirin NSAIDs (NANSAIDs) such as
loxoprofen and diclofenac. Similarly, antithrombotic agent users
were defined as patients who took anticoagulants (warfarin or dab-
igatran) and/or antiplatelet agents other than LDA (ticlopidine,
clopidogrel, cilostazol, etc.).
The patients were divided into either the first-half group
(2002–2007, n = 363) or the second-half group (2008–2013, n =
356). We compared the clinical characteristics between the two
groups, including H. pylori status and intake of NSAIDs, anti-
thrombotic agents, H2RA and PPI.
Statistical Analysis
Parametric data were expressed as the mean ± SD (range), and
compared between the groups using the Student t test. Nonparamet-
ric data were expressed as frequencies and compared among the
groups using the χ2 test. All variables that were assumed to be associ-
38 Digestion 2015;91:37–41
DOI: 10.1159/000368810
90
80
70
60
Patients (n)
50
40
30
20
10
0
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
First-half group (n = 363) Second-half group (n = 356)
Year
Fig. 1. Annual changes in the number of the patients with PUB.
ated with PUB (p < 0.05) were entered into a multivariate logistic
regression analysis. All statistical analyses were performed using JMP
statistical software (version 8; SAS Institute, Cary, N.C., USA). A p
value <0.05 was considered to be statistically significant for each test.
Results
Annual Change in the Number of Patients with PUB
Figure 1 indicates the annual number of patients with
PUB from 2002 to 2013. The annual number ranged from
33 to 89 cases, and the mean number was 59.9 cases per
year. There was no major change in the last 12 years at our
institution.
Annual Prevalence of H. pylori Infection and
Concomitant Use of NSAIDs and Antithrombotic
Agents in Patients with PUB
Figure 2 shows the annual prevalence of H. pylori infec-
tion and the concomitant use of NSAIDs and antithrom-
botic agents in patients with PUB. The rate of H. pylori
infection seemed to be decreasing year by year. Converse-
ly, the rate of NSAID users gradually increased until 2011,
but thereafter also decreased. There were no significant
changes in the user rate of antithrombotic agents.
Comparison between the First-Half Group and the
Second-Half Group
Table 1 indicates univariate analysis for the compari-
son of the clinical characteristics between the first-half
group and the second-half group. The proportion of pa-
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 Table 1. Comparison of clinical features between the first-half and
% the second-half groups
100 H. pylori
90 NSAIDs
First-half group Second-half p
Antithrombotic agents
80 (n = 363) group value
70 (n = 356)
60
Male/female 251/112 233/123 0.29
50
Age ≥60 years 232 (63.9) 273 (76.7) 0.0002
40
Gastric ulcer/duodenal
30
ulcer 264/99 265/91 0.6
20 Hemoglobin on
10 admission, g/dl 9.2 ± 3.0 8.8 ± 2.9 0.17
0 H. pylori infection 260 (71.6) 206 (57.9) <0.001
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Concomitant drugs
Year
NSAIDs 146 (39.9) 173 (48.6) 0.02
NANSAIDs 98 (27.0) 132 (37.1) 0.004
LDA 57 (15.7) 62 (17.4) 0.54
Fig. 2. Annual prevalence of H. pylori infection and concomitant
Antithrombotic agents 68 (18.6) 83 (23.3) 0.13
use of NSAIDs and antithrombotic agents in patients with PUB.
Antiplatelet 29 (8.0) 46 (12.9) 0.04
Anticoagulant 43 (11.8) 40 (11.2) 0.8
Both NSAIDs and
antithrombotics 34 (9.4) 52 (14.6) 0.03
tients above 60 years of age was significantly increased in H2RA 39 (10.7) 25 (7.0) 0.08
PPI 6 (1.7) 18 (5.1) 0.01
the second-half group compared with the first-half group
(63.9 vs. 76.6%, p = 0.0002). The prevalence of H. pylori Data are presented as mean ± SD, or n with percentage in pa-
infection was significantly lower in the second-half group rentheses.
