ICU Patients Prevent GI Bleeding

TUGAS EVALUASI SUMBER LITERATUR
Nama : Nesha Mutiara
NPM : 2017210155
Kelas : Pharmaceutical Care (A)
FAKULTAS FARMASI
UNIVERSITAS PANCASILA
JAKARTA
2020

ii
DAFTAR ISI
HALAMAN JUDUL ................................................................................................................i
DAFTAR ISI........................................................................................................................... ii
SOAL NOMOR 1....................................................................................................................1
A. Literatur Primer .........................................................................................................1
B. Literatur Sekunder .....................................................................................................2
C. Literatur Tersier .........................................................................................................4
D. Lampiran Literatur ....................................................................................................5
SOAL NOMOR 2..................................................................................................................32
A. Literatur Primer .......................................................................................................32
B. Literatur Sekunder ...................................................................................................34
C. Literatur Tersier .......................................................................................................35
D. Lampiran Literatur ..................................................................................................37
SOAL NOMOR 3..................................................................................................................66
A. Literatur Primer .......................................................................................................66
B. Literatur Sekunder ...................................................................................................67
C. Literatur Tersier .......................................................................................................68
D. Lampiran Literatur ................................................................................................. 70

1
KASUS NOMOR 1
Dokter menanyakan kepada anda sebagai apoteker, mana yang dipilih
omerprazol dibandingkan ranitidin untuk penyakit gastritis pada pasien usia 50
tahun. Lalu apa obat yang paling anda rekomendasikan?
A. Literatur Primer
Berdasarkan literatur “Comparison between the Preventive Effects of
Ranitidine and Omeprazole on Upper Gastrointestinal Bleeding among ICU
Patients” (terlampir), omeprazole (obat golongan PPI) menjadi pilihan yang
lebih baik dibandingkan ranitidin untuk penyakit gastritis karena dapat
menekan tingkat keasaman lambung 6-10 kali lebih efisien dibandingkan H2-
blockers. Omeprazole juga lebih menguntungkan karena tidak membutuhkan
penyesuaian dosis untuk penderita gagal ginjal.

2
Berdasarkan literatur “A Comparison of Omeprazole with Ranitidine for
Ulcers Associated with Nonsteroidal Antiinflammatory Drugs” (terlampir),
terapi menggunakan omeprazole dengan dosis 20 mg per hari dinilai lebih
efektif dibandingkan ranitidin dengan pertimbangan kemampuan mengobati
dan mencegah gastroduodenal ulcers sekaligus mengendalikan gejala
dyspepsia.
B. Literatur Sekunder
Berdasarkan literatur “Appendix 1: Information from NICE clinical guideline
17 [2004]”, obat golongan Proton Pump Inhibitor (PPI) dapat digunakan untuk
terapi gastritis karena mampu mengurangi asam lambung dengan menghambat
proton pump (hydrogen-potassium adenosine triphosphatase enzyme system)
di dalam lambung.

4
C. Literatur Tersier
Berdasarkan literatur “PPI versus Histamine H2 Receptor Antagonists for
Prevention of Upper Gastrointestinal Injury Associated with Low Dose Aspirin:
systematic Review and Meta-analysis” (terlampir), obat golongan PPI lebih
baik untuk mengatasi tukak lambung dibandingkan obat golongan H2RAs.
D. Lampiran Literatur

