Aliment Pharmacol Ther 2005; 21 (Suppl. 2): 6772.

Preventive therapy for non-steroidal anti-inflammatory drug-induced

ulcers in Japanese patients with rheumatoid arthritis: the current
situation and a prospective controlled-study of the preventive effects of
lansoprazole or famotidine
K. MIYA KE*, N. UEKI*, K . SU ZUKI*, Y . SH INJI*, M . KUSUNOKI*, T. HIRATSUKA*, H. NISH IGAKI*,
A. TA TSUGU CHI*, S. FUTA GAMI*, K. WADA*, T. TSU KUI*, A . NAKAJIMA, S. YOSHINO &
C. SA KAMOTO*
*Third Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
Department of Joint Disease and Rheumatism, Nippon Medical School, Tokyo, Japan
Accepted for publication 13 March 2005

(PPI group), or a prostaglandin E1 analog (PG)

SUMMARY
Background: There is a lack of evidence for the efficacy
of preventive medications for peptic ulcers (PUs) among
long-term users of non-steroidal anti-inflammatory
drugs (NSAIDs) in Japan.
Aim: To estimate the preventive effect by normal dose,
not high-dose histamine-H2 receptor antagonists
(H2RA) for NSAID-induced ulcers.
Methods: We designed two different studies to assess the
efficacy of anti-ulcer agents in rheumatoid arthritis (RA)
in patients treated over a long term with NSAIDs. An
investigative survey divided patients into those not
taking anti-ulcer agents (non-medication group); those
taking mucosal protective agents (mucosal protectant
group), H2RA (H2RA group), proton pump inhibitors
(PG group). The second study compared prospectively
the preventive effects of either famotidine 20 mg bd
(famotidine group) or lansoprazole 15 mg daily (lanso-
prazole group) in patients with PU scars.
Results: The prevalence of PU in the H2RA group was
significantly lower compared to the mucosal protectant
group (P < 0.05), and the mucosal protectant group
was not significantly different to the non-medication
group. The prospective study revealed that the PU onset
rate of the famotidine group was 8% (1/13), and
lansoprazole group was 15% (2/13), indicating no
significant differences between the two.
Conclusions: In Japan, normal-dose H2RA is expected to
be a new PU preventive treatment strategy in patients
requiring long-term NSAID therapy.

PUs develop synergistically.1 The NSAID-treated

INTRODUCTION
The interactions of Helicobacter pylori (H. pylori) infec-
tion and non-steroidal anti-inflammatory drugs
(NSAIDs), the two major causes of peptic ulcers (PUs),
are controversial. A recent meta-analysis reports that
Correspondence to: K. Miyake, Third Department of Internal Medicine,
Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603,
Japan.
E-mail: km366@nms.ac.jp
patients demonstrate a high incidence of developing
endoscopic PUs (520%) as well as a high onset of
complications such as bleeding and perforation, thereby
necessitating a standard methodology for the preven-
tion of PUs in patients on NSAIDs.2 There are numerous
studies on the prevention of NSAID-induced PUs, which
discuss the high preventive effects of proton pump
inhibitors (PPIs), prostaglandin (PG), and high-dose
histamine-H2 receptor antagonists (H2RA). Most of the