(57.9%) than the first-half group (71.6%, p < 0.001). The
NSAID intake rate was higher in the second-half group
(48.6%) than the first-half group (39.9%, p = 0.02). Among
NSAID users, the rate of NANSAID use was significantly Table 2. Multivariate logistic regression analysis of independent
higher in the second-half group than in the first-half group factors predictive of the incidence of PUB between the first-half
(p = 0.004), while the number of LDA users did not differ and second-half groups
between the two groups. Among NANSAID users, 6 pa-
Parameter Odds ratio 95% CI p value
tients in the second-half group were administered selec-
tive cyclooxygenase-2 (COX-2) inhibitor, while no pa- Age ≥60 years 1.51 1.07 – 2.14 0.018
tients in the first-half group received COX-2. Five patients H. pylori infection 0.68 0.49 – 0.96 0.026
were administered only selective COX-2 inhibitor, and 1 NANSAIDs 1.26 0.89 – 1.78 0.193
Antiplatelets 1.39 0.75 – 2.58 0.293
patient both selective COX-2 inhibitor and other NAN-
Both NSAIDs and
SAIDs. There were no patients who were administered antithrombotics 1.11 0.62 – 1.99 0.728
both selective COX-2 inhibitor and antithrombotic agents. PPI 2.29 0.89 – 5.95 0.088
The rates of antithrombotic agent use also did not dif-
fer between the two groups (p = 0.13). Among these pa-
tients, the rate of antiplatelet use was significantly higher
in the second-half group than in the first-half group (p = above 60 years old (odds ratio 1.51, 95% CI 1.07–2.14,
0.04). Furthermore, the rate of use of both NSAIDs and p = 0.018) were significantly different between the two
antithrombotic agents was significantly higher in the sec- groups.
ond-half group than in the first-half group (p = 0.03).
Other factors, such as gender and the rate of H2RA use,
did not differ, while PPI users were more frequent in the Discussion
second-half group than the first-half group (p = 0.01).
In a multivariate logistic regression analysis (table 2), In the present study, we have clarified that the preva-
the prevalence of H. pylori infection (odds ratio 0.68, 95% lence of H. pylori has decreased while the intake rate of
CI 0.49–0.96, p = 0.026) and the proportion of patients NSAIDs has increased during the past 12 years in patients
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Univ. of California San Diego

Impact of H. pylori and NSAIDs on PUB Digestion 2015;91:37–41 39

DOI: 10.1159/000368810
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with PUB. Compared with previous reports [1, 10, 11],
this study observed a greater number of cases for a longer
period of time regarding the chronological changes of the
prevalence of H. pylori infection and concomitant use of
NSAIDs and antithrombotic agents in patients with PUB.
In recent years, the incidence of peptic ulcer disease has
been decreasing in Japan [4]. An epidemiologic survey
conducted by the Ministry of Health, Labour and Welfare
in Japan shows that the annual number of peptic ulcers
was 85,000 in 2002 and 44,000 in 2011. The age-adjusted
prevalence of peptic ulcer significantly decreased 0.34-
fold in both men and women in 2005 compared with 1988
[4]. Such a decrease in the incidence of peptic ulcer was
caused by the decline in the prevalence of H. pylori infec-
tion [1, 10]. Nakajima et al. [4] reported that the age-ad-
justed prevalence of H. pylori infection significantly de-
creased in 2005 (52.7%) compared with 1988 (70.5%). In
this present study, there was no major change in the num-
ber of patients with PUB in the last 12 years, although the
incidence of peptic ulcer disease has been decreasing in
Japan. Kang et al. [12] reported that the proportion of H.
pylori infection in PUB was significantly lower than that
in nonbleeding peptic ulcer (66.8 vs. 75.2%, p = 0.045),
and PUB patients had a higher proportion of history of
LDA and antiplatelet use than nonbleeding peptic ulcer
patients (34.0 vs. 19.0%, p < 0.001). This result is likely to
be compatible with our present findings.