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Tanaffos (2009) 8(4), 37-42
©2009 NRITLD, National Research Institute of Tuberculosis and Lung Disease, Iran
Comparison between the Preventive Effects of Ranitidine
and Omeprazole on Upper Gastrointestinal Bleeding
among ICU Patients
Mehrdad Solouki 1
, Seyed Mehran Marashian 2
, Mehran Kouchak 1
, Majid Mokhtari 1
, Ebrahim Nasiri 1
1 Department of Internal Medicine and Intensive Care, Imam Hossein Hospital, Shahid Beheshti University, M.C., 2 National Research
Institute of Tuberculosis and Lung Disease, Shahid Beheshti University M.C. TEHRAN-IRAN.
ABSTRACT
Background: Critically ill patients may develop visible gastric mucosal injury and stress ulcer soon after admission to an
intensive care unit causing upper gastrointestinal bleeding as an important complication. Histamine-2 receptor antagonist
(H2RA) prophylactic therapy has been documented to significantly decrease the incidence of upper GI bleeding in critically ill
patients. This study was carried out in order to compare the effects of intravenous doses of ranitidine and enteral form of
omeprazole suspension on preventing GI bleeding among ICU patients.
Materials and Methods: This study was a double-blind randomized clinical trial conducted on patients admitted to the ICU at
the Imam Hossein Hospital in Tehran, Iran. The patients were randomly divided into two groups of A and B. In group A,
ranitidine was used as the prophylactic drug against GI bleeding with the dosage of 50 mg two times a day accompanied by
placebo gavages through nasogastric tube. In group B, 20 mg of a suspension of omeprazole two times a day was gavaged
in addition to 2
cc
of a parenteral placebo drug. Of 198 patients admitted to the ICU, 69 patients did not meet the inclusion
criteria and a total of 129 patients enrolled in this study.
Results: During the study 14(20.58%) cases in the ranitidine group and 3(4.9%) in the omeprazole group developed
significant GI bleeding. Incidence of GI bleeding showed a significant difference between the two groups using the chi-square
test. Of the 68 patients receiving ranitidine, 44 (67.7%) died. This rate was 38 in those receiving omeprazole (62%). Of the
patients given ranitidine who faced overt GI bleeding, 12 (85.7%) died. This rate was 3 in the omeprazole group (100%).
Conclusion: This study showed a statistically significant difference between omeprazole and ranitidine in preventing overt GI
bleeding among ICU patients; but it failed to indicate any difference in prophylaxis of clinically important GI bleeding between
the two drugs. (Tanaffos 2009; 8(4): 37-42)
Key words: Gastrointestinal bleeding, ICU, Stress ulcer, Prophylaxis, Omeprazole, Ranitidine
Correspondence to: Solouki M
Address: Department of Internal Medicine and Intensive Care Unit, Imam
Hossein Hospital, Shahid Beheshti University, M.C., Tehran, Iran.
Email address: mehranmarashian@hotmail.com
Received: 6 December 2008
Accepted: 28 May 2009
ORIGINAL ARTICLE
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38 Effects of Ranitidine and Omeprazole on GI Bleeding among ICU Patients
Tanaffos 2009; 8(4): 37-42
INTRODUCTION
Stress-induced upper gastrointestinal (GI)
bleeding is a well-recognized complication in
critically ill patients, particularly in those requiring
mechanical ventilation (1,2). Most critically ill
patients, develop visible gastric mucosal injury soon
after admission to an intensive care unit (3-6).
Although stress-induced gastric injury seems to begin
with impairment of mucosal defense and repair,
presumably due to local ischemia, experimental
studies suggest that, the presence of acid in the
gastric lumen, is critical for the production of gross
mucosal damage and bleeding (6-9).
Gastrointestinal bleeding due to stress ulceration
is an important complication in critically ill patients
(2,10,11) which may lead to high rates of mortality,
morbidity and ICU stay (12-14). On the basis of the
positive results of randomized trials (15-27),
prophylactic measures such as neutralization of
gastric acid and reduction of gastric acid secretion
with Histamine-2 Receptor Antagonist Therapy
(H2RA) have been documented to significantly
decrease the incidence of upper GI bleeding in
critically ill patients (10,28). Many randomized
clinical trials were done to evaluate the preventive
effects of cimetidine, ranitidine, and sucralfate on GI
bleeding in different settings among which a double-
blind, placebo-controlled, randomized trial on 131
critically ill patients in 1993 (10) showed that
patients treated with intravenous cimetidine, had a
significantly lower rate of upper GI bleeding than the
placebo-treated group.
Proton pump inhibitors produce a more potent and
longer-lasting inhibition of gastric acid and also have
less interaction with other drugs than H2RAs. Proton
pump inhibitors (PPI), such as omeprazole, have
recently proved efficacious for stress-related GI
bleeding prophylaxis and are used in many settings
(11,28-30). Omeprazole is commercially available as
a delayed-release capsule containing enteric-coated
granules to protect against acid degradation.
Since mechanical ventilation is a major
independent risk factor for GI bleeding in ICU
patients, this study was carried out in order to
compare the efficacy of intravenous doses of
ranitidine and enteral omeprazole suspension to
prevent overt and clinically important GI bleeding
among mechanically ventilated ICU patients.
MATERIALS AND METHODS
This study was a double-blind randomized clinical
trial conducted on patients admitted to the ICU from
June 2000 to January 2001 at the Imam Hossein
Hospital in Tehran, Iran.
ICU patients, who had been under mechanical
ventilation for a minimum of 48 hours, were
recruited in this study. Using the table numbers
randomly, all ICU beds were divided into two groups
of A and B. This randomization design was used to
avoid the patient selection bias by the ICU personnel.
All the participants had nasogastric tube (NGT),
which is a suitable monitoring for confirming the
upper GI bleedings, if occur. Patients with
pneumonia, current upper GI bleeding, previous
gastrectomy, current usage of 2 doses of prophylaxis,
and those transported from another ICU ward were
all excluded from the study. Written consents signed
by the patients or their family members were
obtained for participation in the study. Of the 198
patients admitted to the ICU, 69 patients did not meet
the inclusion criteria and as a result, 129 patients
enrolled in this study.
Internal and surgical cases were not separated in
this study because being an internal or a surgical case
per se, is not a major risk factor for gastrointestinal
bleeding based on Cook’s study (2).
In group A, intravenous ranitidine was used with
50 mg dosage two times a day accompanied by
placebo gavages through nasogastric tube. In group
B, 20 ml of a suspension of omeprazole two times a
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Solouki M, et al. 39
Tanaffos 2009; 8(4): 37-42
day was gavaged in addition to 2cc of a parenteral
placebo drug.
Omeprazole suspension was prepared by adding
omeprazole granules gathered from the original drug
shape (capsules) and water to apple sauce prepared
with chapped apple. This substance prevents
degradation of omeprazole granules by optimizing
gastric acidity.
Two types of GI bleeding including overt and
clinically important bleedings were evaluated in this
study. If one of the following happens, the situation
is called “overt GI bleeding”: hematemesis, coffee
ground in NGT, melena or hematochezia. Overt
bleeding in addition to at least one of the following
items is called “clinically important GI bleeding”:
• A 20 mmHg decrease in systolic or diastolic
blood pressure during the first 24 hours after
bleeding
• A 20 bpm increase in heart rate or 10 mmHg in
systolic blood pressure in a standing position
• A 2 gr/dl decrease of Hb or 6% HCT during the
first 24 hours after bleeding
• Lack of increase in Hb after infusing 2 units of
packed cell
Blood pressure, heart rate, respiratory rate, oral
and auxiliary temperature, antibiotic usage, major
surgery, dialysis, total parenteral nutrition, gastric
gavage, corticosteroid usage, trauma, coagulation
profile(PT, PTT and platelet count), sepsis
profile(ESR, CRP) and renal function(BUN,
Creatinine) were recorded along with demographic
data, impressions, past medical and drug history. All
medications prescribed for patients were adjusted
according to their renal and hepatic functions.
SPSS11 software was used for data analysis.
RESULTS
Of the 129 participants, 68 were included in group
A (ranitidine group), and the remaining (61) in group
B (omeprazole group). Patients’ age in group A,
ranged from 5 to 85 yrs with the mean age of 49.19
yrs. Group B patients were in the age range of 5 to 95
yrs with a mean age of 52.41 yrs. No significant
difference was found between the two groups in this
regard. In the omeprazole group, there were
32(52.5%) males and 29(47.5%) females. These
numbers were 35(51.5%) males and 33(48.5%)
females in the ranitidine group.
Throughout the study 14(20.58%) given ranitidine
and 3(4.9%) given omeprazole faced overt GI
bleeding and this difference between the two groups
was statistically significant using the chi square test
(p<0.05). The frequencies of the two types of
bleeding are demonstrated in Table1.
Table 1. The frequency of the two types of bleeding among patients
Overt *
Bleeding
Group Positive(%) Negative(%)
Clinically
Important(%)
A 14(20.58) 54(79.41) 4(28.57)
B 3(3.9) 58(96.1) 1(33.34)
* P value < 0.05
Average duration of hospitalization in ICU was
7.67 days (7.67±7.2) in the omeprazole group and
6.16 days (6.16±8.04) in the ranitidine group. This
difference was not statistically significant. Table 2
shows the duration of hospitalization and mechanical
ventilation.
Table 2. Mean ICU hospitalization days and mean duration of
mechanical ventilation
Case
Group
ICU
Hospitalization(day)
Mechanical
Ventilation(day)
A 6.16 ± 8.04 4.96 ±7.94
B 7.67 ± 7.2 6.54 ± 6.94
P value > 0.05
Of the 68 patients receiving ranitidine, 44 (67.7%)
died. This rate for patients receiving omeprazole was
38(62%). Of 14 patients given ranitidine who faced
overt GI bleeding 12 (85.7%) died. This rate was 3
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Tanaffos 2009; 8(4): 37-42
(100%) for the omeprazole group. Fisher exact test
showed no significant difference in the mortality rate
between the two groups.
Considering some major risk factors of GI
bleeding including renal failure and coagulopathy,
fisher exact test showed that the incidence of renal
failure and coagulopathy was not significantly
different between the two groups. Other risk factors
showed no significant difference between the two
groups either as demonstrated in Table 3.
Table 3. Major risk factors in patients
Groups
Risk factors
Ranitidine Omeprazole Significance
Hx of GI bleeding 10(14.7%) 9(14.8%) 0.99
Coagulopathy 5(7.4%) 3(4.9%) 0.57
Hypotension 3(4.4%) 4(6.6%) 0.7
Sepsis 6(8.8%) 8(13.1%) 0.43
Renal failure 9(13.2%) 5(8.2%) 1.0
Gavage 34(50%) 37(60.7%) 1.0
Corticosteroid 39(57.4%) 28(45.9%) 0.19
Major surgery 40(58.8%) 34(55.7%) 0.72
Dialysis 4(5.9%) 2(3.3%) 0.8
TPN 1(1.5%) 1(1.6%) 1.0
Hx of anti ulcers 13(19.1%) 8(13.1%) 0.36
Head trauma 19(27.9%) 12(19.7%) 0.27
Multiple trauma 8(11.8%) 4(6.6%) 0.31
P-value > 0.05
Figure 1. Flow diagram of the subjects’ progress through the phases of
the study
DISCUSSION
Based on current findings, GI bleeding is one of
the major causes of increased mortality and
morbidity rates as well as ICU hospitalization and its
related costs. Many researchers have tried different
preventive strategies and various medications to
solve the mentioned complications of GI bleeding.
The majority of these studies only got conflicting
results in this regard.
In a survey by Daley and colleagues (31) in
America on 2000 physician members of the society
of critical care medicine (SCCM), it was shown that
H2RAs were the initial therapy for preventing GI
bleeding between 1995 and 1999 which have been
replacing by PPIs during the recent years because of
their permanent effects on parietal cells, increased
availability and marketing and also flexibility in
administering different formulations.
Jung and co-workers (32) in their study in 2002
stated that PPIs could be an alternative therapy for
H2RAs in preventing GI bleeding among
mechanically ventilated ICU patients.
We designed this study according to the
randomized control trial conducted by Cook D.J. (33,
34) and colleagues comparing the prophylactic
effects of ranitidine and sucralfate on upper
gastrointestinal bleeding among ICU patients in
1998. NG tube monitoring was applied for
confirming upper GI bleeding besides the defined
criteria to identify this problem. We, (like many
previous studies on this topic specially Cook’s work)
did not evaluate gastric acidity and only focused on
the degradation effect of gastric acid on omeprazole
granules. Apple sauce-based omeprazole suspension
solved this problem by optimizing the PH in the
stomach. Our randomized control trial supported the
priority of omeprazole in preventing stress ulcer and
overt upper GI bleeding among ICU patients in
comparison to ranitidine.
There was no significant difference between the
two drugs in preventing the clinically important GI
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Tanaffos 2009; 8(4): 37-42
bleedings. However, omeprazole might be a better
choice for preventing upper GI bleeding considering
its ability to suppress gastric acidity more efficiently
(6-10 times) compared to H2-blockers in non-ICU
settings, exceeding interactions of H2-blockers with
other drugs, no need for adjustment in renal failure
cases, and less drug tolerance compared to H2-
blockers. The recent increase in usage of PPIs
mentioned by Daley and their aforementioned merits
would make them more popular prophylactic agents
compared to H2RAs, although there was a low
significant difference between PPIs and H2RAs in
terms of effectiveness.
In this study we only focused on the rate of GI
bleeding after prescribing the two drugs and not their
availabilities, mechanisms of effects or difficulties of
usage. The other most important limitations of the
current study were the low sample size and being
single-central which did not allow us to generalize
our findings. Therefore, further studies with larger
sample sizes through multi-central clinical trials are
required on this matter.
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al. A comparison of sucralfate and ranitidine for the
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Volume 338 Number 11 719
OMEPRAZOLE VS. RANITIDINE FOR ULCERS ASSOCIATED WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS
A COMPARISON OF OMEPRAZOLE WITH RANITIDINE FOR ULCERS ASSOCIATED
WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS
NEVILLE D. YEOMANS, M.D., ZSOLT TULASSAY, PH.D., LÁSZLÓ JUHÁSZ, PH.D., ISTVÁN RÁCZ, PH.D.,
JOHN M. HOWARD, M.D., CHRISTOFFEL J. VAN RENSBURG, M.MED.(INT.), ANTHONY J. SWANNELL, M.B.,
AND CHRISTOPHER J. HAWKEY, D.M., FOR THE ACID SUPPRESSION TRIAL: RANITIDINE VERSUS OMEPRAZOLE
FOR NSAID-ASSOCIATED ULCER TREATMENT (ASTRONAUT) STUDY GROUP*
ABSTRACT
Background Suppressing acid secretion is thought
to reduce the risk of ulcers associated with regular
use of nonsteroidal antiinflammatory drugs (NSAIDs),
but the best means of accomplishing this is un-
certain.
Methods We studied 541 patients who required
continuous treatment with NSAIDs and who had ul-
cers or more than 10 erosions in either the stomach
or duodenum. Patients were randomly assigned to
double-blind treatment with omeprazole, 20 mg or
40 mg orally per day, or ranitidine, 150 mg orally
twice a day, for four or eight weeks, depending on
when treatment was successful (defined as the res-
olution of ulcer and the presence of fewer than five
erosions in the stomach and fewer than five erosions
in the duodenum, and not more than mild dyspep-
sia). We randomly assigned 432 patients in whom
treatment was successful to maintenance treatment
with either 20 mg of omeprazole per day or 150 mg
of ranitidine twice a day for six months.
Results At eight weeks, treatment was successful
in 80 percent (140 of 174) of the patients in the group
given 20 mg of omeprazole per day, 79 percent (148
of 187) of those given 40 mg of omeprazole per day,
and 63 percent (110 of 174) of those given ranitidine
(P0.001 for the comparison with 20 mg of omepra-
zole and P0.001 for the comparison with 40 mg of
omeprazole). The rates of healing of all types of le-
sions were higher with omeprazole than with raniti-
dine. During maintenance therapy, the estimated
proportion of patients in remission at the end of six
months was 72 percent in the omeprazole group and
59 percent in the ranitidine group. The rates of ad-
verse events were similar between groups during
both phases. Both medications were well tolerated.
Conclusions In patients who use NSAIDs regular-
ly, omeprazole healed and prevented ulcers more ef-
fectively than did ranitidine. (N Engl J Med 1998;338:
719-26.)
©1998, Massachusetts Medical Society. From the Department of Medicine, University of Melbourne, Western
Hospital, Melbourne, Australia (N.D.Y.); the Second Department of Inter-
nal Medicine, Semmelweis University Medical School, Budapest, Hungary
(Z.T.); the Second Department of Medicine, Borsod County Teaching
Hospital, Miskolc, Hungary (L.J.); the First Department of Medicine, Petz
Aladár Teaching County Hospital, Gyor, Hungary (I.R.); the Division of
Gastroenterology, Department of Medicine, London Health Sciences,
London, Ont., Canada (J.M.H.); the Department of Gastroenterology,
Tygerberg Hospital, Tygerberg, South Africa (C.J.R.); and the Department
of Rheumatology and Rehabilitation, City Hospital (A.J.S.), and the Divi-
sion of Gastroenterology, University Hospital (C.J.H.), Nottingham, Unit-
ed Kingdom. Address reprint requests to Dr. Yeomans at the Department
of Medicine, University of Melbourne, Western Hospital, Footscray, Victo-
ria 3011, Australia.
*Other members of the ASTRONAUT Study Group are listed in the Ap-
pendix.
ONSTEROIDAL antiinflammatory drugs
(NSAIDs) are commonly used to treat
pain and inflammation.1 Their use is fre-
quently limited by gastrointestinal side
effects, ranging from dyspeptic symptoms to life-
threatening bleeding or perforation of gastroduode-
nal ulcers,2-4 especially in the elderly.4
NSAIDs are thought to cause mucosal injury by
several mechanisms.5 Some have a direct toxic action
N
on the gastric mucosa that is exacerbated by acidity,
since acidity promotes the absorption of NSAIDs in
their non-ionized form.6 They also impair prosta-
glandin-dependent mucosal protective mechanisms.
When the surface cells have been damaged by either
of these mechanisms, a second wave of injury medi-
ated by luminal acid often occurs and generates
deeper ulcerative lesions.7 Prior approaches to pre-
venting the side effects of NSAIDs have included
treatment with histamine H2-receptor antagonists to
inhibit acid secretion and the administration of pros-
taglandin analogues to replace the depleted endog-
enous prostaglandins. However, H2-receptor antago-
nists are not very effective for healing or preventing
NSAID-associated gastric ulcers during continued
therapy with NSAIDs, although they speed healing8
and help prevent duodenal ulcers.8-10 The use of
prostaglandin analogues such as misoprostol is lim-
ited by gastrointestinal side effects such as diarrhea
and abdominal cramps.11
In short-term studies, the proton-pump inhibitor
omeprazole prevented aspirin-induced gastric muco-
sal damage and lesions.12,13 Omeprazole heals ulcers
effectively and is equally efficacious for gastric or
duodenal ulcers in the presence or absence of NSAID
treatment.14,15 We compared the efficacy of omepra-
zole and ranitidine in patients with gastroduodenal
ulcers and erosions associated with continuous NSAID
therapy.
METHODS
Study Design and Recruitment
The study, conducted between August 1992 and April 1995,
was an international double-blind, randomized evaluation of
The New England Journal of Medicine
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720 March 12, 1998
omeprazole and ranitidine for healing and preventing gastro-
duodenal lesions in patients receiving long-term treatment with
NSAIDs. The study was conducted in 73 centers in 15 countries,
in accordance with the principles of good clinical practice16 and
the Declaration of Helsinki (Tokyo amendments).
The study had two phases: a healing phase and a maintenance
phase.
Healing Phase
Patients of either sex, 18 to 85 years of age, who had any con-
dition requiring continuous therapy with NSAIDs above specified
therapeutic doses (no maximal dose), and not more than 10 mg
of prednisolone or its equivalent per day, were recruited. The
minimal (and mean) daily oral doses of the commonly used
NSAIDs were as follows: 50 mg (113 mg) of diclofenac, 50 mg
(111 mg) of indomethacin, and 500 mg (775 mg) of naproxen.
The patients underwent endoscopy, and those found to have any
or all of the following were invited to enter the study: ulcers that
were 3 mm or more in diameter, more than 10 erosions in the
stomach, and more than 10 erosions in the duodenum. Erosions
were assessed with the modified Lanza scale.9,10 Major exclusion
criteria were neck instability that would compromise endoscopy,
concurrent erosive or ulcerative esophagitis, pyloric stenosis, ma-
jor active gastrointestinal bleeding, or disorders that might mod-
ify the absorption of study drugs.
All patients provided written informed consent. They were ran-
domly assigned (in blocks of three per site) to receive oral double-
blind treatment with 20 mg of omeprazole (Losec, Astra Hässle,
Mölndal, Sweden) per day, 40 mg of omeprazole per day, or 150
mg of ranitidine (Zantac, Glaxo Wellcome, Research Triangle Park,
N.C.) twice daily for four or eight weeks, depending on when
treatment was successful. Treatment success was defined in ad-
vance as the disappearance of ulcer and the presence of fewer than
five erosions in the stomach, fewer than five erosions in the duo-
denum, and not more than mild dyspeptic symptoms. Patients in
whom treatment remained unsuccessful after eight weeks received
40 mg of omeprazole per day for a further four or eight weeks.
The patients visited the clinic monthly and continued to take
NSAIDs throughout the study.
Maintenance Phase
Patients in whom treatment was successful in the healing phase
were eligible for the maintenance phase if they used therapeutic
doses of NSAIDs at least five days per week, had no concurrent
erosive or ulcerative reflux esophagitis, and had no abnormalities
in the laboratory tests regarded as clinically important by the in-
vestigator. The patients were randomly assigned (in blocks of two
per site) to treatment with either 20 mg of omeprazole per day
or 150 mg of ranitidine twice daily for six months. They were
evaluated after one, three, and six months and if they had trou-
blesome dyspeptic symptoms or adverse events. Treatment failure,
specified in advance, during the maintenance phase was defined
as a finding of any of the following: gastric or duodenal ulcer,
more than 10 erosions in the stomach, more than 10 erosions in
the duodenum, moderate or severe symptoms of dyspepsia, or ad-
verse events resulting in the discontinuation of treatment. When
a patient withdrew from the study, both randomized treatment
and assessment of its effectiveness ceased.
Clinical and Laboratory Assessments
At all visits, the esophagus, stomach, and duodenum were ex-
amined endoscopically for erosions or ulcers and biopsy speci-
mens were obtained from gastric ulcers to rule out malignant
conditions. Antral-biopsy specimens were obtained at the begin-
ning of the healing phase to evaluate the patients’ Helicobacter py-
lori status with the urease enzyme test (CLO test, Delta West,
Bentley, Australia). Patients infected with H. pylori were not treat-
ed for the infection, because there was no evidence that this ben-
efited them17,18 and because H. pylori–stimulated mucosal synthe-
sis of prostaglandin has been suggested to be beneficial for
NSAID-associated ulcers.19
Patients were asked standardized questions about their overall
upper gastrointestinal symptoms and dyspeptic symptoms (epi-
gastric or abdominal pain, heartburn, nausea, vomiting, upper
abdominal bloating, and empty feeling in stomach) during the
preceding seven days. Their overall symptoms and individual
symptoms were graded as absent, mild (easily tolerated), moder-
ate (interfering with normal activities), or severe (incapacitating;
leaving the patient unable to perform normal activities). Safety
assessments were based on the reported symptoms, adverse
events, and the results of standard blood screening. We assessed
compliance by measuring the amount of medication that was re-
turned.
Statistical Analysis
We compared the rates of successful treatment in all patients
who received at least one dose of medication using a Mantel–
Haenszel life-table test combining data at four and eight weeks.
We also calculated the rates of healing of gastric ulcer, duodenal
ulcer, and erosions separately and compared the rates between
treatment groups using the Mantel–Haenszel test. A logistic-
regression analysis of prognostic factors that may have influenced
the success of treatment at four weeks included treatment, site
and type of lesion, ulcer size, H. pylori status at entry, blood
group, type of arthritic disease, smoking status, age, and sex. Up-
per gastrointestinal symptoms were analyzed by Wilcoxon’s test,
with stratification according to severity at enrollment.
The length of time to treatment failure in the maintenance
phase was compared between treatment groups with remission
curves estimated by Kaplan–Meier life-table analysis and the log-
rank test. To evaluate possible prognostic factors, a Cox regression
model was used with the duration of remission as the dependent
variable.
The study was designed to have a power of at least 80 percent
for two-sided tests at the 1.7 percent level of significance in the
healing phase (with the Bonferroni adjustment for the three pair-
wise comparisons) and at the 5 percent level in the maintenance
phase. The primary efficacy analysis used an intention-to-treat ap-
proach that included all patients meeting major entry criteria who
had taken at least one dose of medication. The safety analysis in-
cluded all patients who received at least one dose of medication
and for whom there were safety data, regardless of whether they
met the entry criteria for the trial. For these reasons there were
small differences in the numbers of patients included in the effi-
cacy and safety analyses. No interim analyses were conducted. For
cases in which data censoring arising from the use of the life-table
approach to data analysis prevented valid statistical comparisons,
P values are not presented.
RESULTS
Characteristics of the Patients
Healing Phase
Of 541 patients randomly assigned to treatment,
535 were included in the efficacy analysis according
to treatment actually received (174 received 20 mg
of omeprazole per day, 187 received 40 mg of
omeprazole per day, and 174 received 150 mg of ra-
nitidine twice daily). Three patients who received no
trial drug, one patient who did not receive an
NSAID, one whose NSAID dosage was below the
required threshold, and one in whom inflammation
was not verifiable were not evaluated. Demographic
characteristics, endoscopic findings, H. pylori status,
and the various underlying arthritic diseases requir-

