CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2003;1:51–56

Sucralfate Therapy in NSAID Bleeding Gastropathy

JUAN–R. MALAGELADA,* ARTURO RODRÍGUEZ DE LA SERNA,‡ HANS GERT DAMMANN,§

MIQUEL PONS,㛳 CARLOS ARMAS,¶ MIQUEL SALA,# XAVIER TENA,** ENRIQUE CELDRÁN,‡‡
and ANTONI MESA‡‡
*Department of Gastroenterology, Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona; ‡Department of Internal Medicine,
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; §Wissenschaftliches Institut, Hamburg, Germany; 㛳Department of Rheumatology,
Hospital Municipal de Badalona, Badalona; ¶Department of Rheumatology, Hospital Clı́nico Universitario “Lozano Blesa,” Zaragoza;
#Department of Internal Medicine, Hospital de Figueres, Figueres; **Department of Rheumatology, “Germans Trias i Pujol,” Badalona; and
‡‡Department of Clinical Research, Merck Farma y Quı́mica, S.A., Mollet del Vallés, Barcelona, Spain

Background & Aims: A randomized, double-blind, place-
bo-controlled, multicenter study was conducted to as-
sess the efficacy of 2 g sucralfate suspension in treating
gastric mucosal lesions caused by long-term treatment
with nonsteroidal anti-inflammatory drugs (NSAIDs).
Methods: Only patients given NSAIDs continuously for at
least 2 months with positive fecal occult blood (FOB)
and endoscopically confirmed mild to moderate muco-
sal lesions (Lanza scale, grades 2– 4) were included.
After 1-week run-in phase, patients were stratified into 2
groups according to gastropathy-related symptoms dur-
ing the preceding 7 days (symptomatic vs. asymptom-
atic) and randomized to 2 g (10 mL) of sucralfate sus-
pension or placebo twice a day over a 6-week period.
NSAIDs were given according to each patient’s dosage
schedule and always after meals. Results: Twenty-five
patients received sucralfate and 25 received placebo. At
the end of the study, 68% (17/25) of patients given
sucralfate had no lesions (Lanza grade 0) on endoscopy
compared with 35% (8/23) in controls (P ⴝ 0.042). The
Lanza grades in patients given sucralfate were signifi-
cantly improved compared with the placebo patients
(P ⴝ 0.022). Conclusions: In this target population se-
lected according to positive FOB test and endoscopic
evidence of mucosal injury, chronic administration of
sucralfate significantly decreased NSAID-induced gastric
erosions.
onsteroidal anti-inflammatory drugs (NSAIDs) are
N widely used to treat pain and inflammation, with
more than 700 million prescriptions written worldwide
every year.1 The therapeutic benefits of NSAIDs are well
established, and, as a rule, these agents possess an en-
hanced safety margin. However, widespread use in in-
dustrialized countries has led these drugs to become the
leading cause of serious adverse events following a phar-
macologic therapy.2,3 Gastroduodenal toxicity accounts
for 21%–25% of reported adverse reactions in patients
taking these drugs in combination with other medica-
tions.4 – 8 Inhibition of gastroduodenal prostaglandin
(PG) synthesis by NSAIDs9 impairs PG-dependent mu-
cosal protective mechanisms and facilitates the develop-
ment of ulcerative lesions with a high rate of complica-
tions, such as hemorrhage and perforation.3,10,11
Dyspepsia or gastrointestinal intolerance is the most
common cause of NSAID withdrawal,12 and about 10%–
12% of all patients given NSAIDs discontinue treatment
because of direct adverse effects including mucosal dam-
age and bleeding.13,14 The prevalence of severe gastroin-
testinal lesions caused by ingestion of NSAIDs varies
between 10% and 30% for the gastric mucosa and be-
tween 2% and 19% for the duodenal mucosa,15 and the
risk is dose-dependent. The development of new cyclo-
oxygenase (COX) 2–specific inhibitors offers promise of
NSAIDs with improved gastrointestinal tolerability, but
the use of these new compounds has not become gener-
alized yet.