2005 Blackwell Publishing Ltd 67

68 K. MIYAKE et al.
evidence has been accumulated in Europe and the US.3
Considering that Japan has a higher H. pylori infection
rate than these two regions and records many hypoc-
hlorhydria cases due to atrophy, preventive effects by
normal dose, not high dose, H2RA are expected.4, 5
Patients with rheumatoid arthritis (RA) require long-
term therapy with NSAIDs. Additionally, mental stress
by chronic arthritis symptoms and the concomitant use
of multiple agents such as PSL and immunosuppressive
agent may affect ulcer formation and ulcer healing. In
1991, the Japan Rheumatism Foundation conducted a
large-scale epidemiological survey among RA patients
taking NSAIDs over a long term. The results showed the
incidences of gastric ulcer and duodenal ulcer were
15.5 and 1.9%, respectively. Although the need to
prevent NSAID-induced PU is recognized, there is a lack
of evidence in Japan, and the efficacy of preventive
medications has yet to be elucidated. In this study,
therefore, we conducted an investigative survey on PUs
in RA patients treated over a long-term with NSAIDs to
verify the efficacy of anti-ulcer agents. Furthermore, we
also compared the preventive effects between normal-
dose H2RA and PPIs in patients with PU scars who
were identified through the PU survey.
MATERIALS AND METHODS
Current status of ulcer prevention
Patients. The duration of the survey period was from
February 2003 to June 2004. Subjects were RA patients
over 20 years of age visiting the RA department of our
hospitals as out patients. They had been using NSAIDs
for more than 1 month before baseline, and the
prognosis assumed to continue the same treatment for
another 6 months or more.
Patients excluded were those who were given treat-
ment with over 10 mg/day in prednisolone-equiva-
lency, did not give consent to endoscopic examinations,
started PPIs or PG therapy within 1 month, or had a
history of stomach resection or H. pylori eradication
therapy; as well as lactating women, female patients
planning pregnancy, those with renal disorder, or
patients showing other serious laboratory findings.
The subject pool was derived collectively from RA
department out patients of our hospitals. Those consid-
ered eligible for inclusion were requested to join
regardless of whether they developed dyspepsia symp-
toms.
2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21 (Suppl. 2), 6772
Prior to the survey, patient consent was obtained via a
signed consent form. An interview was given and
questionnaires were completed, after which upper
endoscopy was performed.
The study protocol is approved by the ethics committee
of the hospital.
Evaluation by endoscopy. In the endoscopy, ulcers and
erosions were recorded according to the esophagus,
gastric region (body, angular region and antrum),
duodenum (bulb and postbulbar). Ulcers were defined
as mucosal loss over 3 mm or mucosal loss accompan-
ied by fold convergence. Ulcer scars were interpreted as
lesions indicating fold convergence without mucosal
loss. Erosion was defined as mucosal loss less than
3 mm without fold convergence.
Histology. During each endoscopic examination, biopsy
specimens from the antrum and corpus were obtained
for the histochemical analysis of gastritis. Antrum
biopsy specimens were taken within 2 cm of the pylorus
and corpus specimens were obtained from the mid-
portion of the greater and lesser curvatures. One or two
biopsy specimens, which contained gastric mucosa
sufficient to study the number of intra-mucosal lympho-
cytes, severity of gastritis, and occurrence of H. pylori,
were taken from each region. The specimens were fixed
in 10% buffered formalin, embedded in paraffin, cut into
sections, and then stained with hematoxylin-eosin for
histological analysis and Giemsa stain for H. pylori
detection. The degree of inflammation, activity, H. pylori
density, atrophy and intestinal metaplasia was assessed
according to the modified updated version of the Sydney
system and classified into four categories as follows: 0,
none; 1, mild; 2, moderate; and 3, severe.6
Patient evaluation. Patients were evaluated after obtain-
ing their consent to participate in the study. A range of
data was collected from endoscopic findings regarding
details of NSAIDs and other medications, past history
of PUs, abdominal symptoms, severity of chronic
arthritis, urine tests and general hematochemistry.
Patients were asked to complete a daily progress card
on abdominal symptoms (epigastric pain, loss of
appetite, heartburn, nausea and vomiting) and dosing
conditions.
The presence of H. pylori infection was determined by