ing treatment with NSAIDs were similar at base line
among the three groups (Table 1). The most com-
monly used NSAIDs in the group as a whole were
diclofenac (29 percent of patients), indomethacin
(23 percent), and naproxen (16 percent). Most pa-
tients had rheumatoid arthritis or osteoarthritis.
Maintenance Phase
At the end of the healing phase, 432 patients were
enrolled in the maintenance phase after randomiza-
tion, of whom 425 patients were included in the ef-
ficacy analysis according to treatment received. Sev-
en patients could not be evaluated: six because they
declined to continue in the study, and one because
of noncompliance with the NSAID regimen. The
patients had similar base-line characteristics (Table
1) and were well balanced with respect to treatment
received during the healing phase (data not shown).
Clinical Efficacy
Healing Phase
At eight weeks, treatment was successful in 80
percent (140 of 174) of the patients in the group
given 20 mg of omeprazole, 79 percent (148 of
187) of those given 40 mg of omeprazole, and 63
percent (110 of 174) of those given ranitidine
(P0.001 for the comparison with 20 mg of omep-
TABLE 1. BASE-LINE CHARACTERISTICS OF THE PATIENTS INCLUDED IN
THE EFFICACY ANALYSIS.
CHARACTERISTIC HEALING PHASE MAINTENANCE PHASE
OMEPRAZOLE,
20 mg/DAY
(N174)
OMEPRAZOLE,
40 mg/DAY
(N187)
RANITIDINE,
150 mg
TWICE DAILY
(N174)
OMEPRAZOLE,
20 mg/DAY
(N210)
RANITIDINE,
150 mg
TWICE DAILY
(N215)
Sex (M/F) 49/125 73/114 53/121 64/146 66/149
Age (yr)
Mean
Range
56
25–80
57
26–80
57
20–82
56
31–78
56
20–80
Mean weight (kg)
Men
Women
80
70
79
68
74
68
76
71
78
68
Mean height (cm)
Men
Women
173
161
172
160
172
160
173
161
172
161
no. of patients
Previous gastrointestinal
disease
Dyspeptic symptoms 139 157 144 177 176
Peptic ulcer 51 53 60 53 68
Bleeding 17 17 19 16 15
Current gastrointestinal
disease
Duodenal ulcer
with or without
erosions
36 42 42 41 56
Gastric ulcer with or
without erosions
70 67 70 81 74
Duodenal ulcer and
gastric ulcer with or
without erosions
7 5 5 3 10
Erosions only 61 73 57 85 75
Maximal ulcer diameter
(all sites)
5 mm 18 20 17 25 17
5–9 mm 53 55 70 60 81
10 mm 42 39 30 40 42
Helicobacter pylori status
Positive 83 91 72 104 100
Negative 77 76 86 85 96
Unknown 14 20 16 21 19
Disease requiring NSAIDs
Rheumatoid arthritis 79 74 81 99 88
Osteoarthritis 59 69 54 67 71
Psoriatic arthritis 10 13 7 16 11
Ankylosing spondylitis 8 8 8 11 12
Others 11 14 14 11 18
Combinations 7 9 10 6 15