The rates of use of NSAIDs and antithrombotic agents
are increasing because of the increase in the elderly popu-
lation, which has led to greater musculoskeletal and joint
disorders and arteriosclerotic disease [3, 13–15]. In the
present study, patients with PUB in the second-half group
were older than those in the first-half group. In Japan, the
birth rate is decreasing and average life expectancy is in-
creasing, leading to a more elderly population (≥65 years)
[16]. The rapid increase of the elderly population in recent
years has been associated with the increased use of NSAIDs
and antithrombotic agents. In a population-based study in
Spain, adjusted relative risk of upper gastrointestinal
bleeding associated with use of NSAIDs and LDA was 5.3
(95% CI 4.5–6.2) and 3.7 (95% CI 3.0–4.5), respectively
[17]. Furthermore, the odds ratio of the combination of
NSAIDs and LDA was 12.7 (95% CI 7.0–23.0) [17]. Ootani
et al. [18] showed that NSAID use contributed to 28.4% of
bleeding ulcers. Our present study showed that the NSAID
intake rate in PUB was significantly higher in the second-
half group than the first-half group.
An increasing number of patients are being given an-
tithrombotic agents for vascular protection [19]. A recent
meta-analysis showed that LDA increased the risk for
40 Digestion 2015;91:37–41
DOI: 10.1159/000368810
gastrointestinal bleeding and the risk increased with ac-
companying use of clopidogrel and anticoagulant thera-
pies [20]. It is known that warfarin, which is more com-
monly used in cardiovascular diseases, raises the gastro-
intestinal bleeding risk [21]. In our present study, the rate
of antiplatelet use, except for LDA, was significantly high-
er in the second-half group than the first-half group. We
suggest that this result may be caused by the increased
concomitant use of antithrombotic agents because of the
increase in elderly population [1]. Recently, dual anti-
platelet therapies with combinations of LDA and another
antiplatelet have become a standard therapy in patients
with coronary artery diseases treated with drug-eluting
stents [19]. Such combined antithrombotic therapies fur-
ther increase the threat of PUB compared with antiplate-
let monotherapies [14].
It should be noted that the prevalence of H. pylori infec-
tion was markedly decreased during the study period, as
reported previously [1, 4, 10], but the annual number of
patients with PUB did not change significantly. We specu-
late that the increase of NSAID and antiplatelet intake and
the decrease in H. pylori infection might have influenced
the development of PUB to almost the same extent.
The first choice of treatment for NSAID-induced mu-
cosal injury should be discontinuation of NSAIDs. If it
is not possible to discontinue NSAIDs or LDA, patients
might be switched to a selective COX-2 inhibitor [22] or
use of an additional PPI [4, 13, 23]. For prevention of the
recurrence of NSAID-induced peptic ulcer, administra-
tion of a PPI has been recommended [13, 23]. In our
study, PPI users were more frequent in the second-half
group than the first-half group in our study. This result is
suggested to be caused by the preventive use of PPI for the
recurrence of NSAID-induced peptic ulcer, which has
been covered by health insurance in Japan since 2010.
Our present study has a number of limitations. First,
with regard to the data collection, the retrospective and
single-center nature of the study is a potential source of
selection bias. Second, drugs other than NSAIDs might
be influencing the results, such as selective serotonin
reuptake inhibitors and bisphosphonates, which were not
analyzed. Finally, we did not sufficiently investigate un-
derlying diseases that might be associated with PUB in all
patients, such as hypertension, cardio-/cerebrovascular
disease, diabetes, inflammatory bowel disease or multiple
trauma. These limitations may have influenced the pre-
cise analysis of the present study.
In conclusion, the present study indicated that the
cause of PUB clearly shifted from H. pylori infection to
the use of NSAIDs over the 12-year period of study. It
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seems that the use of NSAIDs/antithrombotic agents has
increased with the aging of the population, and the prev-
alence of H. pylori infection has decreased as a result of
the improvement in hygienic conditions and the imple-
mentation of eradication therapy.