Sucralfate, the aluminum salt of sucrose octosulfate, is
an antiulcer drug that increases the release of endogenous
PGE2 from the gastric mucosa16,17 and exerts a trophic
effect by activating genes encoding for epidermal growth
factor and its receptors.18,19 Thus, its mode of action is
different from alkalinizing agents, such as antacids or
antisecretory agents. It can be described as mucosal-
protective because it strengthens the natural defense
mechanisms of the gastrointestinal tract and because it
seems to protect the ulcerated area against attack by acid
and pepsin.
It has been shown that sucralfate reduces mucosal
damage from various strong irritants including etha-
nol20,21 and NSAIDs.16,22,23 Accordingly, it may be pos-
Abbreviations used in this paper: FOB, fecal occult blood; NSAID,
nonsteroidal anti-inflammatory drug; PG, prostaglandin.
© 2003 by the American Gastroenterological Association
1542-3565/03/$35.00
doi:10.1053/jcgh.2003.50008
52 MALAGELADA ET AL.
tulated that this agent may be useful to prevent gastric
mucosal lesions in patients taking NSAIDs. In fact, the
effectiveness of sucralfate coadministered with NSAIDs
in long-term therapeutic regimens has been assessed in a
few placebo-controlled studies.24 –26 In these studies,
however, the presence of peptic and nonpeptic symptoms
at baseline was an indispensable criterion for patients’
enrollment and elective endoscopic assessment. Unfortu-
nately, it also resulted in heterogeneous patient groups,
many of whom did not have significant gastroduodenal
lesions, only symptoms. To prevent selection bias related
to the presence of upper gastrointestinal symptoms, we
designed the present study to include only patients with
positive fecal occult blood and endoscopically confirmed
mild to moderate mucosal lesions. Thus, we have evalu-
ated the efficacy of sucralfate in the healing of gastric
bleeding lesions induced by chronic treatment with
NSAIDs in both symptomatic and asymptomatic indi-
viduals, all of whom had proven mucosal injury.
Materials and Methods
A randomized, double-blind, placebo-controlled, mul-
ticenter, multinational, phase III study was conducted to
evaluate the efficacy of 2 g (10 mL) sucralfate suspension,
administered orally twice a day, in treating gastric mucosal
lesions caused by long-term treatment with NSAIDs.
Subject Population
Between October 1996 and June 1998, patients with a
definitive diagnosis of rheumatoid arthritis, ankylopoietic
spondylitis, osteoarthritis, or psoriatic arthritis attending the
outpatient clinics of the Services of Rheumatology of 7 acute-
care teaching hospitals or practices in Spain and Germany were
eligible to participate in the study provided that oral or rectal
NSAIDs within a predetermined dose range had been contin-
uously taken for at least 2 months before the study. The
allowed daily doses of the commonly used NSAIDs were as
follows: 100 –150 mg of diclofenac, 500 –1000 mg of
naproxen, 75–150 mg of indomethacin, 600 –1800 mg of
ibuprofen, 10 –20 mg of piroxicam, 60 –120 mg of acemeta-
cin, 10 –20 mg of tenoxicam, 300 – 600 mg of etodolac, 100 –
200 mg of ketoprofen, and 7.5–15 mg of meloxicam.
Patients of both sexes and of any ethnic group, above 40
years of age (postmenopausal or surgically sterilized women or
women using a reliable contraceptive method), in whom there
were no anticipated changes in their anti-inflammatory ther-
apy schedule within the next 10 weeks were included. Exclu-
sion criteria were as follows: known hypersensitivity to the
study medication including NSAIDs or history of drug-in-
duced anaphylactic shock; concurrent treatment with steroids
at a daily dose ⱖ10 mg of prednisone (or its equivalent); severe
gastrointestinal disorders including carcinoma, Zollinger-Elli-
son syndrome, active peptic ulcer, and bleeding esophagitis;
hematemesis, melena, or gastrointestinal perforation; antiulcer
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 1, No. 1
treatment with H2-receptor antagonists, proton pump inhib-
itors, and cytoprotective drugs; history of gastric surgery;
history of portal hypertension (hepatic encephalopathy, esoph-
ageal varices, and/or portocaval shunt); and drug or alcohol
abuse in the past 5 years or concurrent consumption of more
than 60 mg ethanol per day. Ingestion of low doses of antacid
as needed for symptomatic relief was allowed (see later). All
patients provided written informed consent and the study
protocol was approved in advance by the Institutional Review
Boards or ethical committees of the participating centers. The
trial was conducted in accordance with the Declaration of
Helsinki (Hong Kong amendments) and the standards of
“Good Clinical Practice for Trials on Medicinal Products in the
European Community” (approved by the Committee for Pro-
prietary Medical Products on July 11, 1990).