722 March 12, 1998
razole and P0.001 for the comparison with 40 mg
of omeprazole). The success rates were similar when
all 541 patients were analyzed according to the
treatment assigned.
The rates of healing of all types of lesions were
higher in patients treated with 20 mg or 40 mg of
omeprazole than in those treated with ranitidine
(Fig. 1). The rates of gastric-ulcer healing during
the eight-week period were significantly higher with
20 mg of omeprazole (84 percent, P0.001) and
40 mg of omeprazole (87 percent, P0.001) than
with ranitidine (64 percent). When the data were
analyzed to include patients with concurrent duode-
nal ulcers initially, the respective values were 81 per-
cent (62 of 77 patients), 86 percent (62 of 72), and
64 percent (48 of 75). The rates of healing of duo-
denal ulcers were also higher with 20 mg of omep-
razole (92 percent, P0.03) and 40 mg of omepra-
zole (88 percent, P0.17) than with ranitidine (81
percent). When the data were analyzed to include
patients with concurrent gastric ulcers initially, the
respective values were 93 percent (40 of 43), 87 per-
cent (41 of 47), and 79 percent (37 of 47). The
rates of healing of erosions were also higher with 20
mg of omeprazole (89 percent, P0.008) and 40
mg of omeprazole (86 percent, P0.19) than with
ranitidine (77 percent). There were no significant
differences between the two doses of omeprazole for
the three types of lesions. The number of patients in
whom treatment was not successful after eight weeks
as judged by the persistence of moderate-to-severe
symptoms was low: none in the group given 20 mg
of omeprazole, one in the group given 40 mg of
omeprazole, and two in the ranitidine group. The
major reasons for treatment failure were therefore
lack of healing of ulcers or erosions.
Most patients obtained relief from upper gastro-
intestinal symptoms within the first four weeks of ei-
ther treatment. However, the percentage of patients
with improvement of overall symptoms at four weeks
was significantly greater in the group given 20 mg
of omeprazole than in the group given ranitidine
(P0.04 by Wilcoxon’s test). Only 6 percent of
those treated with 20 mg of omeprazole had mod-
erate-to-severe symptoms at four weeks, as com-
pared with 52 percent at base line, whereas 12 per-
cent of those treated with ranitidine had such
symptoms, as compared with 50 percent at base line.
By eight weeks, most patients had mild symptoms or
were free of symptoms, and the differences between
the groups were not significant.
Maintenance Phase
During the maintenance phase, patients treated
with 20 mg of omeprazole were in remission (de-
fined as the absence of a relapse of lesions, dyspeptic
symptoms, and adverse events leading to the discon-
tinuation of treatment) significantly longer than
those treated with ranitidine (P0.004 by the log-
rank test). The estimated proportion of patients in
remission at the end of six months was 72 percent
in the omeprazole group and 59 percent in the ra-
nitidine group (Fig. 2).
All categories of relapse were more common with
ranitidine than with omeprazole. Gastric ulcers re-
curred in 5.2 percent of the patients treated with
omeprazole (11 of 210), as compared with 16.3 per-
cent (35 of 215) of those treated with ranitidine.
The respective proportions with a recurrence of duo-
denal ulcers were 0.5 percent (1 of 210 patients)
and 4.2 percent (9 of 215) and with erosions only,
5.7 percent (12 of 210) and 7.0 percent (15 of 215).
Figure 1. Cumulative Rates of Healing of Gastric Ulcers, Duodenal Ulcers, and Erosions at Four and
Eight Weeks during Treatment with 20 mg of Omeprazole Daily, 40 mg of Omeprazole Daily, or 150
mg of Ranitidine Twice Daily.
0
100
0 8
20
40
60
80
4
Week
Gastric Ulcers Duodenal Ulcers Erosions
NO. OF PATIENTS HEALED/TOTAL
20 mg of
omeprazole
40 mg of
omeprazole
47/70 59/70
45/67 58/67
Ranitidine 35/70 45/70
Healing
(%)
0
100
0 8
20
40
60
80
4
Week
20 mg of omeprazole 40 mg of omeprazole Ranitidine
32/36 33/36
35/42 37/42
31/42 34/42
0
100
0 8
20
40
60
80
4
Week
50/61 54/61
51/73 63/73
37/57 44/57