endoscopic biopsy or antiH. pylori IgG antibody based
on the updated Sydney system. If H. pylori infection was
 PREVENTIVE THERAPY FOR NSAID INDUCED ULCERS
detected by either method, the patient was identified as
positive.
Serum antiH. pylori IgG was measured by enzyme
linked immunosorbent assay (ELISA) (Determiner
H. pylori Antibody J, Kyowa Medics, Tokyo, Japan). In
this assay, an antibody ELISA value of less than 30 was
taken to indicate the absence of detectable antibodies,
whereas a value of more than 50 indicated the presence
of IgG antibodies. The levels of pepsinogens I and II were
measured by specific radioimmunoassay (RIA) (LS
Pepsinogens I and II, Eiken, Tokyo, Japan).
The perspective controlled study on preventive effects of
lansoprazole and normal-dose famotidine
Sealed envelopes were used to randomly assign patients
identified with peptic ulcer scar by endoscopy into two
groups: 20 mg of famotidine twice a day (famotidine
group) and 15 mg of lansoprazole per day (lansoprazole
group). Famotidine was settled in the normal dosage
approved for PU treatment, and lansoprazole was settled
at the dosage approved for the maintenance therapy of
reflux esophagitis in Japan.
The endpoints were after 24 weeks of treatment and
when recurrence of gastric or duodenal ulcer was found
in endoscopy performed as a result of severe gastric
symptoms (abdominal pain, vomiting, hematemesis and
melena) during therapy.
Statistical analysis
Significant differences between continuous variables
were analysed using two-tailed paired Students t-test.
Multiple comparisons were analysed by one-way
analysis of variance followed by the Fishers projected
least significant difference (PLSD) test. Data analyses
were performed with a standard biomedical software
package (StatView J-4.5; Abacus Concepts Inc.,
Berkeley, CA, USA), and differences with a P value
less than 0.05 were regarded as statistically signifi-
cant.
RESULTS
Current status of ulcer prevention
The total of 194 patients were invited to undergo
endoscopic screening for entollment: 23 patients were
unwilling to undergo endoscopic examination, and 171
2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21 (Suppl. 2), 6772
69
patients accepted the invitation. Of these 171 patients,
18 patients were not receiving long-term NSAID
treatment, and two patients were admitted. Therefore,
20 patients were excluded from the study.
To verify the ulcer-preventive effects of anti-ulcer agents
in patients with PU induced by long-term use of NSAIDs,
the demographic factors and prevalence of PUs were
compared according to the use of anti-ulcer agents in this
survey. For anti-ulcer agents, the remaining 155 patients
were divided into those not taking anti-ulcer agents (non-
medication group); those taking mucosal protective
agents (mucosal protectant group), H2RA (H2RA
group), PPI (PPI group), and prostaglandin E1 analog
(PG) (PG group). No significant differences were seen
when comparing age, sex, PU history, NSAIDs using
condition and H. pylori infection, while the PPI group
showed a significantly high use of PSL compared to the
group not taking anti-ulcer agents (P < 0.05, Table 1).
The prevalence of open PU in RA patients who received
long-term NSAID treatment was 21.9% (34/155: 30
gastric ulcers, four duodenal ulcers). The prevalence of
PU in the H2RA group was significantly low compared to
the mucosal protectant group (P < 0.05, Table 2). On
the other hand, the prevalence between the non-
medication and the protectant groups and between the
non-medication and the H2RA groups were not statis-
tically significant (respectively, P 0.681 and 0.470).
The perspective controlled study on preventive effects of
proton pump inhibitors and H2RA
The PU scars were found in 32 of 155 patients who
underwent endoscopy. Those with PU scar were then
asked to take part in a control trial on ulcer preventive
effects comparing normal-dose famotidine and lansop-
razole. Six out of 32 patients did not agree to take the
endoscopy 6 months later, while the remaining 26
consented to participating in this trial. Table 3 shows
the data of these 26 subjects (13 famotidine-treated
patients vs. 13 lansoprazole-treated patients). No signi-
ficant difference was found between the two groups
regarding age, sex, duration of RA disorder, severity of
chronic arthritis, preferences, history of PU, abdominal
symptoms, H. pylori infection and prednisolone using
conditions (Table 3).
The intention-to-treat analysis revealed that the PU
onset rate of famotidine 20 mg twice per day (famot-
idine group) was 7.7% (1/13), and lansoprazole admin-
istered at 15 mg/day (lansoprazole group) was 15.4%
70 K. MIYAKE et al.