References
1 Fujinami H, Kudo T, Hosokawsa A, Ogawa K,
Miyazaki T, Nishikawa J, Kajiura S, Ando T,
Ueda A, Sugiyama T: A study of the change in
the cause of peptic ulcer bleeding. World J
Gastrointest Endosc 2012;4:323–332.
2 M, Krieger T, Ecker T, Leandro G, Malfert-
heiner P: Meta-analysis of bismuth quadruple
therapy versus clarithromycin triple therapy
for empiric primary treatment of Helicobacter
pylori infection. Digestion 2013;88:33–45.
3 Arroyo MT, Forne M, de Argila CM, Feu F,
Arenas J, de la Vega J, Garrigues V, Mora F,
Castro M, Bujanda L, Cosme A, Castiella A,
Gisbert JP, Hervas A, Lanas A: The prevalence
of peptic ulcer not related to Helicobacter py-
lori or non-steroidal anti-inflammatory drug
use is negligible in southern Europe. Helico-
bacter 2004;9:249–254.
4 Nakajima S, Nishiyama Y, Yamaoka M, Yasu-
oka T, Cho E: Changes in the revalence of He-
licobacter pylori infection and gastrointestinal
diseases in the past 17 years. J Gastroenterol
Hepatol 2010;25(suppl 1):S99–S110.
5 van Leerdam ME, Vreeburg EM, Rauws EA,
Geraedts AA, Tijssen JG, Reitsma JB, Tytgat
GN: Acute upper GI bleeding: did anything
change? Time trend analysis of incidence and
outcome of acute upper GI bleeding between
1993/1994 and 2000. Am J Gastroenterol
2003;98:1494–1499.
6 Åhsberg K, Höglund P, Staël von Holstein C:
Mortality from peptic ulcer bleeding: the im-
pact of comorbidity and the use of drugs that
promote bleeding. Aliment Pharmacol Ther
2010;32:801–810.
7 Mellemkjaer L, Blot WJ, Sørensen HT, Tho-
massen L, McLaughlin JK, Nielsen GL, Olsen
JH: Upper gastrointestinal bleeding among
users of NSAIDs: a population-based cohort
study in Denmark. Br J Clin Pharmacol 2002;
53:173–181.
8 Nakamura S, Matsumoto T, Sugimori H, Esa-
ki M, Kitazono T, Hashizume M: Emergency
endoscopy for acute gastrointestinal bleeding:
prognostic value of endoscopic hemostasis
and the AIMS65 score in Japanese patients.
Dig Endosc 2014;26:369–376.
Impact of H. pylori and NSAIDs on PUB
Disclosure Statement
None.
9 Kurata JH, Nogawa AN: Meta-analysis of risk
factors for peptic ulcer: nonsteroidal antiin-
flammatory drugs, Helicobacter pylori, and
smoking. J Clin Gastroenterol 1997;24:2–17.
10 Fujisawa T, Kumagai T, Akamatsu T, Kiyo-
sawa K, Matsunaga Y: Changes in seroepide-
miological pattern of Helicobacter pylori and
hepatitis A virus over last 20 years in Japan.
Am J Gastroenterol 1999;94:2094–2099.
11 Sasaki H, Nagahara A, Hojo M, Asaoka D,
Matsumoto K, Osada T, Watanabe S: Ten-
year trend of the cumulative Helicobacter py-
lori eradication rate for the ‘Japanese eradica-
tion strategy’. Digestion 2013;88:272–278.
12 Kang JM, Kim N, Lee BH, Park HK, Jo HJ,
Shin CM, Lee SH, Park YS, Hwang JH, Kim
JW, Jeong SH, Lee DH, Jung HC, Song IS:
Risk factors for peptic ulcer bleeding in terms
of Helicobacter pylori, NSAIDs, and antiplate-
let agents. Scand J Gastroenterol 2011; 46:
1295–1301.
13 Shimizu S, Nakamura S, Kishino M, Konishi
H, Shiratori K: Role of antithrombotic thera-
py and nonsteroidal anti-inflammatory drug
use in bleeding gastroduodenal ulcers. Intern
Med 2009;48:631–637.