Prognostic Factors
Healing Phase
The factors associated with a significantly greater
likelihood of successful treatment in the healing
phase were treatment with 20 mg of omeprazole
(P0.04 for the comparison with ranitidine), the
presence of duodenal ulcers or erosions (both
P0.001 for the comparison with gastric ulcers), fe-
male sex (P0.04 for the comparison with male
sex), and H. pylori–positive status (P 0.05 for the
comparison with negative status). At eight weeks the
respective rates of successful treatment among H. py-
lori–positive patients and H. pylori–negative patients
were 83 percent (69 of 83 patients) and 75 percent
(58 of 77) in the group given 20 mg of omeprazole,
82 percent (75 of 91) and 71 percent (54 of 76) in
the group given 40 mg of omeprazole, and 72 per-
cent (52 of 72) and 55 percent (47 of 86) in the ra-
nitidine group.
Maintenance Phase
In the maintenance phase, treatment with 20 mg
of omeprazole and a positive test for H. pylori were
both associated with a significantly greater likeli-
hood of remaining in remission. The estimated pro-
portions of H. pylori–positive patients and H. pylori–
negative patients who remained in remission at six
months were 79 percent and 60 percent, respective-
ly, in the group given 20 mg of omeprazole and 66
percent and 53 percent, respectively, in the raniti-
dine group. An analysis that included only patients
with ulcers showed that those with smaller ulcers at
the initial endoscopy had a significantly higher prob-
ability of successful treatment in the healing phase
(P0.003) and of continued remission during the
maintenance phase (P0.008) than those with larg-
er ulcers. For this analysis, ulcer size was used as a
continuous variable.
Safety
Unfavorable changes in any laboratory variable re-
garded by the investigator as clinically relevant were
classified as adverse events. Data on 533 patients in
the healing phase were available for the evaluation of
adverse events. The overall rates were high: 30 per-
cent in the group given 20 mg of omeprazole, 38
percent in the group given 40 mg of omeprazole,
and 40 percent in the ranitidine group. In part this
may reflect the fact that most of the patients had
chronic arthritis.
Data on 426 patients in the maintenance phase
were available for the evaluation of adverse events.
The mean duration of exposure to the study drug
was longer in the omeprazole group than the raniti-
dine group (151 days vs. 131 days). The frequencies
of adverse events were similar in the omeprazole
group (64 percent) and the ranitidine group (58
percent), despite the longer duration of exposure to
the study drug in the omeprazole group. The six
most common adverse events in each phase of the
study are summarized in Table 2, along with the
proportions of patients who discontinued the study
because of adverse events or for other reasons. A
bleeding duodenal ulcer developed in one patient
after 10 days of maintenance treatment with omep-
razole. The patient was hospitalized and treated
with 20 mg of omeprazole twice daily orally and
2 units of blood, and the bleeding stopped.
DISCUSSION
When peptic ulcers develop in patients taking
NSAIDs, the preferred approach is to stop the NSAID
when possible.20 Ulcers heal slowly during treatment
with H2-receptor antagonists when NSAIDs are con-
tinued and more quickly when they are stopped.8,14,21
However, stopping the NSAID therapy may exacer-
bate the underlying arthritis. We compared the abil-
ities of omeprazole and ranitidine to heal and pre-
vent NSAID-associated gastroduodenal lesions in
patients receiving continuous NSAID therapy. Be-
cause we studied patients with lesions at base line,
who are at higher risk for ulceration than patients
without lesions,22 our study is relevant to clinical sit-
uations in which ulcer prophylaxis would be consid-
ered. Omeprazole has also been shown to be effec-
tive in placebo-controlled trials in preventing ulcers
in patients who are taking NSAIDs but who are at
lower risk for ulceration.23,24
The main end point for the healing phase was suc-
Figure 2. Estimated Rates of Remission among Patients Treated
with 20 mg of Omeprazole Daily or 150 mg of Ranitidine Twice
Daily for up to 26 Weeks.
P0.004 by the log-rank test for the difference between groups.
0
100
0 26
20
40
60
80
4
2 6 8 10 12 14 16 18 20 22 24
Week
Omeprazole
Ranitidine
Ranitidine
P0.004
Omeprazole
210
215
205
205
177
160
145
114
NO. AT RISK OF RELAPSE
Patients
in
Remission
(%)

724 March 12, 1998
cessful treatment, defined as complete healing of ul-
cers, the disappearance of erosions or a marked re-
duction in the number of erosions, and the presence
of no more than minimal symptoms of dyspepsia.
Treatment failure in the maintenance phase was de-
fined as reappearance of these features or the discon-
tinuation of treatment due to adverse events. We
chose these end points before the study began be-
cause we believed that patients would consider suc-
cess in all these areas to be the most desirable out-
come. These goals were more demanding than those
in most previous studies,8-11,14,15,22-25 especially since
the primary assessment was based on all patients
treated. Nevertheless, treatment was successful in 80
percent of the patients given 20 mg of omeprazole
daily for eight weeks in the healing phase, and this
treatment was clearly superior to 150 mg of raniti-
dine twice daily. The rates of healing of gastric ul-
cers, duodenal ulcers, and erosions were all better
with either 20 mg or 40 mg of omeprazole than
with ranitidine. Use of the higher dose of omepra-
zole provided no obvious advantage overall (rate of
successful treatment, 79 percent).
Our study was not designed to investigate compli-
cations of ulcers, since very large numbers of pa-
tients would be required to yield significant results.
A bleeding duodenal ulcer developed in one patient
after 10 days of maintenance treatment with omep-
razole. In the whole program, including the study
reported by Hawkey et al.26 in the next article in this
issue as well as an assessment of prophylaxis among
patients who were initially free of ulcers,24 only 1 of
654 patients who were taking 20 mg of omeprazole
and 2 of 331 patients who were taking placebo had
such complications.
In previous studies, the use of standard doses of
H2-receptor antagonists has been disappointing with
respect to preventing NSAID-associated ulcers. A
400-mg dose of cimetidine each night for 10 months
was ineffective.25 Two large placebo-controlled trials
of ranitidine showed a substantial reduction in the
incidence of duodenal ulcers during NSAID treat-
ment, but no effect on gastric ulcers.9,10 This is a
problem, since most ulcers that develop during
NSAID treatment are gastric,27-29 as we also found.
A large, prospective evaluation showed that therapy
with H2-receptor antagonists does not reduce the
risk of ulcer complications in NSAID users.30 Find-
ings such as these led to the conclusion that NSAID-
associated gastric ulcers are not caused by acid.31
However, our findings challenge this view. The rate
of continued remission was significantly higher with
omeprazole than with ranitidine, presumably be-
cause of the greater inhibition of acid induced by
omeprazole.32 In keeping with the view that acid
suppression is required to prevent NSAID-associated
gastric damage, Taha et al. recently showed that high-
dose famotidine (40 mg twice daily) gave better
*All other drugs were given in a double-blind manner.
†The main other reason was unwillingness to continue in the study (four
patients in the group given 20 mg of omeprazole, four in the group given
40 mg of omeprazole, six in the ranitidine group, and three given open-
label omeprazole).
‡The main other reason was unwillingness to continue in the study (sev-
en patients in the omeprazole group and seven in the ranitidine group).
TABLE 2. INCIDENCE OF MODERATE-TO-SEVERE ADVERSE EVENTS
IN ALL PATIENTS AND REASONS FOR DISCONTINUATION
OF TREATMENT AND FOLLOW-UP IN PATIENTS INCLUDED
IN THE EFFICACY ANALYSIS.
VARIABLE HEALING PHASE
OMEPRAZOLE,
20 mg/DAY
(N173)
OMEPRAZOLE,
40 mg/DAY
(N185)
RANITIDINE,
150 mg
TWICE DAILY
(N175)
OPEN-LABEL
OMEPRAZOLE,
40 mg/DAY*
(N81)
Mean duration of
exposure to
drug (days)
36 37 40 41
Most common ad-
verse events
(% of patients)
Diarrhea 1.7 1.6 4.0 2.5
Arthritis 2.3 0.5 3.4 2.5
Headache 0.6 1.1 2.3 3.7
Nausea 0.6 1.6 1.7 2.5
Constipation 0.6 0.5 2.3 1.2
Flatulence 0.6 0.5 2.3 1.2
Discontinuation of
treatment
(% of patients)
10.2 10.1 14.1 3.9
Adverse event or
lack of efficacy
2.8 3.2 8.5 1.1
Other reasons† 7.4 6.9 5.6 2.8
MAINTENANCE PHASE
OMEPRAZOLE,
20 mg/DAY
(N210)
RANITIDINE, 150 mg
TWICE DAILY
(N215)
Mean duration of
exposure to
drug (days)
151 131
Most common ad-
verse events
(% of patients)
Arthritis 2.4 3.2
Rheumatoid
arthritis
4.3 1.4
Vomiting 2.9 2.3
Abdominal pain 2.9 1.9
Diarrhea 3.3 1.4
Respiratory tract
infection
2.4 2.3
Discontinuation of
treatment
(% of patients)
14.5 13.3
Adverse event 6.1 3.2
Other reasons‡ 8.4 10.1