Study Procedures
Eligible patients underwent examination of stool for
occult blood. Those patients who had a positive fecal occult
blood test underwent endoscopic assessment of gastroduodenal
lesions, evaluation of gastropathy-related symptoms, physical
examination, and laboratory tests during a 1-week run-in
period. Fecal occult blood (FOB) test was performed on sam-
ples of 3 different stools using a commercial diagnostic kit
(HemoFEC; Boehringer Mannheim, Mannheim, Germany).
Bleeding was considered to be actually present when at least 2
of the 3 samples were positive. Endoscopy was performed after
an overnight fast with either pharyngeal anesthesia or intra-
venous sedation. Erosion was defined as a mucosal break usu-
ally of ⬍5 mm in diameter without definite depth in the
stomach, duodenum, or both. Erosions were assessed with the
modified Lanza scale12 and defined as grade 0, no lesion; grade
1, presence of 1 lesion; grade 2, 2– 4 lesions; grade 3, 5–10
lesions; grade 4, ⬎10 lesions; and grade 5, ulcer (mucosal
breaks of at least 5 mm in diameter with unequivocal depth in
the stomach, duodenum, or both). The participating endosco-
pists at each center were experienced and the Lanza scoring
system discussed among them, but no specific training mate-
rial was used.
The investigator asked patients whether they had heartburn,
abdominal fullness, nausea/vomiting, epigastric pain/cramp-
ing, and loss of appetite during the preceding 7 days. Mild or
occasionally mild gastropathy-related symptoms were graded
as 1, moderate or occasionally moderate as 2, often moderate as
3, occasionally severe as 4, and often severe as 5. Patients who
scored ⱖ5 points (sum of the scores of the 5 symptoms) were
considered symptomatic, whereas patients with ⱕ4 points
were regarded as asymptomatic. Those patients scoring 20
points or higher were not randomized and withdrawn. Other
investigations included antibody testing for Helicobacter pylori
status (ELISA); routine laboratory tests; barium enema exam-
ination or colonoscopy; and measurements of body weight,
pulse rate, and blood pressure using a standard cuff sphygmo-
manometer. Diastolic blood pressure was determined as Ko-
rotkoff sound V.
January 2003
Patients with negative FOB test and/or endoscopically con-
firmed gastric carcinoma or Lanza grade 0, 1, or 5 lesions were
excluded as were patients with malignant tumors of the colon
and rectum, renal impairment (serum creatinine concentration
1.5 times above the upper normal limit), liver dysfunction
(twice or higher above the upper normal limit of at least 2 of
the following parameters: plasma albumin level, serum alanine
and aspartate aminotransferases, alkaline phosphatase, and
␥-glutamyl transpeptidase); uncontrolled hypertension with
diastolic blood pressure ⬎100 mm Hg; and those requiring
iron administration with hemoglobin values ⬍10 g/dL.
Randomization and Treatment Phase
After the 1-week run-in phase (screening visit, days
⫺7 to ⫺1), patients were stratified into 2 groups according to
gastropathy-related symptoms (symptomatic vs. asymptom-
atic) and randomized to treatment with sucralfate or placebo
by a computer-generated randomization list. Investigators at
each center contacted by phone the coordinating center for
allocation of treatment number. Telephone randomization en-
sured that the final groups were balanced with regard to
history of peptic ulcer. Patients were instructed to take the
study medication, i.e., 5 mL sucralfate suspension (1 g sucral-
fate) or 5 mL placebo suspension with the same organoleptic
characteristics, twice a day, the first dose (2 sachets) before
breakfast and the second dose (2 sachets) before dinner.