14 Taha AS, Angerson WJ, Knill-Jones RP,
Blatchford O: Upper gastrointestinal haemor-
rhage associated with low-dose aspirin and
anti-thrombotic drugs – a 6-year analysis and
comparison with non-steroidal anti-inflam-
matory drugs. Aliment Pharmacol Ther 2005;
22:285–289.
15 Sostres C, Gargallo CJ, Lanas A: Nonsteroidal
anti-inflammatory drugs and upper and low-
er gastrointestinal mucosal damage. Arthritis
Res Ther 2013;15(suppl 3):S3.
16 Domon K, Hirano N, Otsuka T, Fujitsuka Y,
Takeuchi M, Kikuchi Y, Nakano S, Igarashi Y:
Clinical evaluation of hemorrhagic gastrodu-
odenal ulcer in the elderly: is Helicobacter py-
lori infection a risk factor for hemorrhage?
Dig Endosc 2012;24:319–324.
17 Lanas A, García-Rodríguez LA, Arroyo MT,
Gomollón F, Feu F, González-Pérez A, Zapa-
ta E, Bástida G, Rodrigo L, Santolaria S, Güell
M, de Argila CM, Quintero E, Borda F, Piqué
Digestion 2015;91:37–41
DOI: 10.1159/000368810
JM: Risk of upper gastrointestinal ulcer bleed-
ing associated with selective cyclo-oxygen-
ase-2 inhibitors, traditional non-aspirin non-
steroidal anti-inflammatory drugs, aspirin
and combinations. Gut 2006;55:1731–1738.
18 Ootani H, Iwakiri R, Shimoda R, Nakahara S,
Amemori S, Fujise T, Kikkawa A, Tsunada S,
Sakata H, Fujimoto K: Role of Helicobacter
pylori infection and nonsteroidal anti-inflam-
matory drug use in bleeding peptic ulcers in
Japan. J Gastroenterol 2006;41:41–46.
19 Nakamura K, Akahoshi K, Ochiai T, Komori
K, Haraguchi K, Tanaka M, Nakamura
N,Tanaka Y, Kakigao K, Ogino H, Ihara E,
Akiho H, Motomura Y, Kabemura T, Harada
N, Chijiiwa Y, Ito T, Takayanagi R: Charac-
teristics of hemorrhagic peptic ulcers in pa-
tients receiving antithrombotic/nonsteroidal
antiinflammatory drug therapy. Gut Liver
2012;6:423–426.
20 Lanas A, Wu P, Medin J, Mills EJ: Low doses
of acetylsalicylic acid increase risk of gastro-
intestinal bleeding in a meta-analysis. Clin
Gastroenterol Hepatol 2011;9:762–768.
21 Hurlen M, Abdelnoor M, Smith P, Erikssen J,
Arnesen H: Warfarin, aspirin, or both after
myocardial infarction. N Engl J Med 2002;
347:969–974.
22 Hawkey C, Laine L, Simon T, Beaulieu A,
Maldonado-Cocco J, Acevedo E, Shahane A,
Quan H, Bolognese J, Mortensen E: Compar-
ison of the effect of rofecoxib (a cyclooxygen-
ase 2 inhibitor), ibuprofen, and placebo on the
gastroduodenal mucosa of patients with os-
teoarthritis: a randomized, double-blind, pla-
cebo-controlled trial. The Rofecoxib Osteo-
arthritis Endoscopy Multinational Study
Group. Arthritis Rheum 2000;43:370–377.
23 Yeomans ND, Tulassay Z, Juhász L, Rácz I,
Howard JM, van Rensburg CJ, Swannell AJ,
Hawkey CJ: A comparison of omeprazole
with ranitidine for ulcers associated with non-
steroidal antiinflammatory drugs. Acid Sup-
pression Trial: Ranitidine versus Omeprazole
for NSAID-Associated Ulcer Treatment (AS-
TRONAUT) Study Group. N Engl J Med
1998;338:719–726.
132.239.1.230 - 4/14/2015 1:52:36 PM
Univ. of California San Diego
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