protection against NSAID-associated gastric ulcer
than the standard dose (20 mg twice daily) or pla-
cebo.28 Although our study did not include a place-
bo group, three other recent trials showed substan-
tial reduction in the incidence of NSAID-associated
gastroduodenal ulcer in patients treated with 20 mg
of omeprazole as compared with placebo for three
or six months.23,24,26
The analysis of prognostic factors showed that
treatment was more likely to be successful in patients
with smaller ulcers at the initial endoscopy. This was
no surprise, since ulcer size has often been noted to
affect the healing rate, with larger ulcers healing more
slowly,33 but we did not expect those with larger ul-
cers initially to be more likely to relapse during the
maintenance phase. This finding should be added to
the list of risk factors that may be clinically useful
when one is deciding whether to recommend preven-
tive therapy in patients who are receiving NSAIDs.
There is disagreement whether H. pylori infection
increases the risks associated with NSAIDs.34,35 Al-
though it would seem logical to remove all poten-
tially ulcerogenic factors, when the study started we
were aware of data showing that H. pylori could ab-
rogate NSAID-associated reductions in gastric mu-
cosal synthesis of prostaglandins19 and that H. pylori
status did not influence the risk of NSAID-associat-
ed bleeding ulcers.17,18 We therefore decided not to
eradicate H. pylori. We found higher rates of success
in H. pylori–positive patients than in those who were
negative for H. pylori during both phases of the
study regardless of treatment assignment. We stud-
ied a selected group of patients, and proving that
H. pylori infection is beneficial to NSAID users
would require a formal randomized study.
In conclusion, in patients taking NSAIDs daily,
we found that treatment with 20 mg of omeprazole
daily is superior to ranitidine with respect to healing
and preventing gastroduodenal ulcers and erosions,
as well as controlling dyspeptic symptoms.
Supported by Astra Hässle, Mölndal, Sweden.
Dr. Yeomans serves as a consultant for Searle Australia.
We are indebted to Dr. M. Frame for valuable help with the draft-
ing and editing of the manuscript, to all study personnel who took
part at each clinic, and to all those who were involved in packing
the study drugs, monitoring the study, and processing the data.
APPENDIX
The following persons participated in the ASTRONAUT Study: Steer-
ing committee — N. Yeomans, A. Swannell, C. Hawkey, S. Eriksson, A.
Walan; Coordinating group — M. Bjersing, I. Florén, K. Gillon, M.
Jallinder, G. Långström, J. Lindfeldt, J. Naesdal, K. Rutgersson, I. Wilson;
Belgium — M. Cremer, M. De Vos; Canada — M. Oravec, R. Beaudry,
P
. Paré, D. Lloyd, G. Michaud, A. Farley, K. MacCannell, R. Rossman, J.
Wright, L. Scholar, P
. Gagnon, N. Chiba, I. Dan Dattani, B. Haraoui;
Czech Republic — V. Liskovcova, D. Bastecka, P
. Bradna, K. Sirova, J.
Vachtenheim; Denmark — K. Lauritsen, J. Andersen, J. Rask Madsen; Ire-
land — J. Crowe, N. Keeling, P
. O’Connell, M. Molloy; Finland — S.
Kyrönpalo-Kauppinen, T. Jääskeläinen, P
. Hannonen, R. Luukkainen, P
.
Järvinen, E. Jukka, P
. Nuotio, T. Koivisto, P
. Franzen, T. Tuomiranta, P
.
Saloranta; France — M. Bigard, D. Goldfain, G. Coulanjon, E. Dorval;
Germany — M. Wagner, W. Tenbieg, W. Kriegel; Iceland — B. Thjodleif-
sson, S. Björnsson, A. Theodors; Norway — E. Kittang, E. Lind, D.
Malm, R. Breckan, H. Waldum; Slovak Republic — I. Rybar; South Af-
rica — A. Simje, J. Louw, S. Spies; United Kingdom — O. Epstein, C.
Moran, M. Davis, D. Fine, P
. Mills, W. Burnham, D. Foster, A. Collins, A.
Wade, P
. Prouse, J. Mathews.
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65-9.

RESEARCH ARTICLE
PPI versus Histamine H2 Receptor
Antagonists for Prevention of Upper
Gastrointestinal Injury Associated with Low-
Dose Aspirin: Systematic Review and Meta-
analysis
Chen Mo1,2
, Gang Sun1
, Yan-Zhi Wang1
, Ming-Liang Lu1
, Yun-Sheng Yang1
*
1 Institute of Digestive Diseases, Chinese PLA General Hospital, Beijing 100853, China, 2 Cadre Ward No.
2, the General Hospital of Chinese Armed Force Police, Beijing 100039, China
* sunny301ddc@126.com
Abstract
This study compared proton pump inhibitors (PPIs) and histamine H2 receptor antagonists
(H2RAs) for prevention of low-dose aspirin (LDA)-related gastrointestinal (GI) erosion, ulcer
and bleeding. Electronic databases including PubMed, Embase, Cochrane Central Register
of Controlled Trials, Chinese National Knowledge Infrastructure, Chinese Biomedical Litera-
ture Database, and WanFang Data were searched from the date of their establishment to
December 31, 2013. Randomized controlled trials comparing PPIs and H2RAs for preven-
tion of GI injury associated with low-dose aspirin (LDA) were collected. Two reviewers inde-
pendently abstracted studies and patient characteristics and appraised study quality using
the Cochrane risk-of-bias tool. Meta-analysis was performed using RevMan 5.1 software.
We included nine RCTs involving 1047 patients. The meta-analysis showed that PPIs were
superior to H2RAs for prevention of LDA-associated GI erosion/ulcer [odds ratio (OR=0.28,
95% confidence interval (CI): 0.16–0.50] and bleeding (OR=0.28, 95% CI: 0.14–0.59). In
conclusion, PPIs were superior to H2RAs for prevention of LDA-related GI erosion/ulcer and
bleeding. Higher quality, large, multicenter RCTs are needed to demonstrate the preventive
effect of the two acid-suppressive drugs.
Introduction
Rationale
Low-dose aspirin (LDA) is usually defined as 75–325 mg daily. The mechanism of gastrointes-
tinal (GI) injuries associated with LDA can be subdivided into topical and systemic effects.
With the widespread use of LDA in primary and secondary prevention of cardiovascular and
cerebrovascular diseases, the incidence of LDA-related upper GI injuries, including gastric
PLOS ONE | DOI:10.1371/journal.pone.0131558 July 6, 2015 1 / 13
OPEN ACCESS
Citation: Mo C, Sun G, Wang Y-Z, Lu M-L, Yang Y-S
(2015) PPI versus Histamine H2 Receptor
Antagonists for Prevention of Upper Gastrointestinal
Injury Associated with Low-Dose Aspirin: Systematic
Review and Meta-analysis. PLoS ONE 10(7):
e0131558. doi:10.1371/journal.pone.0131558
Editor: John Green, University Hospital Llandough,
UNITED KINGDOM
Received: March 23, 2015
Accepted: June 3, 2015
Published: July 6, 2015
Copyright: © 2015 Mo et al. This is an open access
article distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: The authors have no support or funding to
report.
Competing Interests: The authors have declared
that no competing interests exist.