NSAIDs were given according to each patient’s dosage sched-
ule and always after meals. The NSAIDs were continued
without dose reduction through the entire study period. Al-
lowed concomitant medications included intramuscular gold
salts, paracetamol, and antacids (magaldrate 400 mg) at the
physician’s discretion. The duration of the study was 6 weeks
from the time of initial drug administration (visit 2).
Assessments were carried out at 2-week intervals with in-
terim visits every 7 days. At each visit, patients received a box
containing the randomized study medication for the next
14-day treatment period including 28 extra sachets as a reserve
medication. Compliance was assessed by counting the number
of sachets the patient returned. Gastropathy-related symptoms
were assessed at each visit, whereas FOB test and endoscopy
were repeated at the end of the study. The presence of adverse
events as well as their severity and putative relation with the
study medication were assessed by the investigator at each
follow-up assessment.
Statistical Analysis
The primary efficacy end point was to compare Lanza
grades of the gastric mucosa assessed by endoscopy at the end
of the study between sucralfate- and placebo-treated patients.
Secondary efficacy end points included a comparison of the
following variables between patients in both treatment groups:
healing success defined as Lanza grade 0 at the end of the
study; rate of FOB negative test at the end of the study; mean
scores of each gastropathy-related symptom and the sum of
symptom scores for the subset of symptomatic patients; inci-
dence of gastric complications, such as ulcer, upper or lower
CYTOPROTECTION OF SUCRALFATE 53
gastrointestinal bleeding, or perforation; assessment of erosions
or hemorrhagic lesions in the duodenum by endoscopy at the
end of the study; amount of antacids; and occurrence of adverse
events.
According to an estimated healing rate among placebo-
treated patients of 40%, a total of 120 patients (60 per
treatment group) would be required to detect differences as
small as 30% in the healing rate among treatment groups with
a statistical power of 1-␤ ⫽ 0.9 and ␣ level of 0.05. The
primary efficacy analysis used an intention-to-treat approach
that included all patients meeting inclusion criteria who took
at least one dose of medication. The Fisher exact test, the exact
test for 2 ⫻ c contingency tables, and the Wilcoxon rank-sum
test were used for statistical analysis. Data were analyzed with
the Statistical Analysis Systems (SAS) software package and
with StatXact (Cytel). The level of significance was set at P ⬍
0.05 based on two-tailed testing.
Results
Configuration of Study Population
The study was stopped when 51 patients had been
recruited because entry rate was slow. However, the
blinding of the study was maintained until the statistical
analysis was performed as described in the study proto-
col. One eligible patient scored Lanza grade 1 for the
gastric mucosal lesion and Lanza grade 0 for the duode-
num on endoscopic examination at the screening visit
and was not randomized.
Thus, the study population consisted of 50 patients,
25 assigned to the group of treatment with sucralfate and
25 to placebo. The main target variable was missing for
2 patients randomized to placebo. Treatment groups
were comparable with regard to baseline characteristics.
History of peptic ulcer was recorded in 6 (24%) patients
in the sucralfate group and in 4 (16%) in the placebo
group. On the other hand, gastropathy-related symptoms
were present in 14 (56%) assigned to sucralfate treat-
ment and in 13 (52%) allocated to placebo. Antibody
testing for Helicobacter pylori status was positive in 20
cases (sucralfate 9, placebo 11) and negative in the re-
maining 30 (sucralfate 16, placebo 14).
Treatment Outcome
Results of treatment are shown in Table 1. At the
end of the study, 42 days after randomization, lesions in
the stomach at endoscopy as measured by the Lanza scale
were significantly reduced in patients given sucralfate
compared with patients given placebo (P ⫽ 0.022).