Table 1. Baseline characteristics of patients with rheumatoid arthritis receiving long-term NSAID therapy in current status of ulcer
prevention

Non-medication Mucosal protectant H2RA PPI PG

Characteristic (n 9) (n 96) (n 36) (n 9) (n 5) P value

Age
Mean 61.4 60.0 62.7 63.4 61.4 NS
Range (s.d.) 4.2 1.2 1.3 5.2 4.4
Female (%) 9 (100) 82 (85.4) 32 (88.9) 7 (77.8) 5 (100) NS
Duration of arthritis (years)
Mean 14.2 14.5 16.1 13.7 17.8 NS
Range (s.d.) 2.8 1.1 2.0 2.8 4.2
Smoker (%) 2 (22.2) 18 (18.8) 7 (19.4) 2 (22.2) 1 (20.0) NS
Alcohol (%) 2 (22.2) 27 (28.1) 7 (19.4) 1 (11.1) 1 (20.0) NS
Past history of peptic ulcer
Mean 11.1 13.8 27.8 37.5 20.0 NS
Range 11.1 3.6 7.6 18.3 2.0
H. Pylori infection (%) 6 (66.7) 51 (54.3) 18 (50.0) 5 (55.6) 2 (40.0) NS
Prednisolone (%) 6 (66.7) 81 (84.4) 32 (88.9) 9 (100) 4 (80.0) <0.05*

*P value was compared between the non-medication and PPI groups.

NS, no statistical significance.

Table 2. Current status of ulcer prevention in patients with rheumatoid arthritis receiving long-term NSAID therapy

None (n 9) Mucosal protectant (n 96) H2RA (n 36) PPI (n 9) PG (n 5)

Peptic ulcer (%) 2 (22.2) 27 (28.1)* 4 (11.1)* 1 (11.1) 0 (0)

*P < 0.05.

(2/13), indicating no significant differences between the
two groups (Table 4).
On the other hand, in the per-protocol analysis, one
out of 13 famotidine-treated patients developed nausea
and one out of 13 lansoprazole-treated patients devel-
oped constipation and taste disorder. These two patients
were therefore excluded from the study. Furthermore,
six in the famotidine group and four in the lansoprazole
group were also taken out of the study due to changes
in NSAID dosage after the start of trial or failure to
follow medication instructions during the trial. In the
per-protocol analysis, no significant difference was seen
in the PU onset rate between the two groups (Table 4).
DISCUSSION
In the present study in patients with PU induced by
long-term NSAID treatment, the prevalence of open PUs
in RA patients who received long-term NSAID treat-
ment was 21.9% (34/155: gastric ulcer, 30; duodenal
ulcer, 4). The endoscopic PU incidence in patients
treated with NSAIDs has been shown to be 520%.
A large-scale epidemiologic survey among RA patients
on the long term use of NSAIDs was conducted by the
Japan Rheumatism Foundation in 1991. It revealed
that the incidence of gastric and duodenal ulcers was
15.5 and 1.9%, respectively. Advanced age of over
65 years is a risk factor for the development of NSAID-
induced ulcers, and the development of noticeable
symptoms is reportedly slow or non-existent.7 The PU
prevalence in this trial was slightly higher than the JRF
survey, possibly because the average age in the
foundations survey was 56.9 years, whereas it was
61.0 years in this study. This suggests that even though
elderly individuals are prone to ulcers due to reduced
mucosa protective function,810 it is difficult to make an
ulcer diagnosis owing to the lack of apparent symptoms,
resulting in the continued use of NSAIDs.11, 12
On current status of ulcer prevention, the PU preval-
ence was significantly lower in the H2RA group than the
mucosal protectant group, suggesting that H2RA may
have the preventive efficacy for PU comparable with that
of PPI and PG. By contrast, the PU prevalence of the
mucosal protectant group was not significantly different

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21 (Suppl. 2), 6772
 PREVENTIVE THERAPY FOR NSAID INDUCED ULCERS 71