mucosal erosion, peptic ulcer and bleeding, has increased annually. A retrospective study
found that 50% of patients who were long-term LDA users were taking concomitant gastro-
intestinal protective drugs [1]. Researchers have also found that physicians have poor aware-
ness of LDA-induced GI damage [2], so the prevention of LDA-associated GI injuries has been
an important topic for cardiologists and gastroenterologists.
Objectives
It is well known that proton pump inhibitors (PPIs) reduce the incidence of LDA-associated GI
ulcers and bleeding [3–7]. However, concerns about PPI–clopidogrel interaction, overprescrib-
ing of PPIs [8] and side effects of PPIs [9–11] have increased in recent years. Histamine H2
receptor antagonists (H2RAs) are more cost-effective and safer compared with PPIs. Taha et al.
confirmed that standard doses of famotidine decrease LDA-associated GI injuries and suggested
that high-dose H2RAs are an alternative to PPIs to prevent LDA-associated GI bleeding [12].
Rostom et al. pointed out in their systematic review that PPIs were superior to H2RAs for pre-
vention of nonsteroidal anti-inflammatory drug (NSAID)-induced gastroduodenal ulcer [13].
Only a few studies have investigated prevention of LDA-associated GI ulcers and bleeding,
and it has not been established whether H2RAs are a rational alternative to PPIs. The present
meta-analysis compared the effect of PPIs and H2RAs for prevention of LDA-related upper GI
injuries, and attempted to provide the best evidence for clinical decision making.
Methods
The reporting format of this systematic review was based on the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) Statement revised in 2009 [14].
Eligibility criteria
Inclusion criteria. (1) The design of studies was randomized controlled trials. (2) Patients eligi-
ble for inclusion were adults (aged 18 years) who used LDA for at least two continuous
weeks. Studies were included regardless of the patient’s concomitant medication, medical con-
dition and comorbidity. (3) Intervention measures: oral PPIs were used in the experimental
group and H2RAs were used as the control drugs. (4) Outcomes of studies: the incidence of
LDA-related peptic ulcer and upper GI bleeding in the two groups was observed no matter
which was primary endpoint or second endpoint. Exclusion criteria: non-randomized clinical
trials, cohort studies, case–control studies, pharmacokinetic experiments, and case reports.
Search
We conducted a comprehensive literature search of PubMed, Embase, Cochrane Central Regis-
ter of Controlled Trials (CENTRAL), Chinese National Knowledge Infrastructure (CNKI),
WanFang Data and Chinese Biomedical Literature Database (CBM) from their inception to
December 31, 2013. Only studies published in English and Chinese were included. The search
terms included combinations of the following keywords: aspirin, acetylsalicylic, low-dose aspi-
rin, LDA, proton pump inhibitor, PPI, esomeprazole, pantoprazole, omeprazole, rabeprazole,
lansoprazole, histamine receptor antagonist, H2RA, famotidine, ranitidine, cimetidine, nizati-
dine, roxatidine, and randomized controlled trial. The search strategy for PubMed as an exam-
ple is presented below.
#1 aspirin OR acetylsalicylic OR low-dose aspirin OR LDA
PPI versus H2RA

#2 proton pump inhibitor OR PPI OR omeprazole OR esomeprazole OR lansoprazole OR pan-
toprazole OR rabeprazole
#3 histamine receptor antagonist OR H2RA OR famotidine OR ranitidine OR cimetidine OR
nizatidine OR roxatidine
#4 #1 AND #2 AND #3
Study selection
Two independent reviewers (C Mo and YZ Wang) used a predefined relevance criteria form to
screen the studies. After reading the title and abstract, the documents that did not meet the
inclusion criteria and duplicate articles were eliminated. The full text of relevant articles was
screened for inclusion. Discrepancies at any stage were resolved by discussion with a third
reviewer (G Sun). The level of agreement during screening was evaluated using a κ statistic and
we determined a priori that an acceptable level of agreement should be at least 0.60.
Data collection process
The data were extracted after the full text reading. Two independent reviewers (C Mo and YZ
Wang) extracted the data. A third independent reviewer (G Sun) reviewed the data abstraction
and resolved any discrepancies. When multiple publications reported data from the same pop-
ulation, the trial reporting the primary outcome of interest was considered the major publica-
tion. The extracted data included: authors and publication year, medical condition or risk
factor, sample size, intervention measures, drug doses, course of treatment, drug co-adminis-
tration, GI ulcer/erosion or bleeding events, and statistical methods.
Risk of bias in individual studies
Risk of bias in individual studies was assessed using the Cochrane Risk of Bias tool. This tool
assesses the following six domains of bias: sequence generation (decided as low risk, high risk
and unclear risk), allocation concealment (decided as low risk, high risk and unclear risk),
blinding of outcome assessment (decided as low risk, high risk, and unclear risk), incomplete-
ness outcome data (decided as low risk, high risk and unclear risk), selective outcome reporting
(decided as low risk, high risk and unclear risk), and other types of bias (decided as low risk,
high risk and unclear risk). The two reviewers (C Mo and YZ Wang) assessed study quality
independently and the assessments were verified by the third reviewer (G Sun).
Statistical analysis
All analyses were conducted using Review Manager version 5.1. For dichotomous data, sum-
mary statistics were expressed as odds ratio (OR) with 95% confidence interval (CI) for inter-
pretation. Statistical significance level was considered as α = 0.05. Statistical heterogeneity in
the included studies was examined using I2
statistics. If the result of the heterogeneity test was
P0.10, a fixed-effect model was used for the meta-analysis; if P0.10, the sources of heteroge-
neity were investigated. If no obvious clinical heterogeneity and no clear statistical heterogene-
ity occurred, a random-effect model was used for the meta-analysis. If the clinical
heterogeneity was too large, data synthesis should be abandoned and a single research analysis
should be used instead. Sensitivity analysis was performed on some of the results of aggregate
analysis. Potential publication bias was evaluated by funnel plot analysis.
PPI versus H2RA

Results
Study selection
The literature search identified 735 articles: 497 published in English and 238 in Chinese. Five
hundred and seventy-two articles were excluded because they were duplicate publications or
did not meet the inclusion criteria. One hundred and twenty articles were excluded after read-
ing the titles and abstracts. Forty-three full-text articles were retrieved, including 34 articles
published in English and nine in Chinese. Twelve articles were excluded because they were not
RCTs[15–26]; eight because they compared the therapeutic effects[18,27–33]; seven because
they did not investigate upper GI endpoints[34–40]; and seven because they were pharmacoki-
netic experiments[41–47]. The details of References to Studies Excluded in meta-analysis
please see in Supporting Information (S1 File). Nine RCTs fulfilled the inclusion criteria
including three in English [48–50] and six in Chinese [51–56]. Fig 1 shows the flow chart of the
retrieved articles. The level of agreement between the two reviewers was acceptable (κ = 0.67).
Fig 1. Flow chart of retrieved articles.
doi:10.1371/journal.pone.0131558.g001
PPI versus H2RA