Accordingly, the healing rate for patients with grade 0
was significantly lower among placebo-treated patients
than among patients given sucralfate (35 vs. 68%, P ⫽
0.042). Changes in gastropathy-related symptoms dur-
54 MALAGELADA ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 1, No. 1

Table 1. Comparison of Sucralfate-Treated and Placebo- which ulcer prophylaxis should be especially considered
Treated Patients at the End of the Study are subjects with chronic rheumatic disorders, advanced
Sucralfate Placebo age, taking NSAIDs continuously for more than 2
Parameter no. (%) no. (%) P value months, or giving high doses of the anti-inflammatory
Gastric mucosa, Lanza grade 0.0225 agent6,29 –31 with positive FOB test and gastric erosions,
0 17 (68) 8 (35)
preferably with history of peptic ulcer30,32,33 as well as
1 1 (4) 3 (13)
2 7 (28) 9 (39) with concomitant treatment with corticosteroids, anti-
3 0 2 (9) coagulants, or methotrexate.33,34
4 0 1 (4) Prior approaches to preventing the side effects of
5 0 0
Sum 25 (100) 23 (100) NSAIDs have included treatment with H2-receptor an-
Duodenal mucosa, Lanza grade 0.34 tagonist to inhibit acid secretion and the use of prosta-
0 24 (96) 20 (87) glandin analogues to replace the depleted endogenous
1 1 (4) 3 (13)
2 0 0
prostaglandins. However, H2-receptor antagonists are
3 0 0 not very effective for healing gastric erosions or prevent-
4 0 0 ing NSAID-associated gastric ulcers in patients who
5 0 0
Sum 25 23 (100) 0.188
continue ingestion of NSAIDs,35 and prostaglandin an-
Fecal occult blood test alogues, such as misoprostol, are limited by annoying
Positive 1 (4) 5 (21) gastrointestinal side effects such as diarrhea and abdom-
Negative 22 (96) 19 (79) inal cramps. Although proton-pump inhibitors have
Sum 23 (100) 24 (100)
been advocated to overcome poor tolerability of prosta-
glandin analogues, a recent study has shown that gastric
erosions healed significantly better in patients given
ing the study period were not significantly different misoprostol than in those treated with either 20 or 40
between both treatment groups both in regard to each mg of omeprazole.36
individual symptom and in regard to the total symptom Rationale for the use of sucralfate in NSAID compli-
score (sum of the scores of the 5 symptoms) (Table 2). cations are based on putative mechanisms of increase in
The lesions in the duodenal mucosa at the end of the cytoprotection and mucosal surface restitution and re-
study as measured with the Lanza scale was also similar duction of peptic and fibrinolytic activity. In this con-
among sucralfate- and placebo-treated patients (P ⫽ text, it is important to differentiate prophylaxis of either
0.34). acute or chronic NSAID lesions. In a double blind con-
Adverse Events trolled study on the effect of 1 g sucralfate 4 times daily
on gastric prostaglandin formation and microbleeding in
No instance of serious gastroduodenal complica- the intact and aspirin (2.5 g) treated stomach in healthy
tion (ulcer, hemorrhage, perforation) occurred after 42 male volunteers, both gastric microbleeding and DNA
days of treatment. Adverse events recorded in 5 patients loss were significantly lower in subjects given sucralfate
included diarrhea in 3 patients given sucralfate, rectal than in those treated with placebo.37 The protective
bleeding in 1 patient given placebo, and increased serum
effects of sucralfate on spontaneous gastric microbleeding
iron concentration in another patient treated with pla-
were accompanied by increased mucosal biosynthesis and
cebo.