Table 3. Baseline characteristics of patients

Famotidine group Lansoprazole group
with rheumatoid arthritis receiving long-
Characteristic (n 13) (n 13) P value
term NSAID therapy and prospective study
of peptic ulcer prevention by famotidine or Age (s.d.)
lansoprazole Mean 65.6 62.6 NS
Range 1.3 2.3
Female (%) 2 (92.3) 12 (92.3) NS
Duration of arthritis (years)
Mean 16.2 15.9
Range 3.6 2.7
Smoker 4 3
Alcohol 3 5
GUs/DUs/DGUs* 10/2/1 11/1/1 NS
H. Pylori infection (%) 7 (53.8) 6 (46.2) NS
Epigastralgia (%) 2 (15.4) 1 (7.7) NS
Heartburn (%) 5 (38.5) 3 (23.1) NS
Nausea (%) 1 (7.7) 1 (7.7) NS
Appetite loss (%) 3 (23.1) 2 (15.4) NS
NSAID
Loxoprofen 4 5 NS
Diclofenac 4 3 NS
Indomethacin 1 2 NS
Lornoxicam 2 1 NS
Etodolac 1 1 NS
Ketoprofen 1 1 NS
Prednisolone 10 11 NS

*This category shows the number of each disease (gastric ulcer scar (GUs), duodenal ulcer scar
(DUs) or duodenogastric ulcer scar (DGUs)).
NS, no statistical significance.

from the non-medication group. Results of randomized Table 4. Number and incidence of peptic ulcer recurrence by
control trials on sucralfate, which is a typical mucosal famotidine or lansoprazole for patients with rheumatoid arthritis
protectant, has also shown no preventive effects for receiving long-term NSAID therapy

NSAID-induced ulcer.13, 14 Although further studies are Famotidine Lansoprazole

needed in specific fields on the estimation of each group group P value
mucosal protectant, it seems that mucosal protectants ITT
have no clear ulcer preventive efficacy. Number 1/13 2/13
Furthermore, a prospective controlled study was con- Incidence (%) 7.7 15.4 NS
ducted to compare with preventive effects for PU between PP
famotidine 20 mg twice per day and lansoprazole Number 1/6 2/8
Incidence (%) 16.7 25.0 NS
15 mg/day, and the results revealed that the PU
incidence after 6 months did not differ significantly NS, no statistical significance; PP, per-protocol analysis; ITT, inten-
between the two groups. The lansoprazole dosage of tion-to-treat analysis.
15 mg/day has shown the same preventive effects as that
of 30 mg/day.15 Therefore, normal-dose famotidine has ized controlled studies. However, misoprostol causes
the preventing effects comparable with that of lansop- side effects including gastrointestinal symptoms such as
razole for ulcer recurrence in long-term NSAIDs users diarrhea, and restricted dosages for female patients who
with endoscopical PU history, although the estimation of may be pregnant.1618 On the other hand, suppression
preventive effects in the present study may have been of gastric acid secretion by H2RA and PPI are very
limited because of small number and short duration. effective for treating H. pylori-related ulcers and pre-
The preventive effects of PG (misoprostol) on NSAID- venting recurrence. Strong acid suppression is required
induced ulcer have been proven in numerous random- to prevent NSAID-induced ulcers, and there have been

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21 (Suppl. 2), 6772
72 K. MIYAKE et al.
no reports on the effectiveness of normal-dose H2RA in
the prevention of NSAID-induced ulcers. Studies have
been demonstrated that PPIs have the same efficacy as
misoprostol for preventing ulcer recurrence under the
continued use of NSAIDs.19, 20 Reports mainly from the
US and Europe have stated the need for a high dosage of
H2RA if administering it to prevent NSAID-induced
ulcers.21 In Japan, normal-dose H2RA is expected to be
a new PU preventive drug in patients with long-term
NSAID therapy. Helicobacter pylori infection was found
in 50% of the patients. Japan has a high rate of H. pylori
infection compared to Europe and the US. Although
gastric acidity is not evaluated in this study, owing to
hypoacidity due to atrophy, strong acid suppression
may not be required to prevent NSAID ulcers.
Regarding the effects of normal-dose H2RA in the
prevention of NSAID-induced ulcers, further studies are
required focusing on the relationship between gastric
acid secretion function, body atrophy, and H. pylori
infection, as well as the effects of NSAID types and
doses.
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