Study characteristics
All the studies included were published in the US or China between 2009 and 2013. Demo-
graphic and clinical characteristics of the studies included in this meta-analysis are summa-
rized in Table 1. The number of participants in the experimental group ranged from 42 to 163
and the duration of follow-up from 4 to 52 weeks. The PPIs examined were pantoprazole, rabe-
prazole, esomeprazole, omeprazole and lansoprazole, at doses ranging from 10 to 40 mg/day.
The number of participants in the control group ranged from 22 to 148 and the duration of fol-
low-up from 4 to 52 weeks. The H2RAs in the control group included famotidine (20–80 mg/
day) and ranitidine (300 mg/day). The risk factors of patients differed among the RCTs. One
RCT included patients with peptic ulcer or erosions [48]; one RCT included patients who were
negative for Helicobacter pylori and without a history of ulcer bleeding or active ulcers [52];
four RCTs included patients with acute coronary syndrome or myocardial infarction
[49,50,55,56]; and one RCT included older patients who needed long-term LDA treatment
[52]. Three RCTs had endoscopy before and after treatment [48,49,53]. Four RCTs included
patients who co-administered clopidogrel and enoxaparin or another anticoagulant
[49,50,55,56].
Risk of bias across studies
The risk of bias within the eight studies included in the meta-analysis is summarized in
Table 2. Figs 2 and 3 show the risk of bias graph and the risk of bias summary.
Comparison of incidence of LDA-associated GI ulcers/erosions. Seven of the eight
included studies reported the incidence of LDA-associated GI ulcer/erosions in the PPI and
H2RA groups. There was no statistical heterogeneity among the results (I2
= 0, P = 0.70), so a
Table 1. Characteristics of studies included in the meta-analysis.
Prevention Group Control Group
Studies Risk
Factor
Co-
administration
Course n Drug Usage Ulcer/
Erosion
(%)
Bleeding
(%)
n Drug Usage Ulcer/
Erosion
(%)
Bleeding
(%)
Ng 2010
[48]
Ulcer or
erosions
no 48w 65 pantoprazole 20 mg
bid
0 (0) 0 (0) 65 famotidine 40mg
bid
8 (12.3) 5 (7.7)
Ng 2012
[49]
ACS or
MI
Clopidogrel and
anticoagulant
4-52w 163 esomeprazole 20 mg
qd
1 (0.6) 3 (1.8) 148 famotidine 40 mg
qd
6 (4.1) 12 (8.1)
Yano
2012[50]
ACS Clopidogrel 12m 65 Omeprazole 10 mg
qd
- 3(4.6) 65 famotidine 20 mg
qd
- 1(1.5)
Guo M
2009[51]
Not clear no 90d 42 Omeprazole or
esomeprazole
20 mg
qd
6 (14.3) - 22 famotidine 20 mg
bid
5 (22.7) -
Sun RR
2012[52]
Elders no 90d 40 rabeprazole 20 mg
qd
3 (7.5) 0 (0) 40 ranitidine 150mg
bid
11 (27.5) 1(2.5)
Wang YP
2012[53]
HP-, no
ulcer
history
no 90d 23 lansoprazole 30 mg
qd
2 (8.7) 0 (0) 22 famotidine 20 mg
bid
6 (27.3) 1(4.5)
Hu L
2012[54]
Not clear no 90d 50 rabeprazole 10 mg
qd
5(10) - 48 famotidine 20 mg
bid
9 (18.8) -
Lu BJ
2013[55]
ACS Clopidogrel 30d 50 omeprazole 40mg
qd
- 2(4) 50 ranitidine 150 mg
bid
- 9(18)
Wang J
2012[56]
ACS Clopidogrel 90d 43 esomeprazole 20mg
bid
3 (7.0) - 46 famotidine 20 mg
bid
5 (10.9) -
ACS:acute coronary syndrome; MI:myocardial infarction
doi:10.1371/journal.pone.0131558.t001
PPI versus H2RA

fixed-effect model was used for meta-analysis. The result showed that PPIs were superior to
H2RAs (OR = 0.28, 95% CI: 0.16–0.50) for prevention of LDA-associated GI ulcers or erosions
(Fig 4).
Comparison of incidence of LDA-associated GI bleeding. Six of the eight included stud-
ies reported the incidence of LDA-associated GI bleeding in the PPI and H2RA groups. There
was no statistical heterogeneity among the results (I2
= 6%, P = 0.38) and a fixed-effect model
Table 2. Bias risk evaluation of studies included in the meta-analysis.
Studies Random sequence
generation
Allocation
concealment
Blinding Incomplete outcome
data
Selective
reporting
Other bias
Guo M 2009 [51] Low risk Unclear risk Unclear
risk
Low risk Low risk Unclear
risk
Ng 2010 [48] Low risk Low risk Low risk Low risk Low risk Unclear
risk
Yano 2012[50] Low risk Unclear risk Unclear
risk
Low risk Low risk Low risk
Wang YP 2012
[53]
Unclear risk Unclear risk Unclear
risk
Unclear risk Low risk Unclear
risk
Sun RR 2012 [52] Unclear risk Unclear risk Unclear
risk
risk
Ng 2012 [49] Low risk Low risk Low risk Low risk Low risk Unclear
risk
Hu L 2012 [54] Unclear risk Unclear risk Unclear
risk
risk
Wang J 2012 [56] Low risk Unclear risk Unclear
risk
Low risk Low risk Unclear
risk
Lu BJ 2013 [55] Unclear risk Unclear risk Unclear
risk
risk
doi:10.1371/journal.pone.0131558.t002
Fig 2. Risk of bias graph.
PPI versus H2RA

Fig 3. Risk of bias summary.
PPI versus H2RA

was used for meta-analysis. The result showed that PPIs were superior to H2RAs (OR = 0.28
95%CI: 0.14–0.59) for prevention of LDA-associated GI bleeding (Fig 5).
Publication bias
Funnel plot analysis of the seven RCTs of PPIs and H2RAs for prevention of LDA-associated
GI ulcers/erosions indicated an asymmetrical distribution that indicated the presence of publi-
cation bias (Fig 6).
Discussion
Summary of evidence
It is well known that long-term use of LDA increases the risk of upper GI injuries and bleed-
ing [57]. The pathogenetic mechanism involves topical effects of acid reverse diffusion and
Fig 4. H2RAs and PPIs for prevention of LDA-associated GI ulcers/erosions.
Fig 5. PPIs and H2RAs for prevention of LDA-associated GI bleeding.
PPI versus H2RA

systemic effects of inhibiting prostaglandin synthesis through the cyclo-oxygenase-1 pathway.
Anti-secretory drugs are effective in reducing upper GI mucosal injuries and bleeding compli-
cations by inhibiting gastric acid secretion and lowering gastric pH. Studies of prophylaxis for
LDA-associated GI injuries have focused on PPIs, but PPIs are expensive and their long-term
use has side effects such as Clostridium-difficile-associated diarrhea, community-acquired
pneumonia, osteoporosis and fractures [9–11]. LDA is frequently prescribed concurrently
with clopidogrel in dual antiplatelet therapy. However, PPI–clopidogrel interaction increases
cardiovascular risks so the use of PPI with LDA is currently restricted. As traditional anti-
secretory drugs, H2RAs are cost-effective. The American College of Cardiology Foundation
(ACCF), American College of Gastroenterology (ACG) and American Heart Association
(AHA) revised the expert consensus document of 2010 on reducing the GI risks of antiplatelet
therapy and NSAID use, which states that H2RAs are a reasonable alternative to PPIs for the
prophylaxis and treatment of LDA-associated GI injury [58]. However, the preventive effect
of H2RAs is still controversial. The OITA-GF2 study indicated that lansoprazole might be
more effective than famotidine in preventing the development of LDA-related gastroduode-
nal injuries [59]. Ng et al. concluded that H2RAs were inferior to PPIs for preventing LDA-
related upper GI injuries in a cohort study and RCTs [48,49,60]. The present meta-analysis
compared the preventive effect of PPIs and H2RAs in LDA-associated GI injuries, and
explored the advantages of H2RAs, so as to provide more reasonable and cost-effective drugs
for clinical practice.
There were nine RCTs included in our meta-analysis. We found that PPIs were superior to
H2RAs for prevention of LDA-associated upper GI ulcers/erosions and bleeding. However,
among the nine RCTs included, six studies were from mainland China and had small samples
and were poorly reported. The bias of random sequence generation, allocation concealment,
blinding method, incomplete outcome data, and other bias in most of the studies were not
clear, which means that the results of our meta-analysis should be interpreted with caution.
Fig 6. Funnel plot analysis of the trials of H2RAs and PPIs for prevention of LDA- associated ulcers/
erosions.
PPI versus H2RA

Lanas et al. discovered in a case–control study that H. pylori infection increased the risk of
GI bleeding (OR, = 4.7; 95% CI: 2.0–10.9) and indicated that H. pylori infection was an inde-
pendent risk factor for LDA-associated GI bleeding [61]. Only one RCT in our analysis
included patients who were negative for H. pylori, and one RCT showed H. pylori eradication.
Most of our studies did not determine H. pylori infection status, thus, it is not clear whether
infection interacted with LDA to increase mucosal injuries. So, selection bias may have been
present in our meta-analysis.
Limitations
Because meta-analyses are secondary research, their conclusions are influenced by the quality
of the included studies. There were some limitations in our meta-analysis that should be men-
tioned. First, the quality of some studies was low and we need more high-quality, multicenter,
high-standard RCTs in the future. Second, we searched the unpublished articles in English and
Chinese, but were unable to identify all relevant unpublished data to include. Funnel plot anal-
ysis showed that publication bias was also present. Third, we searched articles written in
English and Chinese, but only three RCTs in English were included, and they may have had
reporting bias. Last, All of the nine trials included Asian patients, one from Japan, two from
Hong Kong and the others from mainland China. So the representativeness of patients are not
well enough.
Conclusions
In conclusion, PPIs were superior to H2RAs in preventing LDA-associated GI ulcers/erosions
and bleeding. Some of the RCTs included in our meta-analysis were poorly reported and of low
quality, therefore, our meta-analysis should be interpreted with caution. More multicenter,
high-quality RCTs are needed to compare two anti-secretory drugs for prevention of LDA-
associated GI injuries.
Supporting Information
S1 File. References to Studies Excluded in Meta-analysis.
(PDF)
S2 File. PRISMA Statement.
(PDF)
S1 PRISMA Checklist. PRISMA 2009 Checklist.
(DOC)
Author Contributions
Conceived and designed the experiments: CM YSY. Performed the experiments: CM MLL
YZW. Analyzed the data: CM GS YZW. Contributed reagents/materials/analysis tools: CM GS
YZW. Wrote the paper: CM.
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