luminal release of PGE2 6-keto-PGF1 alpha with a re-
duction in release of thromboxane B2.37 Other studies
Discussion have confirmed the favorable effect of sucralfate on aspi-
Research on prevention of gastrointestinal bleed- rin-induced gastric mucosal damage and acute NSAID-
ing associated with chronic NSAID therapies is highly
relevant because long-term NSAID administration fre-
Table 2. Total Symptom Scores During the Study
quently used for the treatment of arthritis and musculo-
skeletal disorders is well recognized to produce such Total symptom score (⫾SD)

complications.27 In fact, mucosal damage has been dem- Sucralfate Placebo P

onstrated in 50%–75% of arthritic patients under long-
Run-in 7.2 (3.93) 5.5 (3.50) 0.20
term NSAID therapy.28 Although a number of factors Baseline 7.9 (3.65) 5.5 (3.79) 0.07
can modify the risk of major gastrointestinal complica- 2 weeks 3.8 (2.13) 3.7 (3.22) 0.53
tions with NSAIDs and need to be considered when 4 weeks 3.2 (3.83) 3.2 (3.20) 0.89
6 weeks 2.1 (3.82) 2.5 (2.31) 0.23
individual prescribing decisions are made, candidates in
January 2003
associated mucosal injury.26,33,38 – 40 Nevertheless, actual
experience with the prophylactic effect of sucralfate on
gastric mucosal lesions in chronic NSAID treatment is
surprisingly limited.24 –26 It is well known that gastric
erosions can progress to ulcers and can themselves lead to
gastrointestinal bleeding. Approximately, between 25%
and 50% of chronic NSAID users develop gastric ero-
sions, and their presence seems to be associated with a
high risk of subsequently developing a gastric ulcer.41
Several significant and distinctive features of our study
design deserve to be emphasized: Firstly, the use of the
FOB test to screen for bleeding, which was always con-
firmed by endoscopy. In a prospective study, Wroblewski
and Ostberg42 assessed the presence of upper gastroin-
testinal disorders in a series of 170 geriatric inpatients
with positive FOB test. The prevalence of gastroduode-
nal ulcer confirmed by endoscopy or at autopsy was 22%
and the sensitivity of the FOB test was 85%. Signifi-
cantly higher proportions of previous ulcer, iron defi-
ciency anemia, and NSAID and steroid users were found
among ulcer patients than among patients without ul-
cerative upper gastrointestinal lesions. We are aware that
many patients with gastric mucosal lesions may have
been refused entry into the study because of a negative
FOB pre-entry screening. But, conversely, by our ap-
proach we ensured that only patients with definite bleed-
ing lesions would be randomized to the sucralfate or
placebo arms of the study. A number of previous studies
on NSAID-adjuvant preventive trials may have been
inconclusive because entry was based on symptoms.
Symptoms are unreliable indicators in the context of
NSAID treatment for the identification of gastric lesions.
Symptoms do not predict the presence of mucosal dam-
age in NSAID-treated patients in whom the stomach and
duodenum are completely normal at endoscopy have
been reported in 50%– 62% of the cases.7,24 –26,43 Thus,
in contrast to the design of previous studies,24 –26 in our
study the presence of gastrointestinal complaints was not
an inclusion criterion for the recruitment of patients.
Our entry criteria requiring patients treated with
NSAIDs for more than 2 months also prevented the
phenomenon of “gastric adaptation” in which visible
early gastric mucosal injury lessens or resolves com-
pletely within 12 hours to 24 days despite continued
administration of the offending agent.44,45 Finally, the
profile of patients included in the study took into ac-
count different risk factors30,33 (e.g., alcohol ingestion,
potential eradication of H. pylori in the course of the trial,
use of non-allowed concurrent medication, etc.) that may
constitute a source of bias and should be avoided.
CYTOPROTECTION OF SUCRALFATE 55
After a 6-week treatment period with 2 g (10 mL)
sucralfate twice daily, the percentage of patients with no
endoscopic gastric lesions was 68% compared with 35%
in those treated with placebo. In this target population
selected according to a marker of NSAID-related damage
(positive FOB test) and using the most reliable diagnos-
tic means of injury (endoscopy), chronic administration
of sucralfate significantly improved NSAID-induced gas-
tric erosions. Although a direct connection between
treatment of erosions in NSAID-related gastropathy and
bleeding complications has not been established, we
believe that further studies on clinical use of sucralfate in
patients receiving chronic NSAID therapy are warranted.
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Address requests for reprints to: Juan R. Malagelada, M.D., Servicio
de Aparato Digestivo, Hospital Universitari Vall d’Hebron, Passeig Vall
d’Hebron 119-129, 08035 Barcelona, Spain. e-mail: malagela@hg.
vhebron.es.
The authors thank Drs. H. Brinkhoff, P. Krupp, S. Kaspari, and A.
Ansari for their contribution to the study and Dr. Marta Pulido for
editing the manuscript and editorial assistance.